pharmacology

236
Major Topic Abbreviation Major Topic Abbreviation Adrenergic Adrenergic Cholinergic Cholinergic Anesthetics Anesthetics Corticosteroids Corticosteroids Arti-Anxlety Agents Anti-Anxiety Agents Cardioysscular Cardiovascular Antl-Epileptics Anti-Epileptics Cancer/ Chemotherapy Cancer/Chemo Anti-Depressants Anti-Depressants Dilretics Diuretics Anti-Histamires Anti-Histamines H!?oglycemics Hypoglycemics Anti-lnfectives Anti-Infectives Miscellareous Misc, Anti-Psychotics Anti-Psychotics Narcotic Analgesics Narcotic Analgesics Aspirin/Acetamitrophen/ NSAIDs Asp/Acet/NSAIDS Terms/DefinitioDs Terms/Def PHARMACOLOGY Adrenergic Amphetamines are sympathomimetic amines that cause rapid release of: . Dopamine in the brain . Serotonin in the brain . Norepinephrine in the brain . Acetylcholine in the brain 1 Copyright e 2011':0ll - Denbl Decks

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Page 1: Pharmacology

Major Topic Abbreviation Major Topic Abbreviation

Adrenergic Adrenergic Cholinergic Cholinergic

Anesthetics Anesthetics Corticosteroids Corticosteroids

Arti-Anxlety Agents Anti-Anxiety Agents Cardioysscular Cardiovascular

Antl-Epileptics Anti-Epileptics Cancer/Chemotherapy

Cancer/Chemo

Anti-Depressants Anti-Depressants Dilretics Diuretics

Anti-Histamires Anti-Histamines H!?oglycemics Hypoglycemics

Anti-lnfectives Anti-Infectives Miscellareous Misc,

Anti-Psychotics Anti-Psychotics Narcotic Analgesics Narcotic Analgesics

Aspirin/Acetamitrophen/NSAIDs

Asp/Acet/NSAIDS Terms/DefinitioDs Terms/Def

PHARMACOLOGY Adrenergic

Amphetamines are sympathomimetic amines that cause rapid release of:

. Dopamine in the brain

. Serotonin in the brain

. Norepinephrine in the brain

. Acetylcholine in the brain

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Page 2: Pharmacology

Amphetamines pass readily into the CNS and cause a rapid release of norepinephrine inthe brain. Amphetamines increase systolic and diastolic blood pressures and act as weakbronchodilators and respiratory stimulants. They have a high potential for abuse, result-ing in tolerance, psychological dependence, and severe social disability. Abuse causes ex-treme violence and paranoid psychotic behavior Note: Amphetamines and ephedrine areindirectly acting sympathomimetic (sympathetic-type) drugs. These drugs demonstratetolerance and are orally active, unlike epinephrine and norepinephrine.

Therapeutic uses of amphetamines:. Attention Deficit Hl?eractivity Disorder (ADHD; hyperkinesis) dextroamphet-amine (Dexedrine) and a mix of dextroamphetamine with amphetamine (Adderall);(Adderall XR) sometimes used instead ofmethylphenidate (Ritalin).. Narcolepsy - dextroamphetamine (Dexedrine) is used to prevent daltime sleepinessin these patients.. Weight loss - phentermine (Ionamin) - structurally similar to dextroamphetamine.

1. Tyrosine hydroxylase catalyzes the rate limiting step in the synthesis ofnorepinephrine (tr'E) and epinephrine. The enzyme is inhibited by metyro-sine.2. Terrnination oftransrnission by NE takes place primarily by the reuptakeofNE into prejunctional nerves and secondarily into other cells. Monoamineoxidase (MAO) and catechol-O-methyl transferase (COMT) then play a role inmetabolizing the NE.

Page 3: Pharmacology

. An alpha-adrenergic receptor blocker (alpha-blocker)

. A beta-adrenergic receptor blocker @eta-blocker)

Coplright O 20ll-201? Dmral Decks

. Sympathomimetic

. Sympatholytic

. Sympathetic amine

. Adrenergic agent

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Page 4: Pharmacology

:iolcra

-Ji...

Examples ofselective alphal-blockers used in medicine:. Doxazosin (Cardura) used to fieat hypertension. Prazosin (Minipress) used to treat hypertension. Terazosin (Hytrin) manage mild/moderate hypertension; treatment ofbenign pro-static hyperylasia frPd). Tamsulosin (Flomax) used to treat benign prostatic hyperplasia (BPH)

*** These drugs selectively block tr1-type receptors but not o2-type

Important: Alphay-blockerc cause orthostatic hypotension, also known as postural hy-potension. This is a fainting spell which occurs because ofa rapid fall in blood pressure

when moving from the supine to the upright position, as in getting rapidly out ofthe den-tal chair. The symptoms are similar to simple fainting, however the condition is related topositioning. Note: Other adverse effects include tachycardia, nasal congestion and drymouth.

*** Orthostatic hypotention can also result from centrally acting drugs (i.e., clonidineand methyldopa) and direct vasodilators (i.e., hydralazine and diazoxide)

1. Alpha-blockers inhibit the vasoconstrictor response to epinephrine and lev-onordefrin.2. Beta-blockers increase the vasoconstrictor response to epinephrine, but re-

duce the tachycardia resulting from epinephrine.3. MAO inhibitors (i.e., phenelzine and tranylcypromtue) should not be used

with indirectly acting sympathetic drugs (i.e., Tyramine and anphetamines)and with several other drugs such as opioids, especially meperidine.4. Epinephrine and levonordefrin have exaggerated effects when given withneuron depleting agents like reserpine and quanethidine.

Four kinds ofadrenergic receptor blockers: fNorc: Thel are allused to trcsl hlpertension)

L Beta-adreDergic blockers:. Nonselectir€: blocks both betal- and beta2-receptors

. Propmnolol 'Carteolol ' Sotalol

. Nadolol . P€nbutolol . Timolol

. Betal-s€lective:. Atenolol . Esmolol . Betaxolol. Metoprolol . Bisoprolol 'Acebutolol

2. Alpha-adrenergic blockers

. \onselective: blocks both alphat- and alpha2- receptors

' Phentolaminc. Phenoxybenzamine

'AlPhat-selective:. Prazosin . Doxazosin. Terazosin . Tamsulosin

i. Centrally acting Nlpha2-agonists: Act through stimulation ofceDtral inhibitory alpha'-adrenergic rc-ceprors.They inhibit sympathetic cardioaccelemtor and vasoconskictor centers. Stimulation ofalpha-adren-

ergic rcceptors in the brainstem results in rcduccd sympathetic outflow from thc CNS

'Clonidine. Methyldopa

4. \euronal depleting agents: cncompasses awide variety ofdrugs having different mechanisms ofaction.whatever their specific mechanism, the result is usually the same

-a depletion ofmediator in thc nouron

Ierminal or an inability ofth€ medialor to be released from the terminal.. Reserpine - depletes granules containing NE in nerve endings, releases NE. Guanethidine - blocks adrcnergic nerve endings by a series ofactions. Metyrosine - inhibits tytosine hydroxylase; used to treat pheochromocytoma

r-ote; Canedilol and labetalol ar€ nonselective bet|-blockers thai also block alphal-receptors. Tley ate

used for healt failure.

Page 5: Pharmacology

. Epinephrine (Adrena lin)

. Phenylephine Qr'e o - Sy nep hrin e)

. Albuterol (Proventil; Ventolin)

. Isoproterenol

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. Alphal -receptors only

. Betal-receptors only

. Both alphal,2 and betar,2-receptors

. Both alphal and betat-receptors only

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Page 6: Pharmacology

Note: The adrenergic receptors are divided into the subtypes of:. alphal (o.1) and alpha2 (a2). betal (B l) and beta2 (82).

Some common adrenergic agonists, their main us€s and rec€ptor preference:. Epinephrine: reverse anaphylaxis, vasoconstriction, bronchodilation

- alphal, alphal, betal, and beta2. Nor€pinephrine: vasoconstriction

-alpha1, alpha2. and betal. Isoprot€renol: bronchodilation

- beta1, and beta2. Phenylephrine: nasal vasoconstriction

- alphal. and alpha.r. Albuterol: bronchodilation

- beta.). Terbutaline: bronchodilation- betal

. Clonidine: antihlpertensive- alpha2

. \Iethvldopa: antihypertensive- alpha.'

. Dobutamine: cardiac stimulation- alphat, and betal

Adrenergic ReceptorTr"Pe

Characterisfics Neurotransmitters that CombineWith Receptors

Alpha Most common alpha rcccptor Norepinephrine or Epinephrine

-4.lpha: Less common alpha receptor Norepinephrine or Epinephrine

Beia Less common beta rcceplor(found on rclls in heafl)

Norepinephrine or Epinephrine

Betal Most common bcta rcceptor Epifi ephine (No re p i h e p h r i n e ge n e r a I b'combines either weaklJ or not at all)

Remember: Alpha reccptor responses are predominantly ercitatory in nature, while beta receptor ie-

iponses are €\citatory in nature in the heart and inhibitory elsewhere.

Smooth muscle in blood vesselsStomach, intestineKidneyLiver

VasoconstrictionDecreased motility and toneIncreased renin seerctionGlucon€ogen€sis

Smooth musclc in blood vessels

Increased rate and forcc ofcontractionlncreased renin secretion

Bronchial, vascular, coronaryaneriole, uterine smooth muscle,skcletal muscle

Pancreas

Liver

Vasodilation

Deoeased secretionGluconeogenesis

Page 7: Pharmacology

. Tyramine

. Amphetamine

. Epinephrine

. Methamphetamine

. Hydroxyamphetamine

. Doxazosin (Cardura)

. Phenoxybenzamine hydrochloride (Dibenzy line)

. Phentolanine hydrochloride (Regitine)

. Prazosin (Minipress)

. Propranolol (Indera l)

. Terazosrn (Hytrin)

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Page 8: Pharmacology

Two types ofadrenergic agonists:

1. Indirect-acting: are those that cause the rel€as€ of stored norepinephrine at thepostganglionic nerve endings to produce their effects. Tyramine and amphetaminescause release of norepinephrine.2. Direct-acting: are those that interact directly with the alpha or beta receptors.

Direct-acting adrenergic agonists may be receptor selective or receptor non-selective:. Phenylephine : alphal selective agonist. Clonidine : alpha2 selective agonist. Dobutamine = alphat and betal selective agonist. Terbutaline - beta2 selective agonist. Albuterol : beta2 selective agonist. Epinephrine: alphar,2 and betar,2 agonist. Norepinephrine: alphal.2 and betal agonist. Isoproterenol = betal.2 agonist

Remember: Some literature refers to direct and indirect-acting adrenergic agonists as

direct and indirect-acting sympathomimetic ag€nts, These terms are almost always sln-onl mous. They are agents that bring about tissue responses resembling those produced bystimulation of the sympathetic nervous system.

*** Propranolol is a beta-blocker (speclicall- a non-selective beta-blocker)

Alpha-blockers are medications that act by competitively inhibiting the action ofcatecholamines at the alpha receptor site. They act on blood vessels, causing them to relax.Aipha-blockers are commonly used to reduce high blood pressure and to treat an enlarged

prostate. There are two types of alpha-blockers, which are classified according to the alpha

receplor that they block (alphal or alpha).

. Selective alpha antagonists: only block alphal-recepto$ and are more commonly used

ro rreat cardiac conditions (h)pertension) and benign prostatic hyperplasia.. \on-selective alpha antagonists: block both types of receptors and are generally not

used for cardiac conditions because blocking both recepto$ can ca\se tachycardia (rqpid

heart beat) and palpitations (pounding he.qrt beat). They are used in the presurgical

management of pheochromocytoma and sometimes in treating Raynaud's phenomenon.

Some examples of alpha-blockers:. Doxazosin selective alpha,-blocker. Among the alphal-blockers it is the preferedagent for hypenension due to a longer duration of action.. Terazosin selective alphar-blocker. Used to treat benign prostatic hypertrophy.. Prazosin - selectiv€ alpha'-blocker lt is rarely used to treat hypertension due tounwanted adve$e rcactions.. Phenoxybenzamine and phentolamine both are nonselective alphal and alpha2-

blockers. They are used in the presurgical management of pheochromocytoma.

*** Aside from hlpotension, which is a major effect ofalpha-blockade, alpha-blockers cause

relatively few adverse reactions.

Page 9: Pharmacology

. Alphar (d.l) receptors

. Betal (Br) receptors

. Alpha2 (02) receptors

. Beta, (82) receptors

8Coplrighr @ 2011,2012 - Denral Decks

. Vascular smooth muscle

. Presynaptic newe terminals

. Blood platelets

. Fat cells

. Neuons in the CNS

. All of the above

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Page 10: Pharmacology

. Arterioles in skin, mucosa, viscera, andk jdney Itertrrdrce verre^,

Presynaptic nerve endingsPostsynaptic in CNS

lnhibil rorepinephrine r€le3s€Decreased sympathetic tone

. lncreased heart mte

. lncaeased force of contmction

Ane(ioles (on.l arkties in skeletal nuscle)Bronchial and uterine smooth muscl€

There are two main types ofadrenergic receptors:

I . Alpha (o) receptors responsible for most of the excitatory effects such as vaso-

constriction and contraction ofthe uterus and spleen.

l. Beta (R) receptors - responsible for most ofthe inhibitory effects such as vasodila-tion and relaxation ofrespiratory smooth muscle.

\ote: Two fnportant EXCEPIIONS to the above: some alpha receptors mediate relax-atio of gastrointestinal smooth muscle, and some beta receptors mediate increases in the

torce and rate of contractions ofthe heart.

-\lpha receptors fall into two groups:

1. Postjunctional alpha, adrenergic receptors are found in radial smooth muscle ofthe iris. arteries, arterioles, and veins; in the GI tract.2. Prejunctional alpha, adrenergic receptors mediate the inhibition of the release ofnorepinephrine.

Bela receptors fall inlo t\\o groups:

1. Postjunctional betar adrenergic receptors are found in the myocardium (heart), theintestinal tract smooth muscle, and adipose tissue.

2. Postjunctional beta, adrenergic receptors are found in bronchiolar and vascularsmooth muscle.

Page 11: Pharmacology

. Preganglionic sympathetic neurons

. Preganglionic parasympathetic neurons

. Postganglionic sympathetic neurons

. Postganglionic parasympathetic neurons

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. Constricts arteriolar blood vessels (vasoconstriction)

. Relaxes bronchial smooth muscle (bronchodilation)

. Decrease blood volume in nasal tissues

. Causes a hypertensive response

. Produces physiological actions opposite to that of histamine

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Page 12: Pharmacology

The autonomic neryous system f,4NS/ controls involtntary (smooth)rnuscle and gland activity. Bloodpressure,pulse, sweating, bladder, and rectal sphincter tone are regulated by the ANS. Function ofthe hean, eyes, uterus,urinary bladder, and gasEointestinal tract, from the salivaryglands to thc analsphincter, is govemed and main-tained by the ANS.

The ANS is a complcx sct ofncurons that originatc from thc CNS fipe.$callf the h'pothalanur; it is composcd oftwo antagonistic systems. Thc sympathetic nervous system (fron thoraco-hmbar outJlow) ar,d thc parasympa-thetic nervous system (ton cratlial-socrdl ou|lo\,t).The aulononlic nervous system has cholinergic neurons that secrete acetylcholine and adrenergic neurons that se-

crctc norepinephrine. Prcganglionic ncurons ofboth divisions f.\:l rnla/, eli( and paraslnpathetit) are cholinergic,as arc the postganglionic curons ofthc parastmpathetic branch. Postganglionic neurons ofthc sympathctic brancharc usually adrenergic. Onc rXCl'PltON i s thc sympathetic postganglionic ncurons thal inncflate the swcat glands(thei, arc choli ergic = secrcte acelylcholine). Note: Adrcnergic blocking agents block thc cffcct of impulses trans-mittcd by thc adrenergic postganglionic ncurons ofthe sympathetic branch.

CNS ; Somatic NeNous System

Ach G----'------'.._-1 vg Smoolh mmOc

Ach c}--- ----------,.'<achr :'"dblhd'*,"r,r.ts-lAdrcnal

-E - n-n

'meJrlL NE *

Parasymptlhetic division

Autonomic N€rvous System

Sr_npothctic division

Reproduced wilh permission, f.omNeidle EA. and Yagiela JA. Pnamd.o|o&\ an.l Thetureuti..t for De,tista.Mosby. 1989.

HcanArrr G-<Ach-Smoorhmusclc

Glands

Fibcrs ofthe somatic and autonomic nervous systcms, with thc structurcs inncrvatcd by the diffcrcnt libcrs and thc

chcmical nrcdiators rcsponsible for lransmission at the various loci. Dashed lines indicatc postganglionic autonomic

fibcrs.

Therapeutic indications for epinephrine:. To alleviate symptoms ofan acute asthma attack. To treat bronchospasm associated with hypotension, as in anaphylaxis. To treat hypersensitivity reactions. Agent ofchoice for anaphylactic reactions (given sublingually or subcutaneoush)). It is added to local anesthetics as a vasoconstrictor to prolong the activity ofthe local

anesthetic solutions, by decreasing the rate of diffusion and absorption from the injec-tlon site. To restore cardiac activity in cardiac arrest. To relieve congestion ofthe nose, sinuses, and throat

Common side effects: headaches, agitation (anxiei)), and tachycardia.

Important: Epinephrine should be used with caution in patients with high blood pressure

and hyperthyroidism. These patients may have an increased sensitivity to epinephrine.

Page 13: Pharmacology

Epinephrlne is the agent of choice for treating an anaphyhcticreaction because ofits stimulatorv effects on both

alpha and beta adrenergic receptors.

All ofthe following are desirable efTects ofepinephrine that make it theagent of choice for treating an anaphylactic reaction.

. ft has vasopressor activity

. It has bronchodilator properties

. It causes increased cardiac output

. It has a rapid onset ofaction

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false12

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"Epinephrine reversal' is a predictable result of the use ofepinephrine in a patient rvho has received a/an:

. Beta-blocker

. Alpha-blocker

. Adrenergic agonist

. All ofthe above

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Page 14: Pharmacology

Epinephrine is the agent of choice for treating an anaphylactic reaction because of itsstimulatory effects on both alpha and beta adrenergic receptors. Alpha receptor stimula-tion results in a vasopressor response (elevation ofblood pressLtre). Beta receptor stimu-lation results in air way dilation and increased cardiac output. In this way, epinephrinecounteracts the vascular effects of histamine-related anaphylaxis.

Note: Epinephrine is administered either intravenously, sublingually, subcutaneously orintramuscularly. There is a very rapid onset of action when given by these routes.

Other therapeutic indications for the use ofepinephrine:. To control superficial hemorrhage. As a component of local anesthetic solutions to prolong duration ofanesthesia.Asthma bronchodilatorproperties

Explanation of answer: One of the best known effects of the alpha-receptor trlocking

^gents (antiadrenergiy' is their ability to reverse the pressor action of adrenaline fepl-

nephrine).In the absence ofblocking agents, epinephrine and norepinephrine both cause

the blood pressure to rise. After the alpha-receptors have been blocked by an alpha-blocker, the pressor effect of norepinephrine is reduced or abolished while epinephrine

brings about a fall in blood pressure.

This is because epinephrine stimulates both alpha and beta-receptors in the cardiovas-

cular system but norepinephrine only stimulates alpha-receptors (norepinephrine lacksbeta2effbcts). After blockage ofthe alpha-receptors, only the beta-receptors can be stim-ulated.

Note: A pressor response (produces an increase in blood pressure) is mediated by alpha-

receptors and a depressor response (produces a decrease in blood pressure) is mediated

bv beta. receDtors.

Page 15: Pharmacology

. Drowsiness

. Hallucinations

. Arthralgia

. Dry mouth

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r\' - If norepinephrine or eplnephrine wers to stimul|te or combine with. the alpba receptors in the eye, which response would you erpect?\'

. Miosrs (contraction ofthe pupil)

. Mydriasis (dilation of the pupil)

. Neither ofthe above; norepinepkine and epinephrine do not stimulate or combine withalpha receptors in the eye

t5Copyright O 2011,2012 - Denlal Decks

Page 16: Pharmacology

Metoprolol (Lopressor Toprol-XL) is a competitive, betar-selective adrenergic receptorb\ocker (carlioselectlver, which is most similar to Atenolol. It is used in the treatment ofhy-pertension, acute angina pectoris and may be helpful after a heart attack.

Atenolol (Tenormin) is a competitive, betal-selective adrenergic receptor blocker (cardiose-

lective), wtth alo]ig plasma halflife (1or1g du'ation ofdction.). It is used in the treatment ofhy-pertension and chronic angina pectoris. Due to its low lipid solubility, Atenolol is renallyeliminated, minimally metabolized, and has a low potential for causing CNS side effects com-pared to lipid soluble beta-blockers (e.g., Propranololl.

*** Metoprolol and Atenolol are both longer-acting and more predictable than Propranololin producing therapeutic plasma levels. Because they are betar selective adrenergic receptor-blockers, they are also safer to use in patients with a history of asthma or bronchitis.

-{cebutolol (Sectral) is a betar-selective adrenergic receptor blocker (cqrdio.selective). lt is

used to treat hypertension and to control ventricular arrhythmias. It has a low lipid solubil-in. $hich reduces its likelihood of producing adverse Crr-S effects. lt also has mild intrinsics) mpathomimetic activ tly (partial agottist actiritl at beta: rc.eptors) similar to Pindolol.

Important points:

L \\'ith all "selective" beta-blockers, selectivity for the betal receptor is lost at high doses.

-\s the dose is increased they also block the beta2 receptors, thereby having eff'ects on bron-chial smooth rnuscle.l. The most common side effects ofbeta-blockers are weakness and drowsiness.

Organ/Tissue Receptor Type Response to Adr€nergic Agonists

Heart p1

PIp1

0'

Increases conduction velocityIncreases contraction forceIncreases conhaction mteIncreases cardiac output

Anenoles ctl

0:

Constricts cerebral arteriolesDilates skeletal muscle arterioles

Eve ctl Contracts sphincter muscle, producing mydriasis

Lung 0, Relaxes tracheal and bronchial muscles

Intestine ctr,: F r.z

(llDecreases peristalsisContracts sphincter

Urinary bladder c[l

PI

Contracts trigone and sphincter musclesRelaxes detrusor muscle

Uterus cLl

P2

Excites uterine contactionsInhibits uterine contractions

Page 17: Pharmacology

. Levalbuterol (Xop enex)

. Alb]uterol (Proventi I )

. S almeter ol ( S e r e v e n t )

. Metaproterenol (A lup e nt)

. Histamine

. Aminophylline

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Pharmaceutical agents that bring about tissue responses resembling thme l

produced by stimul*tion of the sympath€tic nervous system are called?

. Cholinomimetic

. Antiadrenergic

. Parasympathomimetic

. Sympathomimetic

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Page 18: Pharmacology

Asthma is a respiratory disorder characterized by recurring episodes of paroxysmal

dyspnea, wheezing on expiration, coughing, and viscous mucoid bronchial secrelions.

The episodes may be precipitated by inhalation ofallergens or pollutants, infection, vig-orous exercise, or emotional stress.

Management and prevention ofan acute asthma attack:. Epinephrine, levalbuterol, albuterol, salmeterol and metaproterenol are beta. adren-

ergic receptor agonists. Thus they stimulate the beta recepton in the airway to cause

bronchodilation. They are taken via aerosol inhalers and nebulizers.

Important: Albuterol is the drug of choice as a "tescue" agent during an acute asth-

matic attack.

Note: Arninophylline is an example of a theophylline compound. Theophylline com-pounds are administered orally as bronchodilators in reversible airway obstruction due toasthma or COPD (chronic obstructive pulmonary tlisea.re). These drugs relax bronchial

smooth muscle to improve airway function.

The terms sympathomimetics, syrnpathomimetic amines, adrenergic agonists and adren-

ergic agents are almost always synonymous.

Epinephrine is the sympathomimetic agent used in dentistry. It is the vasoconstrictor foranesthetic solulions and the vasoconstrictor component in gingival retraction cords. As a

component of local anesthetic preparations, it is used to prolong the duration of localanesthesia.

In medicine, sympathomimetics are used as pressor agents to maintain blood pressure

in vascular shock. They are used as bronchodilators for asthma attacks and for allergic

states including anaphylactic shock. Syrnpathomimetics used in medicine include

dopamine, epinephrine, norepinephrine, isoproterenol, and phenylephrine.

Important: Epinephrine is indicated in medicine to treat bronchospasm and hypersen-

sitivity reactions. It is the agent of choice for reversing anaphylactic reactions. lt isused to restore cardiac activity in cardiac arest.

Page 19: Pharmacology

. Reverse an anaphylactic reaction

. Treat hypertension

. Prevent angina pectoris

. Reduce anxiety

. All ofthe above

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A fear re|ction activates the sympathetic division ofthe autonomic nervous svstem to result in:

. Viosis

. Bradycardia

. H)?ertension

. Increased salivation

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Page 20: Pharmacology

The prototypical adrenergic agonist agent is epinephrine, Epinephrine stimulates bothbeta adrenergic receptors and alpha adrenergic receptors within the sympathetic divisionofthe autonomic nervous system. Anaphylaxis is characterized by rapid, extreme reduc-tion in blood pressure and bronchospasms. Epinephrine, upon injectable administration,will rapidly reverse the hypotension by causing vasoconstriction via the alphal recep-tor stimulation; it will dilate the bronchial tubes via beta2 receptor stimulation; it will in-crease cardiac output via betar receptor stimulation on the cardiac muscle.

Epinephrine is:

. Ineffective in treating hypertension because of its alpha receptor stimulatory actions

on the vasculature which could cause an even further elevation ofblood pressure. Contraindicated in angina conditions because its cardiostimulatory effects wouldaggravate this condition. Will not reduce arlxiety but will likely increase anxiety since it has central nervous

system stimulatory effects

Activation ofthe sympathetic portion ofthe autonomic nervous system will cause alphar-adrenergic receptor activation to result in arteriolar vasoconstriction with an associated

elevation of blood pressure leading to hypertension.

. l. Sympathetic activation ofthe eye would result in mydri^sis (dilstion) not\ot!r miosis.

-..--, 2. Sympathetic activation ofthe heart would result in tachycardia, not brady-cardia.3. Sympathetic activation ofthe salivary glands would result in a thick ropey-type salivary flow, not increased salivation.

\liosis (pupillaT, constriction), bradycardia, and increased salivation are physiological

effects all resulting from activation of the parasympathetic division of the aulonomic

nen'ous system.

Page 21: Pharmacology

. Lungs

. Plasma

. Liver

. Kidney

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Page 22: Pharmacology

The amide-type local ancsthctics that are used in dentistry and metabolizcd by the liver includc:

. Lrd,ocaine (Xylocairte) . Ptilocaine (Citane.tt) . A(icain (Ultrucaine)

.Mepivacaine(Carbocoite)'Bup|acarne(Matcaine)'Etidocatnc(Dkranest)

Thesc anesthetics are rnetabolized by the hepatic microsomal enzyme system. The products formcd donot have anesthetic actions and are excreted p marily in the urine as metabolites. These agents shouldbe used wjth caution ornot at all in patients with compromiscd livcr function. Notei The most abundanturinary metabolite of lidocaine is 4-hydroxyxvlidine.

Amides are metabolized by three types ofreactions:

l. Dealkylation ofthe amino terminus2. Hydrolysis ofthe amidc bondL H.vdroxylation ofthe aromatic ring

The amides vary in protein binding. Lidocaine and mepivacaine are bound moderately. Eridocaine andbupivacaine are highly bound. Note: Bupivacaine is more selective for sensory nerves than etidocaine.

\ote: Bupivacainc has the longest duration of action ofany dcntal local anesthetic prescntly available.

-{dlerse effects caused by local anesthetics are categorized into two major grottps:

L Efltcts resulting from toxicitlL E11'ects resulting from allergy

Toricities:. Too much anesthetic in the bloodstream can cause toxicities to the central nervous system

/Cr\t and cardiovascular system. Opioids can increase the systemic toxicity oflocal anesthetics. Esters will show greater toxicity in patients with a hereditary deficiency of plasna es-

terases. Remember: Esters are metabolized by the plasma enzyme plasma pseudo-

cholinesterase, which is a plasma esterase.. The CNS effects include: restlessness, stimulation. tremors. convulsive seizures followedby CNS depression, slowed respiration and even coma. The cardiovascular effects include: bradycardia and reduction ofcardiac outpr.rt

Allergy-':

. Hypersensitivities or allergic reactions to local anesthetics, particularly from the amides,

are rare. These reactions are manifested as dermatological reactions and edema at the in-jection site.. Asthmatic wheezing syndromes have occurred in response to local anesthetic injections. Allergic reactions are more prevalent with the ester-type rather than the amide{ypeanesthetics. They also display cross-allergenicity.. Ester local anesthetic allergic manifestations include: nasolabial swelling, itching, and

oral mucosal swelling. Ilethylparaben, which was used as a perservative, can a)so cause allergies

Lrdocaine 20" w/epinephnne( I : I00,000)

Marcaine 0.5% w,/epinephrine(Bupivacaine Wepinephrine | :200,000)

Articaine 4% Wepinephrine (l : 100,000)

Page 23: Pharmacology

. Decreases sodium uptake through sodium chamels ofthe axon

. Increases potassium outflow from inside to outside the nerve

. Increases the membrane's permeability to sodium

. Increases the excitability of the nerve axon

22Cop'right O 201| -2012 - D€nral Decks

. Ionized form

. Nonionized free-base form

. Both ionized and nonionized free-base forms

23CopFight O 20ll-2012, D€ntal Decks

Page 24: Pharmacology

Whcn a local ancsthctic solution is injcctcd ncar thc nervc, thc solutron intcrfcrcs with the uptakc ofsodium from out-sidc to insidc thc ncrvc. Thc localanesthctic blocks thc spccific sodium channels thcrcby blocking thc sodium uplakc.This dccrcascs thc ncrvc cxcitability below a critical lcvcl and nervc impulscs fail to propagalc along lhc axon. Sinccaxons carry pain scnsations, thcsc scnsalions lvill nol bc carricd and a blockagc ofpain rcsults.

L Local ancsthctics reversibly block ncrvc impulsc conduction and producc rcvcrsiblc loss ofscnsa-: :. lion al thcir administcred site.:Notc*; 2. 1-n.u1 onesthctics havc no effects on potassium at thc ncn,c axon.

l. Small. nonmyelinated ncrvc fibcrs, which conducl pain and tcmperaturc scnsations, arc affcclcdfirsr, follo$cd by touch, proprioccption fpler.fl/re), and skclctal musclc tonc /rroto,r.

D.ug Onret ofBound

Ho*Supplied

Shorr Acdtrg

2-5 min l5 60 nin 5_8% C t /",2%. tv/,Estc. 6-12 min l0 min C to/r,2%.3%

30 60 min 64.J% B 0.5y,. t%. 2'/". 4./,.

l-5 min 45 90 min 17.5% c t%. | .5%, 2%. 3%

60'120 nin 55% B

Long Actlng

5 min 95.6% C 0.25%, 05%,0.15'/"

5-10 hr 91% B

Eslcr i5 min 2-l I'r 75.60/0 t%.24/..34/n

Local anesthetic free bases are fat-s oluble (lipophilic) drugs. They are converted to theirirater-soluble (hydrophilic.l hydrochloride salts to allow preparation ofan injectable so-

lution. ln solution an equilibrium is established between the ionized and the nonionizedtbm.rs ofthe local anesthetic. The proportion ofthe drug in the ionized form depends on

rhe pKa of the drug and the pH ofthe solution. At the usual solution pH of 6.0 or lower,

most local anesthetics are almost completely in the ionized form.

This is important because only the nonionized free-base form ofthe drug can readily pen-

errate tissue membranes. Local anesthesia can only be obtained if sufficient free-base is

ar ailable. The lower the pKa ofthe drug and the higher the pH ofthe solution or injectedtissues. the more free-base will be available.

Once the local anesthetic is injected the buffering capacity and pH of the tissues /zor-nallt T.1) shifts the equilibrium in favor of free-base formation. At physiologic pH of 7.4

approximately 5-20ulo ofthe local anesthetic is in free-base form which is enough to pen-

etrate and cause anesthesia. Ifinfection or inflammation is present, the pH olthe tissues

may be acidic and there is a significant reduction in the concentration of the free-base

form. In this situation, the local anesthetic may not be effective.

Key point of all this: The potential action olall local zuresthetics depends on the abilityofthe anesthetic salt to liberate the free-base.

Note: Ifyou inject lidocaine (pKa = 7.8) into tissue that has a pH of 7.8, the lidocaine willexist in an equal mixture ofionized and nonionized forms which will be more than enough

to Droduce aresthesia.

Page 25: Pharmacology

. Pentobarbital

. Secobarbital

. Chloral hydrate

. Meperidine

21Cop)'right O 201 | ,2012 - Denral Decks

. Liver

. Lungs

. Plasma

. Kidneys

25Cop)ri8hr O 20ll -2012 - Denial Decks

Page 26: Pharmacology

;'Nnt"q"

"'"ee;;l

Traditionally chloral hydrate has been used orally in the preoperative managem€nt ofthe anxious pediatric dental patient. It has an unpleasant odor and a bitter, caustic taste,

which can be partially masked in a flavored syrup. Chloral hydrate is rapidly absorbedafter oral administration with an onset of 15 to 30 minutes. Its duration ofaction is about

4 hours.

For use in children, chloral hydrate is available as a 500 mg/5 ml solution. The usual

dose for a child is 50 mg/kg up to a maximum of lg. Important: Children will often entera period ofexcitement and irritability before becoming sedated. It affects brain centers

that control wakefulness and alertness. Chloral hydrate does not relieve pain.

l. Chloral hydrate is a prodrug and is metabolized to the active metabolite,trichloroethanol.2. Chloral hydrate's metabolite (trichloroethanol) may displace warfarin fromits protein binding sites resulting in an increase in the hypoprothrombinemic re-

sponse to warfarin.3. Sedative effects and/or respiratory depression with chloral hydrate may be

additive with other CNS depressants - monitor for increased effect. These

other CNS depressants include ethanol, antidepressants, narcotic analgesics,

and benzodiazepines.,1. Be careful when using Chloral hydrate, serious toxicity can result if the

dose is not controlled.

Ester-t!'pe local anesthetics all have an ester grouping within their chemical structure. Anester grouping is essentially a bridge or link containing the COOCH2-configuration.

Amide-tJ*pe local anesthetics all have an amide grouping within their chemical structure. Anamide grouping is essentially a bridge or link containing the - CONHCH2-configuration.

Ester-type local anesthetics are mainly available as topical anesthetics and include

benzocaine (which does not have an qmi o terminus end therefore cloes not become charged,

thus it is poorl), soluble in water), tet:acaitrrc, and dibucaine. They are also available as

medical anesthetic preparations such as propoxyc atne (Ravocaine). Ester-type localanesthetics are no longer available as dental anesthetic injectable preparations because oftheir relatively high incidence of allergy. Only the amides are presently available as dental

injectable local anesthetic agents. These include lidocaine, mepivacaine, prilocaine,

bupivacaine, and articaine.

Ester-type local anesthetics are metabolized by the plasma enzyme plasma cholinesterase.

Another name for this enzyme is pseudocholinesterase. This enzyme splits the ester linkagervithin the chemical structure rendering the anesthetic ineffective. Procaine (Novocaine) was

one of the original est€r-type anesthetics. When procaine is metabolized by plasma

cholinesterase, a highly allergic compound called para aminobenzoic acid lPl BAfor short)

is formed. Many patients developed an allergy to PABA. Note: PABA can decrease the

effectiveness of sulfonamides (antibiotics).

)iote: Other chemicals that act like local anesthetics:. Diphenhydramine: H 1 antihistamine. T€trodotoxin: found in a number oftissues ofthe puffer or blowfish. Saxitoxin: is produced by certain stmins ofalgae

Remember: Dyclonine hydrochloride is unusual in that it has a ketone linkage between the

aromatic moiety and the rcst ofthe anesthetic molecule. It is used as a topical.

Page 27: Pharmacology

. Biliary tract disease

. Type II diabetes

. Rleumatoid adhritis

. Hepatic disease

Coplright O 201l-2012 , Dental Dects

Which trical anesthetic has no place in the routine practice of dentistry? :'.]

. Articaine

. Cocaine

. Lidocaine

. Bupivacaine

. Prilocaine

Coplrighr O20ll,20l? - Denral Deck

Page 28: Pharmacology

*** Remember: All amides are rnetabolized primarily in the liver, and the metabolites

are then renally excreted.

Priloc^ite (Citanesrl is a local anesthetic ofthe amide class, used for nerve block, epidural

and regional anesthesia. It has an intermediate duration ofaction and is longer acting than

Lidocaine. Prilocaine produces less vasodilation than do equal amounts ofLidocaine flis somev'hat less potent thqn Lidocaire). It is available as a 4olo solution with or withoutepinephrine, which prolongs the anesihetic effect.

Prilocaine is metabolized to orthotoluidine, a product that can produce m€themoglo-

binemia, a condition that is characterized by increased levels of methemoglobin in the

blood. Note: This methemoglobin is less effective than hemoglobin in catrying oxygen

in the blood.

Prilocaine is about one-half as toxic as Lidocaine, but since methemoglobinemia is apossible reaction, Prilocaine is not used for patients with hypoxic conditions ofany kind.

\ote: EMLA Cream is a eutectic mixture oflidocaine 2.5% and prilocaine 2.5% formu-

lated as an oil in water emulsion. In this eutectic mixture, both anesthetics are liquid at

room temperature and the penetration and subsequent systemic absorption ofboth prilo-caine and lidocaine are enhanced over that which would be seen if each component incn stalline form was applied separately as a 2.5olo topical cream.

Cocaine is a naturally occurring ester ofbenzoic acid and was the first local anesthetic

used in dentistry and medicine. It is potent and extremely toxic, and it is the only local

anesthetic that causes definite vasoconstriction (all other locql anesthetics qre va'sodildtors). Cocaine is commercially available in a variety of forms and is applied to mu-

cous membranes of the oral, laryngeal, and nasal cavities for use as a topical anesthetic.

Cocaine causes significant euphoria (most likely due to its blockqde of reuptake ofdopantine in the bralzl, and abuse can lead to a physical dependence. Despite being an ex-

cellent local anesthetic, the risk of abuse and the intense local vasoconstriction it pro-

duces prevent cocaine from being more widely used clinically. Important: Cocaine has

no place in the routine practice of dentistry.

The pharmacology ofcocaine is unique among local anesthetics in that the drug inhibitsthe uptake ofcatecholamines by adrenergic newe terminals. It therefore potentiates the ac-

tion ol endogenously released and exogenously administered sympathomimetic amines

such as dobutamine, dopamine, or epinephrine. It increases the risk of developing car-

diac arrhythmias and hypertension (i.e., cocaine incresses the pressor activity oJ these

$)mP at homim e t ic am i n e s ).

Page 29: Pharmacology

. The pH rises, thus inactivating the anesthetic

. The pH rises, thus decreasing available free base

. The pH decreases, thus decreasing available free base

. The pH remains the same, the extracellular fluid dilutes the anesthetic

28Coplriglt O 2011,2012, Denbl Decks

A dental rnesthetic carpule contains 1.8 ml of a 27o solutionof lidocaine with 1:100,0fi) epinephrine. How much lidocline

and epinephrine does the carpule contain?

.3.6 mg lidocaine and 0.18 mg epinephrine

. 3.6 mg lidocaine and 0.018 mg epinephrine

.36 mg lidocaine and 0.18 mg epinephrine

. 36 mg lidocaine and 0.018 mg epinephrine

29Coplriglt O 20ll-2012, Denral Decks

Page 30: Pharmacology

At body pH (7.4), a local anesthetic when infiltrated, will chemically exist as a portionwhich is ionized (has a proton attached) and as a portion which is non-ionized (ha.s noproton attqched). Note: A proton is nothing more than a hydrogen (H.) alom. That por-tion which is ionized has difficulty penetrating the nerve and will not be effective. Thatportion which is non-ionized will penetrate the n€rve to cause anesthesia. That portionwhich is non-ioniz€d is also known as the free base. The more proportion ofthe anes-

thetic which is in the free base form. the more effective it will be.

When tissue conditions are normal (p11 7.4), approxrmately 10-207o portion ofan infil-trated local anesthetic is in the form of the free base (non-ionized form). This is enoughto penetrate the nerve to cause anesthesia. When tissues are acidic, as in the case of tis-sue infection, less free base portion exists and more ionized portion is present. There isnot enough free base form to penetrate the nerve to cause anesthesia. Therefore, the localanesthetic when infiltrated to the tissue site is not effective at the normal anesthetic doses.

KeJ- to question: I ml ofa 2olo solution oflidocaine with l:100,000 epinephrine contains

20 mg of lidocaine and 0.010 mg of epinephrine.

A dental carpule contains 1.8 ml solution. Therefore, 1.8 ml of2% solution oflidocainewith I : 100,000 epinephrine contains 36 mg of lidocaine and 0.018 mg epinephrine.

Epinephrine (vaso constrictor) is included in local anesthetics for the following reasons:

. It prolongs the duration ofaction

. It reduces toxicity

. It reduces the rate ofvascular absorption

. lt provides a hemostatic effect to reduce bleeding at injection site

Page 31: Pharmacology

.7.5 milliliters

. l0 milliliters

. 15 milliliters

. 20 milliliters

30

Coplaigh O 201l-201? Dmtal Decks

'\The maximum reconmended dose ofa local anesthetic that c|n be

tdministered to r child < 10 years ofage is determined by: ,

' .{ge

. $'eight

. Height

. Gender

31

Coplright C 20ll-2012 - De alDecks

Page 32: Pharmacology

lmportant information to solve qucstions ofthis type:. There arc 20 mg ofLidocaine in every milliliter of2%o Lidocaine. 3n0 mg (maximal recommended dose) - 20 ng (in every mL) = 15 mLs. 20 mg x 1.8 mL ffu every carpule) = 36 mg / I carpule. 300 mg - 36 69 = 3.3 carpttles (8 cdrpules of 224 Lldocaine can be used)

Remember; Lidocaine has serious drug interactions with beta-blockers and cim€tidine that de-crease lidocaine clearance 3070 or more. Propranolol, metoprolol, and nadolol are reported to re-ducc lidocaine clearance due to the decreasg in cardiac output caused by thc beta-blockers.Decreased cardiac output rcsults in reduced liver blood flow which explains the decline in Iido-carne clearance caused by these drugs. Cimetidine also decreases lidocaine clearance, but thcmcchanism ofthe interaction is different. Because cimetidine does not change liver blood llow. itis believed that cimetidine decreases lidocaine clearance by inhibiting hepatic microsomal en-z1mes. Lidocaine clearancc may be accelerated by concomitant use ofphenobarbital or pheny-toin. Bolh ofthese agents are known to be hepatic drug metabolizing drug inducers, and this islhe Drobable mcchanism oftheir druc interaction with lidocaine.

Erample: For Lidocaine (2%) wrth epinephrine, a dosage of 4.4 mg/kg should not beexceeded (wL\imum is 300 ng).

:{ote: I kg = 2.3 lbs

2Yo: 20 mg I mLx 1.8 mL /l carpule = 36 mg/l calpule

Page 33: Pharmacology

. Large myelinated fibers

. Small unmyelinated fibers

. Small myelinated fibers

. Large unmyelinated fibers

32

CopyrSh O 20ll-2012 - Denbl Decks

. 100 mg/kg

. I mg&g

. 300 mg,&g

33

Cop].rjght O 20: l-2012 - Dental Deks

Page 34: Pharmacology

*** These conduct pain and temperature

Important: They depress the large myelinated fibers last. The small nerves have thegreater surface-volume ratio (this accounts for the rapid onset ofaction).

Clinically the general order of loss of function is as follows:l. Pain2. Temperature3. Touch4. Proprioception5. Skeletal muscle tone

Note: Pain threshold refers to the lowest level ofnain a natient will detect.

Remember: Local anesthetics reversibly block nerve impulse conduction and producethe reversible loss of sensation at their administration site. They do not produce a loss

of consciousness. They appear to become incorporated within the nerve membrane or tobind to specific membrane sodium ion channels, restricting sodium pemeability rn re-sponse to partial depolarization.

In a tlpical 70 kg adult male, the dose of 7 mghg would equate to a total of490 mgs.

Thus. the maximum recommended amount of articaine that could be given to a 70 kg

adult in one appointment is 490 mgs.

The table belo*' shows the following number of dental cartridges containing 1.7 ml vofume of solution to provide the indicated amounts of articaine hydrochioride 4% and epi-nenhrine l:100.000.

Number of Cartridges(1.7 ml)

Articaine HCL (4%)(mg)

Epinephrine l:100,000(mg)

1 68 0.017

2 136 0.034

3 204 0.051

4 272 0.068

5 340 0.085

6 408 0.102

7 476 0.119

8 544 0.136

Page 35: Pharmacology

. Oral

. Inlalation

.IV

.IM

34

Cop"ighr O 20ll-2012 - Denral D€cks

\All of the following are advantages of using nitrous oxide analgesia

EXCEPT one. Which one is the EXCEPTIOM

. Rapid onset ofaction

. Lou,ers pain threshold

. Produces euphoria

. Pleasant induction

. Titratable

. Rapid and complete recovery

. Mrtually no adverse effects in absence ofhypoxia

. Therapeutic sedative for many medically compromised patients

. Suitable for all ages 35

Copyrighr O 20ll-2012 D€nral Decks

Page 36: Pharmacology

*** The agent used most frequently is nitrous oxide.

Nitrous oxide is a slight sweet smelling, colorless, inert gas. It must always be coupledwith no less than 207o oxygen, Nitrous oxide is quickly absorbed from the lungs and isphysically dissolved in the blood. There is no biotransformation, and the gas is rapidlyexcreted by the lungs when the concentration gradient is reversed. It is recommendedthat the patient be maintained on oxygen for 5 to l0 minutes after the sedation period.

Dose response for nitrous oxide (always given in mixture with oxygen):. l0o/o - 20%o: tingling ofhands, feet, body warmth. 20o/o - 40oh: mild sleepiness, relaxation, some analgesia, mind dissociation, height-ened auditory perception. Above 507o: this is too much nitrous

-nausea. sweatinq

*** Rapid onset: 5 minutes*** Rapid recovery: 5 minutes

\ote: Nitrous oxide does not provide enough analgesic effect to preclude the use oflocalanesthesia in dental surgery or restorative procedures. Local anesthetics must be used

along rvith nitrous oxide.

Remember: Nitrous oxide has minimal depressant effects on the cardiovascular sys-tem and no skeletal muscle relaxant properties.

*** \itrous oxide elevat€s pain threshold

Important points about nitrous oxide:. The main therapeutic effect of nitrous oxide is relaxation/sedation (it is used in con-

scious sedqtion). Mild analgesia is a secondary effect. It is not a respirutory depressant.. The first symptom ofnitrous oxide onset is tingling of the hands.. Nitrous oxide has no local anesthetic properties. Therefore, the addition oflocal anesthesia

is necessary in procedures in which pain is anticipated.. Long term exposure to low doses ofnitrous oxide has been shown to increase the inci-dence ofspontaneous abortions. Environmental contamination by nitrous oxide can be keptto a minimum by employing a scayeng€r syst€m.. Nitrous oxid€ is stored under pressure (7 50 psi) in sleel cylinderc (in q liquid state) pairltcd

blue. Oxygen is stored in green tanks.. Nitrous oxide delivery machines come pre-equipped with a failsafe m€chanism that

will not allow less than 20y" oxygen to be delivered to the patient.. lt is a nonirritating, colorless gas with a slightly sweet odor and tasteless lt is very sta-

ble and inert chemically at room temperatures.. It has a rapid ons et (blood:gas solubility coelrtcient : 0.47) and termrll'attorr.. It is 1.5 times heavier than air.. Nitrous oxide will diffuse into air-containing cavities within the body faster than nitrogen

diffirses out. This results in a temporary increase in either the pressure and/or volume ofthe cavity depending upon the distensibility ofits walls. This is most noticeabl€ in the bowel. Nitrous oxide interacts with vitamin Bt2 synthesis in the human body by interfering withthe enzyme methionin€ synthas€, depl€ting the body of vitamin -B12. When nitrous oxide

is used heavily and over an extended period of time, vitamin 812 depletion will probably

become a major problem, as it can cause brain and nerve damage.

Page 37: Pharmacology

. Halothane

. Enflurane

. Isoflumne

. Sevoflurane

. Desflurane

CoplriSh O 201 I -20 12 - Denral Deck.

37

Coplrighl O20ll-2012 - Dental D€ck!

Page 38: Pharmacology

Inhalation ancsthctics arc drugs which are vaporized tiom thc liquid form and inhaled to produce geneml anesthesia.

Thcse diveisc dnrgs are relatively simplc lipophilic molccules ranging from cthcrs such as halogenated hydrocarbons

such as halothane and halogenatcd ethcrs such as isofluranc, cnflumne, scvoflumne, and desflumnc.Note: Vaporization ofthcsc liquids occus in a vaporizer and dclivery to the patient occurs through an anestbcsia ma-

chine via a nasal mask.

Essential Components of Anesthesia:

. Analgesia - perception ofpain eliminated

. Htrpnosis - unconsciousness

. Depression ofspinal motor r€flexes

. Musclc rclationHypotheses of General Anesthesia:

. Lipid Theory: bascd on the fact that anesthetic action is corrclatcd with the oil/gas coefficicnts.The higher the solubility ofancsthctics is in oil, thc grcater is thc anesthctic potency.. Protein (Receptor) Theoryi based on the fact that ancsthctic potcncy is conelated with thc ability of ancsthct-ics to inhibit enzynes activity of a pure, soluble protein. Also, attempts to cxplain thc GABAA rcceptor is a po-

tcntial targct of ancsthctics acton.. Binding theory: anesthetics bind to hydrophobic portion of the ion channel.

Phermacokinetics of lnhsled Anesthetics:. Amount that rarches the brain

- Indicatcd by oil:gas ratio (lipid soluhili\,). Partial Pressure of anesthetics

- 5% ancsthctics = 38 mmHg. Sofubility of gas into blood (blood-g.ts solubiliry coelficient)

- Thc lower the blood:gas ratio, the morc anesthctics will arrivc at thc brain. Cardiac Output

- Incrcased CO = greater induction time

\lAC hean alveolar concentration).. A measurc ofpotency. I MAC is the concentration necessary to prcvent responding in 50o% ofpopulation. Valucs ofMAC are additive:

- Avoid cardiovascular depressive concenration ofpotcnt agcnts

Epinephrine, a vasoconstrictor' is included in dental local anesthetic preparations for the

following three reasons:

L It prolongs the duration oflocal anesthesia.

2. To provide a hernostasis such that local bleeding is conlrolled or reduced.

3. To delay the absorption ofanesthetic into the systemic circulation thus reducing the

chance of systemic toxicities.

Page 39: Pharmacology

Which stage of general anesthesia begins with unconsciousness?

. Stage I

. Stage II

. Stage III

. Stage IV

38CopFighr O 201 l-:012 - Dental Decks

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

39

Coplrighl O 201 l-2012 - Dotal Decks

Page 40: Pharmacology

Four stages ofgeneral anesthesia:

. Stage I: Amnesia/analg€sia

. Stage II: Delerium: begins with unconsciousness and ends with loss of€yelid rellex, purposcless move-ments and h)per-reaction, dilated pupils, reflex vomiting, tachycardia, and hlTe.tension. Stage llli Surgical rnesthesia: four planes with progressive loss ofreflexes and n1uscle control. Stage IV: Medullary paralysis: cessation ofrcspiration, ending with death without proper trearment

Notei These four stages ofanesthesia apply to the inhalaflts and not to the intravenous general anesthetics.

Agents used lbr generrl anesthesia:. Inhalafion agentsi volatile halogen-containing Iiquids

- Halothane: poses a risk with epinephrine; associated with hepatitis; poor skeletal muscle rclaxant.llowever, it is one ofthe mor€ widely used anesthetics for general surgical anesthesia.

- Desrlurane, sevoflurane, isoflurane and enflurane: pose Jess risk with epinephrine; not associatedwirh hepatitis; good skeletal muscle relaxants.

\ote: Nitrous oxide fN,O) is not considered a gencral ancsthetic since hlpoxic levels are required to produccanesthesia. It is considcred a sedative. It is used alone to produce sedation or in combination with the aboveagenrs to supplement the anesthetic response. lt is a gas at room temperaturc and pressure.

.Intrar'enous agents:. f ltrashort-acting barbiturates: thiop€ntal (Pentothal) and methohexit^l (Brei[al). Benzodiazepines: di^zeptm (yaliun), tuidazol^m (Versed.),

^nd lor^rcp^m (Ativan)

. \eurolep(ic-opioid combinations which are called neuroroleptanalgesics combine fentanyl loprorrl.)trd d.operidol (a phenothiazine). Other agents:

. Propolol (Diprivan), a short-acti g hypnotic agent; vasodilator

. Ketamine (Ketalar). is considcrcd a dissociative anesthetic. It blocks N-methyl-D-asparateA,VDA) (glutanale) rccpetors. Nofer In some circumstances, ketamine has been known to produceillusions or hallucinations that are enhanced by environmental stinruli {rpon eme.gence liom anes-thesia. Diaz€pam is giv€n with ketamine to avoid this.. Etomidate (Anitlate): is a carboxylated imidazole derivative \\.hich acts similar to the ultrashon-acting barbituratcs.

Nitrous oxide is unable to produce general anesthesia except ifit is given at concentrations greater

rhan 80q'o. At thesc concentrations, thc lack ofoxygen would cause hypoxia in the paticnt. lnhalantaneslhetics such as halothane and isoflurane can produce general anesthcsia al concentrations ap-

pro\imating 3-5%. As such they are very useful in anesthesia.

\rtrous is used to produca sedation and mild analgesia. It is usually used in concentrations of30-509'o along rvith pure oxygen. lt is a colorless, nonirritating gas at room tempemture and prcssuc,

and is not flammable nor cxplosivc. The onset of sedation is within 5 minutes and the recovery is

lu:t as rapid. lt is excreted unchanged by th€ lungs. The most common complaint from patients

taking nitrous oxide is mild nausea.

\ote: -\l*ays give patient 10070 oxygen at thc end ofthe pfocedure to prcvent diffusion hypoxia.

-\dlerse effects ofnitrous oxide:. Decreased mental performance, audiovisual ability, and manual dexterity..A.t high doses and/or high exposure: reduced t'ertility, spontaneous abortions, neurological

and lrdney disease as well as bone marrow suppression

Nrlrous oxide is contraindicated in patients:. Head injury. With bowel obstruction. Pneumothorax. Middle ear and sinus disease. With upper respiratory infections. COPD (emph),sema ol bt'onchitis). In the first trinester ofprcgnancy. With whom communication is difficult fi.e., autistic ptttietlts). Having a contagious disease since it is difficult to sterilize entire tubes

Important; Prolonged exposure (e.g., morc than 24 hou,'s./ causes bone marrow depression.

Page 41: Pharmacology

. Water

. Bisulfites

. Lidocaine

. Epinephrine (v as oc o nstri c to r)

40

Copyrighr O 20ll-2012, Dmral Decks

Of the amide-type local anesthetics, which is the only one that ismetabolized in the bloodstrcrm rather than the liver?

. Articaine (Septocaine, Zorcaine)

. Vepivacaine (Ca rbocaine)

. Lidocaine (Xylocaine)

. Prilocaine (Citanest)

. Bupiv acaine (Marc aine)

41

Copyrighr @ 20ll 201? - DentalDecks

Page 42: Pharmacology

Patients may exhibit hypersensitivity to sulfites contained in some anesthetic solutions.Sodium metabisullite prevents the oxidation (deterioration) ofthe epinephrine vaso-constrictor in those commercial preparations containing epinephrine. Most ofthe patientsreacting to bisulfites have a history of asthma and the airway is hyperactive to the sulfites.Allergic reaction usually results in an asthmatic slardrome ofwheezing and bronchial con-striction. Bisulfites are present in only those commercial preparations containing vaso-constrictor. Preparations without vasoconstrictor such as mepivacaine 3olo (Carbocaine37o) do not contain bisulfites.

Important: All local anesthetics except cocaine are vasodilators, however, mepivacainehas Iess of a vasodilator effect compared to the others and, therefore, is the drug chosen\\'hen a vasoconstrictor is not used with the local anesthetic.

\ote: Hypersensitivity or allergic reactions to local anesthetics, particularly the amides,are much more rare than allergic reactions to the bisulfites.

.\nicaine (Septocaine, Zorcaine) isan amide-type local anesthetic. However, it is chem-icalll unique in that it has an €ster group attached to its molecule which can be acted

upon by plasma cholinesterase to render it ineffective. Therefore, it is the only amideq hich is metabolized in the bloodstream and not the liver. Rapid metabolism ofthis ester

bond gives it a short halflife.

.{nicaine is supplied as articaine HCL 4% solution with epinephrine l:100,000 ard as ar-ticaine HCL 4olo solution with epinephrine l:200,000. It is indicated for local, infiltrative,or conductive anesthesia in both simple and complex dental and periodontal procedures.

The onset ofanesthesia following administration ofarticaine has been shown to be I to 6minutes after injection. Complete anesthesia lasts approximately I hour.

Articaine is contraindicated in patients with hypersensitivity to local anesthetics oftheamide type or to sodium bisulfite.

Page 43: Pharmacology

. 10olo decrease in the time for normal sensation to retum

. 25olo decrease in the time for normal sensation to retum

. 50olo decrease in the time for normal sensation to rehrrn

. 80oZ decrease in the time for normal sensation to retum

42Coprighr O 201 l-?012 - Dental Dects

. Prevents the influx ofsodium into the neuron bv blockins neuronal channels

. Causes vasodilation and increased blood flow in iniection area

. Prevents the efflux ofsodium out of the neuron

. Causes vasoconstriction and decreased blood flow in iniection area

43Coplright O 201 I -20 l2 - Denral Decks

Phentolamine mesyhte (OraVerse) is a drug used to reverse coft tissueanesthesia and th€ associat€d functional deficits resulting from a localdental anesthetic containing a yssoconstrictor. Which statement best

d€scribes its mechansim ofaction?

Page 44: Pharmacology

Thus if a local anesthetic such as lidocaine with epinephrine normally takes about 180

minutes to wear off, after phentolamine injection, the anesthetic will wear offin approx-imately 90 minutes. This represents a 50o% decrease in time for normal sensation to be re-tored.

Note: OraVerse dose is based upon the number of cartridges of local anesthetic withvasoconstrictor administered.

. l/2 a caftridge (0.2mg) of OraYerse if ll2 cmidge of anaesthetic was administered

. I cartridge (0.1mg) of OraYerse if I carhidge of anesthetic was administered

. 2 cartridges (0.8mg) of OraVerse if2 cartridges ofanesthetic were administered

Note: OraVerse (so lutionJbr injection/dental cartridge) is administered as a submucosaliniection,

Phentolamine rnesylate (OraVerse) rs an alphat-adrenergic receptor t locker. Phento-

lamine mesylate competitively blocks alpha-adrenergic receptors to produce brief an-

tagonism of circulating epinephrine and norepinephrine and antagonism of the

r asoconstrictor in the anesthetic preparation. This results in vasodilation of the bloodvessels. The local anesthetic is thus carried away at a more rapid rate from the injectionsite resulting in a more rapid retum to normal nerve sensation.

Page 45: Pharmacology

All of the following drugs are benzodiazepines EXCEPT one.Whtch one is the EXCEPIIOM

, Chlordiazepoxide (Li brium )

. Diazepam (Yalium)

. Flvazepam (Dalmane)

. Mrdazolam (Versed)

. Alprazolam (Xanax)

. Zolpldem (Anbie )

. Tiazolam (Halcion)

. Oxazepam (Serai

. Temazepam (Resortl)

. Clorazepate (Tr anxene) 44Coplri8h Cr 20ll-2012, DfrtalDecks

. CNS depression (drcwsiness and sedation)

. GI disturbances (nausea, vomiting and diarrhea)

. Confusion

. Respiratory depression

. Disorientation

. Ataxia

45Coplyighr O 201 l-2012 - Dental Deck!

Page 46: Pharmacology

The benzodiazepines are used as oral preparations to alleviate anxiety and to inducc sleep,and intravenously to cause conscious-scdation for outpatient surgery. Benzodiazepinesact by potentiating the action ofGABA, an amino acid and an inhibitory neurotansmitter, whichresults in increased neuronal inhibition and CNS depression. Tolerance and physical dependencecan occur with prolonged high dosage. They seem lo be much saler than barbituratcs. Other use-

ful properties include being an anti-conwlsant and a skeletal musclc relaxant.

Pharmacological effects of benzodiazepines: antianxiety, sedation, anticonvulsant, amnesia, and

skeletal muscle rclaxation.

Adverse effects:. CNS e{Iects - fatigue, slurred speech, drowsiness/sleepiness and conf'usion (do not drivea cqr). Gl effects dry mouth, nausea. Other effects hypotension, muscle relaxation

Benzodiazepines used orally as tmnquilizen: chlordiazepoxide (Libtittm), di.azepam (Val-

irn). alprazolam (Xonax) and lorazepam (Ativan).Those used as hypnotics to overcome in-somnia: flurazepam (Dalmane) andtiazolam (Halcion). Drazepam (Valium) ar'd ClonazepamtKlonopin ) can be used as anticonvulsants. Midazolam (Ilersed) comes as a liquid for pre-operative sedation in children and as injectable for IV conscious sedatron.

\ote: Benzodiazepines should never be taken with any form ofalcohol. Serious potentiation

ofthe sedative eflects ofeach will occur leading to unexpected inebriation and respiratory de-

presslon.

Important: Zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata) are anti-insomniaage s (cdlled GABA-BZ Agonisls).These agents appear to act through the potentiation of GABAon benzodiazepine receptors, especially the omega-1 subunit. Note: They have shown no poten-tial for causins addiction.

The benzodiazepines have clinically useful antianxicty, scdative-hypnotic, anticonvulsant and skele-

ial muscle relaxanl propcrties. They exert their main effect on central GABA-nergic neurons. Withnomral dosrng, thc benzodiazepines have little effect on respiratory systcms in healthy individuals.

The benzodiazepines (especially diazepam, lorazepam and midazolan) arc important adjuncts inrhe practice of ancsthesiology. They may be used as preoperative scdatives and induction agents,

as \\ cll as supplcrncntal agents for the maintenance ofanesthesia. Important Thc benzodiazepines,

barbiturates and narcotic analgesics all produce sedation and have the ability to produce de-pendence.

The pharmacokinetics ofindividual benzodiazepines difler, and thcrelbre there is a wide range inspeed of onset and duration of action anrong these compounds. Following oral administration,

most ofthe benzodiazepines are rapidly absorbed and highly bound to plasma protein. ln general,

most of the metabolitcs are conjugated with glucuronic acid and excreted in the urine and f-eces

Note: cl,-Hydroxylation is a rapid route ofmetabolism that is unique to triazolam, midazolaln, and

alprazolam. This accounts for the vcry mpid metabolism and short sedative actions ofthese drugs.

1. The term tranquilizer rcfers to a drug that promotes tranquility by calming, sooth-

ing, quieting orpacifying without sodating or depressant e{lccts. Antipsychotic agcnts

arc considered to be major tranquilizers and antianxigty agents fuenzodiazepites) are

considercd to be minor tranquilizers.2. For the treatment of insomnia due to anxiety the benzodiazepines llurazepam,

temazepam and triazolarn are usually prescribed.

3. lmportant: Flumazenil (Mazicon), a bcnzodiazepine antagonist, may bc used to rc-

verse thc residual effects ofbenzodiazepines in the evcnt ofan overdose.

4. tfthe benzodiazepines are i.effective in helping with insomn ia, zolpidem (Ambien),

eszopiclone (L nesta), or zaleplon (Sonata) are ot\en weful. Thesc are anti-insomnia

agents (called GABA-BZ Agonists).

Page 47: Pharmacology

. GABA (gamma-aminobutyric acid) receptor

. Norepinephrine r€ceptor

. Dopamine receptor

. Serotonin receptor

46Copyrighr O 2011,2012 - Dental Dects

. Rash, itch

. Vouth, throat ulcers

. Drowsiness, fatigue

. Difiiculty with urination

17CopltiShr O 20ll-2012 - Dental Decks

Page 48: Pharmacology

Buspirone (BuSpar) is an orally administered antianxiety agent with a short halfJife (2-4 hours). It is not chemically related to the benzodiazepines, or any other anxiolyic agent.Buspirone also differs from other antianxiety agents in that it does not possess anticon-vulsant or muscle relaxant properties, does not impair psychomotor function and doesnot cause sedation (lacks CNS depressant activiry) or physical dependence.

The exact mechanism ofaction olbuspirone is unknown. However, it has a higher affin-ity for serotonin receptors in the CNS and a lesser aflinity for the benzodiazepine-GABA receptors.

Important: The antianxiety effect is achieved via a partial agonist effect on CNS sero-tonin 5 -HTla receptors that occurs without affecting the benzodiazepine receptors orcausing CNS depression.

Remember: GABA-BZ agonists have a chemical struchrre that is dissimilar frorn those

ofthe benzodiazepines and on the sedative hypnotics. These agents appear to act throughthe potentiation ofGABA on benzodiazepine r€ceptors, especially the omega-l subunit.They are used primarily for insomlia. They have exhibited some anxioll4ic action butthey have little effect on skeletal muscle or seizure thresholds. They appear to have min-imal disruptive action on the normal sleep cycle, thus preserving deep sleep. Note: Theyhave shown no potential for causing addiction. Examples include Zolpidem (l mbien), es-

zopiclone (Lunesta), and zaleplon (Sonata). -fhese drugs have short halfliv€s f1 /o 2how s).

Diazepam is prescribed in the treaftnent ofanxiety, nervous tension, muscle spasm, and

as an anticon!'ulsant. Contraindication to use: Acute narrow angle glaucoma.

It is used intravenously as the agent ofchoice to reverse status epilepticus induced by a

local anesthetic overdose. Diazepam affects the limbic system olthe brain lcontrols emo-

/iori. It has a high therapeutic index, produces some degtee ofannesia, and can be locallyirritating to tissue and may produce local thrombophlebitis when given intravenously.

\ote: Propylene glycol, which is in the ry mixture, is the main cause ofthrombophlebitis.

Page 49: Pharmacology

. Ulhashort-acting

. Short-acting

. Intermediate-acting

. Long-acting

48Coplright O 201 I -20 l2 - Denral Decks

The brief duration of general anesthetic rction of anultra-short-acting barbitumte is due to what factor?

. Rapid rate ofmetabolism in the liver

. Lorv lipid solubility, resulting in a minimal concentration in the brain

. High degree ofbinding to plasma proteins

. Rapid rate ofredistribution from the brain to peripheral tissues

. Slow rate ofexcretion by the kidneys

49Coplright @ 201t-2012 - Dental Decks

Page 50: Pharmacology

The length ofaction can be related to the lipid solubility with the ulhashort being the most lipid solu-bJe and the long acting having thc least lipid solubility. Thcy are mctabolized in the liver, These drugspossess serious drug dependence potential. They do not possess significant analgesic propefiies. The

length ofh)?notic action ofthe four different classes after a single dose are as follows:

. Ultrashort-acting: 5 to 20 minutes

. Short-acting: I to 3 hours

. Intermediate-acting: 3 to 6 hours

. Long-acting: 6 to l0 hours

Agents:. Ultrashort-acting: for induction of general anesthesia. Examples include thiopental (Pentothal)

and methohexital fBr"evildl,.. Short-actingi for treating insomnia. Examples include secobarbital (Seconal) and pentobarbital(Nenbutal).. Intermediate-acting: for treating insomnia. Examples include amobarbital (An.vtal) and bfiabatbital lButisol).. Long-acting: for treating certain types ofseizures. Examples include phenobarbital (Z uminal),me-phobarbital ( Mebarul ) and pi'n]id.one (Mysoli ne).

Remember: Barbiturates do not possess analgcsic properties.

Important concept for anticonvulsant effect of lo.rg-acting barbittrates (i.e. phenobatbital)t Ba'r-

brrurates rvork by inhibiting the depoladzation ofneurons by binding to the GABAreceptors, which en-

hances the iransmission ofchloride ions. They also increase the threshold for electrical stimulation ofthemotor conex. Remember: Benzodiazepines work similarly to barbin-rates, but they also increase the

number of chloride channels whilc facilitating the transmission of chloride ions. This suppresses the

:pread of seizlrre activity but does not abolish abnormal discharge from a focus.

\ote: The cause ofdeath from acute barbiturate poisoning or overdosage is respiratory failure. Other

ad\erse reactions include CNS depression, euphoria, and habituation. The most important therapeutic

measure to be taken in a case ofbarbifurate poisoning is to assure adequate respiration.

Remember; These agents will maintain anesthesia only while in the brain. Because oftheir high lipid solubility, these agents will rapidly leave the brain for other tissues; thusthe patient wakes up within a few minutes of administration.

Eramples of ultra-short-acting barbiturates include thiopental (Pentothal) and metho-

he\ital (.B/?l,tal/. These agents are administered by intravenous injection.

Contraindications to the use of ultra-short-acting barbiturates for general anesthesia:

. Porphyria

. Lir er dysfunction (thet- are metabolized in the liver)

. Emphysema

. Previous addiction to sedative hypnotic drugs

Remember: These drugs have the ability to produce dependence.

Page 51: Pharmacology

All of tle following statements concerning barbiturates are true

. Barbiturates may increase the half-lives of drugs metabolized by the liver

. Barbiturates depress neuronal activily by increasing membrane ion conductance(primarily chloride), reducing glutamate-induced depolarizations and potentiating theinhibitory effects of GABA

. Compared with benzodiazepines, the barbiturates exhibit a steeper dose-response rela-tionship

. Barbiturates may precipitate acute porphyria in susceptible patients

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All the following are classified as antiepileptics fiXCEPI one.Which one is the.EXdEPIlON?

. Gabapenth lN euro h t i n )

. C arbamazeplne (Tegretol)

. Phen -\1oin (Di lantin)

. p Tsp1fsisns (Ryt hn o l)

. Phenobarbttal (Lutn i n a I)

. Dlazepam (l/alium)

. Yalproic acid, (Depakene)

. Ethosuximide (Zaron t in)

. Primidone (Mysoline)51

Copright O 20ll-2012 - Dental Decks

Page 52: Pharmacology

*** This is falsel barbiturates may decrease the halflives of drugs metabolized by theliver. Barbiturates induce the formation ofthe liver microsomal enz),nes that metabolizedrugs. This leads to an increased clearance ofthe affected drugs and possibly leads to adecrease in the drugs effectiveness.

The uses ofthe barbiturates are determined by their duration ofaction:1. The ultrashort-acting agents are used intravenously for the induction of general

anesthesia. For extensive procedures, they are used to induce stage III surgical anes-

thesia. For very brief procedures, they may be used alone.

2. The short-acting agents can be used orally for their hypnotic, calming effect. These

agents can be given preoperatively, before a dental appointment, to allay anxiety.3. The intermediate-acting agents can also be prescribed to relieve anxiety before a

dental appointment, although their effects will last longer than those of the shoft-act-ing agents. These agents are used for daytime sedation and for the treatment of insom-nia (they suppress REM sleep).,1. The long-acting barbiturates are used primarily for daytime sedation and the treat-ment ofepilepsy.

Generally the primary pharmacological effects ofthe barbiturates involve the brain and

spinal cord (CNS -

depression ofl. At sedative doses barbiturates do not effect or have

linle effect on the cardiovascular and respiratory systems. Barbiturates are metabolizedin the liver. The chronic use ofthe barbiturates causes an increase in liver microsomal en-

z)me activity that appears to be the result ofincreased synthesis ofenzyme. These drugspossess serious drug dependence potential. They do not possess significant analgesic

DroDerties.

*** Propsfenone /Rr1/rnol./ is an antianhlthmic agcnt uscd to trcat both vcnlricuiar arrhythmias and supmvcntric-

ular tschlcardias.

.\seizureisanakcrationinbchavior,functio,and,/orconsciousncssthatrcsultstiomanabnormalclcctricaldischargcol ncurons rn thc brain. Epilepsy, or th€ tcrm scizurc disordcr, is uscd to dcscribc chronic unprovokcd rccurrcnt

srizur.s. Serzurcs as classiflcd as eilher panial or generalized, bascd on horv thc abnormal brain activity bcgins.

. Partial seizures: when scizurcs appcar 1() rcsult from abnormal activit] in just onc pan ofthe brain.

. Generalized seizuresi seizures that sccm to in\rclve all ofthc brain. Fourrypcs ofgcncraiizcd seizurcs cxist; ab-

sence tnlso Lalle.! pdit md1). myoclonic, ttonic and tonic-clonic scizurcs (ulso culled grand nal).

F!.: xrr.ir antiepifeptic /.rnti@t1fllsant) dr$gs, thc cxact mechanism for rcducing scizDrc activity is not clcarly un-

Jrrsii\id. All incrcasc thc threshold ofthc CNS to convulsivc stimuli or inhibit thc sprcad ofscizurc activiry Thc

:nri,r!1:!'prlc drugs /,{fDrl can bc groupcd into thc following classes:

lHldantoinsfPhen]toin/D//drrnrlisuscdinthctrcatmcntoftonicclonic(grandnal)sciz\\rcs.ltprolongsthc.ti.cri\c rcfBctory pcriod by blocking ncuronal sodium channcls. Phcnytoin-induccd gingival hyperplasis is

common and ma] pa.tially or totally obscurc thc crcwns oftccth. Thc ratc ofdcvclopncnl oflhis condition can

bc diminishcd by proper oral hygicnc.L GABA analogs: The cxacl mcchanism ofaction ofvalproic acid /Dcpdkdn.i and thc ncwcr GABA analogs is

not clcarly undcrs@od. Al1 ofthcm incrcasc thc actions ofGABA, in inhibilory ncurotransmittcr Thcy may in-hibit thc voltagc-dcpcndent sodium channcl, thcrcby stabilizjng thc ncuronal membranes. [xamplcs oflhc ncwcrGABA analogs include: gabapcntin (Neuro tin), divalprocx sodium fDryakote), fclbamzlc (Felbaror, lamotrig-inc (Lan ida l) , prc9abal;n lLlrirc ) , t;a$abirc lcabitril) , and ropiftr..,arc (Topumar) .

3. Succinimides: Ethosu\imlde (Zaro tifi)t \tscd in thc trcatmcnt of abscncc scizures.

4. Barbituratesi Phenob^rbital (Lut inal.)wo*s by inhibiting dcpolarization ofncurons by bindinglo the GABArcccptors, which cnhanccs lhc transmission ofchloridc ions. Primidone (t|r.!o/ir?i is mctabolizcd lo phcnobar-

bital and phcnylcthylmalonanide /PtM,4/, which havc anticonvulsant activity.5. Benzodiazepines; work similarly to barbituratcs, but thcy also incrcasc thc numbcr ofchloridc channcls whilcfacilitating thc transmission ofchloridc ions. Examplcs includc diazepam (lhlium), clo azcpam (Klonopnt), and

lomzcpam /,lrl|rl,r. Not€: Di^zeprm (Ilalium) is uscd for status cpilcpticus and in cmcrgcncy trcatmcnt ofseizures.May cdusc drcwsrncss. dr7lincss. dnd ata\id.6. Misceffaneous: oxcarbazcpi^c (hilepttrl),lcvctiftccl^m (Kepptu), and c rbgm zepine (hegreol).C^rba-mazepine is uscd as prophylaxis for partial scizurcs ilh complcx symptomatology including psychomotor and

tcmporal lobc scizurcs. It is also uscd to treat tonicclonic scizurcs /grdrd nd, and trigcminal ncuralgia. It rarclycauscs aplastic ancmia,

Page 53: Pharmacology

. Imipramine Qof'anil)

. Amitr ipty line ( E I ai l)

. Desipramine (Norpramin)

. N ortiptyline (P am e I o r)

. Doxeprn (Sinequan)

52

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\Which drug is the current drug ofcholce for the treatment ofthe manic

phase ofbipolar disorder (or manic4epressive syndrome)?

. Phenobarbital

. Irnipramine

. Lithium

. Haloperidol

53

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Page 54: Pharmacology

The tricyclic antidepressants are generally considered to be the drugs of first choice forthe treatment ofunipolar disorder (depresslor). These drugs inhitlit the neuronal re-up-take of norepinephrine and s€rotonin (5-HT) in the brain. This results in the potentia-tion oftheir neurotransmitter actions at postsynaptic receptors.

Important: Amitriptyline displays the greatest anticholinergics effects (especially xe-

rostomia), desipramine the least.

Drowsiness is the most frequent CNS adverse reaction. Anticholinergic adverse side ef-fects include: dry mouth, constipation, blurred vision and tachycardia.

The selective serotonin reuptake inhibitors (S,SR1s) have revolutionized the treatment

ofdepression. The most important clinical distinction ofthe SSRIs from all other antide-pressants is their very high specificity for blocking the reuptake of serotonin. Fluoxe-tine (Prozac:)is the prototlpe and has the longest half-life. Paroxetine (Paxil), Sertraline(Zololi) and Fluvoxamine (Luvox) have shorter half-lives and can be given once daily.Citalopram (Celexa) and escilalopram (Lexapro) are used for generalized anxiety disor-ders. These drugs are also effective for treating panic attacks. Side effects include nau-

sea. headaches, anxiety, agitation, insomnia, and sexual dysfunction.

Bipolar disorder for manic-clepressive syndrome) is characterized by cyclical changes in af-

fectir e state between the manic and depressive phases ofbehavior Bipolar patients cycle be-

r$ een rhe trvo aflbcted states.

Lithium salts are by far the most important drugs for suppressing mania in patients with af-fective disorders. It is not useful for the acute manic episodes. Lithium can prevent the oc-currence ofboth the depressive as well as the manic episodes in some but not all the patients.

Antidepressants are often administered with lithium to manage the depressive phase ofthe ill-ness if lithium alone is not sufficient. Note: Lithium works inside the cell to prevent the for-mation of inositol triphosphate and diacylglycerol. These substances serve as secondmessengers within the CNS and may have widespread influence on neuronal function.

Approximately 2570 of patients who suffer from mania do not respond to lithium. Carba-mazepine (qtl anticonvulsant) andvalproic teid (also an a ticonwlsant) may be effective insome relractory cases. Note: Carbamazepine blocks sodium channels and valproic acid blocksboth sodium and calcium channels.

Neurofeptic agents (also referrecl to as anti-psychotic agents or msjor trqnquilizersl are used

in the acute manic episodes. Chlorpromazine, which is a phenothiazine, and Haloperidol,*'hich is not a phenothiazine but acts in a similar fashion, are effective in quelling the exhememania and psychotic behavior

. 1. The most common side effects of lithium, including Gl irritation, fine handi\ote*. ftsm61 muscular weakness, polyuria, thint, sleepiness, and a sluggish feeling, are

;;.-1 often associated with initial therapy and usually fade within I to 2 weeks.

2. Severe intoxication results in vomiting, diarrhea, unconsciousness, and convul-sions.3. Sodium restriction leads to greater retention oflithium in the kidney.4. Diuretics and some NSAIDs reduce lithium excretion and mav cause lithiumtoxicity.

Page 55: Pharmacology

Monoamine Oxid nse (IWAO) iahibltors are often us€d as third-lineNgents in cases of refractory and atypical depression.

Whlch Tiro drugs below are MAO inhlbitors?

. Doxepin (Sinequan)

. Tranylcypromine (P arnate)

. lmipr arnine (Tofr an i I )

. Phenelzine (Nerdil)

54

Coplright O 20ll-201? Denral Decks

\The vasoconstrietor epinephrins in local anesthetic injections must be used

cautiously in patients taking all ofthe following antidepressant drugsEXCEPT one in qrder to avoid transient and signilicant increases in

blood pressure. Which one is the ,EXCEPTIOM

. Tncyclic antidepressants (i.e., Elavil)

. Selective serotonin reuptake inhibitors (i.e., Prozac and Paxil)

. Serotonin and norepinephrine reuptake inhibitors (i.e., Effexor and Cynbalta)

Cop)rightO 20ll-2012 - D€nbl Decks

Page 56: Pharmacology

MAO inhibitors are used are often used as third-line agents in cases ofrefractory and atypi-cal depression. MAO inhibitors antagonize the action of monoamine oxidase (MAO) re-sponsible for the degradation of the naturally occurring monoamines

- epinephrine,

norepinephrine, dopamine, and serotonin. It is theorized that the increased level ofmonoamines in the brain is responsible for the antidepressant effect ofthe MAO inhibitors.

Note: Local anesthetics containing epinephrine are genemlly contraindicated in patients whoare taking MAO inhibiton.

The major limitation for the widespread use of the MAO inhibitom for the treatment of de-

pression has been the potential for serious adverse side effects, including hypertensive cri-sis. rvhich can be fatal. A hypertensive crisis can occur within several hours after ingestion

of a substance that contains tyramine. Tyramine releases norepinephrine and other sympath-

onrimetic amines, thereby raising blood pressure. Early symptoms include occipital headache,

palpitations, stiff neck, nausea, vomiting, and sweating. Among the drugs that interact with\1AO inhibitors are meperidine (Demerol), epinephrine and ephedrine.

l. Miscelianeous antidepressants include:\ot€ . Mirtazapine (Remeron): alphaz -noradrenergic antagonnist

. Bupropion (Wellbrr'tu ,SZ/: norepinephrine / dopamine rer.rptake inhibitor

. Trazodone (Desl,rel): mechanism not clear; possible serotonin reuptake in-hibitor

These trvo categories (tt'iclclic qntidepressants snd serotonin and norepinephrine teup-

rake inhihitors) of antidepressant drugs significantly increas€ norepinephrine levels in tis-

sues. ln rhe presence of a vasoconstrictor administered via a local anesthetic injection,

the patient could experience significant elevation of blood pressure due to the vaso-

pressor actions of the combination.

\ote: The selective serotonin reuptake inhibitors fi.e., Prozac and Paxil) have no such

effect on norepinephrine in tissues and interaction with a vasoconstrictor like epineph-

rine is not an issue.

Page 57: Pharmacology

. Tricyclic antidepressants (i.e., Elavil)

. Selective serotonin reuptake inhibitors (i.e., Prozac and Paxil)

. Serotonin and norepinephrine reuptake inhibitors (i.e., Effexor and Cymbalta)

. Monoamine oxidase inhibitors (i.e., Nardil)

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Coplright @ 201l-2012 - Denhl Decks

. Yenlafaxine (Effexot)

. N orntpryLine (P am e lor)

. Desrpramne (N o rprami n)

. Desvenlafaxine (Prrsfiq)

. Sertraline (Zoloft)

. Duloxetine (Cym b a I t a)

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Page 58: Pharmacology

These two categories ofantidepressant drugs induce significant dry mouth in:up to 75yo

ofpatienls taking these medications. These effects are due to the secondary anticholin-ergic nature ofthese agents. Note: Drug-induced dry mouth must be treated palliativelywith artificial salivary substitutes.

The seldctive serotonin reuptake inhibitors (i.e., Prozac, Paxil) and monoamine oxidaseinhibitors have no secondary anticholinergic effects and therefore do not cause any sig-

nificant dry mouth.

Five major categories of antidepressant drugs:. Tricvclic antidepr€ssants:

. Amitriptyline (E/avll)

. Doxeprn (Sinequan)

. Imipramine (Tof'anil)

. Serotonin and norepinephrine reuptake inhibitors:. Yenlafa:.l.ine (Elfexor) . Desvenlafaxine (Pristiq). Nortriptyline (Pamelor) . Duloxetine (Cymbalta). Desipramine (Norpramin)

. S€lective serotonin reuptake inhibitors:. Citaloqam (Celexa) . Paroxerine (Paxil). Escitalopram (Lexapro) . Sertraline (Zoloft). Fluoxetine (Prozac)

. Second generation miscellaneous:. Bupropror. (Wel I butrin). Trazodone (Desyrel). Nefazodone (Serzone). Mirtazrpine (Remero n)

. Monoamine oxidase inhibitors:. Phenelzine Q'{ardil). Tranylcypromine (P arn at e ). Isocarboxazide (Marylan)

Page 59: Pharmacology

. Diphenhydramin e HCL (Benadryl)

. Chlorpheniramine maleate (Chlor-Trimeton)

. Cimetidine (Tagamet)

. Loratadine (Clantin)

. Desloratadine (C lari n ex)

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. Prostatitis

. GERD (heartburn)

. Toxic-shock slndrome

. Renal failure

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Page 60: Pharmacology

*** Cimetidine is an antihistamine H2-receptor blocker.

Antihistamines are antagonizing agents that compete for receptor sites with natuml hista-mine, which is stored preformed in cyoplasmic granules of tissue mast cells and blood ba-

sophils. It is released in response to lgB-mediated (immediate) allergic reactions and playsan important role in hay fever, urticaria and angioneurotic edema. Note: Histamine also playsan important role in the control ofacid secxetior] (HCL) in the stomach.

There are two t)?es of histamine receptors, H1-receptors, which play an extremely importantrole in allergic reactions and H2-receptors, which are important in gastric acid secretion. The

antihistamines are divided into H,and H2-receptor blockers depending on the histamine re-

ceptor they compete for.

H1 receptor blockers include:

1. First-generation (classical) agetts:. Diphenhydramine HCL (Benadryl) and chlorpheniramine maleate (Chlor-Trimetron)*** These agents have a broad spectrurn of action which includes antihistaminic, an-

ticholinergic, antiserotonergic, antibradykinin and s€dative propefiies.

l. Second-generation agents:. CetiiztneHCL Qfrlec), fexofenadine HCL (Allegra),lorctadine (Claritin) and deslo-

ratadne (Clarinex)*"* Most ofthese agents, because oftheir poor CNS penetratjon (do not ctoss the blood-hrain barrier). cause less sedation and drowsiness than the first-generation agents.

lmportant points: All ofthe H,-receptor blocke$ do not preYent the release of histamine but

rather compete with free histamine for binding at Hl-receptor sites. ln general, the binding iscompetitive. however, some second-generation agents bind non-competitively at higher doses.

Common side effects include drowsiness, dizziness, anticholinergic effects /dry moutlt, ose

and thrcat), and nausea. They can both stimulate and depress the CNS.

H2-receptor antagonists compete with histamine at the H2-receptor. Histamine produces

a s ide variety ofphysiologic actions in many tissues. While H2-receptors are located inthe GI tract and in vascular and bronchial smooth muscle, H2-receptor antagonists com-pete * ith histamine only in the GI tract. Inhibition of histamine at the parietal cell in-terteres u ith one of several mediators for signaling the parietal cell to secrete acid.

H'-bfockers incfude: cin.retidine (Iaga met), ranrtrdrne (Zantac), famotidlne (Pepcitl) and

ntzatidire (Axicl).These agents are all rev€rsible competitive antagonists ofthe actions

of histamine on H,-receptors. These agents are used to treat acid-peptic disease, espe-

cialll duodenal ulcers and occasionally gastric peptic ulcers. These drugs are also used to

treat Zollinger-Ellison syndrome (a hypersecretory disease) and gastroesophageal refluxdisease /GERDJ.

Note: Cimetidine has an antiandrogen effect (can lead to impotence, Ioss oJ libido, andgtnomastia).It also inhibits liver metabolism which can lead to an increase in activityofother drugs such as warfarin and carbamazepine.

Page 61: Pharmacology

. Hl-receptor site

. H2-receptor site

60Copyright O 20ll-2012, Denial Decks

. Cephalexin

. Cephradine

. Amoxicillin

. Tetracycline

6lCoplrighr O 201 l -20 1? , Dertal Dech

Page 62: Pharmacology

Antihistamines are antagonizing agents that compete for receptor sites with natural his-tamine. The two types of histamine antagonists are:

l. H1-receptor antagonists: competitively block H1-receptors blocking the effects ofhistamine at these receptors. They block the vasodilation, they block the constrictionofthe bronchi and they block capillary permeability which histamine ordinarily causes.

The blockade ofthese effects of histamine overcomes the svmDtoms of seasonal aller-gies.

. Actions of Hl antihistamines:- Blocks pain and itch, vasodilation and bronchoconstriction due to histamine- Reduces motion sickress: first-generation only (i.e., Diphenhydramine HCL

anrl c h I orpheniramine maleate)- Promotes sleep: first-generation only

Remember: The second generation Ht-receptor antagonists have the following charac-

teristics: Longer halfJives than first generation (l2-24 hours as opposed to 3-6 hours forfirst generation), they do not cross the blood-brain barrieq they produce little or no seda-

tion. and have a higher risk of cardiac arrhythmias (long QT ellbct). Examples includeCetirizine HCL (Zyrtec), fexofenadine HCL (AIIegra),loratadine (Cla tin) and deslo-

raradine (Clarinex).

:. H2-r€ceptor antagonists: competitively block H2-receptors, blocking the effects ofhistamine at these receptors. Examples ofthese drugs include: cimetidine (Tagamet),

n tidine (Zontac), famottdine (Pepckl) and nrzatrdine (Axrd). They block secretion ofstomach acid and are used in the treatment ofduodenal ulcers.

\ote: Histamine is found in all tissues, particularly in mast cells and blood basophils.It is released in allergic and inflammatory reactions.

From the "Advisory Statement, Antibiotic Prophylaxis for Dental Patients with Total JointReplace)nent" published by the American Dental Association and the American Acad-emy' ofOnhopedic Surgeons, in the J Amer Dent Assoc 1997; 128(7):1004-8 and J AmerDent Assoc 2003;134:895-898

-either cephalexin, or cephradine or amoxicillin can be

used as the drugs ofchoice lor standard prophylaxis medication in the patient with a totaljoint replacement.

. Cephalexin (Keflex) is a lst generation cephalosporin; prophylaxis dose is 2 grams

orally I hour prior to the dental procedure.

. Cephradine (Velose, is a lst generation cephalosporin; prophylaxis dose is 2 grams

orally t hour prior to the dental procedure.

. Amoxicillin is a mernber of the penicillin family; prophylaxis dose is 2 grams orallyt hour prior to the dental procedure.

\ote: For patients not allergic to penicillin and unable to take oral medications the

suggested medications are cefazolin f4 lst generation cephalosporin) or ampicillin (mem-

ber of the penicillin family). The regimen is as follows:

. Cefazofin (Ancefl 1 gor ampicillin 2 g intramuscularly or intravenously t hour priorto the dental Drocedure

Page 63: Pharmacology

. Affects cell membrane

. Interferes with protein synthesis

. Affects cell wall

. Interferes with normal biosynthetic pathways

62

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Mefloquine fzanlum) belongs to a chss of drugs which is useful intreating which ofthe following conditions? ,,

. Valaria

. AIDS

. Hepatitis

. Cancer

. Chlamydia

63Cop)righl O 20ll -2012 - Dental Deks

Page 64: Pharmacology

Mechanisms of action ofantibiotics on the bacteria cell:

. Agents affecting cell wall:- Penicillins - Vancomycin - Lnipenem- Cephalosporins - Cycloserine- Bacitracin - Aztreonam

. Agents interfering with protein synthesis:

- Tetracycline - Erythromycin - Azithromycin- Aminoglycosides - Lincomycin - Clarithromycin- Ch loramphenicol - Clindamycin

. Agents interfering with normal biosynthetic pathways:

- Sulfonamides- Trimethoprim- Fluoroquinolones (i.e., ciproJloxacin, norJloxacin, Ievo;floxacin, moxiJloxac'in, andgentilloxacin)

\ote: The most corruron clinical cause of bacterial resistanc€ is the use of antibiotics* hen they are not indicated.

\'falaria is a devastating parasitic disease transmitted through the bite ofinfected Anophe-les mosquitoes. Endemic to tropical and subtropical areas ofAsia, North and South Amer-ica. the Middle East, North Africa, and the South Pacific. Plasmodium vivax is the most

common of four human malaria species (P falciparum, malariae, ovale, and vivax). P.

r ir ax causes up to 65% of malaria in India and is becoming increasingly resistant tomalaria drugs. By contrast, P falciparum is the most deadly species and the subject ofmost malaria-related research and literature.

\fefloquine (Lariam) has been shown to be effective in treating malaria caused by allfour malaria species.

Other antimalarial drugs are:

. Chloroquin (Aralen)

. Combination ofatovaquone and proguanil (Malarone)

. Halofantrine

. Quinine

. Conrbination of sulfadoxine and pyrirnethamine (Fansidar)

Page 65: Pharmacology

. Penicillin \fK

. Cefaclor (Ceclor)

. Penicillin G

. Erythromycin

64Coplrighl C 201 1,2012 - Dental Decks

\Tetracyclines ore the drugs of lirst choice in the treatment ofall of the

lollowing EXCEPT one. Which one is the EXCEPTIOM

. \{ycoplasma pneumonia

. Chlamydia infections

. Rickettsial infections

. Staphylococcal infections

55Coplright O 201 I 2012, Dental Decks

Page 66: Pharmacology

Cefaclor is a member ofthe cephalosporin family ofantibiotics. The cephalosporins are peni-cillin-like in action against bacteria. They are bactericidal antibiotics and act like the peni-cillins and interfere with cell wall synihesis through inhibition of the synthesis of thepeptidoglycan in the cell wall. The antibiotic binds to the enzymes fi. e., transpeptidase) thatbuild/maintain the cell wall. This makes the cell wall osmotically unstable. Bacteda eventu-ally lyse, resulting in death ofthe cell. Cephalosporins act against a wide range ofgram-pos-itive and gram-negative bacteda.

Cunently there are four generations of cephalosporins. Each newer generation has signifi-cantly greater gram-negative antimicrobial properties than the preceding one, and a de-

creased maximum acti\ ity against gram-positive organisms.

Important c€phalosporins within each generation:

. First: cephalexin (Keflex), cephradine (Velosqf, cefadroxrl (Duncefl, cefazoin (AnceJ).

Most active against S. aureus, Group A Beta-hemolytic streptococci, and Pneumococcus.. Second: cefaclor (Ceclor), cefuroxime (Ceftin), cefoxrtin (Mefoxn), cefprozrl (Cefzil),

cefpodoxime /Zartlr). Still have eJficacy against gnm-postivie organisms but also possess

good activity against E. coli and H. influenzae.. Third: cefixime (Suprax), cefoperazoqe (Cefobid), ceftriaxone (Rocephir. Have thebroadest spectrum ofactivity ofall cephalosporins and are extremely effective against gram-

negati\e organisms. They are more active against E. coli, Klebsiella pneumoniae, Enter-

oh:rcrer. Salmonella. and Shigella.. Fourth: cefeprme (Maxipime). Effective against Pseudomas aeruginosa.

\ote: Approximately 107o of individuals expressing allergy to the penicillin family ofantibiotics will have cross allergenicity to the cephalosporins.

Remember: Antibiotics containing this betalactam ring are referred to collectively as beta-lactam antibiotics and include the penicillins, cephalospodns, and the two newer groups ofaeents. the carbaDenems and the monobactams.

Popular Tetracyclines include:

. Tetracycline: used to treat acne, gonorrhea and syphilis in patients allergic to peni-

cillin. exacerbations of chronic bronchitis, Mycoplasma infections and Chlamydia

infections, and Rickensia infections.

. \Iinocycline (Minocin): used to treat acne, anthrax and meningococcal prophylaxis.

. Dox) clclin€ (Vibramycin)| used to treat infections caused by Rickettsia, Chlamydiaand \{ycoplasma; altemative to mefloquine for malaria prophylaxis and treatment ofslphilis.

Page 67: Pharmacology

. Macrolide class ofartibiotics

. Cephalosporin class of antibiotics

. Quinolone class ofantibiotics

. Glycopeptide class of antibiotics

66CopriShr C 20ll-2012 - Dental Deck

. CNS effects

. GI effects

. Hematologic effects

. Renal effects

Copyrighr o 201 1,201 2 - Dertat Decks

Page 68: Pharmacology

Azithromycin (Z-Pak, Zithromax) and clarithrornycin (Biaxin) are members of themacrolide class ofantibiotics in which erythromycin is the prototype agent,

The bacterial spectrums ofactivity ofLzithromycin and clarithromycin are similar to thatof erythromycin but possess greater intrinsic activity against H. influenzae and Heli-cobacter pylori. These two macrolides concentrate within macrophages, making themuseful against organisms that are taken up by macrophages such as Mycobacterium aviumintracellulare.

The significant tissue penetration ofboth agents and the prolonged elimination half-lifeof azithromycin (l l -14 hours) allows for once-daily dosing for azithromycin and twice-daily dosing for clarithromycin.

Note: Macrolide antibiotics are generally used to treat infections caused by streptococcal

bacteria and respiratory infections generally. They are also active against syphilis, Lymedisease and leprosy and tuberculosis. The macrolides can have a toxic effect on the liver,causing liver toxicity andjaundice and so should not be given to people who have an un-

derlying liver problem such as an infection with hepatitis C.

\facrolides are bacteriostatic. The mechanism of action involves inhibition of proteins! nthesis that results from binding specifically to the 50s ribosomal subunit. This causes

the Rr\A to dissociate from the ribosome and prevents protein synthesis.

Remember: Intrinsic activity is a measure ofthe ability ofa drug once bound to the re-

ceptor to generate an effect activating stimulus and producing a change in cellular activ-it-v.

Adverse Gl effects are reported for approximately 2lo% ofpatients receiving er)thromy-cin. about 107o ofpatients receiving clarithromycin, and less than 504 for azithromycin.

In general, oral bioavailability of erythromycin is poor. It is readily inactivated by stom-

ach acid, and several salts have been developed to overcome this drawback.

. Erylhomycin stearate (E4tthrocin)

. Erylhromycin ethylsuccinate ft.t S.)

**" Since they are destroyed by stomach acid, erythromycins are usually entedc coated.

This is a term designating a special coating applied to tablets or capsules which prevents

their release and absorption oftheir contents until they reach the intestines

\ot€: Er,,lhromycin is metabolized in the liveq excretion is mainly via the bile

Page 69: Pharmacology

. Neomycin

. Streptomycin

. Tobramycin

. Gentamicin

. Penicillins

. Erytfuomycins

. Acetylsalicyclic acid (Aspirin)

. Para-aminobenzoic acid (PABA)

68

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Page 70: Pharmacology

Aminoglycosides are potent bactericidal antibiotics that act by creating iissures in the outcrmembrane of the bacterial cell. They are particularly active against aerobic, gram-negativebacteria and act synergistically against certain gram-positive organisms. Gentamicin is themost commonly used aminoglycoside, but amikacin may be particularly effective againstresistant organisms. Aminoglycosides are used in the treatmcnt of severe infections of theabdomen and urinary tract, as well as bacteremia and endocarditis. They are also used forprophylaxis, especially against endocarditis. Resistance is rare but increasing in frequency.Avoiding prolonged use, volume depletion and concomitant administration of other potentiallyncphrotoxic agents decrcases the risk of toxicity. Single daily dosing of aminoglycosides ispossible because of their rapid concentration-dependent killing and post-antibiotic effect andhas the potcntial for decreased toxicity.

Aminoglycosides:. Gentamicin (Garamycit), Amikacin (Aniken), and"tobramycin (Nebci ). These are effec-tive against serious infections caused by aerobic gram-negative bacteria, including E. Coli, En-terobacter, Klebsiella, Proteus, Pseuodomonas aeruginosa, and Serratia.. Streptomycin: The first aminoglycosidc and q,as shown to be effcctive in the treatment oftu-berculosis. ls seldon used today.. \eom]cin (Myi/iadn, and Kanamycin (Ka trer)i Due to its toxic potential ncomycin isused only topically or locally /e.g, in the GI tract). Kanamycin is rarely used bccause of itsmarked lendency to cause ototoxicity.

l. Aminoglycosides may cause severe neuromuscular weakness lasling hours to days\ot6 because oftheir potential curarelike effect. Aminoglycosides may aggravate muscle

- rvcakness in patients with muscular disorders such as myasthenia gravis, infant botu-lism, or parkinsonism.2. Aminoglycosidcs bind incvcrsibly to thc 30s ribosomal subunit of bacteria, subse-quently inhibiting protein synthesis.3. Two wcll-known adve$e effects are ototoxicity and nephrotoxicity.

Sulfonamides are often referred to as "sulfa drugs" because their molecules contain sul-fur atoms. They have a different antibacterial mechanism from that ofthe antibiotics. The

sullbnamides are structurally similar to PABA and this similarity is the basis for their an-

tibacterial actions. PABA is needed by bacteria for the synthesis of folic acid. In tum,lblic acid is needed for the synthesis of cellular components within the bacteria to allowfor cell growth. Because of structural similarities between sulfonamides and PABA, the

sulfonamides compete with PABA and are able to inhibit the actions of PABA. WithPABA inhibited, folc acid is not synthesized within the bacteria, and bacterial cellulargrowth is inhibited. Sulfonamides are predominantly bacteriostatic agents.

Examples of sulfonamides: Sulfacetamide, Sulfadiazine, Sulfadoxine, Suliamethizole,Sulfamethoxazole, Sulfanilamide, Sulfasalazine, and Sulfisoxazole.

1. Sulfonamides are not used for treatment of dental infections because ofa

,,Note*:.. low degree of effectiveness against oral pathogens.

',.,1::;:r,:,:: 2 Sulfonamides are used in medicine primarily for the treatment of urinarytract infections.3. Bactrim is the brand name for the combination of trimethoprim and sul-

famethoxazole. It is considered the drug of choice for many urinary tract in-fections. Bacteria susceptible to Bactrim include E. coli, Pneumocystis carinii.

Klebsiella pneumoniae, Haemophilus influenzae and Salmonella species

4. The trimethoprim component is an antimicrobial and the sulfamethoxazoleis one ofthe sulfonamides.5. Hypersensitivity reactions ate common. Although blood dyscrasias are rel-

atively rare, they can be fatal.

Page 71: Pharmacology

. Penicillin VK

. Erythromycin

. Cephalexin (Keflex)

. Clindamy cin ( C I e o c i n)

. Vancomycin

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. Penicillin

. Tetracycline

. Chloramphenicol

. Doxycycline

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Page 72: Pharmacology

Clindamycin binds to the 50s ribosomal subunit, blocking bacterial protein synthesis.Its use is restricted by its side effects such as severe diarrhea and pseudomembranouscolitis. These side effects are caused bv the oversrowth of the bacterium known as

Clostridium difficile.

Clindamycin is bacteriostatic and is active against most gram-positive (i.e., Streplococ-cus pneumonioe, viridans, antl pyogenes as v'ell qs Staph),lococcus aureus) and manyanaerobic organisms, including the anaerobic gram-negative bacteria Bacteroides frag-ilis.

In dentistry, clindamycin is an alternate antibiotic in the following situations:

. When an.roxicillin cannot be used for the standard regimen for prevention of bacter-ial endocarditis in patients undergoing dental procedures. For treatment ofcommon oral-facial infections caused by aerobic gram-positive cocciand susceptible anaerobes. For prophylaxis for dental patients with totaljoint replacement

Important: Clindamycin can be given to patients allergic to penicillins since there is nocross all€rgenicity between penicillins and clindamycin.

\ote: \bncomycin is given IV and is used most often in serious or life-threateningstaph)lococcal or streptoccocal infections. It remains the drug ofchoice for severe cases

ofClostridium difficile. Adverse effects include ototoxicity which may be pemanent and

the "red man" syndrome which is characterized by a sudden and profound fall in bloodpressure with or without a maculopapular rash over the face, neck, upper chest, and ex-

Eemlnes.

Chlorarnphenicol is a broad-spectrum antibiotic effective against gram-positive anderam-neqative bacteria and against anaerobes. It is used as a second or third line drug inmedicine to treat serious infections due to organisms resistant to other less toxic antibi-otics. For example it can be used to treat the following: Typhoid Fever, Bacterial Menin-gitis. Anaerobic Infections, Rickettsial Diseases, and Brucellosis.

Chlorarnphenicol inhibits protein synthesis in bacteria and, to a lesser extent, in eukary-oric cells. The drug readily penetrates bacterial cells, probably by facilitated diffusion.Chlorar.nphenicol acts primarily by binding reversibly to the 50s ribosomal subunit.

The most important adverse effect of chloramphenicol is on the bone marow Chloram-phenicol affects the hematopoietic system in two ways:

. by an non-dose-related idiosyncratic response manifested by aplastic anemia, lead-ing in many cases to fatal pancytopenia. by a dose-related toxic effect that presents as anemia, leukopenia, or thrombocytope-nla

Important: The risk of aplastic anemia does not contraindicate the use of chloram-phenicol in situations in which it is necessary; however, it emphasizes that the drug shouldnever be employed in undefined situations or in diseases readily, safely, and effectivelytreatable with other antimicrobial agents.

Note: Fatal chloramphenicol toxicity may develop in neonates, especially premature ba-bies" when they are exposed to excessive doses of the drug. The illness, the gray babysyndrome, usually begins 2 to 9 days after treatment is started.

Page 73: Pharmacology

Nitazoxanide fllirro,) is an oral antiprotozosl ag€ntus€d to treat which of th€ following conditions?

. Leprosy

. Malaria

. AIDS

. Dianhea caused by Clostridium diflicile

. Dianhea caused by Giardia lamblia

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CoplriShr O 20ll-2012 Dental Decls

.Isoniazid

. Streptomycin

. fufampin

. Ethambutol

. Pyrazinamide

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Page 74: Pharmacology

*** This type of diarrhea is an intestinal infection also known as Giardiasis, and is the

most common protozoan infection in the United States.

Antiprotozoal Agents:. Nitazoxanide (Alinia): is an antiprotozoal agent which is used in the treatment ofGiardia, and those protozoal infections caused by Cryptosporidium parvr,rm. Its mech-

anism is to interfere with the electron transfer reaction wilhin the protozoa essential to

anaerobic metabolism., Atol.a'quone (Mepror): is an antiprotozoal agent used to treat Pneumocystitis cariniipnetmonia (PCP) in patients who are intolerant to co-trimoxazole.. Eflornithine (Vaniqa): has orphan drug status for the treatment of meningoen-cephalitic stage ofTr)?anosoma brucei gambiense tnfection (sleeping srcinesy'. Thisdrug is also indicated to be used as a cream to reduce unwanted hair from face and ad-jacent areas under the chin.. Furazolidone (Furoxone)'. is a antiprotozoal agent used to treat dianhea caused bysusceptible Giardias lamblia and Vibrio cholerae.. Jletronidazole (Flab-l): is a synthetic antibacterial and antiprotozoal agent that iseflective against Trichomonas vaginalis, which causes trichomoniasis. In addition, itis one ofthe most effective drugs available against anaerobic bacterial infections. These

include infections caused by Helicobacter pylori, Clostridium difficile, Bacteroidesspecies and Fusobacterium species. Note: Alcohol should be avoided because metron-idazole and alcohol together can cause severe nausea, vomiting, cramps, flushing, and

headache. It should is not used in pregnancy because of potential adverse effects on

the fetus.

Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis. The anti-tubercular drugs either inhibit the growth ofthe bacteria or kill the bacteria. Because the

\llcobacterium organism tends to develop resistance to any single antitubercular drug,

combination drug therapy is standard in the treatment oftuberculosis.

.A.ntitubercular drugs:. lsoniazid: often given in a four drug regimen along with rifampin, pyrazinamide and

ethambutol. Streptomycin: often given in combination with isoniazid. Rifampin: usually given in combination with other agents. Ethambutol: usually given in combination with olher agents. Pl razinamide: popular in combination with rifampin

]Iechanism of action:. Isoniazid: is bacteriostatic for resting organisms and bactericidal for dividing organ-

isms. It interferes with lipid and nucleic acid biosynthesis in growing organisms.. Streptomycin: is a bactericidal antibiotic. It acts by interfering with normal protein

s)rlthesis.. Rifampin: inhibits DNA-dependent RNA-polymerase activity, thereby supressing

RNA synthesis. It can be bacteriostatic or bactericidal and is most active against bac-

teria undergoing cell division.. Ethambutol: impairs cellular metabolism, causing cessation of cell multiplicationand cell death. It is bactericidal and is active only against Mycobacterium.. Pyrazinamide: the mechanism ofaction is unknown. It may be bacteriostatic or bac-

tericidal against M. tuberculosis, depending on the concentration.

Page 75: Pharmacology

. Herpes zoster

. Genital herpes

. Herpes simplex type 1 (HSv-|)

. Papilloma virus

71Copyrighl O 20ll-2012 - Denhl Deck

. Didanosine

. Zidowdine

. Ritonavir

. Indinavir

. Delavirdine

Coplrishr O 2011-2012 - Dental Decks

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Penciclovir (Denavi is a cream formulation indicated for the treatment of recurrentherpes labialis (cold sores) in adults. This condition is caused by the herpes simplex type1 virus. Penciclovir is not available for systemic dosing.

Penciclovir (Denavir) inhibits viral action by selectively inhibiting herpes viral DNAsynthesis and therefore resulting in the inhibition ofviral replication,

Other agents indicated for use in treating the condition ofherpes labialis are:

. Acyclovir tablets

. Acyclovir cream

. Docosanol cream (lbreva)

. Lysine tablets

. Valacyclovir caplets (Valtrex)

AIDS has been recognized since l98l as a unique clinical syndrome brought on by in-fection with the human immunodeficiency virus | (HIr/-l) or virus 2 (HIV-2).The major

cellular defect caused by infection with HIV is a depletion ofT cells, primarily the sub-qpe T-helper cells kaown as CD4 cells. This results in a compromised immune system,

* hich becomes susceptible to opportunistic infections.

HIV is a type ofretrovirus that is responsible for the fatal illness flom AIDS. A retrovirus

has R\A as its nucleic acid and uses the enzyme reverse transcriptase to copy lts genome

into the DNA olthe host's cells chtomosomes. This DNA segment is then permanently

incorporated into the host cell's DNA within the nucleus. The integrated DNA segment can

produce nerv RNA in the cytoplasm of the host cell. The new RNA in tum synthesizes viralproteins, which are eventually passed on to other host cells such as the immune system

macrophages. Ultimately enough ofthe human immune cells are compromised such that

immune function is lost.

The HIV drugs such as didanosine @ rand name Wdex), zidovtldine (brand name Retro-

vil), ritonrvir (brand name Norvry', and indinavir @rand name Crixivan) work by in-hibiting certain steps in the HIV inlection process within the target cells to halt the

destruction of the immune system by the HIV retrovirus.

Page 77: Pharmacology

. Bacitracin

. Amphotericin-B

. Polymyxin-B

. Neomycin

76CoplaiSht @ 201l-2012 - Dental Decks

. Penicillin

. Erythromycin

. Nystatin

. Chloramphenicol

nCoP)right @ 201l-2012 - D€ntal Decks

Page 78: Pharmacology

This is an antifungal agent given intravenously or orally for the treatment ofsevere sys-

temic fungal infections caused by fungi such as Candida species. Bacitracin, polymyxin-B and neomycin are not antifungal agents. These are antibiotics effective against sus-

ceptible bacteria. Antibiotics in general do not have antifungal properties.

Candidiasis is an infection, usually ofthe oral cavity or vagina, with a candida species, usually C.albicaDs, which causes an inflammatory, pruritic infection characterized by a thick, white dis-charge. It is common, especially in patients who have a deficiency in T-ly,rnphocytes, or who are

receiving chemotherapy, and in immunosupressed individuals /,4lDSpalie s).Thisyeast-like fungiis a normal inhabitant of the oral cavity and vaginal tract, however it is normally held in checkb; the indigenous bacteria ofthese areas. Note: Angular cheilitis Oilateral ulcers at the comer ofrhe ntoutht has been linked to C. albicans.

Remember: Nystatin and clotrimazole are the two antifungals that are used as "swish and swal-fo\r'' to treat oral candida infections. Nystatin (Mycostatin) is taken as an oral suspension to besn ished around thc mouth and swallowed. Clotrj.lri.azolc (M))celer, is taken as a troche (lozenge)\\hich is slorvly dissolved in the mouth and swallowed. They work by binding to sterols in the fun-gal cell rnembrane, increasing permeability and permitting the leakage ofintraccllular componcnts.This leads to the death ofthe atTected fungal cell.

Note: The suffixes ofthe following generic drug narnes are indicative ofthe conespsonding drugclasses:

. "azole" = azole-type antifungal drugs (e.9., clotrimazole)

. "coxib" = COX-2 inhibitors fe&, celecoxib)

. "dipine" = dihydropyridine calcium channel blockers (e.g., nicardipine)

. "olol" = beta-adrenergic receptor blockers (e.g., naclolol )

. "ilol" or "alol" = beta-adrenergic receptor blocker that also blocks alphal-adrenergic receptors(e.g., canedilol or labetalol). "onium" or "urium" : quatemary ammonium compounds, usually competitive peripheral act-ing skeletal muscle relaxers (e.9., pancuronium). "osin" = alphar-adrenergic reccptor blockers (e.g., terazosin). "pril" - ACE inhibitors (e.g., enalapril). "sartan": angiotensin II receptor blockerc (e.9., olmesartan). "statin" = HMG-CoA reductase inhibitor (e.9., atoflastatin)

Page 79: Pharmacology

. Penicillin V

. Penicillin G

. Ampicillin

. Amoxicillin

. Penicillin VK

. Amoxicillin

. Penicillin G

. Ampicillin

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Page 80: Pharmacology

All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactamring structurejoined to a thiazolidine ring. The betalactam ring is essential for its anti-tracterial activity. This basic structure is synthesized by the penicillium mold from twoamino acids, L-cysteine and L-valine. Antibiotics containing this betalactam ring are re-

fered to collectively as beta-lactam antibiotics and include the penicillins,cephalosporins, and the two newer goups ofagents, the carbapenems and the monobac-

tams.

Penicillln G (benzylpenicillin) is the prototype for comparison. By side chain substitutions(speciJically, this means substituting other groups at the R position ofthe penicillin mol'ecule) of thebasic 6-aminopenicillanic acid molecule, the semi-synthetic penicillins are

produced which are more acid stable, have a broader spectrum, or are penicillinase re-sistant.

Other naturally occrming penicillins include:. Penicillin VK (Pen Vee K, V-cillin K) - preferred for treating oral infections because

it is more acid stable (more reliable oral absorption). Penicillin G parentzl (Pfzeryen) - always given by IM route. Penicillin G benz hine (Bicillin C-R) always given by IM route. It is used for the

treatment of syphilis and prevention ofrheumatic fever

Remember:L Penicillins are bactericidal; they inhibit cell wall synthesis.

2. Probenecid increases blood levels of natural penicillins and may be given concur-

rently for this purpose.

Acid stable penicilhns (may be used orally) include:. Penicillin VK. Amoxicillin. Ampicillin. Nafcillin. Oxacillin. Cloxacillin. Dicloxacillin

Extended spectrum penicillins include:. The aminopenicillins -

Ampicillin and Amoxicillin

Broad spectrum penicillins include:. Piperacillin. Ticarcillin*** These two penicillins have the widest spectrum ofall the penicillins

Penicillinase-resistant penicillins include:. Nafcillin. Oxacillin. Cloxacillin. Dicloxacillin

Page 81: Pharmacology

. Penicillin \{K

. Tetracycline

. Erythromycin

. Amoxicillin

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. Tetracycline

. Clindamycin

. Ampicillin

. Cefaclor (Celcor)

. Penicillin VK

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Page 82: Pharmacology

Premedication requirements for patients with valvular heart disease or congenital cardiac de-

fects. If in doubt, have patient consult their physician as to need.

CurrentAmerican Heart Association Guidelines: Published June 2007, JADA Volume 138,

page 142.

Standard Regimen. Amoxicillin

- Adults: 2.0 g orally 30-60 minutes prior to appointment- Children: 50 mglkg (not to exceed adult dose) orally 30-60 minutes prior to appointment

Allergy to Amoxicillin:Note: Only ifallergy is not ofanaphylactic type. Any one ofthe following can be used.

. Clindamycin-Adults: 600 mg orally 30-60 minutes prior to appointment-Children: 20 mg,&g orally 30-60 minutes prior to appointment

'Cephalexin-.\dult.: 2.0 g orally 30-b0 minutes prior to appointment-Children: 50 mg/kg orally 30-60 minutes pdor to appointment

..{zithromycin-Adults: 500 mg orally 30-60 minutes prior to appointment-Children: l5 mg/kg orally 30-60 minutes pdor to appointment

. Clarithromycin-Adults: 500 mg orally 30-60 minutes prior to apporntment-Children: l5 mg/kg 30-60 minutes pdor to appointment

It is prudent to use an antibiotic with narrow spectrum ofaction and one that is bacterici-dal in order to minimize the development ofbacterial resistance. Penicillin VK has these

properries. Ampicillin has a broader spectrum of action than penicillin VK and cefacloris a broad spectrum cephalosporin. Tetracycline and clindamycin are bacteriostatic an-

tibiotics and not bacteriocidal.

Note: The major disadvantage of the penicillins is their rather high incidence ofallergicreactions. Approximately l0olo ofthe general population is allergic to penicillins. This in-cidence probably holds for any ofthe specific penicillins since there is cross allergy fromone to the other Skin rash (a delayed reaction) is the most prevalent allergic manifesta-

tion. Life threatening anaphylaxis can occur, but is very rare, particularly with oral dos-

ing. In non-allergic individuals, penicillins at normal therapeutic doses have virtually no

side effects what so ever Penicillins are bactericidal' that is, they actually cause death ofthe invading bacteria.

Page 83: Pharmacology

. Penicillin VK

. Dicloxacillin

. Amoxicillin

. Piperacillin

. Tiazolarn (Hzlcion)

. \4ethotrexate

. Calcitrol

. Candesartan

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\-

Which ofthe following has a clinicrly sign icantdrug interaction with Amoxicillin?

Page 84: Pharmacology

Members ofthe penicillin family having the broadest spectrums ofaction are piperacillinand ticarcillin. In addition to being active against gram-positive cocci (streptococci,staphylococci, pneumococci), and gram-positive rods (bacillus and otfters), these agents

are active against Pseudomonas, Proteus, Klebsiella, and Bacteroides

These antibiotics are recommended for the treatment of urinary tract inf€ctions andother infections caused by susceptible gram-negative Pseudomonas species and Proteusspecles.

Penicillin VK has a relative limited spectrum of action against aerobic gram-positivecocci and anaerobes.

Dicloxacillin has a similar spectrum as penicillin VK but is active against penicillinase-producing staphylococcus.

.{moxicillin is an aminopenicillin which has an extended spectrum ofaction which in-cludes not only aerobic gram-positive cocci and anaerobes, but some gram-negative bacillisuch as Hemophilus, Proteus and Salmonella. Ampicillin also falls into the category ofan aminopenicillin.

Important: None ofthe penicillins are aclive against viruses, fungi, rickettsiae or other

nonbacterial orsanisms.

*** Amoxicillin in large doses inhibits the renal tubular secretion of methotrexate,thereby causing higher, prolonged serum levels ofmethotrexate.

Aminopenicillins (enpicillin and amoxicillin) are characterized by the amino substitu-

tion ofpenicillin G. They are able to penetrate gram-negative bacteria more readily than

are the natural penicillins or the penicillinase-resistant penicillins. However, the

aminopenicillins are not stable to beta -llct^ma;ses (penicillinase) of either gram-positive

or gram-negative bacteria.

Note: Gram-negative bacteria that are susceptible to aminopenicillins include: H.in-fluenzae, some E.Coli and Proteus mirabilis.

Ampicilf in (Pol1,cillin, Onipen) and Amoxicillin (Amoxil, Larotid) are ttsedprimarily totreat infections such as otitis media, bronchitis, sinusitis, and acute bacterial cystitis caused

by susceptible organisms. Compared with ampicillin, amoxicillin has a higher oral ab-

sorption, higher serum levels, a longer halflife, and is less likely to cause adverse GI ef-lects (diarrhea). Amoxicillin is given orally; ampicillin can be given orally or IV.

)rlote: Ampicillin and amoxicillin are preferred agents in the treatment ofurinary tractinfections caused by susceptible enterococci (which are facultatively anaerobic, gram-positive cocci that grow in short chains under extreme conditions mainllt in the intestine).

Page 85: Pharmacology

. Amoxicillin and clalulanate potassium (Augmentin)

. Ampicillin and sulbactam (Unasyn)

. Cloxacillin

. Dicloxacillin

84Coplright O 2011,2012 , Denbl Decks

Which of the followlng bacterial enzymesbelong to the fanily of beta-lactamases?

. Cephalosporinase

. Penicillinase

. AT?ase

. Protein kinase

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Page 86: Pharmacology

A functional part ofthe chemical molecule of all the penicillins is the so-called betalac-tam ring, which is a four-membered imbedded ring structure consisting ofthree carbonsand one nitrogen atom which is responsible for the antibacterial activity of penicillins.Any alteration to the beta-lactam ring will also alter the antibacterial activity. Penicillinaseis an enzyme secreted by bacteria which splits open the betalactam ring. This renders thepenicillin molecule ineffective against those penicillinase secretors.

Cloxacillin and dicloxacillin resist the actions ofpenicillinase because they have a pro-tected beta-lactam ring which prevents the actions ofthe enzyme.

Augmentin and Unasyn contain the agents clavulanate potassium and sulbactam re-spectively which block the actions ofpenicillinase from reaching the betalactam ring.

The majority ofpenicillins are directly excreted into the urine through renal tubular cellsecretion. Probenecid (Benemid), an inhibitor of renal tubular cell secretion raises theblood ler els ofthe penicillins by diminishing their tubular secretion. Probenecid is some-times given simultaneously with penicillin to raise the blood levels for increased activ-irr. \ote: Probenecid is a drug used to treat gout.

Beta-lactamases are €nzymes produced and secreted by a wide range of gram-positiveand gram-negative bacteria as a defense weapon against cephalosporin and penicillinantibiotics. These enzymes destroy the beta-lactam nucleus within these antibiotics bysplitting open the betalactam ring structure. This action renders the antibiotic ineffec-tir e. Those beta-lactamases that work against cephalosporins are called cephalospori-nases, and those that work against penicillins are called penicillinases.

By combining clavulanic acid with a penicillin, the betalactamase enzyme is penna-

nently inhibited by the acid, and the antibacterial activity ofthe penicillin is n.raintained.

One popular commercial preparation is Augmentin, which contains arnoxicillin andclavulanate potassium. Augmentin is used orally as pill or liquid form. Sulbactam is an-

other beta-lactamase inhibitor lt is available for intravenous and intratnusculat use com-

bined with ampicillin under the brand name Unasyn.

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. Imipenem

. Probenecid

. Hydrochlorothiazide

. Aztreonam

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Whlch antlbiotic is used cautiously du€ to its side effects

@seudomembranous colitis, severe GI upset)?

.\

. Azithromycin (Zithromax: Z-Pak)

. Clindamycin

. Penicillin VK

. Cephalexin (Keflex)

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Page 88: Pharmacology

*** This elevates and prolongs the serum concentrations ofthe antibiotic when high tis-sue concentrations are necessary.

The majority ofpenicillins are handled by the kidneys as organic acids and excreted bytubular excretion. Probenecid interferes with tubular handling of organic acids withinthe nephron. Drugs affected by probenecid include most cephalosporins and naturalpenicillins, and other betalactam-related antibiotics such as aztreonam and imipenem.

Note: In some cases, probenecid administration can more than double the serum concen-tration olthe affected drug. The halflife is prolonged as well.

lmportant: Nafcillin, oxacillin, cloxacillin and dicloxacillin are lipophilic and are ex-

creted by biliary means. No combination with probenecid or dosage adjustment for renal

dy'slunction is necessary for these penicillins.

l. Imipenem is a beta-lactam antibiotic derived from thienamycin and is the\ot€ first drug to be classified as a carbapenem antibiotic. It is curently the drug

of choice for infections due to Enterobacter and Pseudomonas aeruginosa'It is usually combined with cilastatin and is used to treat severe or reslsta.nt ln-fections, especially those that are nosocomial in origin.2. Aztreonam is a parenteral synthetic betalactam antibiotic (classified as a

monobactum). The spectrum is limited to aerobic gram-negative rods(i.e., Kebsiella, Pseuclonlonqs, and Serratia).Ithas no gram-positive or anaer-

obic activity. lt is synergistic with aminoglycosides.

Penicillins:Penicillin VKAmoxicillin.{moxicillin,Clav. Acid /lugn€rtrr)AmpiciUin

Inhibits cell wall synthesisSame

Inhibits 50S ribosomes

Cephrlosporins:Cephalexin /Ke./i".r/C.faclor (Ceclor)

(Xher:Clindamycin

Tetracyclines:Tel€cyclineD oTyxy clir'e ( Yi brary c in )Minocy.llne (Miioc itl : Ares tin)

lnhibits DNAlnhibits cell wall synthesisInhibits 50S nbosomes

Page 89: Pharmacology

Which antibiotic/antimicrobial is associrtedwith the highest incidenc€ ofdrug allergy?

. Crprofloxacin (Cipro)

. Penicillin VK

. Clindamycin

. Mefi oridazole (F I ag! l)

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\Stavudine (a/so fz own as d4T, or Zerit) is an antiretroviral drug used

in the treatment of adults with HIV infection in combinationwith other antiretroviral agents. Which ofthe following

categorles does this agent b€long to?

. Nucleoside reverse transcriptase inhibitor

. Protease inhibitor

. Non-nucleoside reverse transcriptase inhibitor

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Page 90: Pharmacology

Three groups ofallergic reactions to the penicillins:l. Actte (anaphylactic shock): occurs within 30 minutes. Characterized by urticaria,angioedema, bronchoconstriction, GI disturbances, and shock. Death can result in ashort time if treatment is not instituted immediately (parenteral administration ofepinephrine).2. Accelerated: occus 30 to 48 hours after. Manifestations include urticaria, pruritis,wheezing, mild laryngeal edema, and local inflammatory reactions. Not life threaten-ing'3. Delayed: occurs after 2 to 3 days. Approximately 80-90% ofall allergic reactionsoccurring with penicillin are ofthis t1pe. Manifested by skin rashes.

Hypersensitivity reactions occur in up to l07o ofpatients receiving penicillin. Manifes-tations range from a mild rash to anaphylaxis. The rash may be urticarial, vesicular, bul-lous, or maculopapular. Rarely, thrombopenic purpura develops.

lllote: A rash is the most common sign olan allergy to penicillin.

R€member: The mechanism ofaction ofthe fluoroquinolones is inhibition of DNA gy-rase, an enzyme that is essential in the transcription, replication, and repair ofbacterialD\.{. Drugs in this class include ciprofloxacin (Cipro), norfloxacin Qtloroxin),lev-ofloxacin (Levaquin), moxifloxacin (Avelox), and gemifloxacin (Factive). Fluoro-quinolones are active against many gram-positive organisms and gram-negative aerobes,

including Moraxella catarrhalis, Haemophilus influenzae, E. coli, chlamydia, and My-coplasma pneumoniae. They are not active against Clostridium difficile. These drugs are

rr ell tolerated, howevet the most common adverse effects are Gl (e.g., nausea, vomiting,diqrrheq, abdominal pain),CNS (e.g., headache, clizziness, confusion) and dermalologrcle.g., rash, pruritis).

These agents chemically are nucleosides and work by inhibiting the viral enzyme knownas reverse transcriptase, This results in an inhibition ofthe HIV viral RNA from beingmade into a DNA segment; thus the genome ofthe HIV virus is not copied from RNA.Other agents in this class include didanosine (Wdex), zalcitabine (Hivid; ddC) and

zidovudine (Ret ovir ; AZT).

Proteas€ inhibitors suppress viral replication by inhibiting protease' the enzyme re-

sponsible for cleaving viral precursor peptides into infective virions. Some agents in thisclass include indinavir (Crixivan), nelfinavir (nracept), ritonavir (Norvir), and.

saquinivir (lnvirase).

\onnucleoside reverse transcriptase inhibitors inhibit the catalytic reaction of reverse

transcriptase that is independent ofnucleotide binding. Some agents in this class includedelavirdine (Rescriptor), adefovfi (Hepsera) and nevirapine (Wramune).

Page 91: Pharmacology

. Photosensitivity

. Nausea

. Bone marrow disturbances

. Diarrhea

. Discoloration ofteeth and enamel hypoplasia in young children

90Coplright O 2011,2012, Denbl Decks

. Penicillin VK

. .{mpicillin (P o l:tc i I I in)

. Cloxacillin (Cloxapen)

. Amoxrcrlhn (Amoxil)

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Another common adverse effect is the occurrence ofopportunistic (superintbction) in-fections caused by Candida albicans, This is due to the wide spectrum of antibacterialaction which alters normal flora. Examples include both vaginal and oral candidiasis.These conditions are also known as vaginal and oral yeast infections.

Members of the tetracycline family ofantibiotics include:

Short acting: . Tetracycline (Generic)Intermediateacting: .Demeclocycline (Declomycin)Long acting: . Minocycline (Minocin)

. Doxycycline (4bramycin)

Remember: The usefulness of the tetracyclines in the treatment of odontogenic infec-tions is limited since they can cause "yeast'' infections very easily. They have been used

as alternatives to penicillin in patients with ANUG (acute necrotizing ulcerative gin-gil lll.r/ u'ho require antibiotics.

\ote: In adults, Fanconi syndrome can be caused by various things that damage the kid-ne1s. including certain medications (azathioprine, cidolbvir gentamicin, and tetrucy-c/ire). Fanconi syndrome is a disorder ofthe kidney tubules in which certain substances

normally absorbed into the bloodstream by the kidnevs are released into the urine instead.

These trro antibiotics are characterized by the amino substitution of penicillin G. They\\ ork against many gram-positive organisms and some gram-negative bacteria such as

Haemophilus influenzae, some Escherichia coli, and Proteus mirabilis. They are not peni-cillinase resistant. They are used for upper respiratory infections.

The major difference in the drugs is the higher oral absorption, higher serum levels, and

longer half-life for amoxicillin compared with ampicillin. Amoxicillin is given orally;ampicillin can be given orally and IV

Remember: Oral amoxicillin is recommended as the drug ofchoice for standard general

prophylaxis for bacterial endocarditis in patients undergoing invasive dental procedures.

Note: Parenteral ampicillin is recommended as the drug of choice in patients unable totake oral medications and who are not allergic to penicillin for prophylaxis for bacter-ial

Page 93: Pharmacology

. Affect bacterial cell wall

. Affect bacterial DNA

. Affect bacterial protein synthesis

. Interfere with bacterial metabolic pathways

. Bacterial cell wall destruction

. Prevent protein synthesis in the bacterial cell

.Interfere with nucleic acid synthesis

. Cause mutations within bacterial DNA

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Basic mechanisms of actions ofantibiotics:

. Affect bacterial cell wall:- Penicillin family- Cephalosporin family

. Agents affecting bacterial DNA:- Fluoroquinolone family (i. e., ciproJloxacin)- Meronidazole (F lagt l)

. Agents affecting bacterial protein synthesis:

- Tetracycline family- Erythromycin family- Clindamycin- Chloramphenicol

. Agents interfering with bacterial metabolic pathways:

- Sulfonamides (sulfa drugs)

The tetracyclines inhibit protein synthesis by binding to the 30 S subunit ofthe bacter-

ial ribosome. The inhibition of this ribosomal function interferes with the attachment ofthe growing amino acid chain thus preventing complete formation of peptides from the

ribosome. Since no peptides are formed, no proteins are formed. Since proteins are nec-

essary for the bacterial cell to metabolically function, the lack thereof will cause a static

state in which the bacterium becomes nrlnerable to phagocltosis by the body's imrnune

S-v"SIem.

Absorption of the tetracyclines from the GI tract is inhibited by divalent and trivalentcations such as CA--, Mg.-, Fe-., and Al**.. These ions form chelation products with the

tetracyclines and thus prevent their absorption. This is why tetracyclines should not be

given with milk and dairy products (contain Ca--), iron-containing vitamins (contain

.Fet!, mineral supplements containing these irons, or antacids (contain Mg").

Page 95: Pharmacology

. Cephalosporins

. Ampicillin

. Tetracycline

. Penicillin G

. Penicillin VK

. Bactericidal; 30s

. Bactericidal; 50s

. Bacteriostatic; 30s

. Bacteriostatic; 50s

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Erlthromycin is a antibiotic which binds to theribosomal subunit of susceptible bacteria, The result is the

inhibition of protein rynthesis.

Page 96: Pharmacology

The tetracyclines are a goup of broad-spectrum, bacteriostatic antibiotics that inhibitprotein synthesis in the susceptible organism by binding to the 30S ribosome subunit,thereby impeding the binding of aminoacyl IRNA to the receptor site on the messenger

RNA ribosome complex. The inlibition ofthis ribosomal function interferes with the at-tachment ofthe growing amino acid chain thus preventing complete formation ofpeptidesfrom the ribosome. Since no peptides are formed, no proteins are formed. Since proteinsare necessary for the bacterial cell to metabolically function, the lack thereof will cause

a static state in which the bacterium becomes vulnerable to phagocytosis by the body's im-mune system.

T€tracyclines are useful in treating the following infections:. Medical infections caused by susceptible gram-positive and gram-negative bacteria. Infections caused by Mycoplasma, Chlamydia , Protozoa or Rickettsia. Exacerbations of chronic bronchitis. L)ryne disease (caused by Bon'elia burgdorferi). Treatment ofacne. Treatment of gononhea and syphilis in patients allergic to penicillin. Dental: treatment ofperiodontitis associated with the presence of Actinobacilliusactinomycetemcomitans (AA) (i.e., Iocalized aggressive periodontitis)

Important: Tetracyclines are not the drug of choice for Streptococcus or Staphylococ-

cus.

Erythromycin-type antibiotics are members of the Macrolide family of antibiotics.

Members of the Macrofide family /generic and brand names) are.

. Azithromycin (Zithromax; Z-Pak)

. Cl ar ithr omy cin ( B i ax in )

. Erythomycin base (E-mycin; Eryc)

. Erythomycin ethylsuccinate lE E S./

. Erythromycin stearate (Etythrocin)

All of the €rythromycins are very effective against gram-positive bacteria but not so

effeclive against gram-negative bacteria.

AII ofthe erythromycins act through the same mechanism to bind to the 50s ribosomalsubunit ofsusceptible bacteria. This causes the RNA to dissociate from the ribosome andprevents protein synthesis.

\ote: GI Tract upset is the most common side effect of the erythromycins (tqke with

food.1.

Page 97: Pharmacology

. Tetracycline

. Penicillin VK

. Metr onidazol e (F l a gy l)

. Clindamycin

. Acyclovir (Zovirax)

. Oseltamli (Tamillu)

. -{mantadine (Symmetrel)

. fumantadine (Flumadine)

. Zanarnivir (Relenza)

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The photosensitivity reaction caused by the tetracycline family of antibiotics results inthe appearance ofred rashes or blotches over the skin in the presence of sunlight.

Common adv€rse effects caused by the other agents:

. Penicillin VK: hypersensitivity resulting in skin rash and rare anaphylaxis

. Metronidazole (Flagyl): dizziness, headache, and nausea

Note: Metronidazole is not a true antibiotic since it is not found in natural organ-

isms; it is a synthetic substance produced in the chemical laboratory.

. Clindamycin: diarrhea, abdominal pain; known to cause pseudomembranous colitis

Oseltamivir (Iarr iflu) and zanrmivir (Relenza) inhibit influenza virus neuraminidaseenz! mes. potentially altering virus particle aggregation and release. Tamiflu and Relenza

are both used to treat acute illness due to influenza (A or B) infectior'.

Acyclovir (Zovirax) is an antiviral that inhibits DNA synthesis rather than neuraminidase

enzymes.

Amantadine is a synthetic anti-viral drug that can inhibit the replication of viruses incells. lt was initially used to prevent influenza A during flu season, and, if given within24 to 48 hours of the onset of flu symptoms, to decrease the severity of the flu. Lateramantadine was found to cause improvement in the symptoms ofParkinson's disease.

Not€: The mechanism of amantadine's antiviral activity involves interference with a viralprotein, M2, which is required for the viral particle to become "uncoated" once taken in-side a cell by endocytosis.

Rimantadine is a synthetic anti-viral drug that can prevent viruses in cells from multi-plying. Like amantadine, rimantadine initially was used to prevent influenzaA during fluseason, and, if given within 24 to 48 hours after the onset of flu symptoms, to decrease

the severity ofthe flu. Rimantadine is chemically related to arnantadine, but rimantadinehas fewer side effects on the nervous system than amantadine. Note: Rimantadine appears

to exen its inhibitory effect early in the viral replicative cycle, possibly inhibiting the un-

coating ofthe virus (similqr to amantadine s nechanism oJ action).

Page 99: Pharmacology

. Tetracycline

. Doxycycline (Wbramycin)

. Minocycline (Minocin)

. Penicillin VK

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. Laryngeal edema

. Ufiicada (welts that itch)

. Severe hypotension

. GI disturbances

. Bronchoconstrictron (ah'wqy constriction)

. Shock

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Penicillin VK is not harmful to the fetus when taken by pregnant mothers. [t is not in-corporated into bony tissue or in the teeth ofchildren like the tetracyclines.

Note: Tetracycline and all members of the tetracycline family are contraindicated inchildren up to 8 years old and in pregnant women. Tetracyclines have the ability tochelate calcium ions and become incorporated in the bony tissues. The teeth ofchildrenwho have been given the drug may develop a greenish-brown discoloration. This effectis sometimes seen in the newly erupted teeth of infants whose mothers have receivedtetracycline during pregnancy.

R€member: Penicillins, which are bactericidal against susceptible organisms, disrupts) nthesis ofthe bacterial cell wall and compete for and bind to specific enzyme proteinsthat catalyze transpeptidation and cross-linking. The enzymes to which tbey bind arecalled penicillin-binding proteins (PBPs). They consist of transpeptidases, transglyco-sylases. and D-alanine caboxykinases and are implicated in the final phases ofbuildingand reshaping ofthe bacterial cell wall while it is growing and dividing.

**" This reaction most conmonly occurs with parenteral administration ofpenicillin.

This reaction can be fatal if countermeasures such as the injection ofepinephrine are nottaken promptly. Epinephrine prevents the release of substances from mast cells and an-

lagonizes the actions of histamine and leukotrienes of smooth muscle.

The most common adverse effect ofpenicillin therapy is an allergic reaction. These re-

actions occur in up to 109/o of patients receiving penicillin. The most common manifes-ration is a mild rash.

Allergic reactions to penicillin are classified into three groups:

l. fmmediate onset reactions (araphylaxis) ocatr within 30 minutes; Ig-E mediated.

2. Accelerated allergic reactions arise 30 minutes to 48 hours after administration.Urticaria, pruritis, wheezing, and local inflammatory reactions. In general, not life-threatening.3. Delayed - allergic reactions take longer than two days to develop. 80-90% ofpeni-cillin reactions are ofthis type. Basic skin rashes, which are generally mild.

Page 101: Pharmacology

. The phenothiaz ines

. The thioxanthenes

. The butyrophenones

. The benzodiazepines

. Chlorpromazine (Thorazine)

. Halopeidol (Haldol)

. Prochlorperazine (C omp azin e)

. Thioridazine

r De-h--"-i--

. Trifl uoperazine (St e laz ine )

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All of tbe following are phenothiazi nes EXCEPT oae.which one is the cXcrPZolv?

Page 102: Pharmacology

Antipsychotics, also known as major tranquilizcrs orneuroleptics, are used commonly in the treatmcntof a variety ofpsychotic disorders. By fa. the most widely used group ofantipsychotic agents uscd inmedicine are the phenothiazines, followed by the butyrophenones and the thioxanthenes.

The first antipsychotic on thc markct, chlorpromazine, is the key drug among the phenothiazine an-tipsychotic agents. Currently, antipsychotics are divided into two gcncrations. The first generation in-cludes thc older, "typical" drugs that treat the positive but not the negative symptoms associated with a

psychotic state. Second-generation drugs have far fewer extrapyramidal symptoms fEPt and tardivedyskinesia fDJ, and they are used to treat both positive and negative symptoms ofschizophrenia. Note:With the exception ofrispcridone, th€y are prolactin sparing.

The exact mechanism of antipsychotic drug action is unknown. These drugs are thought to work byblocking postsynaptic dopamine receptors in the h,?othalamus, basal ganglia, limbic system, bminstem,and medulla, and to some extent serotonin receptors-

Typicaf antipsychotic drrgs (frst generationJ are more potent antagonists ofD2 dopamine receptorsthan ofDr receptors. First generation drugs include the phenothiazines (chlorpromazine, fluphenazine,perphena:ine, procltlorperazine, trifluoperazine, mesoridazine, and thioidazine), the thioxanthines( thiothixene) and the btrytophenor\es (haloperidol).

\e\\er (second generallor/ or atypical antipsychotic agents affcct different receptor sites compared* ith first generation antipsychotics. They bind dopamine, including D1, D2, Da, and D5 receptors, withselecrilely lor limbic dopaminc rcceptors. They have increased affinity for serotonin /J-11I, receptors

compared $ith D" receptors. They exhibit reduced ability or an inability to induce EPS. Second gener-

alion agcnts include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Important:

|. ^ripipr^zole

(Abilrj,/ is the first ofa new class of atypical antipsychotic agents called dopaminesistem stabilizers or dopamine partial agonists.It combines the actions ofD2 and serotonin 5-HT2a

recePtor antagonism.:. Clozapine is specific for limbic rec€ptors and not for striated (muscle) r.ceptors,which explainsthe low incidence ofEPS andTD.

.{ntipsychotic agents include:. First generation (lr^pical) agentsl

I . Phenothiazines:. Chlorpromazine (Thorazine). Perphenazine. Thioridazine. Prochlorperazine (Compazine). T rifrtroperczrne (S t e I azin e)

L But'"rophenones:

. Haloperidol is a highly effective antipsychotic drug used to treat schizophrenia. ln ad-

dition it has been found to be effective in the heatment ofTourette's s).ndrome.

i. Thioxanthenes:. Thiothixene is a less potent antipsychotic. It is used for the treatment ofschizophrenia.

. Second generation (a\)pical) ag€nts: this group includes clozapine, risperidone, olanzap-

ine. quetiapine, ziprasidone, and aripiprazole. These drugs are effective in treating schizo-phrenia and exhibit reduced ability or an inability to induce EPS.

Adyerse effects of antipsychotic drugs:

. Dystonia and akathisia (an unpleasant sensation of motot' restlessness)

. Long QT-interval syndrome and ultimately increase the risk of fatal arhythmias

. Neuroleptic malignant syndrome

. Parkinsonism

. Antimuscarinic effects

. Orthostatic hypotension

. Con\.ulsions

. Mesoridazine

. Fluphenazine

Page 103: Pharmacology

. Chlorpromaz ine

. T hioridazine (Me I I ar i I)

. Risperidone (Risp erdo I)

. Azelastrne (Astelin)

. Quetiapine (Seraquel)

. Clozapine (Clozaril)

. Olanzapine (Zyprexa)

. Halopeidol (Haldol) 102Coplrighr O 2011,2012 - Dmtal Decks

. Onhostatic hypotension

. Sedation

. Headache

. Dry mouth

. Muscle spasms ofthe oral-facial region

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Which statement describ€s the extrapyramidal syndrome (EPS)caused by the phenothiazine'type lntipsychotics?

Page 104: Pharmacology

*** Azelastine (Astelin) is an antihistamine nasal spray.

Antipsychotics are primarily indicated for treatment ofpsychosis associated with schiz-ophrenia, paranoia, and manic symptoms of manic-depressive illness

Typical antipsychotic drugs (lirst generation) are more potent antagonists of D2dopamine receptors than ofDl receptors. First generation drugs include the phenoth-ia,zines (chlorpromazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine,mesoridazine, and thioridazine) , the thioxanthines (/riothixene) and the butyrophenones(haloperidol). Note: Haloperidol is a potent dopamine antagonist.

Newer (secontl generation) or atypic l antipsychotic agents affect different receptor siles

compared with first generation antipsychotics. They bind dopamine, including D1, D2,

Da, and D5 receptors, with selectively for limbic dopamine receptors. They have increased

at'linity for serotonin (5-HT ) receptors compared with D2 receptors. They exhibit reduced

ability or an inability to induce EPS. Second generation agents include clozapine, risperi-done. olanzapine, quetiapine, ziprasidone, and aripiprazole.

Ertrapyramidal syndrome lEP.l) refers to a variety of signs and symptoms that are a

result ofthe blockade ofdopamine receptors in specific brain regions. These symptomsinclude: Parkinsonlike movements (shufiIecl gait, pill-rolling eJlbct oJ fngers), musclerigidiry. spasms ofneck and facial muscles, tremors, and loss of muscle movement.

Tardive Dvskinesia (TD) is a serious, irreversible neurological disorder that can ap-pear at any age. Tardive Dyskinesia is a side effect of taking antipsychotic/neurolepticsdrugs. Symptoms involve rurcontrollable movement ofvarious body parts, including the

body trunk. legs, arms, fingers, mouth, lips, or tongue. About 20 percent ofpeople takingantipsvchotic/neuroleptic drugs for more then one year will be affected.

Remember: Newer (second generation) or atypical antipsychotic agents affect differ-ent receptor sites compared with first generation antipsychotics. They bind dopamine, in-cluding Dl, D2, Da, and D5 receptors, with selectively for limbic dopamine receptors.

They have increased alfinity for serotonin (5-HT) receptors compared with D2 recep-tors. They exhibit reduced ability or an inability to induce EPS. Second generation

agents include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripipra-zole.

Important: Clozapine is specific for limbic receptors and not for stdated (muscle) re-ceptors, which explains the low incidence of EPS and TD.

Page 105: Pharmacology

. Tinnitus (ringing in the ears)

. Yertigo (dizziness)

. Nausea

. Hallucinations

. Respiratory alkalosis

. Vomiring

104Copyright O 20ll-2012 Dental Decks

. Percodan

. Vicodin ES

. Motrin

. Naprosyn

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Page 106: Pharmacology

An overdosage of saficyl^tes (aaie aspirin /o-riciry/ is life threatening and requires intensive support-ivc trcatment in a hospital. Initial symptoms include respiratory alkalosis with hypcrpnea and tachypnea,

nausea, vomiting, hlpokalemia, tinnitus, headache, dizziness, confusioq dehydration, hyperthermia, hy-pcractivity, and hcmatologic abnormalities, progressing to coma and respiratory collapse.

Chronic aspirin toxicity presents with the following signs and symptoms: salicylism, CNS effects,

bleeding and GI disnrrbances.

Aspirin inactivates the enzyme known as cyclooxygenase. Sincc cyclooxygenaso synthesizes thcprostaglandins, the inhibition ofthis enz''rne results in the inhibition ofprostaglandin synthesis. As a

result, aspirin is analgesic, antipyretic (ever reducing), and anti-inflammatory. Aspirin is an irreversible plat€let inhibitor and can reduce blood clotting to prolong bleeding. Note: Aspirin inhibitsboth COX-l and COX-2.

Low doses of aspirin taken regularly can have a cardioprotective effect. These doses reduce throm-

boxane production in platelets to result in the inhibition ofplatelet aggregttion. In this way, aspirin has

the ability to inhibit the formation of life-threatening thrombi (6/0011clo/s/.

The lirer appearc to be the principal site for salicylate metabolism, although other tissues may also be

in\ ol\ ed. Ihe three chicf metabolic products ofsalicylic acid are salicyluric acid, the cthcr or phcnolicglucuronide and the ester or acyl glucuronid€. Excretion ofsalicylates occurs principally via the kid-n€), through a combination ofglomerular filtration and tubular cxcrction, in the form offree salicylicacid. salic] luric acid, as well as phenolic and acyl glucuronidcs.

Contraindications to the use ofaspirin:. Ble€ding disorders (aspirin will increase bleeding tine)' Do not use in children with viral infections (i.e., i,fluenzu or chiclerpoxl with or without fever due

ro a potcniial association with Reye's syndrome (this s), dlotne is a serious neutulogical defecl). Pregnancy (especictlly during the thit'd lrinester)

' P€ptic ulcers faipil'i nay cduse bleeding ofthe GI tracl). .{sthma; rhinitis; nasal polyps. Concomitant use of anticoagulants

.\dYil contains 200 mg ofibuprofen and may be sold over-the-counter; whereas, Motrincontains .100 mg of ibuprofen or higher and can only be sold with a prescription.

\onsteroidal anti-inflarrunatory drugs (NSAID, have anti-inflammatory effects result-ing frorn their ability to inactivate the enzyme prostaglandin endoperoxide synthase f.]-cloon'genase).By doing this they inhibit the cyclooxygenase step ofthe arachidonic acid

cascade and thus reduce local prostaglandin synthesis. NSAIDs also have analgesic, and

antip)'retic actions.

Remember: The traditional NSAIDs such as ibuprofen, naproxen and aspirin inhibitCOX-2 along with COX-I. Thus they are effective in reducing pain and inflarnrnation,but are capable ofinducing gastrointestinal ulcers. The COX-2 selective inhibitors willreduce pain and inflammation without any significant risk ofcausing gastrointestinal ul-cers.

For the traditional NSAIDS such as ibuprofen, naproxen, and aspirin, because they in-hibit both COX-1 and COX-2 enzymes, they belong to the category of non-selectiveCOX inhibitors. For celecoxib (Celebrcx), because it inhibits COX-2 enzyme only' it be-

longs to the category oICOX-2 sel€ctive inhibitors.

Note: Rofecoxib (Woxx) and Valdecoxib (Bextra) are also COX-2 selective inhibitors

that u,'ere removed from the market because they were found to have added cardiovas-

cular risks in some Datients.

Page 107: Pharmacology

. Ibuprofen (Motrin, Advil)

. Acetaminophen (Ty I e n o I )

. Aspirin

. Naproxen sodium (l/eve)

. Codeine

. Acetaminophen

. Hydrocodone

. Ibuprofen

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Page 108: Pharmacology

Acetaminophen has no effect on platelets nor the coagulation pathways and does notaffect bleeding times or prothrombin times even with high doses.

Acetaminophen has two major pharmacological actions: an analgesic effect and an an-tipyretic (ever redticey' effect. Acetaminophen is not effective enough to reduce severe

pain, but it is effective in reducing mild to moderate pain. Acetaminophen is a weak in-hibitor of prostaglandin format ion.

Large doses ofacetarrinophen can cause liver toxicity. Alcohol can seriously increase thehepatotoxic potential of acetaminophen. There are approximately 100 deaths annuallydue to liver toxicity produced by ingesting large continuous doses of acetaminophen.Acetaninophen very rarely causes drug sensitivities and can be given to patients havingan allersv to asnirin.

Ibuprofen inhibits the production of prostaglandins in peripheral tissues at sites where

pain and inflammation are present. Inhibition of prostaglandin production reduces the

inflammatory respons€ at sites of surgery, injury or infection. Reduction of inflamma-

tion results in reduction ofperceived pain.

Acetaminophen is a weak inhibitor ofprostaglandin production in peripheral tissues.

Thus, the inflammatory response is not affected to any great degree. Acetaminophen re-

duces pain through mechanisms other than inflammatory reduction. lt is unclear exactlyhow acetaminophen uorks to reduce pain.

Codeine and h1-drocodone are narcotic analgesics that effectively reduce pain but do

not reduce inflammation. Narcotics work within the brain to block ascending pain im-pulses traveling from the periphery into the brain.

Affect blood clotting

Associated with Reye's s)ryldrome

Page 109: Pharmacology

. Phenobarbital

. Ibuprofen

. Hydrocodone

. Meperidine

. Codeine

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. Leukotrienes

. Cltokines

. Prostaglandins

. Interlerons

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NSAIDs reduce the production ofassociated with pain and inflammation.

Page 110: Pharmacology

Ibuprofen is an NSAID and is classified as a non-narcotic analgesic. Non-narcotic anal-gesics have no liability for abuse or addiction. They are not a controlled substances.

Phenobarbital is a barbiturate used as a sedative and to treat epilepsy. Barbiturates allhave the potential to cause abuse and addiction, and are controlled substances requiringa DEA number fiom the prescriber.

Hydrocodone (Wcodin), meperidine (Demerol) and codeine are narcotic analgesicswith the potential to cause abuse and addiction. They are all controlled substances re-quiring a DEA number from the prescriber

Important: NSAIDs can inhibit the antihypertensive effect ofACE inhibitors, beta-

blockers. and diuretics.

Non-steroidal anti-inflammatory drugs 0y'S,4/Dl, inhibit the cyclooxygenase step ofthe arachidonic

acid cascade and thus inhibit thc activity ofprostaglandin synthetase. Prostaglandins are a group ofhormonc-like substances that mediate a range of physiological functions, such as metabolism and

nen e transmlsslon.

\SAIDs have analgesic, antipyretic, and anti-inflammatory properties (similat to aspitin). They

are used for pain control, afihritis, and painful menstruation. Advcrsc reactions include GI upset @os-sible ulcers), and prolongation of bleeding irme (reduction in plqtelel aggregatiotl). Contraindica-tions to ihe use ofNSAlDs are impaired renal function, pregnancy, and GI disease 1r.r/cers)

Eramples offSAlDs:. Proprionic acid derivatives:. Flurbiprofen (,lnsaid) 'Oxaprczin (Daypro) ' Naproxen sodium (Anaprox, Aleve). Ibuprofen (Motrin, Advil) . Ketoqofen (Orudis). \aproxen (Naprosvn) 'Fenoprofen (Nalfon)

. .{cetic acid derivatives:. Indomethicin llndocll . Dicloferac sodirm (Votaren), Etodolac (Lodine) . Ketorolac (Toradol). Sullndac (Clinoril)

. Alkanoic acid derivatives:. Nabumetone (Relqfen)

. Fenamic acid derivatives:. Meclofenamatc (M ec lomen ). Mefenamic acid lPorsle4

. Oxicams. Piroxicam (Feldene). Meloxicam (Mobic)

. Cox-2 inhibitors. Celecoxib (Celebrcx)

Page 111: Pharmacology

. Ibuprofen

. Acetaminophen

. Aspirin

. Naproxen

. Nabumetone

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. Amlodipine @y'onasc)

. Enalapril (Yasotec)

. Ptroxrcarn (Feldene)

. Prednisone

. F osamax (Alendronate sodium)

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Page 112: Pharmacology

Acetaminophen inhibits central prostaglandin synthesis -it

is analgesic for low intensitypain and antipyretic. Because it is less effective than salicylates (asplrlr/ in blocking pe-ripheral prostaglandin synthesis, it has no anti-inflammatory activity and does not affectplatelet function and therefore will not affect clotting time. Note: In large doses p Z 5 g within8 hours), acelaminophen can cause hepatic necrosis.

Concurr€nt use with the following drugs may increase the risk of hepatotoxicity: barbitu-mtes, hydantoins, carbamazepine, rifampin, sulfi npyrazone, and ethanol.

Acute overdosage ofacetaminophen can result in hepatotoxicity and is life threatening. Ace-tominophen is metabolized to a highly toxic int€rmediate product, which normally is detoxi-hed by glutathione. When glutathione is depleted, the toxic intermediate attacks other cells,causing necrosis. Syrnptoms that appear in the ltrst 24 hours are nausea, vomiting, drowsiness,

lethargy, malaise, and confusion. Note: N-acetylcysteine (NAC) is the specific antidote foracetaminophen poisoning.

Acetaminophen is preferred over aspirin when an analgesic or antipyretic drug is indicatedand also the patient:

. Is asthmatic . Is allergic to aspirin

. Is at added risk for an ulcer . Is taking drugs such as probenecid or methotrexate

. ls experiencing bleeding

. Is taking anticoagulants

Remember: Aspirin and Nonsteroidal Anti-inflammatory Agens (Ibuprofen, Naproxen,

\qbumetone, and others) inactiYate the enzyme known as cyclooxyg€nase. Since cyclooxy-genase s).nthesizes the prostaglandins, the inhibition ofthis enzyme results in the inhibitionof prostaglandin synthesis. Cyclooxygenase has an acronym ofCOX' Thus the Nonsteroidal

Anti-inflammatory Agerrts (NSAlDs) are also known as COX inhibitors. As a result, they

ha\e analg€sic, antipyretic, and anti-inflammatory actions. NSAIDS must be used cau-

riously in patients with peptic ulcer disease.

Piroxicam (Feldene) is a non-steroidal anti-inflammatory drug Qr'SlID) that inlibitsprostaglandin synthesis. Il is used to manage inflammatory disorders and used for the

symptomatic treatment ofacute and chronic rheumatoid arthritis and osteoarthritis.

Prednisone is a corticosteroid and has anti-inflammatory actions. It is used for the treat-

ment ofa wide variety of inflammatory diseases including rheumatoid arthritis and os-

teoarthritis.

R€member:

. Common side effects ofNSAIDs such as piroxicam (Feldene) incl'tde:

- Gastric irritation- Heart bum- Nausea

. Short-term side effects of corticosteroids such as prednisone include:

- Insomnia- Indigestion- Arthralgia

. Long-term side effects of corticosteroids include:

- Edema (abdominal distension)- Psychological disturbances- Peptic ulcer- Osteoporosis- Muscle weakness

Page 113: Pharmacology

. Salicyclates

. Opiates

. COX-2 selective inhibitors

. Non-selective COX inhibitors

. Steroidal anti-infl ammatories

112Copright O 201 l-2012 - Denial Decks

. Epinephrine

. Norepinephrine

. Acetylcholine

. Dopamine

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Page 114: Pharmacology

Cyclooxygenase, or COX, is the enzyme which produces prostaglandins. Two forms ofCOX exist: COX-I, and COX-2. The COX-I enzyme produces prostaglandins in the GITract. The prostaglandins formed act as a protective substance against the formation ofgastrointestinal ulcers. The traditional NSAIDs such as ibuprofen, naproxen, aspirin.and others inhibit the COX-I enzyme thus diminishing the fomation of the protectiveprostaglandins. Gastrointestinal ulcers are therefore a potential adverse effect with these

drugs. The COX-2 enzyme produces prostaglandins at the sites of surgery infection andinflammation. When this enzyme is inhibited, less prostaglandins are produced and there

is less pain and inflammation. The traditional NSAIDs such as ibuprofen, naproxen and

aspirin inhibit COX-2 along with COX-I. Thus they are effective in reducing pain and

inflamrnation, but are capable of inducing gashointestinal ulcers. The COX-2 selectiveinhibitors will reduce pain and inflammation without any significant risk ofcausing gas-

trointestinal ulcers.

For the traditional NSAIDs such as ibuprofen, naproxenJ and aspirin, because they in-hibit both COX-l and COX-2 enzymes, they belong to the category of non-selectiveCOX inhibitors. For celecoxib (Celebrex), because it inhibits COX-z enzyme only' itbelongs to the category of COX-2 selective inhibitors.

The COX-2 selective inhibitors:

Are not salicylates because they are not aspirin drugs

- Are not opiates because they do not work like morphine

- Are not steroidal antiinflammatories because they are not corticosteroids such as hy-droc ort isone

Chofinergic is a term for a nerve ending that releases acetylcholine (ACh) as the prrmary

neuotransmitter; also, a synapse in which acetylcholine is the primary neurotansmitter.

Acetylcholine receptors are called cholinergic recepton. They are subdivided as follows:. Muscarinic receptors fsites,):

- At neuroeffector sites for all postganglionic cholinergic neurons (this is chqracteris-

tic of a ll parasympathetic postgqnglionic nerves)

- At neuroellector sites ofpostganglionic sympathetic n€rYes to the sweat glands and a

few blood vessels (tl ese postganglionic nerves are also cholinergic)

. Nicotinic receptors (silesr:

- At the skeletal neuomuscular junction (involving sonatic nerves)- At ganglionic sites /*** The same type of nicotinic receptor is present in sympatheticganglia, parasympathetic gangliq, and the adrenal medulla)

*** Drugs that resemble ACh in chemical structure and bind to these receptors imitate the ef-

fects of parasympathetic postganglionic activity.

Important:

L Preganglionic neurons ofboth divisior's (parasympathetic a (l sympathetic) are cholin-ergic. as are postganglionic neurons ofthe parasympathetic division.2. Postganglionic neurons ofthe sympathetic division are usually adrenergic.

1. The action of acetylcholine at postganglionic parasympathetic sites is often

\ote3 referred to as a muscarinic response.

.. 2. The term nicotinic response is used to describe the stimulating action ofACh&tt:' on the ganglia, as well as its actiol at the neuromuscular junction of skeletal

muscle.3. Muscarinic receptors are usually linked to Go, phospholipase C (PLC), andCa".

Page 115: Pharmacology

. Slowing ofthe heart

. Dilation ofthe pupils

. The stimulation ofthe smooth muscles of the bronchi, GI tract, gallbladder, bile duct,bladder and ureters

. The stimulation ofsweat, salivary tear and bronchial glands

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. Atropine

. Scopolamine

. Gl) copynolate (Robinul)

. Vecamylamine (Inversine)

. Propantheline (Pro -Banthine)

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All of the following are antimuscarinlc agents .EXCrPf one.Which one is the IqXCEPTIOM

Page 116: Pharmacology

*** This false; cholinergic action constricts the pupils.

Cholinergic actions:

. The stimulation ofsweat, salivary, tear and bronchial glands

. The stimulation ofthe smooth muscles ofthe bronchi, GI tract, gallbladdel bile duct,

bladder and ureters (i.e., urinotion). Slowing ofthe heart (bradycanlia). Constriction ofthe pupils 0n rosrt

Important: Acetylcholine is the chemical mediator at all autonomic ganglia andparasympathetic postganglionic synapses. It is also the transmitter substance of the

neuromuscular junction in skeletal muscle (local anesthetics prcvent or rcduce the lib-eration of ACh at the NMJ) and sweat glands. Acetylcholine causes an alteration in cellmembrane permeability to produce the above actions.

.{nticholinergic actions:.The secretions of all glands in the nose, mouth, pharynx and respiratory tract is in-hibited (unpIeasant "dry mouth"). An inhibitory effect on motility throughout the GI tract fmal cause constipatio and

uritla4 retention). The heart rate increas€s (tachycardia). -\ rise in body temperature. Dilation of the puprls (mydriasis)

\ot€: Termination of transmission by ACh takes place primarily by metabolism by acetyl-cholinesterase located on postsynaptic or postjunctional membranes.

*** Ilecamylamine is a nicotinic ganglion-blocking drug.

The tvpical effects ofanticholinergic drugs include r.r.rydriasis, antispasmodic actions and

reduction in gastric and salivary secretiorrs (dry moutlr).lmportant: These drugs are con-traindicated in patients with glaucoma.

These drugs have no intrinsic activity oftheir own; they simply occupy the receptor site

and pre\ ent acetylcholine from occupying the same receptor Accepted therapeutic indi-cations include treating Parkinson's disease, motion sickless, postoperative bladder syn-drome and traveler's diarrhea.

Inhibit salivation and excessive secretions prcoperatively;control ofupper airway sccrctions

Travclcr's diarrhca and antisecretory

To produce mydriasis and cycloplegia

To prevent or reduce motion sickness

Page 117: Pharmacology

. Mecamylamine

. Hexamethonium

. Tetraethylammonium

. Trimethaphan

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, Tubocvraflne (Curare)

. }liYacuium (Mivacron)

. Succinylcholine (Anectine)

. Vecuronium (Norcuron)

. Doxacurium (Nuromax)

. P anntr onium ( P av u I o n)

. Atracuium (Tracrium)

. Cisatr actiurn (N im b ex)

. Rocuronium (Zemuron)'117

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Page 118: Pharmacology

*** Hexamethonium, trimethaphan, and tetraethylammonium are no longer available inthe U.S. for clinical use.

Nicotinic receptor antagonists (nicotitlic blocking agents) are divided into ganglion-blocking drugs and neuromuscular blocking drugs.

Remember: two major types of nicotinic receptors:

1. Those at the skeletal neuromuscular junction ofthe somatic system*** Neuromuscular blockers act here

2. Those at the autonomic ganglionic sites (both sympathetic atxd pqrasympathetic)*** Ganglionic blockers act here

Aldrough they are among the most potent agents available, ganglionic-blocking drugs are

seldom used because ofthe annoying and sometimes disabling parasympathetic ttlock-ade. The side effects (caused by parasympathetic blockade) tnc\rde a very pronounced

xerostomia, constipation, blurred vision, and postural hypotension. These drugs have only\'ery limited clinical uses.

\Iecam.'-lamine (nversile) is used clinically for:

. The treatment of severe or malignant hypertension

. An emergency hypertensive crisis*** lt cause a rapid and reversible fall in blood pressure that enables it to ilrlnediatelyreverse an emergency hypenensir e crisis.. A "bloodless field" surserv

\euromuscular blocking drugs are important for producing complete skelctal muscle relaxation and

facilitate endotracheal intubation, as an adjunct to surgical anesthesia. These agcnts interact with nico-

linic receptors at ihe skeletal neuromuscularjunction.

Thcrc are t$o classes ofneuromuscular blockers:

l. \ondepolarizing: These agents competitively compete with acetylcholine at the nicotinic recep-

rrrr. Thesc agents bind to nicotinic cholinergic receptors and prevent acetylcholine from stimulating

moror nenes. resulting in muscle paralysis. The prototlTre nondepolarizing agent is tubocurare /Cr-|rrrer Other agents include mivacurium, vecuronium, doxacurium, pancuronium. atracunum,

crsatracurium and rocuronium. Note: Neostigmine or pyridostigmine (which are cholineslerase i4-hibitots) can reverse the blockade ofthese agents.

:. Depol^rhing (non-(onpelilire): S:'lccinylcholine (Afiecttue) is thc only member ofthis group used

rn the Unired Statcs. It acts like a nicotinic agonist and depolarizes (dese/tsilizes) theneuromuscular

end pla1e. It binds to the ACh receptor and stimulates depolarization causing initial excitation fol-lo\1ed bt- block of n eurotransmis sion and muscle paralysis.Important: Succinylcholine should be used with caution in patients with low Ievels of pseudo-

cholinesterase, which breaks down succinylcholinc. Respiratory failure may result.*** Succinylcholine may cause muscarinic responses such as bradycardia and incrcased glandular se-

cretions,

Very important: The major danger ofall ofthese ncuromuscular blocking drugs is too much paral-ysis (the patient cdnnol hrealhe).

1 Dantrolene is an skeletal muscle relaxing agent that acts within the skeletal muscle fiberrather than on the neuromuscularjunction fdoes not block the icolinic receptors).lt inhibitsthe depolarization-induced release of Car- from the sarcoplasmic reticulum The principaltherapeutic applications ofdanffolene are for the re lief of spasticities associated with upper

motor ncuron disorderc (i.e., slroke, cerebral palsv, and muhiple sclercsis) and for the pro-phylaxis and treatment of malignant hyperthermia.2. Botulinum toxin A fBolo-rl acts on the motor nervc terminal to prcvent the release ofACh. It is used in ophthalmology to relax the extraocular muscles, and for muscle dystonias

as well as to remove wrinkles.

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. Physostigmine

. Edrophonium

. Pyridostigmine

. Phentolamine

. Neostigmine

. Acetylcholine

. \4ethacholine

. Bethanechol (Urecholine)

. Dobutamine

. Carbachol (Isopto-Carbachol)

. Pilocarpine hydrochloride

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Alf of the foffowing are cholinergic d .:ltgs EXCEPT one.Which one is the -EXCEPIIOM

Page 120: Pharmacology

*** Phentolamine (and phenotybenzamine) are prototypes ofnon-selective alpha-adrenergic

receptor blockeIS.

Cholinesterase inhibitors act by blocking the enzyme (qce4,lcholi esterase) that degrades

acetylcholine in the brain. This results in more acetylcholine in the s).naptic cleft and enhances

cholinergic transmission. These drugs act as indirect agonists at both muscarinic and nicotinicsites. Examples of cholinesterase inhibitors include:

. Edrophonium: reversible; very short duration ofaction; used to reveffe cumre-type drugs

. Neostigmine: reversible; extended duration ofaction; used to reverse curare-type drugsand to treat myasthenia gravis. Physostigmine: reversible; short duration ofaction; used for glaucoma, and for an anti-dote for atropine. Pyridostigmine: reversible; extended duration ofaction; used to treat myasthenia gravis. Tacrine: reversible; extended duration of action; used to Alzheimer's disease. Donepezil: reversible; extended duration ofaction; used to Alzheimer's disease. Malathion: irreversible; long duration ofaction; used as an insecticide. Sarin: ineversible; long duration ofaction; used as a nerve gas

Three cholinesterase inhibitors are commonly prescribed for Alzheimer's disease:

. Donepezil (Aricept), approved to treat all stages of Alzheimer's disease

. Rivastigmine (Exelon), approved to treat mild to moderate Alzheimer's

. Gafantamine (Razadyne), approved to treat mild to moderate Alzheimer's

\ote: The stimulation of the skeletal muscle by excess acetylcholine eventually resultsin muscle oaralvsis.

*** Dobutamine is an adrenergic agonist.

Cholinergic drugs are compounds that mimic the actions of the endogenous neurotransmitter acctyl_

chofine /,4 Clrl. Direct-acting, or cholinomimetic, agents combine with cholinergic receptors (muscorimic

or nicotinic or both), to cause a response in an effector. These drugs include ACh, various choline-ester

congeners ofACh, and some alkaloids. With few exceptions fi.e., nicotine and olher ganglionic stintu-

1drlt, these agents exe.t prominent muscarinic or parasympathomimetic effects. These drugs are

longerlasting than ACh because they are not subject to rapid metabolism like ACh. ACh is metabolized

by acetylcholinesterase, located near receptors forACh. In the plasma and other sites, ACh (and many

olher esters) are rnetabolized by pseudocholinesterase. The other cholinergic agonists used as drugs are

metabolized slowly or not at all by these enzymes.

Direct-acting agents:. Choline esters: The most noticeable effects ofthese drugs are a fall in blood pressure attributable

to generalized vasodilation, flushing ofthe skin, a slowing ofthe heart rate, and an infieased tone and

actilit-v of both the CI and urinary tracts. Topical application ofthese drugs to the eye causes miosis

and a decrease in innaocular pressure. These dmgs include:. Acet:-lcholine chloride: used in ophthalmology to produce miosis. Bethanechol: used for postoperative abdominal distcnsion and urinary rctention. Carbachol: used in ophthalmology to produce miosis

. Cholin€rgic alkaloidsi These drugs include muscarine, pilocarpine, nicotine and lobeline. Pilo-carpine is the most useful alkaloid being employed as a miotic and to treat open angle glaucoma Pi-

locarpine is also used to stimulate salivary flow in patients suffedng ftom xerostomia due to radiation

therapy in the treatment ofhead and neck cancer.

Indirect-acting agents:

. Cholinesterase inhibitors: These drugs include physostigmine, edrophonium, pyridostigmine,neostignine, malathion and sarin. They inhibit acetylcholinesterase at both mucarinic and nicotinicsites. They are indirect agonists at both muscarinic and nicotinic sites.

Note: Ifany ofthe cholinergic agents are administered before acetylcholine, the action ofacetycholinewill be enhanced and prolonged.

Page 121: Pharmacology

. Produce a dry field for taking impressions

. Calm an anxious patient

. Treat dry mouth by inducing salivation

. Reduce nausea

120Cop).righr O 2011,2012 - Dental Decks

All of ihe following statements concerning edrophonium Nrre trueEXCEPT one. l'/hich one ls the EXCEPZOM

. It is a direcGacting cholinergic agonist (cholinomimetic)

. It is a rapid-acting, short-duration, injectable cholinesterase inhibitor

. It is the drug of choice for diagnosing myasthenia gravis because of its rapid onset ofaction and reversibility

. It is also useful in differentiating a myasthenic crisis from a cholinergic crisis

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Page 122: Pharmacology

Cholinergic drugs used in dentistry are: Pilocarpine (Sa/agezl, and Cevimeline (Evoxac).

. Pifocarpine (Salagen) - is indicated for treatment ofxerostomia caused by salivarygland hypofunction resulting from radiotherapy for cancer of the head and neck. It'spharmacologic category is cholinergic agonist. Prevalent side effects are excess sweat-

ing and nausea./heartbum/diarrhea due to the cholinergic nature ofthe drug.

. Cevimefine (Evoxac) - is indicated for the treatment of symptoms of xerostomia inpatients with Sj<igren's syndrome. It's pharmacologic category is cholinergic agonist.

Prevalent side effects are increased sweating and nausea/heartburn/diarrhea due tothe cholinergic nature ofthe drug.

*** This is falsei edrophonium is an indirect-acting cholinergic agonist (cholittomimetic) as

are pyridostigmine, physostigmine, and neostigmine (thq, are qll cholinesterase inhibitors).\ote: These drugs are indirect agonists at both muscarinic and nicotinic sites.

Pyridostigmine is prescribed in the treatment ofmyasthenia gravis, however edrophoniumis used to diagnose myasthenia gravis and not in the treatment ofit due to its Yery short du-ration of action,

Symptoms ofa cholinergic crisis include bradycardia (decreased heart rate),lacrimation, ex-

treme salivation, vasodilation and muscle weakness. Because a cholinergic crisis can result inmuscle weakness like that ofa myasthenic crisis, distinguishing the two conditions may be dif-ficult. Administration ofa short-acting cholinomimetic such as edrophonium will improve a

ml asrhenic crisis but wors€n a cholinergic crisis.

Remember: Typical cholinergic effects caused by stimulation of acetylcholine receptors

kholi ergic receptorg include salivation, miosis, excessive sweating, flushing, increased GImotility and bradycardia.

Page 123: Pharmacology

rPoisoning with an organophosphrte cholitrssterase

inhibitor can be treated with:

. Edrophonium

. Carbachol

. Pralidoxime

. Nicotine

. Miosis

. Flushing

. Bronchoconstriction

. Increased GI motility

. Increased urination

. Tachycardia

. Salivation

. Increased urination

. Sweating

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123Coplrighr O 20ll-2012 Dental D€cts

Page 124: Pharmacology

Pralidoxime (Protopam) is a cholinesterase reactivator which is used as an antidote to

reverse muscle paralysis resulting from organophoshate anticholinesterase pesticidepoisoning. It is also used to reverse the effects of an overdosage of anticholinesterase

agents used in the treatment ofmyasthenia gratts (i.e., pyridostiSmine and ambenomium).

Symptoms of organophosphate poisoning include: excessive salivation, bronchocostric-

tion, diarrhea and skeletal muscle iasciculations (twitching).

Organophosphates are esters ofphosphoric acid and an organic alcohol that inhibit the

enzyme cholinesterase.

Examples include:. Isoflurophat€: used in the treatment ofglaucoma. Malathion: a widely used insecticide. Parathion: an insecticide. Echothiophate: used in the treatment ofglaucoma. Tabun: one ofthe most potent and toxic nerve gases

. Soman: nerve gas

. Sarin: nerve gas

*** Bradlcardia is a muscarinic effect ofcholinergic agonists.

Direct-acting cholidergic drugs include: methacholine, carbachol, bethanecol and pjlocarpine.

Indirecl-acting cholin€rgic drugs (cholikesterase inhibltor.r/ includc: physostigmine, edrophonium,

neostigmine. pyridostigmine, malathion, echothiophate, sarin and soman.

Effects of anticholinesterases: Muscarinic:. Miosis . Bronchoconstiction. Salivation .lncreased GI motility

'Sweating ' Urination. Bradycardia

Nicotinic:. Muscle twitching. weakness. Tachycardia. Increase in BP

Antimuscarinic drugs block the effect ofacetylcholine and all drugs that stimulate muscarinic rccep-tors. Atropine and scopolamine arc prototlpes. Other antimuscarinic drugs include: glycopltolate,propantheline, benztropinc, cyclopcntolate, tropicamide, trihexyphenidyl, homatropine, oxybutynin, and

rpralroplum.

Antimuscarinic drugs produce the following effects:. Salivary glandsr red\tced secretion (atropine). GI tract: reduced peristalsis, reduced secrelion (ptupa theli e, g6\:opvrrolate). Su eat glands: reduced sectetion (atropilte). E1-es: mydriasis /lotuatropine, clclopentolale, tropicamide). Bronchi: bronchodilation, reduced secretion (ipratropium). Bladder: urinary retcnt\or (oq'but)nin). C\S: antimotion sickness 6copolamine)

antitremor activity -to

treat parkinsonism fbenztrcp[ e, trihe$'phenidyl)

l. Coohaindications for using antimuscarinic drugs include: narrow-angle glaucoma, prc-static h)?crplasia, and tachycardia.2. Pilocarpine and cevime\ne (both cholinergic dsorTr.J/t are used to stimulate salivary flow3. SAL-TROPINElatropine sulfate, USP tablelt is indicatcd to reduce salivation and is en-

dorsed with the ADA Seal ofAcceptance

Noreq;

Page 125: Pharmacology

. Atropine sulfate

. Carbachol

. Glycopyrrolate (Robinul)

. Belladonna derivatives

. Propantheline bromide (Pro-banthine)

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. Triamcinolone

. Cortisol

. Dexamethasone

. Prednisone

. Prednisolone

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Page 126: Pharmacology

*** Carbachol is a direct-acting cholinergic drug.

The other drugs are all classified as anticholinergics. They block postganglionic cholin-ergic fibers.

Contraindications to their use include:. Glaucoma. Cardiovascular problems. Obstruction of the GI or GU tract. Asthma

These drugs also reduce spasms of smooth muscle in the bladder, bronchi, and intestine;

relax the iris sphincter; d€cr€ase gastric, bronchial, and salivary secretions; decrease per-

spiration; and accelerate impulse conduction through the rryocardium by blocking vagal

imoulses.

Tte corticosteroids are steroid hormones produced by the rdrenal cortex, They consist oftwo major

groups:

l. Glucocorticoids: have irnportant effects on metabolism, catabolism, immunc responses and in-flammation. Tle majo ty ofthe anti-inflammatory and immunosuppressive actions ofthe glucocor-ticoids are probably the result of their action on arachidodic acid metabolism. They induce thesynthesis of a protein that inhibits pbospholipase A2, thus decreasing the production of both

prostrglandins and leukotrienes.

The major natural glucocorticoid is cortisol. The synthetic glucocorticoids include hydrocortisone(Cortef), .ortisone, prednisone (Delatasone), predrisolone (Delta-Cortef), dexamethasone(Decadtuh), triamcinolone (Aristocort), firethylyprednisolone fMed,"d/), and betamethasone lce-s/or?e/. Glucocorticoids are most often used as anti-jnflammatory and immunosupprcssive agmts.

Adverse effects ofthe short-term administration ofsystemic glucocorticoids include secondary in-fections, hlperglycemia, and a range ofmood and behavioral changes. Loog-term therapy may cause

osteoporosis, cataracts, hypertension, myopathy, and adrenal ins!fiiciency.

2. Mineralocorticoids: regulate sodium and potassium reabsorption in the collecting hrbules ofthekidney. The major natural mineralocorticoid in humans is aldosterone. Other mineralocorticoids in-clude deoxycorticosterone and fludrocortisone. Mineralcorticoids are used in replacemcnt thcrapyin hypoadrenocorticism or Addison's disease.

\ote: Corticosteroids do not cure any disease. They represent replacement only in Addison's disease.

Contraindicrtions to conicosteroid use include: latent TB or fungal infection, AIDS, herpes infectionsand patients with peptic ulcer disease (specrfcally, gastric ulcers)

-these drugs themselvcs may cause

pephc ulcers.

Toric effects ofthe corticostercids include growth inhibition, hlperglycemia, osteoporosis, psychosis and

salt retention.

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All of the following are pharmacologic effects of glucocorticoidsEXCEPT Orc. WbiCh ONE iS thE EXCEPTIOM

. Stimulate protein breakdown, which results in increased plasma amino acid levels

. Stimulate gluconeogenesis in the liver and inhibit peripheral glucose use

. Impaired wound healing

. Reduce the immune response

. Decreased lipolysis

.Inhibit local edema, capillary dilation, migration and activation of white blood cells,and phagocytosis by macrophages

. Increase hemoglobin concentration and increase the numbers ofcirculating red bloodcells and platelets

copy'igl e zor11!112 - o*orn."r,

. Dexamethasone

..Aldosterone

. Cortisol

. Prednisone

. Triamcinolone

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*** This is false; glucocorticoids affect the mobilization of fats from areas of deposition. IncreasedIipolyisis occurs in areas ofadipose accumulation, and serum fatty acid concentration increases.

Other effects of glucocorticoids include an anti-inflammatory action, immunosuppression, and ananti-allergenic action. Note: These effects occur in target cells following the interaction ofthe steroidwith a specific glucocorticoid receptor

\ote: Beclomethasore, budesonide and flunisolide are special glucocorticoids /used as inhalers) thathale been developed for use in chronic rsthmr and bronchial disease. These agents readily penetrate

the airFay mucosa but have very short half-lives aft€r they enter the bloo4 so that systemic effects andtoricity are greatly reduced.

Remember: The pharmacologic effccts of mineralocorticoids include an increase in sodium rctentionand an increase in potassium depletion which can lead to edema and hypertension if excessive andmay lead to dehydration and hypotension ifinsulficielt.

*** Cortisol, prednisone, dexamethasone, and triamcinolone are all glucocorticoids.

Aldosterone is secreted by cells located in the zona glomerulosa ofthe adrenal cortex.

The secretion ofaldosterone is regulated by ACTH and by the renin-angiotensin system

and is very important in the regulation of blood volume and pressure. Aldosterone pro-

motes rerbsorption ofsodium into the blood from the glomerular filtrate. Potassium is

lost in the urine because of the electronegativity that is created by the reabsorption ofsodium in the kidney tubules.

Note: Increased blood aldosterone levels will result in high sodium and low potassiumlevels in the plasma.

Remember: Decreased sodium concentration causes the juxtaglomerular cells of the

kidneys to secrete renin, which converts angiotensinogen to angiotensin I. AngiotensinI is converted to angiotensin II, which, in tum, stimulates the adrenal cortex to release al-dosterone.

, -,- ,. 1. Addison's disease is caused by the hyposecretion of aldosterone and corti--rNote{,] sol.

*if' 2. ADH (Vasopressin) decreases the production of urine by increasing the re-

absorption of water by the renal tubules (it increases the permeobiliry of the

collecting ducts and distal tubules). Without ADH, there would be extremeIoss ofwater into the urine.3. At high concentrations, ADH causes arterioles to constrict (increases bloodDressure).

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. Hydrocortisone

. Prednisone

. Cortisone

. Fluticasone (Flonase)

. Methylpredrisolone (Medro I)

. Hydrocortisone

. \{ethylprednisolone

. Prednisone

. Compazine

. Triamcinolone

. Dexamethasone

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Page 130: Pharmacology

Corticosteroids in the inhaled form, decrease the inflammation in the airway in asthma.

Reduction of inflammation enhances the bronchodilating effects ofthe beta2-adrenergicagonists.

The following are some ofthe other popular inhaled corticosteroids used in the treatmentof asthma:

. Triamcinolone (Azmacort)

. Beclomethasone (B eco n.tse )

. Budesonide (Pulmicort)

. Flunisolide (AeroBid)

Note: Inhaled steroids very often cause a fungal infection ofthe mouth and throat.

Combination products used in the treatment ofCOPD and asthma include:

. albuterol/ipratropir'l'm (Combivent)

. fluticasone/salmeterol (Advair Diskus)

. budesonide/formoterol (Symbicort)

Important: Leukotriene modifiers act on inflammatory mediators ofasthma, the LTs

lalso htoutr as slo$.reqcting substance of anaphylnris [SRS-A]), which contributes toainr ay obstruction. There are two subclasses: (l) Leukotriene receptor antagonists whichinclude montelukast (Singulair) and zafirlukast (Accolate) (2) 5Jipoxygenase inhibitortleukotriene s!nthesis inhibitor) which includes zileuton (Z,tflo).

*** Prochlorperazin e (Compazine) is an anti-psychotic medication in a group ofdrugs calledphenothiazines.

T\\'o r-ypes of corticost€roids:

L Glucocorticoids affect carbohydrate, lipid, and protein metabolism. They are used as to

treat numerous disorders, primarily through their anti-inflammatory and immunosuppres-

slve acnons.2. Mineralocorticoids regulate sodium and potassium metabolism.

l. These dmgs are used to treai a variety ofconditions which include asthma, arthri-

tis, allergies, aphthous stomatitis, lupus erythematosus, and TMJ pain.

2. Contraindications to their use include latent infections (fingal, viral, or bacte'

ndr, AIDS, herpes infections, gastric ulcers, and congestive heart failure.

3. Adverse reactions include Cushing's syndrome (obesit)' qnd weakening oJ uus-cles), hyperglycemia, osteoporosis, peptic ulcers, and an increased risk of infec-

tion.4. Corticosteroids do not cure any disease. They represent replacement only in Ad-

dison's disease.

Inhaled corticost€roids used for asthma do not achieve significant blood levels to cause the

advene effects listed above for systemic agents. Populal aerosol corticosteroids are triamci-nolone (Azmacort), beclomethason€ freconase),fluticasone (Flovmt) andbudesonide (Pal-

nicott). Localized infections with Candida albicans occur frequently in the mouth and pharyrx

with repetitive use of inhalant corticosteroids.

Nasal spray corticosteroids used for seasonal allergies also do not achieve significant blood

levels, and are use for their localized effects. Popular nasal spray corticosteroid products are

triamcinolone fNasocorf , fl uticasone (Flonase) and budesonide (Rhinocort).

Page 131: Pharmacology

All of the following drugs ar€ direct vasodilrtors .EXCEPZ one.

Which one ls the TXCEPZOM

. Hydralazine (Apre s o I ine)

. Diazoxide (Prcglycen)

. Captopril (Capoten)

. Sodium nitroprus side Qtlipride)

. Nitroglycerin (Ni tros tat)

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\AII ofthe following drugs are used ao prevent or to provide relief of angina

pectork EXCEPT one. Which one is the EXCEPTIOM

. Nitroglycerin Qtt i t ros tat)

r I<nfl,,rnnhqtp

. Nifedipine (Procardia)

. Dlltiazem (Cardizem)

. Propranolol (Indera l)

. lsosorbtde (Isordil)

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Page 132: Pharmacology

*** Captopril is an angiotensin-converting enzyme inhibitor.

Direct vasodilators exert their antih)?ertensive effect by a direct vasodilator action onthe smooth muscle of arterioles, resulting in a decrease in peripheral resistance andblood pressure. Compensatory responses may be marked and include salt retention and

tachycardia. Adverse side effects include GI upset, headache, dizziness and tachycardia.

Not€: nitroprusside, diazoxide, hydralazine and nitroglycerin are parent€ral va-sodilators which are used in hypertensive emergencies.

Calcium channel blockers are also effective vasodilators firclirect) ?J]'dhavebeen applied

to the management ofhypertension. Vertpamil (Calan SR), Nifedipine (Procardia), and

Diltiazem (Cardizen) have been given orally for the treatment of mild to moderate hy-pertenslon.

Remember: Hydralazine and minoxidil are peripheral vasodilators.

*** Isoflurophate is an organophosphate cholinesterase inhibitor used in the treatment

ofglaucoma

Angina pectoris is the pain in the heart and chest which occurs during the occlusionofcoronary arteries. Triggers that can cause occlusion are physical exertion, increased

blood pressure, and vasoconstriction. Antianginal drugs work by reducing cardiac rate

and force, reducing peripheral vascular resistance, or dilating coronary blood vessels.

Nitroglycerin is a coronary artery vasodilator. It relaxes blood vessels to provide in-creased blood flow and oxygenation to the heart muscle. It is sublingually effective within2-4 minutes. The nitroglycerin skin patch releases the drug over a 12 hour period to pro-\ ide sustained blood levels for prevention ofangina. The two most common adverse ef-fects caused by nitroglycerin are orthostatic hypotension and headache.

\ifedipine lProca rdia) and diltia,zem (Carulizem) are calcium channel blockers used to

prevent angina attacks. These drugs are used to dilate coronary blood vessels for im-prored blood flow to heart muscle. Note: Calcium channel blockers as a class have been

associated with causing gingival hyperplasia.

Propranolol (lnderal) ts representative ofthe beta-blockers used to prevent angina at-

tacks. Atenolol (Tenormin) is another popular beta-blocker used for this purpose. Beta-

blockers are used to decrease the work load ofthe heart such that less oxygen is required.

Page 133: Pharmacology

Amyl nitrile is used ln ths emergency ir€atmentof cyonide poisoning because it:

. Oxidizes hemoglobin

. Irreversibly binds cyanide

. Competes with cyanide for binding ofcy4ochromes

. Inhibits tubular reabsolption ofcyanide

132Coplyight C 201 l-2012 - Deutal Decks

. Is dependent upon a normal cardiac rhythm

. Directly increases the force ofmyocardial contractions

. ls antagonized by beta-blockers

. All ofthe above

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*** Amyl nitrite oxidizes hemoglobin to methemoglobin which binds cyanide tightly,keeping it in the peripheral circulation and preventing its access to tissues.

Amyl nitrite is a vasodilator and a highly volatile substance administered by inhalationonly. It is the most rapidly acting ofthe antianginal drugs, producing effects within l0seconds. Its duration of action is only 3 to 5 minutes. Because of its extreme potency,

there are uncomiortable side effects that invariably occur with rts :use (ainting and apounding headache). lmportant: This drug is rarely prescribed and is not the first drugofchoice in treating angina. It is abused to produce euphoria and as a sexual stimulant.

Other anti-anginal drugs include:

1. Nitrate: Nitroglycerin*** This drug is the single most effective agent available for the management ofacuteangina episodes. Note: It dilates mostly veins.2. Non-nitrate vasodilator: Dipyridamole (Persantine)

3. Beta adrenergic blocking drugs: reduce cardiac rate and force. P ropr anolol (l ndera I). Nadolol (Corgard). Atenolol (Tenormin)

-1. Calcium channel blocking drugs: dialte peripheral and coronary blood vessels

. ltrapamil (koptin, Calan)

. Diltiazem (Cardizem)

. N rfediorne (P ro card ia )

*** This positive inotropic effect is independent ofa normal sinus rhythm and adrcnergic stimulation.

Thc cardiac gf]cosides are often called "digitalis" because several come from the digitalis (lbxglove)

plant. Digoxin /larroxir) is the most versatile and widely used.

\otei The) are used to trcat most supraventricular arrhythmias, cardiogenic shock and chronic heart

lailure.

These drugs help the heart beat more strongly (posilire inotopic effect), more slo\\ly (bradycardia) ^nd

more elficientl].Cardiac gl]cosides inhibit the Na*-K*-AlPase membrane pump by inhibiting the adenosine triphos-phate enz)-mes (transport ATPase or Na-K-ATPase). Na*-K*-ATPasc splits adenosinc triphosphatc in

the nel\e and muscle cell and thus provides the energy necessary for transporting sodium across the cell

membranc. Key point: This inhibition of thc NalK*-AIPase enzyme leads to an increased calciumion influx u'hich augm€nts the positive inotropic effect ofcardiac glycosides. Adverse side effects in-

clude nausea and vomiting, appetite loss, dianhea, ventricular anhyhmias, heart block, and visual and

mental disturbances. Contraindications to thci.use include ventricular fibrillation andventricular tachy-

cardia.

Drug interactions: Many drugs aff'ect digoxin levels. However, digoxin docs not affect the levels ofotherdrugs. ln addition, when beta-blockcn are added to digoxin in patients with AV conduction abnormali-ties, complete heart block can result. Erythromycin. clarithromycin and tetracycline may increase digi-talis absorption and toxicity. Thyroid replacement therapy incrcases dose requirements ofdigoxin. D gs

that lower plasma potassium levels ae.&, lhiazide and loop diurelics/ increasc digitalis toxicity

Drug treatment of mild to moderate heart failure proceeds in the following order:(l) Diuretics in pa-

tients \1ith fluid retention (2) ACEIS orARBS in all paticnts unless contraindicated (3) Beta-blockers in

all stable inininalJluitl relention) p^tients unless contraindicatcd and (4) Digoxin. Note: Ifthese med-

ications are not suflicient to control heart failure, the following additional drugs may be given: (1)

Spironolactone (a aldosterone antctgorlist) (2) Nitrates and hydralazine and (3) Calcium channel block-ers (i.e., amlodipine and felotlipine only)

Remember: Most drugs useful in treating cardiac arrhythmias act primarily by increasing the re-fractory period ofcardiac muscle.

Page 135: Pharmacology

. Captopril (Capoten)

. Hydralazine (Apres o line)

. Enalapril (Vasotec)

. Lisinopil (Zestril)

. Fosinopril (Monopri l)

. Propranolol (Inderal)

. Acetbutolol fsectra,

. Metoprolol (Lopressor)

. Yeraparnil (Calan)

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*** Hydralazine is a direct peripheral vasodilator.

ACE inhibitors interfere with the conv€rsion ofangiotensin I (d veak rasoconstictol) to angiotensinll (a highly e.f;[ective constrictor). Thcy do this by being inhibitors of angiotensin-convcrting enzyme(,1CEl. These drugs are used to treat hypertension and congestive heart failure. Adverse cffects includc

cough, hypotension, neuhopcnia, anorexia alrd pol]uria. Note: They can alter the sense oftaste and ina few rare cases, cause angioneurotic edema.

Angiotensin II is a potent vasoconstrictor and is a stimulus for aldosterone release from the adrenal

glands. Reduction in aldosterone secretion results in less waterabsorption and sodium/potassium ex-

change in the distal renal tubule, causing a slight increase in serum potassium. ACE inhibitors inhibitthe breakdown ofbradykinin, a potent and naturally occurring vasodilator, by blocking thc cnzymc kin-inase IL This though, is thought to be the causc ofthe cough commonly experienced by patients who take

this class ofdrugs.

OtherACE inhibitors f,4Ct1t include:. Benaz,eptll (Lotensir./ . Moexipril fLr?i|ascl 'Quinapril (Accupril) 'Captopril (Capoten). R^rnipfll (Altdce) . Trandolaprll (Mat ik) ' Lisinopril (Zestil) ' Elan |{il (Uasolec)

Angiotensin lI reccptor blockerc f,4RBs/ include:

. Losarlan (Coaaar)

. \'alsafian (Diotan)

. C andesanan (Atacand)

. Eprosaftan (Tevete ) .lrbesarlan (Avapro)

. Olmesaftan (Benicar)

. Tebllisafian (Mica rd i s)

*** ARBs block the effects ofangiotensin II by blocking the binding ofangiotensin II to its rcccptors.

Thc: do not effect bradykinin. Adverse effects jnclude dizziness, diarrhea and myalgia.

Thc antih) pcnensive effects ofARBs have been provcn comparable with those ofthe ACEIs ACEIs and

{RBs are ofparticular values for the reatment ofhypettensive patients who have concomitant illnesses

iuch as diabetcs, rcnal insufficicncy, left ventricular dysfunction, and CHF

\ote: ACE inhibitors and Angiotensin II receptor blockers indirectly inhibit fluid volume increases

\\hen interfering with angiotcnsin II because angiotcnsin II stimulates thc r€lease ofaldosterone, whichpromotes sodium and water retention.

Thc \ aughan-williams classification system traditionally has been used to classity antianhyth-

mic drugs. This scheme places the available agents into onc of four classes, usually denoted byRoman numcrals I lV This systcm is loosely based on the channel or receptor involvcd.

Class l: Sodium channel blockers. Class I drugs are further classified on the basis oftheir effects on action potential duration:

. lA agcnts include; Qu:Lnidinc (Quinidex), procatnamide (Procan SR/ and disopyramidc py'or-

paceJ. These agents prolong thc action potential.. fB agents include: LidocainelX.ylocai e). mexiletine (Mexilil) and tocainide (Tonocard.

These agents short€n the action potential.. fC agents include: Flecainide (Tambocor) and propafenone (Rythnol). These agents have

no effect on action potential dulalion.

Cfass II: Beta-adrenergic blockers Propranolol (Inderal) is the prototype antianh)'thmicbeta-blocker Other drugs in this class include: esmolol (Breibloc) acetbutolol (Secn'al) ar'd

metoprolol (Lopressor). These agents increase refractory period, decrease conduction veloc-

ity and reduce automaticity.

Cfass IfI: Potassium channel blockers - Amiod^rone (Cordarore) is the prototype drug in thisclass. Sotalol (Betapace), tbutilide (Corvert) and dofetilide (Tiko$n) arc also in this class.

These drugs increase refractory period and reduce automaticity.

Class Il': Calcium channel blockers Yerapamil (Calan)is the prototype. Diltiazem is also

included in this group. These drugs increase refractory period, decrease conduction velocityand reduce automaticity.

Note: Miscellaneous antiarrhythmic drugs include: adenosine (Adenocard) which increases

refiactory period and reduces automaticity and digoxin (Lanoxin) which increases the force

ofcontraction ofthe heart muscle and decrease conduction velocity.

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. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

136

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. Anglna

' Hlpertension

. Suprayentricular tachyarrhy'thmias

. All ofthe above

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Page 138: Pharmacology

Procainamidc is a Class lA antianhythmic agcnt that is uscd in thc trcatment ofseveral cardiac ar-rhythmias including atrial fibrillation, atrial flutter, parcxysmal atrial tachycardia. and ventriculartachycardia. It is not used as an antihypertensive. It is a derivative ofthe ester local anesthetic pro-caine. Procainamide has properties similar to those ofother Class lA agcnts, quinidine and disopy-ramide. These drugs decrease myocardial conduction velocity, excitability, and contractility byinhibiting the influx of sodium through "fast" channels oI the myocardial cell membrane, therebyincreasing the rccovery period al1er repolarization. Note; Quinidine is prirnarily used to treatsupmventricular tachyanhythmias.

Remember; Generally speaking, the use ofbeta-blockers (Class II agents) as antianhythmics is

reserved fbr patients who require only control ofventricular ratc during atrial tachyarrhythnias orwho have mildly symptomatic vent cular arrhythmias. Side effects includc bradycardia and hy-potension.

Important: Amiodarone (Cordatone) is generally considered a Class Ill agcnt even though it also

blocks sodium channels, a Class I action. It is uniqu€ in that it is the most potent and "broad-spec-

trurn" antianhythmic compound cunently available. It blocks sodium, calcium, and potassium

channels as rvell as beta rcceptors. Il has impressive ellicacy in suppressing both supraventricularand \ enlricular arhythmias. Note: Adverse effects include pulmonary fibrosis, thyroid abnormal-

iti!-s. skin discoloration, and peripheral neuropathy.

L Cornmon adverse effccts ofsome antiafihythmics:\ot.s . Procainamide: nental changes, torsade de pointes (TDP - i.s an uncontnutn vari-

a t ofvetlti'icul4r |acht-cqrdia). Quinidine; hypotension, cinchonism @ eadache, ringing in lhe ears, deafness), awltorsade de pointes. Lidocaioei convulsions. Propranolol; bronchoonstriction, heart block. Calcium channel blockers: flushing, headache, hypotension, gingival hyperplasiaand reduced cont.actilitv ofthe heart

\-erapamif is the prototypical Class lY (celciu channel blockers) antiarrhythmic agent. It jn-

hibits the intraccllular entry ofcalciurn through the slow channels ofthe calcium dependent tissues

of the myocardium, rvhich are concentrated in the SA and AV nodcs. It is the drug ofchoice for the

suppression ofparoxysmal supraventricular tachycardias stemming from the AV node (wlrlclr

is characteri:ed by a rcpid cer.liac rate, usually 160-190 per minule). Of the calcium channel an-

tagonists available, only vcrapamil and diltiazem possess significant antianhythmic activity.

Note: Calcium channel blockers (e.g., verapanril, dillazem and nifedipile) are useful as

antianginal agents and antihypertensive agents as rvcll. They block calcium cntry through the mem-

branous calcium ion channels ofcardiac and vascular smooth musclc. This has thrcc cffccts:

1. Peripheral arteriolcs dilate (vasodilato,", and total periphcral rcsistance deoreascs, reducingafter-load and reducing myocardial oxygen requirements.

2. lncreases oxygen delivery to the myocardium.

3. Reduces blood pressurc ifhypertension is present.

lmportant; Nilrites (amyl nilrite) and nitratcs (nittoglyceri\) are fast-acting antianginal agents

that are uscd to relieve acute anginal attacks.

\ote: For angina, nitroglycerin and nifedipinc arc usually used before verapamil.

Page 139: Pharmacology

. Enoxapadn (Lovenox)

. Dalteparin (Fragmin)

. Tinzaparin (Innohep)

. Clopidogel (PIavLx)

. Abciximab (Reopro)

. Anagrehde (Agrylin)

. Epttfibatide (I nt e gri lin)

. Tirofiban (Aggrastat)

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*** Clopidogrel fPlarrt inhibils blood clolting by inhibiting platelet aggregttion in an irreversible manne.

a . - - _ L Thcsc typc ofanticoagulants agcnts f/olr mols.ular \|eight hepdin, arc uscd to treat acute symp_

:tyotedr tomadc dcep vcin lhrombosis. Tlrcy arc uscdlo preventdccpvcin thronlbosis following knce orhip su.-

: -.... :,: scry'l;i;*:.- 2. Thcy arc administcrcd subcutancously sincc they arc unablc lo bc absorbcd frorn the Gl tract.

3. Standard heparin consists ofcomponcnts wilh molccolar wcights ranging from 4.000 to 30.000 dal-

tons with a mean of 16,000 daltons. Low molecular-lieight heparins rangc in molccular wcights from2,000 to 8,000 daltons.4- Heparin acts at multiplc sites in ihc coagulatior systcm and binds with antithrombin III at two spc-

citic sites, rcsulting in irs anticoagulanl cffcct- At thc first sitc factor Xa is tlcutlalizcd and at ihc scc-

ord silc factor lIa A,rr?rrbr, is ncutralizcd.5. Low molecular tleight heparins havc a small eflect on pa(ial thromboplastin timc but strongly in-hihit factor Xa hol lla).6. Thc antidote fbr heparin is protamine; thc antidotc lbr warfarin is vitamin K.

Class Subclass Gcneric/tr|d€ Name

Heparrn group Heparin heparin sodium

Low molecular weight heparin €noxaparirlllov€nox

dalteparin/Fragmin

tinzaparir/Innohep

Hepadnoids danaparoid/Orgaran

fondaparinutAnXtra

Direct thrombin inhibitors bi\ alirudin/Aneiornax

a4atrobal'Argatroban

lepirudinr?.efludan

Oral anticoagulanls warfanr/Coumadin

anisindione,tt4iradon

Glrcoprotein IIb,4Ila inhibitors are reversible antiplatelet agents uscd !o prcvcnt acut€ cardiac ischemiccomplicfiions and used in paticnts with acute coronarv svndrome. Thev are adntinistered imtravcnously.

Tleie a{cnts block the plafelet glycoprotein IIb/IIIa receptor, rhe binding site for fibrinogen, von Willebrandr'3.tor. and othcr ligands. Inhibition of binding at this final common receptor reversibly blocks phtel€t ag-gregation and prevenls thrombosis- Platclet aggregation inhibition is revcrsible following ccssation ofthc lV3cmr:inration ollhc drug minutes after an intruvenous infusion. Note: The glycoprotein IIb/lIIa inhibitorsh3! i a raPid onset ofaction, Their maximal antiplatelet effect occur within minutes after an intravenous in-1-li[]r Important: Thc most serious adverse effects of GPIIb/llla anragonists include major bleeding, in-'- .. . ::h:.rl hcn un hrce u.lJ rhromboc\ ron(nir.

Class Subchss Generic/trad€ Name

Plar€ler aggregation inhibitors Tflrditional acetylsalicylic acid/aspirin

dipyridamol€,4ersrnlin€

Adensosine diphosphate-inducedplatelel-fi brinogen binding inhibitors

clopidogrel/Plavix

ticlopidine/Ticlid

Plalelet Slycogen IIb/IIIa inhibitors

ep!ifi bat;de,{ntegrelin

Plarelet-r€ducing agent Phosphodiesterase III inhibitors anagrelide/Asrylin

cilostazolry]€tal

Thrombolytic agents

stieptokinase/Streptase

tenecteplase/TNKase

urokinase/Abbokinase

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. Lepirudin (Reflidan)

. Dznapnord (Orgaran)

. Bivalirudin (Ang io m ax)

. PTT (Partiol Thromboplastin Time)

. PT (Prothrombin Time)

. Platelet count

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These agents are administered intravenously for prevention ofpost-operative deep veinthrombosis following elective hip replacement surgery; for prophylaxis or treatment ofthrombosis in adults with heparin-induced thrombocytopenia.

Their mechanism ofaction is through the direct inhibition of thrombin within the co-agulation pathway, thus inhibiting fibrin formation.

This test is a one-stage t€st for detecting certain plasma coagulation defects owing to a

deficiency offactors V VII, or X. Thromboplastin and calcium are added to a sample ofthe patient's plasma and simultaneously, to a sample from a normal control. The lengthof time required for clot formation in both samples is observed. Thrombin is formed fromprothrombin in the presence ofadequate calcium, thromboplastin, and the essential tissue

coagulation factors. A prolonged PT therefore indicates deficiency in one ofthe factors,

as in liver disease, vitamin K deficiency, or anticoagulation therapy with the drugcoumadin.

International Normalized Ratio (/r'R/. Once prothrombin times are determined, they are

expressed as an INR value. INR stands for International Normalized Ratio and essen-

tially is the ratio ofthe prothrombin time measured in the patient divided by a standardprothrombin time value, and multiplied by a constant. An INR value of I means normalprothrombin times ofapproximately l2 seconds; normal blood clotting would be present.

INR values greater thar 1 indicate that there is an anticoagulant effect. The higher theINR value, the greater the anticoagulant effect. Many patients taking anticoagulants have

INR values of2-3 and even uo through 6.

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\- All oftle following conditions are manrged by using anticoagutants andsnti-platelet agents l9xcEPI one. which one is the EXCEPTI0M\-t

. Coronary Artery Disease (CAD)

. Angina Pectoris (Unstable Angina)

. Myocardial Infarction (Heart Attack)

. Stroke

. Hypertension

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. HPG-CoB Reductase Inhibitors

. HCG-CoG Reductase Inhibitors

. tMG-CoA Reductase Inhibitors

. HCG-CoB Reductase Inhibitors

143Cop)"ighr O 201l-201? DmialDecls

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Anticoagulants such as warfarin (Coamadin) and anti-platelet agents such as aspirin andclopidogrel (Plavix) are nsed in the conditions listed for the following reasons:

. Coronary artery disease (ClD): will help prevent threat ofmyocardial infarction inCAD patients.. Angina pectoris (anstable angina): will help prevent thrombus from forming withinthe coronary arteries.. Myocardial infarction (MI): drugs that prevent blood clotting have been shown toprevent the threat of future infarcts.. Stroke: will help prevent thrombus from forming thus preventing threat ofa cerebralembolism.

Note: Unless there are other accomparying cardiovascular problems such as those listedabove. anticoagulant drugs are not necessary in the treatment and management of hy-penension. These drugs do nothing to lower blood pressure.

Coronart artery disease fClD/ is a condition ofnarrol'ing ofthe blood vcsscls oflhc hcarl rcstncting oxygcn flowro heart musclc. lt has been cor.clatcd with the lcvcls ofblood cholcstcrol and triglyccridcs. Ifnot trcatcd, CAD can

lcad ro mloca.dial infarction (heart otkrck).D gs such asthc statins, \\'hich lowerblood cholcstcrol arc cficctivc inmlrrjrizing the threat ofCAD.

Currcnrl]. six classcs ofantihyperlipidemic drugs arc availablc. and cach class has its own mcchanism tor lot\'cringl::rd 1c\ cls r-ote: Thctwo major lipoprotcins that arc targctcd arcVLDLSand LDLs. Thc primary lipids ofVLDLS;J. rhc Ingl!ccridcs. \r'hcrcas thc primary lipids ofLDLS arc cholcstcryl cslcrs. Highcr levcls ofLDL incrcasc thc risk

rf..rrdio\ascular drscasc, whercas highcr lcvcls ofVLDL incrcasc the risk ofpancrcalitis.

' H\lG-CoA Reductase inhibitors: thc cnzymc 3-hydroxy-3-mcthylglutaryl cocnzymc A (H]tlc-Co,l) rcdnc-rri. is n..ccssary in thc kcy stcp to synthcsizc cholcsterol. When thc "statin" drugs inhibit this cnzymc, cholcs-lrrol rs nor produccd in thc livcr and blood lcvcls dccrcasc. Thc family of "statin drugs" includc atorvasaatin,l,frforl. simr'rstatin (ZoLor). flu\sstatin (a€r.or, lovastatin (Mewcor) pr^v^st^tin (Prarachol) and rostt-r.statin /ar.,r/o,"/.. Fibric acid derivatites: thcirprimary lipoprotein effect is to dccrcase trigiyccridc andraisc HDL concentrations.

Tlc] do fiis by incrcasing lipoprotein lipasc activity, which rcsults in i crcascd catabolism ofVLDL. Examplcsin c:udc gem fi brozi I /lop id) and fenofrbr^te (Tricor) .

. Bile acid sequestrants: thesedrugs bind tobilc acids, bilc acid scqucstrants increa-sc thc divcrsion ofcholcstcrolro bilc acid slnthcsis, lowcr intraccllular storcs ofcholesterol, and res lt in crcascd caiabolism ofLDLby the

lr\.r E\amplcs include cholestymmine fQuc"stdn), and colesevel^m (WelchoU.

. Other agents: nicotinic acid lrtdcin) ;s bclicvcd to act on a hormonc-scnsitivc lipasc; this lcads to inhibition ofrcleasc offrcc fatty acids from adiposc tissuc /@ob,srt. Thc inhibition oflipolysis lcads to reduccd frcc fatly acidrranspon ro thc liver and thcrcforc dccrcascd syrlhcsis ofVLDL.. Combination products: examplcs includc lovast^tinlni^cin (Adicor)

^nd ezetimibe/simvastatin (l/ttoritt).

. Selectivc cholestcrol absorption inhibitors: ezetimibe /Zsltdl is thc firsl agcnt in a ncw class ofdrugs that ap-

pcar to act on thc brush border of intcstinal cpi(hclial cclls. whcrc it sclcctivcly inhibits $c absorption ofcholcs'terol from dictary and biliary sourccs.

Important: The "statin" dnrgs have thc capability to increase the breakdo*'n ofskeletal muscle thereby re-leasing muscle protein. Ifthc protein overloads the kidneys, renal failure could result. The ert'thromycin drugs

enhance the capabilities ofthc "statins" to cause this effect.It is advisable for patients medicatedwith a "statin"druts nor to be gi\en eryhromycin nroducts.

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ACE Inhibltors inhibit the conversion ofinactive angiotensin I tothe angiotensin II, a vasoconstrictor.

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

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. Erythromycin

.lbuprofen

. H]drocodone

. Penicillin VK

. Azrtbromyctn (Z-Pak)

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Whlch of the drugs below can prolong th€ QT interval of cardiac electricalconduction and thus can lncrease the risk ofcardiac arrhythmias?

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Antihypertensiv€ agents arc classified by mechrnisms otaction:. Diuretics: irclude thiazide and thiazideJike fNd CIJ inhibitors.) such as hydrochlorothiazide (HCTZ) andfoop diuretics such as furosemide /Zasi.r/ and brmet aide (Bumer). These drugs inhibit sodium reab-sorption in renal tubular cells within the kidney !o cause excess sodium and u nary excretion resulting inreduced blood volume.

. Beta-adren€rgic receptor blockers (6era-bloct?/sl: rcduce the volume ofcardiac output irlto the circu-lation resulting in reduce peripheral pressure. Two types:

l. Cardiosefective beta-blockefs (bela rreceptor block in heart muscle/: examples includ€ at€nolol(Tenormin). metopfolol (Lopressor, Toprol XL),

^ceb\tolol (Secral), esmolol (Brevibloc)

2. Non-cardioselective (beta I and beta, beta-blockers: examples include nadolol (Corya ), pro-pr^nolol lndera0, tirnolol (Betinol), pellbntolol (Levatol), and sot^lol (BetapaL")*** Note: labetalol Ard ndate) and c^rledilol (Col€g) are non-selective beta-blockers that also blockalphar receptors.

. Alpha-adr€nergic receptor blockers: cause dilation ofarterioles and veins and reduce peripheral vacu-

lar resistance.Two tvpes:

L Cardioselective alpha-blockers (alpha sreceptor blockert: examples includ€ doxazosin fcdr"-dut tl). pf^zosin (Mi iprcss)^11d,ter,'zosin (Hvtrin).l. \on-cardioseleclive (alphal and alpha) alpha-blockcrs: cxamples include phentolamine /R?grt-ir., and phenoxybenzamine (Dibe zNline.).

. Angiotensin-converting enzyme inhibitors (ACE Inhibitors), examples includc lisinoprll (P nivil:Zet ti l)- r^fiipril (Altace) and etral^pril (Vdsolec/i inhibit thc convcrsion of inactive angiotensin I tothe angiotensin II, a vasoconstrictor. This results in peripheral vasodilation and secondarily, an in-crease in urinary volumc cxcrction. Both actions result in reduced blood pressure.. Angiotensin II receptor blockers f/nBt: examples include losartan (Cozaar), \alsartan (Dio-l anl and candesaftalr (Atacand). ARBS block the effects of angiotcnsin II by blocking the bindingofangiotensin Il to its receptors. They do not effect bradykinin.. Calctum channel blockers examples include Verapamil (Calail),

^mlodipine lNorvasc), dilti-

Azem /Cardizen), and nifedipine (Procardia): inhibit calcium entry into vascular smooth musclecausing vasodilation ofcoronary and peripheral blood vessels thus iowering blood pressure.

Erlthromycin is one ofthe drugs confirmed to prolong the QT interval and is accepted

as ha\ ing a risk ofcausing anhythmias. The QT interval is measured as the time and dis-rance benveen the Q point ofthe QRS complex and the end ofthe T wave in the ECG trac-

lng. -{ long QT syndrorr.re was first described in the 1950's as a congenital syndromein\'olving QT interval prolongation and syncope and sudden death. These congenital long

QT svndromes were characterized by a peculiar electrocardiographic appearance of the

QRS complex involving a premature atria beat followed by a pause, then a subsequent

sinus beat showing marked QT prolongation and deformity. This type ofcardiac arrhyth-mia was originally termed "torsade de pointes" (from the french " t**isting of the points ").

Erythromycin, an antibiotic used to tr€at bacterial infections, is considered as having arisk of causing torsade de pointes, an unusual adverse reaction for an antibiotic.

Clarithromycin, an antibiotic within the erlthromycin family also causes prolongation

ofthe QT interval.

Azithromycin, another member of the erythromycin family of antibiotics is not associ-

ated with prolonging the QT intewal.

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. Antibiotics

. Aromatase inhibitors

. Antimetabolites

. Alkylating agents

. Antimicrotubular

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. Chronic leukemias

. Lymphomas

. AIDS

. Myelomas

. Carcinomas ofthe breast and ovary

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Exemestane is an irreversible, steroidal aromatase inactivator. It prevents conversion ofandrogens to estrogens by tying up the enzyme aromatase. In breast cancers wheregrowth is estrogen dependent, this drug will lower circulating estrogens.

Exemestane is used in the treatment ol advanced cancer in post menopausal womenwhose disease has progressed following tamoxifen therapy.

Letrozole (Femara) worksby a similar mechanism as above. It is used as first line treat-ment ofhormone receptor positive or metastatic breast cancer in postmenopausal women.It is also indicated as an extended adjuvant treatment of early breast cancer in post-menopausal women who have received 5 years ofadjuvant tamoxifen therapy.

The alkJ-'lating agents contain a diverse group ofcompounds which all form alkyl bonds

to nucleic acids. All ofthese agents share a similar mechanism of action and mechanism

of resistance. The alkylating agents lorm covalent bonds with nucleic acids, and pro-

reins. The N-7 position ofguanine is a common binding site.

Hodgkin's diseasc and oiher lymphomasLymphomas, leukemias, multiple myeloma, neuroblasloma,

retinoblastoma, and cancers ofthe breast and ovaryChronic lymphocytic leukemiaHodgkin's disease and other lymphomas

Nitrogen ,Vustsrds:Ilechlorethamine (Marlalget,Cy-clophosphamide 1C1 rorar/

Chl or ambI'cil (L e u ke r a n)l\telphalan (Alkerat)

Several types ofcancer, including brain cancerSeveral types ofcancer, including brain cancer and Hodgkin's disease

Seveml types ofcancer, including brain cancer

Nitrosoureas:callnustine (BCN U, B iCN U)Lomtstine (CC NU, Cee NU)Sen\usline (Me I hy I - CC N U)

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. Immune modulators

. Monoclonal antibodies

. Colony stimulating factors

. Interferons

. Immunosuppressants

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These drugs stimulate the production ofneutrophils and erythroid progenitor cells inthe hematopoietic process.

. Darbepoetin alpha: induces erythropoiesis by stimulating the division and differ-entiation of erythroid progenitor cells. It is used to treat anemia associated with chronicrenal failure.

. Pegfilgrastim Qtleulasta): stimulates the production, maturation and activation ofneutrophils. It is used to decrease the incidence of infection by stimulation of granu-locyte production in patients with nonmyeloid malignancies.

. Sargramostin (Leukine)z is used for myeloid reconstitution after autologous bonemarrow transDlantation.

Listed below are the eight classes ofdrugs used in chemotherapy:

1. Alkylating agents - these agents alkylate DNA such that it cannot replicate. Popularagents include Cisplatin and Cyclophosphamide,2. Anthracyclines these agents destroy DNA such that the cell cannot replicate. Popularagents include Daunorubicin and Doxorubicin.3. .{ntibiotics - these antibiotics are not used for antibacterial therapy but were specificallydesigned for cancer chemotherapy. The agent in this class is Dactinomycin.-1. -{ntimetabolites - these agents interfere which selected biochemical reactions necessary

tbr cell growth. Popular agents are s-Fluorouracil (5-FU), 6-Mercaptopurine and

\Iethotrexate,5. -\ntimicrotubular - affects the microtubular assembly with cells to inhibit cell mitosis.The popular agent is Paelitaxel (Taxol).

6. -{ntiestrogen these agents block the tumors on which estrogen has a stimulatory effect.

The popular agent is Tamoxifen (Nolvadex).? \'inca Alkaloids - these are mitotic spindle poisons. Examples include Vinblastin€ and

\-incristine.8. Gonadotropin hormone-releasing antigen - these inhibit gonadotropin secretion, an

action \\,hich is effective in reducing certain carcinomas. The popular agent is Leuprolide.

\ote: The anticancer drugs Asparaginase and Interferons do not fall within any category

but are used in the treatment ofcertain cancers. Asparaginase deprives tumor cells ofcertainamino acids such that protein production is blocked. Interferons boost the immune system.

Agents used in treating breast canc€r:

. Antiestrogens: tamoxtfen Q''lolvadex), fulvesttant (Fasloder), andtorcmifene (Fqreston).

. Aromatase inhibitors: letrozole /Feuara) and exernestar\e (Aromasi )

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. Nausea and vomiting

. Hair loss (alopecia)

. Blood test abnormahties (low magnesium, low calcium, low potassium)

. Peptic ulcers

. Changes within the tissues ofthe oral cavity such as mucosititis

. Low white blood cells

. Low red blood cells (anemia)

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. Renal failure

. Alopecia

. Peripheral neuropathy

. Glaucoma

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Cisplatin is ar\ anti-cancer ("antineoplastic") chemotherapy drug. It is classified as an "alkylatingagent."

Remember: Alkylating agents these agents alkylate DNA such that it cannot replicate. Popular agents

include Cisplatin and Cyclophosphamide.

Notes about cisplatin side ellects (a d dost chemotherapy drugs):. Most people do not experience all ofthe side effects. The side effects are often predictable in terms oftheir onset and duration. The side effects are almost always reversible and will go away after treatment is complete.. The side effects and their severity depend on how much of the drug is given. In other words, high

doses may produce more severe side effects.

The most common side effects ofchemotherapy are:

. Anemia . Low WBCS

. Fatigue . Xc.ostomia

. Hair loss . Mucosititis

. lncreased chance ofbruising, bleeding, and infection

. \ausea and vomiting

Orher lesr common side effects include:. Appetite and weight changes. \ene and muscle problems. Dn and/or discolored skin

. Kidney and bladder iritation

. Sexual and fertility issues because ofeffects on reproductiveorgans

\ot€: Mucosititis is a common reaction to cancer chemotherapy. [t is an inflammation ofthc mucous

membranes. During chemotherapy and radiation therapy, mucosal tissues begin to desquamate and de-

leiop into ulcerations. Thc mucosal int€grity is broken and is secondarily infected by oral flora. Pallia-

rive treatment is indicated formucositis. The antineoplastics such as 5-fluorouracil (JFU), methotexateand doxorubicin are commonly associated with the development ofoml mucosihs.

Alopecia (hair Ioss) occurs with administration ofmost clremotherapeutic agents one to

tlr o weeks after treatment. Other common side effects include GI upset, increased inci-dence ofinfection (especially Candidias,9, and degeneration of lymphatic tissue.

Remember: Most chemotherapy drugs have been shown to be teratogenic in humans

and should be avoided by pregnant women.

\ot€: \Iethotrexate mav cause ulceration of the oral tissues.

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. G0 phase or resting phase ofthe cell cycle

. S phase ofthe cell cycle

. G; phase ofthe cell cycle

. G2 phase ofthe cell cycle

. Hydrochlorothiaz ide (HCIZ)

. Furosemide (Zasry'

. Spironolactone (l ldactone)

. Triamterene (Dyrenium)

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*** The S phase ofthe cell cycle = DNA synthesis

Antimetabolites are one ofthe oldest and most important classes ofantineoplastic agents.

They attack the cells in the S phase of the reproduction cycle by interfering with the

biosynthesis ofthe purine and pyrimidine bases.

Important: Alopecia (hair loss) occtrs with the administration ofmost chemotherapeu-

tic agents one to two weeks after treahrent. Other common side effects include GI upset,

increased incidence ofinfection fespecially Candidiasis), and degeneration of lymphatic

tissue.

Remember: Most chemotherapy drugs have been shown to be teratogenic in humans

and should be avoided by pregnant women.

Diuretics are used to tr€at congestive hcart failure by relieving edema and symptoms ofdyspnea arising liompulmonary congestion. They are also used to treat h].pertension, and in the management ofedema associated

$irh heparic or renal disease.

Cetegories of widely used diuretics:

. Thiazides: inhibit sodium reabsorption in th€ distal portion ofthe renal tubule within the kidney causing

increased excretion ofsodium andwater Prototpe agent is hydrochlorothi^zide (HCTZ) Otherexamples

include chlorothiazide (Diuril), indapamid. (Lozol), and metolazon (Zarcxolyn). Note: Thes€ drugs can

cause hypokalemia (ab nornally lot level ofpotarsium in lhe blood) ,hponatremia (abnormally loN' level

of sodium in the blood)and may increase plasma uric acid.. Loop diuretics: inhibit reabsorption ofsodium and chloride in the ascendiog Loop ofHcnle thus causing

increased secretion ofwater, sodium and chloride. Proto0pe agent is furosemide (rasir. other examples

include bumetanide (B umer), eth^crynic ^cid

(E.1ecfin), nnd torcefiide (Demadat) . Note| These drugs can

cause hr?eruricemia, tinnitus, hearing loss, hlponatremia and excessive fluid loss.. Potassium-sprring diuretics:

. Sodit|m channel blockers: these agents inhibit sodium reabsorption through sodium channels in renal

epithelial cells. This inhibition creates a negative potential in the luminal membranes ofprincipal cells,

located in the distal convolutedtubule and collecting duct. Negative potential reduces secretion ofpotas_

sium andhydrogen ions- Conserve potassium while caus ing diuresis. Thus, no potassium is lost fiom the

body as is the case with other diuretics such as the lhiazides and loops- Triamlerene (D)'refiiutfi) and

amiloride (Midamor) are examples of this drug group.. Aldost€rone antagonists: thes€ drugs competitively inhibit the aldostercne receptor This causes in-crcased amounts of sodium and water to be cxcreted, while potassium is retained Spironolactone f,4!dactone) and epleJerone (1aplal are examples.

** Fixed-dose combination therapy: Dyazide is the brand name for the combination oftriamterene and

hldrochlorothiazide filcfz). Tlis product combines the potassium-sparing diuretic with HCTZ for geater

eflicacy than eith€r on€ individually.

Notei Positive itrotropic dlngs (drugs that make muscle contract more forcefullv) canbe used in the acute

trerlment of heart failure, these include dobutamine, dopamine, inamrinone, and milrinone These drugs

may be given intravenously to stimulate heart conhactions and help keep blood circulating They are only used

temporarily because long-term use shortens life.

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Which of the following is a pharmacologie antagonist ofaldosterone in the collecting tubule?

. Mannitol (Osmifuol)

. Glycerrn (Glyrol)

. Spironolactone (Aldactone)

. Urea (Ureaphil)

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. Glyburide (DiaBeta)

. Vetformin (Glucophage)

. Glipizide (Glucotrol)

. Glinepiide (Anaryl)

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Potassium-sparing diuretics result in increased sodium and decreased polassium con-centrations at the end ofthe distal convoluted tubules. There are two cat€gories ofpotas-sium-sparing diuretics:

l. Antagonist of aldosterone in the collecting tubules:. Spironolactone (Aldactone)

Note: Spironolactone has been found to be effective in the treatment of primaryaldosteronism. It may be useiul in the treatment of heart failure because hyperal-dosteronism is comfironly seen in this condition.

2. Block the sodium channels in the collecting tubules:. Triamterene (Dyrenium). Amiloride (Midamor)

*** The most impodant toxic effect of potassium-sparing diuretics is hyperkalemia.

Osmotic diuretics are highly filtered by the glomerulus and exert a solute-induced di-uresis in the proximal tubule. They are used to reduce excess edema associated with neu-

rosurgery or traura to the CNS. Examples include: mannitol, glycerin, and urea.

Remember: Carbonic anhydrase inhibitors fi.e., lcetazolamide) arerelatively weak di-uretics because ofthe ability of more distal sites in the loop ofHenle to increase theirre-absorption of sodium. Note: Acetazolamide is used to prevent and reduce the symptoms

of altitude sickness.

*** Metformin is classified as a biquanide

Antidiabetic agents or oral hypoglycemic agents are drugs used as adjuncts to dietto treat non-insulindependent diabetes mellit\rs (tfpe 2 diabetes)that cannot be controlled by diet alone.

. SulfonJ-lureas, the first drug group introduced into the U.S. in 1955, close potassium channels inccll mcmbranes, stimulate the beta cells to produce more insulin., and incrcase the sensitivity oftar-geI organs to insulin.

. The original "first g€neration " sulfonylureas include tolbnt^mide (Orittdse), tol^z nride (Toli-

ndrel. and chlorprop^mide (Diabinese). These drugs work well in lowering the blood sugat butthel,ha\'e a major drawback. Bccausc they bind to proteins in the blood, thcy can be dislodged byother medications that bind to thcse same proteins. Once dislodged, their activity can increase tap-idlr'and lead to low blood sugars.

. Second gen€ration sulfonylureas includc glipizide (Glucotol), Elyburide (Micronase) andglimepiride (Amaryl).These drugs have an advantage for those who use other medications since

rhey do not bind to carrier proteins in the blood. Bccause ofthis, drug interactions that may cause

lorr blood sugars are less likely.

. Biquanides: metlotfiin (Glucophage.) primarily decreases hepatic glucose production. It also has

minor effects on insulin sensitivity in both the liver and peripheral tissues. It has no direct effect on

lhe pancreas and therefore does not enhance insulin secretion.

. Thiazofidinediones: rosiglitazone (Avandia) and pioglit^zone (Actos) increase senstivify in themusclc and liverby improving control ofglycemic utilization. This in tum reduces circulating insulin

levels. Notei Functioning beta-cells are required for these medications to work.

. Meglitinides: repaglinide (Prundin) and oateglinide /Slarllxl lower blood sugar by stimulatingthe rclease ofinsulin fiom the pancreas in short bursts. Note: Functioning beta-cells a.e required forthcsc medications to work.. o-Glucosidase inhibitors: acarbose fPl€coreJ and miglitol /Gf,set act through inhibition ofpan-creatic d-amylase and membrane-bound intestinal cr-glucosidc hydrolase enzymes. This enryme in-

hibition delays glucose absorption. These enzymes do not enhance insulin secretion

Page 157: Pharmacology

. Short-acting insulin with a duration of6-8 hours

. Long-acting insulin with a duralion of20-24 hours

. Intermediate-acting insulin with a duration of l0-16 hours

. Rapid-acling insulin with a duration of3-4 hours

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AII of lhe following are elfects of insulirt EXCEPT one.Which one is the EXCI'PZIO ry

. Decreased gluconeogenesis

. Increased triglyceride storage

. Decreased protein s)'nthesis

. Increased glycogen synthesis

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Page 158: Pharmacology

Insulin preparations mimic the activity ofendogenous insulin, which is required for theproper utilization ofglucose in normal metabolism. They are used in type 1 diabetes andin type 2 diabetes which cannot be controlled completely by the oral antidiabetic drugs or

by diet alone.

Rapid-acting Onset Peak Duration

Insulin aspart (Vovolog) 5- l5 min t-3 hours 3-5 hours

Insulin glulisine (lpi dra) 5-15 min 30-90 min 3-4 hours

lnsdin li spr o (Hum a I o g) 30-90 min 3-4 hours

Short-acting

lnsulin reg ar (Humulin R) 30-60 min 24 hours 6-8 hours

Intermediate-acting

NPH (Humulin N) 2-4 hours 6-10 hours 10- l6 hours

Long-acting

lnsulin detemir (L ev em i r ) t hour No peak 6-24 hours

lnsulln glar gine (L an tus ) 2 hours No peak 20-24 hours

lmportant: Hypoglycemia (low blootl sagay' is the most serious complication ofinsulinthempy. Symptoms include: sweating, weakness, confusion, slurred speech and blurred vi-sion. Administration ofa concentrated glucose source will relieve mild hypoglycemia.

*** This is false; insulin increases protein slrnthesis.

Insulin is a pancreatic hormone secreted by the pancreatic beta-cells of the islets olLangerhans and is essential for the metabolism of glucose and for the homeostasis ofblood glucose (it reduces blood glucose by increasing the {onversion to glycogen and

-/at. Insulin injection is by subcutaneous administration.

Remember: Insulin is required in treating type I diabetes mellitus because the beta cellsof the pancreas are devoid of insulin. In treating type 2 diabetes mellitus, oral hypo-glycemics can often be used because the beta cells are able to secrete insulin, although ina more sluggish manner

Page 159: Pharmacology

. Fast onset, short duration

. Slow onset, short duration

. Fast onset, long duration

. Slow onset, long duration

. Prothrombin

. Fibrin

. Heparin

. Plasmin

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Humulin 70/30 mixture is a popular form ofinsulin that many diabetic patients take. ltsadvantage is that after a single injection, the regular insulin component /30o2) provides a

fast onset ofblood sugar control beginning one-half hour after injection and the insulinNPH component (702o) starts acting within a couple ofhours to provide a long durationofblood sugar control.

Note: Using either agent alone would not provide both the fast onset of insulin actionalong with the long duration.

Mixtures Onset Peak Duration

Humulin 70130 30 min 2-4 hours l4-24 hours

Novolin 70130 30 min 2-12 hours Up to 24 hours

Novolog 70130 l0-20 min 1-4 hours Up to 24 hours

Humulin 50150 30 min 2-5 hours l8-24 hours

HumalogT5/25 15 min 30 min - 2hours l6-20 hours

Premixed insulins are a combination of specific proportions of intermediate-acting and

rapid-acting or short-acting insulin in one bottle or insulin pen (the numbers followingthe brqnd name indicate the percentage of each 4,pe o./ insulin).

Heparin is contained within mast cells and basophils. These cells occur tn connectivetissue and in extracellular spaces near blood vessels.

Remember: Heparin not only neutralizes tissue thromboplastin, but also blocks throm-

boplastin generation.

1. The administration ofheparin will result in an increase in bleeding time due\ot6 ro a potentiation of antithrombin III thereby inactivating thrombin. This pre-

- \'ents the conversion offibrinogen to fibrin.?. It is used for prophyla-ris and treatment of thromboembolic disorders.

Page 161: Pharmacology

. Etanercept (Enbrel)

. Infliximab (Remicade)

. Adalimumab (Humira)

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Tnazolam (Halcion), a pre'operative sedative in dentistry, is metabolizedin the liver by the P-450 isoform CYP 3A4 enzyme. Drugs which lnhibit

the actions of CYP 3A4 would affect triazolam in which wav?

. Cause an increase in serum levels oftriazolam

. Cause a decrease in serum levels oftriazolam

. Cause no change in serum levels of triazolam

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Page 162: Pharmacology

There are currently three tumor necrosis factor alpha (TNF) inhibitors FDA approved forthe treatment ofRA (listed in order oftheir approval Jbr k4):

. Etanercept (Enbrel) is used to reduce the signs and symptoms ofactive rheumatoidarthritis in patients who have had inadequate response to one or rnore disease-modifr-ing anti-rheumatic drtgs (DMARD).It is a recombinant DNA-derived protein whichbinds to tumor necrosis factor alpha (l'ly'F).

. Infliximab (Remicade) is used to treat Crohn's disease and rheumatoid arthritis.Infliximab is a chimeric monoclonal antibody that binds to tumor necrosis factor alpha(TNF) thereby reducing the inflammatory actions ofthis endogenous compound.

. Adalimumab (Humira) is a fully human anti-TNF monoclonal antibody with highspecificity for TNF. Adalimumab binds specifically to TNF and blocks its interactionwith the p55 and p75 cell surface TNF receptors, thereby interfering with endogenousTNF activity. Adalimumab binds to both soluble as well as cell bor.urd TNF. It is ad-

ministered by subcutaneous injection every two weeks but can be increased to weekly,ifneeded. Adalimumab is effective in RA, Psoriatic arthritis, and ankylosing spondyli-tis, and Crohn's disease.

\ote: Tumor necrosis iaclor alpha (TNF) is a pro-inflammatory cytokine produced bymacrophages and lymphocfes. It is lound in large quantities in the rheumatoid joint and

is produced locally in the joint by synovial macrophages and lymphocyes infiltrating thejoint synovium. TNF is one ofthe critical cytokines that mediate joint damage and de-

struction due to its activities on many cells in the joint as well as effects on other organs

and bodv svstems.

Triazolam is known to interact with drugs that inhibit its metabolism via the CYP 3A4enzyme. Drugs that inlibit the metabolic pathway may have a profound effect on the

clearance oftriazolam. The resultant effects would be an increase in serum concentrations

\\ith an associated unexpected increase in the actions of triazolam. Consequently,

triazolam should be avoided in patients receiving very potent inhibitors ofCYP 3,A.4.

-\ntifungaf agents (itroconazole, ketoconazole, Jluconazole, miconazole, voriconazole)can significantly elevate the serum levels of triazolam resulting in toxicity with thera-

peutic doses. These antifungal agents inhibit the CYP 3A4 isoform responsible for he-

paric metabolism oftriazolam. Thus the normal metabolism oftriazolam is inhibited.

Do not administer triazolam to patients taking any ofthese antifungal agents.

Page 163: Pharmacology

. Twice a day

. Every 4 hours

. Three times a day

. Four times a day

162Copltight @ 201 l'2012 - Dental Decks

. Pilocarpine (lsopto-Carpine)

. Latanoprost (Xa latan)

. Betaxolol (Betoptic)

. Bimatoprost (L umi ga n)

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Page 164: Pharmacology

Other popular and common abbreviations used when writing prescriptions:

. b.i.d. : twice a day

. t.i.d. : three times a day

. q.l2.h.: every 12 hours

. q.4.h. = every 4 hours

. stat. = immediately

. h.s. : at bedtime

. p.rn. : as needed

. a.c. : before meals

. h. = qfrar ma.la

' Sig. = Label

Note: Always document prescriptions that are given to a patient in the patient's chart,

along with the date they were written and any specilic instructions for patient use.

Remember: . I grain = 65 mg.l ounce = 30 g or 30 mI

Glaucorna is characterized by an increase in intraocular pressure. It is caused by poor

drainage of the aqueoushumor (luid in the eye) and can cause blindness.

. Pilocarpine (1sop to-Carpine)r eye drops in the eyes causes papillary constriction thus

allowing for drainage ofthe aqueous humor to reduce pressure. Latanoprost (Xalatan)z a prostaglandin analog; eye drops in the eye reduces in-traocular pressure by increasing the outflow ofthe aqueous humor. Bet^xolol (Betoptic): abeta-blocker; eye drops in the eye reduces intraocular pressure

by reducing the production of aqueous humor. Bimatoprost fZ, miganl same action as latanoprosl (Xalatan)

Page 165: Pharmacology

' .,The following drugs are noted for causing what prominent oral slde effect?

-

. Amrnipqline (Elavil)

. Diphenlydramin e (Benadryl)

. Atropme

. DiazepNn (Valiun)

'| 64Coprigh O 201| -2012 - Denbl Decks

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both stalements are true

. Both statements are false

16sCop''right O 201 I -2012 - Dental Decks

Page 166: Pharmacology

Xerostomia can be caused by certain drug classes that inhibit the production and secre-tion of saliva.

. Amitriptyline (Elavil) is representative of the tricyclic antidepressants, a class ofdrugs lhat causes significant xerostomia. They probably work through an anticholin-ergic action.

. Diphenhydramine (Bena&yl) is representative olthe sedating-type antihistamines,a class ofdrugs that causes significant xerostomia. They probably work through an an-ticholinergic action.

. Atropine is a powerful anticholinergic which blocks the production of saliva in thesalivary glands. Other anticholinergics will have a similar action.

. Diazepam (Vctlium) is representative of the benzodiazepine tranquilizers. These

drugs have moderate anticholinergic actions to reduce the outflow of saliva.

\ote: The xerostornia actions produced by these classes ofdrugs are reversible with nor-mal salivary flow regained after discontinuance ofthe drug.

*** Levodopa is used in the treatment of Parkinson's disease to replenish th€ brain's supply

ofdopamine, the neurotransmitter thal is deficient in this disorder

Parkinson's disease i/PD) results from a relative excess ofcholinergic activity and a deficiency ofdopamin-ergic actilitr in the basal ganglia. It is a chronic, debilitating disease with no kno$'i cure. Drug treatment forPD has cenrered on increasing the availability ofdopaminc in the CNS, inhibiting the effscts ofacetylcholine,and a$cmpring to prevent further cell m€mbmne damage through neuroprotective trials. Note: The D2-recep_

:..r subllTre is lhe p mary modulatorofboth clinical improv€ment and adverse rcactions such asdystonia and

hrllucinations.

Lerodopa has been thc single most important drug in the treatment ofPD. Administering carbidopa in com-bination \r'ilh levodopa fsir?emet, reduces lhe required dose of levodopa by about 75%. when levodopa is

grr er alone. much ofrhe dose is metabolized befor€ the drug reaches the brain. Therefor€, large doses are re-qurf3d. and these are apt to caus€ unwanted side-effects. Carbidopa inhibits the pcripheral decarboxylation oflerr.dopa. This action simultaneously reduces the likelihood ofperipheml side effecls and allows more lev-riopa ro reach the brain. Since carbidopa does not cross the blood-brain barrier, the levodopa in the brain is

conlened rhere to dopamine. Thus, co-administration ofcarbidopa plus levodoPa in the form ofSinemet al_

lo\\s a significant reduction oflevodopa dosage without rcducing the desired effccts.

Other rntiparkinson agents:. llfonoamine oridas€ B (MA)-B) inhibitorsr seleglline (El.lepy, and rasallllne (Azilect).T1rese drugs ir-reversibly inhibir the enzyme MAO-B, which is responsible for the oxidative deamination ofdopamine in

the brain. This causes dopamine to accumulate in surviving nerve cells and reduces the symptoms ofPD. Gfutamate antagonist (anliirury amartadine ($'mmetrel) appearc to potentiate dopamineryic responses.

. Dopamine agonists: bromocriptine, pcrgolide, apomoryhtne (Apokrn), pramipexole (Mirupex), and ropini-tule (Requi . These d gs are direct dopamine receptor agonists.. Anticholinergic agents (antimuscarinic drugs): benztropine (Cogentin) and ftlhexyphentdyl (Tasmar).

These drugs supprcss central cholinergic activity and may inhibit reuptakc and storage ofdopamine in the

CNS. rhus prolonging the actron of dopamine.. Catechol-O-methyl t r^osfer^se (COMT) ilhibitorsi tolcapone i1zQsma, and entacapone fcotntan) T1\ese

drugs are inhibitors ofCOMT, another enzlme that metabolizes dopamine.. Certain antidepressrnts and antihistamines such as diphenhydramine that have antimuscarinic actions

may be given in the early stages ofdisease.

Page 167: Pharmacology

Which artiarrhlthmic agent is €ffectlve only on the ventricle and is oftenadministered IV to trert life.threatening ventricular arrhythmias?

. Quinidine (Quinidex)

. Lidocaine (Xylocaine)

. Flecainide (Tambocor)

. Propafenone (Ryt hno I)

. None of the above

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Page 168: Pharmacology

When lidocaine is used IV to treat ventricular arrhythmias, it acts on the fibrillating ven-

tricles to decrease the cardiac excitability and spares the atria. It can effectively reverse

a life-theatening situation.

Quinidine is considered as the prototype antianh)'thmic agent and is used primarily totreat atrial fibrillation. It is not effective in treating life-threatening ventricular fibrilla-hon.

Flecainide (Tambocor) is potent antiarrhythmic agent, effective in a wide range ofven-tricular and atrial arrhythmias and tachycardias.

Propafenone (Rythnol) is used to treat both ventricular arrhlthmias and supraventricu-lar tachycardias.

Dr John Doe, DDSI I Any Street

Any Ciry, Any stare 00000(000) 5s5- l2l2

Patient's Name: Age:Date:Patient's Ad&ess:

Amoxicillin 500 mg. tabletsDisp. Four (4) tabs

Sig: Take 4 tabs f2000 mg) 30-60 minutes prior to dental appointment

Signature:

Substitution permissibleSubstitution not permissibleNumber of refills

Notes:. Superscription - Patient's name, address, age, date. Inscription ' Name of drug and the strength ofthe drug fi.e., 500 mg tablets). Subscription - Directions to the pharrnacist (dosage form and amount to be given -

Disp ). Transcription or signa - Directions to the patient (SigJ. Signature - Signature of person prescribing medication must appear

License #Federal Drug Registry #

Page 169: Pharmacology

All of the following drugs are useful for treatingwhrt common medical condition?

. Prednisone

. Gold injections

. Methotrexate

. Nabrmetone (RelaJbn)

. Piroxicam (Feldene)

. Ranitrdine (Zantac)

. Omeprazole (Prilosec)

. Cimetidine (Tagamet)

. Famottdine (Pepcid)

. Lansoprazole ( Prevaci d)

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Which IIIO gastroint€stinal drugs listed below reduce theformation of stomach acid by inhibiting the proton pump

of the stomach parietal cells?

Page 170: Pharmacology

Rheumatoid arthritis (RA) is a chronic inflammatory disease ofjoints that results injoint pain, swelling, and destruction. RA is characterized by chronic inflammation ofthesynovium, which lines the joint. With disease progression, there is the accumulation ofprostaglandins, leukotrienes and other mediators in the inflammatory changes and tissue

destruction in the synovial lining.

How these drugs work in treating rheumatoid artkitis:. Prednisone: decreases the inflammatory response. Gold injections: may decrease prostaglandin production. Methotrexate: unknown, but may affect immune function. Nabumetone fRela/en): an NSAID that inhibits prostaglandin synthesis. Piroxicam (Feldene): ar NSAID that inlibits prostaglandin synthests

\ote: All of the above drugs except gold injections are also useful in the treatment ofosteoarthritis (OA). OAis characterized by progressive loss of articular cartilage. This

may be the result of excessive loads on the joint or other factors. Agents useful in treating OA provide an analgesic and anti-inflarnrnatory action to reduce pain within thejoint.

Hydrochloric acid (l{Cl) is produced by the parietal cells ofthe stomach through a pumpu ithin each cell which pumps protons (H.) into the stomach contents. The pump is calledtbe H-/K' ATPase pump. HCI is used for food digestion but an abundancy can cause

heart bum and acid indigestion. Omeprazole and lansoprazole inhibit the pump such

that no protons are pumped into the stomach contents and thus no HCI is produced. These

nvo drugs are classified as proton-pump inhibitors.

Stomach acid can also be reduced by inhibiting the effects of histamine in the stomach at

the histamine type-2 receptors (H2 receptors). Ordinarily, histamine stimulates the gastric

parietal cells to produce hydrochloric acid. Ranitidine, cimetidine and famotidine blockthe effects of histamine by blocking at the H2-receptors. These tkee drugs are classifiedas H2-receptor blockers.

Both the proton-pump inhibitors and H2-blockers are used to feat heartbum, indigestion,sour stomach, active duodenal ulcer disease and gastroesophageal reflrx disease (GERD).

Remember: Antacids neutralize excess stomach acid by a chemical reaction. Antacidsinclude aluminum hydroxide (Amphogel), bismuth subsalicylate (Pepto-Bismol), calciumcarbonate (Tums) magnesium hydroxide (Maalox) and sodium bicarbonate.

Page 171: Pharmacology

. Heparin

. Vitamin K

. Aspirin

. Cloprdogrel (Plavix)

. Warfarrn (Coumadin)

170Copyight O 20ll-2012 - Denlal Decks

. \4ucositis

. Osteonecrosis ofthe jaw bone

. Angular cheilitis

. Oral yeast infection

. Xerostomia

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What serious dental elfect is associrted with the following drugs:znlendronic

^cid (Zo meta), pamidronate (Aredia), risedrontte (A ctonel),,

ibandronate @azira) and alendronxte (Fosamax)?

Page 172: Pharmacology

Heparin inactivates thombin and prevents the conversion of fibrinogen to f:Jc.rin (bloodclot);w^rfarin (Coumadin) rnterferes with the hepatic synthesis of vitamin-K dependentcoagulation factors lI, VII, IX and X resulting in the inability ofthe coagulation pathwayto form ftbrin (blood clot).

Vitamin K is a group of fat soluble vitamins that are essential for the synthesis of co-agdation factors II, VII, IX and X, and prothrombin in the liver. Vitamin K will enhanceblood clotting rather than inhibit blood clotting.

Aspirin inhibits blood clotting by inhibiting platelet aggregation in an irreversiblemanner. Inhibition ofplatelet aggregation prevents activation ofthe coagulation pathway;thus no fibrin (c/ot) is formed. Aspirin does not affect the coagulation pathway. Discon-tinuation ofaspirin for 5 to 7 days allows for normal clotting time to reappear due to thesvnthesis of new platelets.

Clopidogrel /P/avx) inhibits blood clotting by inhibiting platelet aggregation in an ir-reversible manner. Thus the effects on blood clotting are the same as aspirin. ClopidogrelrPlatix) does not cause gastric ulcers like aspirin does and is the antiplatelet agent ofchoice in patients with history ofulcers.

\ote: Cfopidogrel, aspirin, abciximab (ReoPro), and anticogulants (i.e., heparin) are

used to lessen the chance of heart attack in people who need percutaneous coronary in-ten ention fPCl), a procedure to open blocked arteries ofthe heart.

Zoledronic acid (Zometa), pamidronate (Aredia), fisedrci^te (Acto el), ib^odtonate (Bohiw), and

alendror.ate (Fosamax) are members ofthe bisphosphonate class ofdrugs used to heat and manage

Pag€t's diseas€, osteoporosis and to prevent hypercalcemia ofmalignancy. Bisphoshonate therapy has

been associated with osteonecrosis, primarily ofthe jaw; this has been observed mostly in cancer pa-

tients, but also in patients with postmenopausal osteoporosis and other diagnoscs. Risk factoN include

a diagnosis ofcancer, with concomitant chemotherapy, radiotherupy or corticosteroids; anemia, coagu-

lopalh!. infection or pre-existing dental disease. Symptoms included nonhealing cxtraction socket or an

e\posed jawbone. There is no data addressing whethe. discontinuation oftherapy reduces the risk ofde-\ eloping osteonecrosis. However, as a precautionary measure, dental exams and preventativ€ dentistry

should be perlormed prior to placing patients with risk factors on chronic bisphosphonate therapy.

Important: Bisphosphonates have an affinity for hydroxyapatite crystals in bone and act as antitesorp-

tir e agents. Their primary mechanism ofaction involves inhibition ofosteoclastic bone resorption. Ad-r erse effects /6esider osteohecftrsis of the jaw bor€) include GI symptoms and esophagcal erosions.

Orher agents that have an effect on bone:. SERlls fse/ectil,e eJtrcgen ,eceptor modulatorsl. R^lo\ifeie (Evisla) reduces rcsorption ofboneand decreascs overall bone fumover. It is used for heating osteoporosis.. Hormones:

. Calcitonin: is a naturally occurring hormone that is produced by parafollicular C-cells in the thy-roid gland. It is known to block bone resorption through its potent inhibitory elTects on osteoclasts. Parathyroid hormone: PTH is the primary regulator of calcium and phosphate metabolism in

bone and kidney. Physiologic actions include regulation ofbone metabolism, renal tubular reab-

sorprion ofcalcium and phosphate, and intestinal calcium absorption. Once-daily adminishation ofP'lH (tefiparatide IForleol) stimulates new bone formation via preferential stimulation of os-

teoblastic activify over osteoclastic activity. Note: PTH also acts on th€ kidneys by reducing renal

clearance ofcalcium which increases plasma calcium. It also stimulates the production ofthe ac-

tive form of vitamin D in the kidney.. Vitamin D: helps to ensure that the body absorbs and retains calcium and phosphorus. which are crit-ical for building bone. Note: 1,25-dihydroxycholecalciferol is the biologically active form ofvitaminD (Cholecalciferol)

Page 173: Pharmacology

. Plasmin

. Lysozyme

. Renin

. Heparin

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. Nicotine abuse

. Ethanol abuse

. Opioid abuse

. NSAID abuse

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Page 174: Pharmacology

Renin is proteolytic enz)'rne produced by and stored in the juxtaglomerular apparatusthat surrounds each arteriole as it enters a glomerulus. Renin acts on the precursor sub-stance angiotensinogen, which is manufachrred by the liver and is present in the blood.Renin converts angiotensinogen to angiotensin I. In turn, angiotensin I is converted toangiotensin II by a converting enzyme associated with the walls ofcapillaries, particularlyin the lungs.

Important: "The converting enzyme that converts angiotensin I to angiotensin II is

known as angiotensin converting enzyme or ACE."

Angiotensin II is a potent vasopr€ssor. It not only increases total peripheral resistancebut, by stimulating aldosterone release, leads to an increase in plasma volume, venousretum, stroke voh.rme, and ultimately an increase in cardiac output.

\ote: Aliskiren (Tehuma) is a renin inhibitor used to treat hypertension. This is the

first ofa new class of drugs and little information is available. It is used alone or in com-bination with other agents for the treatment ofhypertension.

Disulfiram is not a cure for alcoholism but is a deterrent to ethanol consumption. Disul-firam is an antioxidant that interferes with the hepatic oxidation ofthe acetaldehyde me-tabolized from alcohol. Specifically it inhibits aldehyde dehydrogenase, a mitochondrial

enz]'me found in the liver Even the ingestion of small amounts ofethanol results in high

concentrations ofacetaldehyde in the body. The unpleasant reaction that occurs (called the

Disulliranr-Ethanol Reaction or DER) consists ofa throbbing headache, dyspnea, throb-

bing in the neck, nausea, copious vomiting, thirst, tachycardia and hypotension.

\ote: lletronidazole, also inhibits aldehyde dehydrogenase.

Ethanol is a sedative-hypnotic drug and is the most important alcohol ofpharmacologicinterest. Its abuse is responsible for many socioeconomic problems. Drugs that are syn-

ergistic with ethanol include diazepan, meperidine, pentobarbital and chlorpromazine.When combined with alcohol these drugs could cause fatal oversedation.

Remember: Synergism refers to the combined action oftwo or more drugs that is greaterthan that achieved with a single drug.

Page 175: Pharmacology

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

174Coplrighr O 201 I -20 l2 - Denral Decks

. Anaphylaxis

. Heart attack

. Syncope

. Urticaria

175Copraight O 20l l-2012 - Dental Decks

Page 176: Pharmacology

Gastric antacids are drugs that directly neutralize the gastric acrd (HCL) secreted in thestomach. Antacid therapy is directed at decreasing the concentration and total load ofgas-tric acid.

Some common over-the-counter antacid products:. Sodium bicarbonate products.

- Alka-Seltzer. Calcium carbonate products:

- Amitone- Tums

. Aluminum hydroxide products:- Altema GEL- Amphojel

. Magnesium hydroxide products:- Milk of magnesia

. Bismuth salt products:- Pepto-Bismol

. \Iagnesium and aluminum products:- Maalox- \4ylanta

*** Aluminum hydroxide is the most potent of these but has less neutralizing capacity

than calcium carbonate or sodium bicarbonate.

Note: Dyspepsia means an impairment ofthe power or function ofdigestion.

Inlaled ammonia irritates trigeminal nerve sensory endings, with a resulting reflex stim-

ulation of medullary respiratory and vasomotor centers. An aromatic amrnonia vaporoleis crushed betrveen the fingers and held near the patient's nose. Note: The administrationoforlgen rrrll aid in combating tissue anoxia.

The sl mptoms of syncope include beads ofsweat on the upper lip, a weak thready pulse,

cold clammy skin, pallor and a dizzy feeling. The loss of normal vasomotor tonus pro-

duces pooling of blood peripherally so that the normal blood volume becomes insuffi-cient. Placing the patient in a supine position and elevating th€ feet gives the patient a

transf'usion ofwhole blood by utilizing the forces of gravity. Note: The head should not

be more than about 10 degrees lower than the rest ofthe body.

Tl pes of syncope:

. Vasor agal ). \eurogenic I Trear uirh high-flowing 1007o oxygen

. C)nhostatic -f

. Hyperventilation syndrome Oxygen is not indicated

Note: 100% oxygen is contraindicated for a person who suffers from chronic obstruc-

tive pulmonary disease (COPD).

Page 177: Pharmacology

. Growth Hormone

. Insulin

. Antidiuretic Hormone (ADH)

. Epinephrine

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. Dopamine

. Aldosterone

. Vasopressin

. Somalotropin

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Page 178: Pharmacology

ADH is a hormone that decreases the production of urine by increasing the reabsorp-tion of water by the renal tubules. Without ADH, there would be extreme loss of water intothe urine. Ethanol (ethyl alcoftoi) inhibits the production ofADH.

Remember: Ethyl alcohol dilates blood vessels of the skin, depresses the CNS, and inblood levels in excess of400 mg o/o usually results in coma and death. Alcohol acts pri-marily on the nerve cells within the brain. Alcohol interferes with communication be-tween nerve cells and all other cells, suppressing the activities of excitatory nervepathways and increasing the activities of inhibitory nerve pathways.

Note: Recent evidence has shown that ftequent ingestion of moderate amounts ofalco-hol in any form (beer, wine, distilled spiits) will reduce the risk of heart disease, par-ticularly in men.

The order in which alcohol affects the various brain centers is as follows:

. Cerebral cortex

. Limbic system

. Cerebellum

. Hypothalamus and pituitary gland

. Medulla lbrain stem)

Grorlth hormone (GI{) is produced by, and secreted from the anterior pituitary gland.

Basic Metabolic eff€cts of growth hormone:. Increased rate ofprotein synthesis in all cells ofthe body. Decreased rate ofcarbohydrate utilization thoughout the body. Increased mobilization offats and use of fat for energy

Human growth hormone is prepared commercially and used as replacement therapy inpatients with growth hormone deficiency. The commercial preparation is prepared as the

purified polypeptide hormone of recombinant DNA origin with the same amino acidsequence as that produced by the pituitary gland.

Human growth hormone is indicated in children for the treatment of growth failure due

to lack ofadequate endogenous growth hormone secretion. It has been used in adults whohave a growth hormone deficiency as a result ofpituitary disease.

Note: Human growth hormone is adminislered as subcutaneous injection or intramuscu-Iar injection, usually tbree times per week.

Page 179: Pharmacology

. Colchicine

. Indomethacin

. Sulfinpyrazone

. Probenecid

. Allopurinol

178Coplriglt O 20ll-2012 - Dental Decks

. Epinephrine

. Norepinephrine

. Chlolpromazine

. Isoproterenol

. Dopamine

. Dobutamine

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Page 180: Pharmacology

The therapeutic management of gout involves three different aspects ofthe disease:

l. Reducing the inflammation during acute attacks: The drug ofchoice is colchicine.Colchicine impairs leukocytic migration to inflamed areas and disrupts urate deposi-tion and the subsequent inflammatory response. It is most effective when initiated 12

to 36 hours after symptoms begin.

Notes:l. Colchicine should never be given IM or subcutaneously (it causes tissue irrita-tion).2. Colchicine can severely damag€ the liver and kidney; long-term therapy maycause bone marrow depression.

Remember: NSAIDs are also important for the treatmenl ofacute gouty arthritis.Indomethacin (rzay cause renal damage or bone maruow depressiar) is most com-monly used.

2. Decreasing uric acid production: Allopurinol (Zyloprin) is the drug ofchoice inthe management ofchronic gout. It inhibits xanthine oxidase, an enzyme that convertshypoxanthine to xanthine, and xanthine to uric acid. May cause GI disturbances.

3. Enhancing uric acid clearance: Uricosuric agents include probenecid (Benemid)and sulfinpyrazone (Anturane). These agents act primarily in the kidney (.yecifcally,the proxintal convoluted tubules) and inhibit the secretion of other weak acids(i.e.. penicillin), in addition to inhibiting the reabsorption of uric acid.

Remember: Normally penicillins and cephalosporins have to be given in high and fre-quent doses due to their high rate of elimination by the kidneys. Their excretion isslowed by giving probenecid.

*** Chlorpromazine is a dopamine antagonist and antipsychotic agent.

Catecholamin€s are any one ofa group of sympathomimetic compounds composed ofa catechol molecule and the aliphatic portion ofan amine. Some catecholamines are pro-duced naturally by thebody (called endogenous) andftnction as key neurological chem-icals (i.e., epinephrine, norepinephrine and dopamine). Note: Epinephrine,\orepinephrine and Isoproterenol are considered to be direct-acting catecholamines.

Drug Clinical ApplicatioDs Comm€nb

Epitr€pkine Anapbylaxis. glaucoma, aslhma, to caus€ Stimulat s th€ myocardiun

\orepinephrine To cause vasoconstriclion in h)?otension Stirmlatcs thc myocardium

Dopamine Shock, head failure lmfirdiaia precursor of NE

Dobulamin€ Shock, hean failure

Dng(Not Catcchol4nine)

Amphctsmin€, phEnmeirEine Narcolepsy, ob€siry, attenrion deficit disorder

Ephedrine Urinary inconlinence, to cause vasoconstriction,decongestion

Pheryl€phrine Tocau\e m)dria,is. rasocon.tricrion. decongesrion

Albuterol. nelaDrolercnol te6utaline Asthma, pr€mature labor

Or},lnet ?oline. xylom€lazoline To cause nasal decongestion (long acting

Page 181: Pharmacology

. Methocarbamol (Ro b axin)

. Cyclobenzaprine (F lexer i l)

. Baclofer (Lioresal)

. Slccinylcholine (Anectin e)

. Carisoprodol (,Sozc)

. Levodopa (Dopar)

. Bromocriptine (Parlodel)

. Pergolide (Permax)

. Halopeidol (Haldol)

. Selegiline (Eldepryl)

. Amantadine (Synmetrel)

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*** Succinylcholine is the prototype depolarizing neuromuscular blocking drug.

Spasmolytic drugs (skeletal muscle relax4,l/t are agents that relieve muscle spasms withoutparalysis. They act in the CNS or in the skeletal muscle cell mther than at the neuromuscu-lar end plate. These drugs are used in certain chronic diseases ofthe CNS (i.e., multiple scle-rosis, cerebtal palsy, cerebrovascular accidents) that are associated with painful musclespasms. By reducing the spasms there is a reduction in pain and improved mobility for the pa-

tient.

Drugs used for chronic muscle spasm:

. Baclofen (Lioresal): is a derivative ofGABA; its site ofaction in reducing muscle spasmsis the spinal cord. It stimulates CABABreceptors that are linled to the G protein. Gt, re-sulting in an increase in K conductance and a decrease in Ca,' conductance. Used is thetreatment of mriltiple sclerosis and other spinal cord diseases. All ofthe other skeletal mus-cle relaxants do not bind to the GABABrecepto$: Diazepam (Valium) and tizanidine(Za aflex) also act rn the spinal cord and are effective muscle relaxants.. Carisoprodol fsoranJ: is used in the treatment ofmuscle spasms and pain associated withacute temporomandibularjoint pain. lts precise mechanism ofaction is not clear but manyeffects have been ascribed to its central deDressive action.

Drugs Lrsed for acute muscle spasm:

. C!clobenzaprine (Flexeril): relieves muscle spasm through a central action, possibly atthe brain stem level. lt is used to relieve acute, painful musculoskeletal conditions. It is notefllctir e for muscle spasm secondary to cerebral or spinal cord disease.. \lethocarbamol (RobcLrin): is a centrally acting muscle relaxant that is used to relieveacute. painful musculoskeletal conditions and in the management oftetanus.

\ote: Quinine is widely used for the effective relief of noctumal leg cramps.

Parkinson's disease is a slowly progressing, dcgenerative disorder of the nervous system. It hasie\craf distinguishing chamcteristics: tremor (shaking) when at rest, sluggish initiation ofmove_mcnls and musclc rigidity. ln Parkinson,s disease, nerve cclls in the basal ganglia degcneratc! re_sultine in lo* er production ofdopamine, ll may be tr€ated fbr ot cured)with a wide varietv ofJ* g.

. Le\ odopa /in couhi ation tith carbidopcJ is the precursor of dopanine. lt is the main treat_ment 1br Parkinson's discase. It is given with carbidopa to incrcase effectrvcness and rcduceride ellects.. Bromocriptine or pergolide are dopamine agonists which are often given in addition to lev_odopa earlv in the treatmcnt to enhance levodopa's action, or may be given laterwhen levodopa,siid. eft'ects become more ofa problcm.

' selegiline is a selectivc inhibitor ofMAo rype B. the enzyme that is rcsponsible for the ox-rdatir c deamination ofdopamine in the brain. It is used as an adjunct to levodopa.'-\mantadine appears to potentiate dopaminergic responscs. Antiparkinsonian actions are un-related to thc antiviral cffects. lt is used in thc early stages for mild diseasc.. Antichofinergic drtgs (benztropine and ttiheryphenidyl, certaitl .uttidepressa ts an.l anti_hi<tunrines such as diphenhydranine) may be given without levodopa in thc early stages ofdis_ease. $ilh lcvodopa in later stages.

1. Dental implications ofAnti-parkinson's agents;\otrs . Anti-Parkinson's agents (mai y levodopa, the direct dopamine dgonists and the

COMT inhibitors) have been associated wilh orthostatic hypotensior.. Xerostomia lcarsed by a ticholinetgics antl MAO_B inhibitorst.. Schedule appointmcnt times based on when the patient is feeling the bcst.. Dyskinesia (abnonnul muscle movenents) caused by some ofthe drugs (nainly let,_odopa, the direct dopamine agonist.s, and the COMT ir*ibito,"t can prescnt a chal_lenge whcn trying to perform dental treatmcnt.

*** Haloperidol is used to treat psychotic syndromes.

Page 183: Pharmacology

. Caffeine

. Doxapram (Dopram)

. Phenobarbital

. Methylphenidate

. Phendimetrazine

. Strychine

142Copyright O 20ll-2012 , D€nial Decks

. Feelings of anxiely and nervousness

. Sleep disruption

. Coughing

. Irritability

. Diuresis

. Stomach complaints

. Palpitations and arrhlthmias

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Page 184: Pharmacology

*** Phenobarbital is a barbiturate (sedative-hypnotic).

CNS stimulants are a heterogenous group ofcompounds that produce various degrees ofstimulation. Analeptic is a term that refers to a CNS stimulant which has the ability toovercome drug-induced respiratory depression and hypnosis. In the past the CNS stimu-lants were widely used therapeutically, but today they have only limited clinical applica-tion. Note: Their use for respiratory depression caused by an overdose ofCNS depressants

is generally not safe or recommended.

Analeptics and respiratory stimulants: doxapram and strychnine. These agents havelimited use, but are occasionally indicated to stimulate respiration when a patient has pul-monary disease or to hasten recovery from a general anesthetic.

Xanthines include caffeine, theophylline and theobromine. These stimulants improvemental alertness. reduce the urge to sleep and elevate the mood. Caffeine is the onlyapproved OTC stimulant. Theophylline and theobromine are weaker CNS stimulantsthan calleine. Theophylline is the only xanthine important in the treatment ofasthma. Itstirnulates the respiratory centers ofthe medulla and is able to cause bronchial dilation inpatients $'ith asthma. Note: It has a low therapeutic index and its metabolism is affected

b1 ser eral other drugs.

Sl mpathomimetic amines include the amphetamines and other related agents fi.e.,nerh.rlphenidate, phendimetrazine, etc). They are potent CNS stimulants. They are used

ro treat narcolepsy, obesity and attention deficit disorder.

Caffeinism is a term used for people who are dependent upon catTeine (i.e., sulfer side efectsli'ctn hating too much calfeine, tdke l.tryer"amounts and neetl to keep drinking calfeine to

function properll).lt is thought to occur ifyou have an intake ofabove 600 to 750 mg ofcaf-terne per day /rrore than 10 cups of coffeel. Drinking more than 1000 mg per day is well into:he to\rc range.

Important: Caft'eine stimulates the CNS unequally, with the cortex being the most and the

:oinal cord beine the least excited.

Page 185: Pharmacology

All of the following drugs on the right are used to treat what condition?

. Dexmethylphenidxte (Fo calin)

. Extended-release methylphenid|te (Concefta)

. Mixed amphetamine salts (Adderal)

. Atemoxetine (S tr att eru)

. Controlled-delivery methylphenidrte (Metadate CR)

. Lisdexamfetamine (Vyanse)

. Insomnia in adults

. Tourette's sy,ndrome in children

. Attention deficit hyperactivity disorder (ADHD)

. lnsomnia in children

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PIIARMACOLOGY

Which of the following drugs is a mernber of theopioid family and reduces GI motility ?

. Loperamide (Imodiun)

. Lorazepam (Ativan)

. Diphenoxylate and atropine (Lonotil)

. Propranolol (hderal)

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Page 186: Pharmacology

Drugs used to treat ADHD:

. Methylphenidate (Ritalin)z arnrld central nervous system stimulant. In children withADHD, this drug results in an increase in attention span, reduction in hyperativity, andan improvement in behavior.. Dexmethylphenidate (Foc in): a form of methylphenidate called dexmethylphen-idate.. Adderal (dextroamphetamine): the brand name for mixed amphetamine salts which

act the same as methylphenidate in treating ADHD.. Atemoxetine (Struttera)t the brand name for atemoxetine, the first non-stimulantapproved for treating ADHD. It is approved for use in children and adults.. Metadate CR: the brand name for a controlled-delivery methylphenidate, anotherlong acting form ofthe drug.. Lisdexamfetamine (Vyvanse): Lisdexamfetamine is a prodrug; after adminishationit is converted to dextroamphetamine (Adderall) in the rntestines and/or liver. The dex-troamphetamine, an amphetamine and stimulant for the brain, is responsible for the ef-fect of lisdexarnfetamine in ADHD.. Extended-release methylphenidate (Concerlq): a long-acting form of methylphen-idate.

Antidiarrheals:

' Opiate and opioid derivatives

- Loper ^mide

( I m mod iu m) |

L Is an anti-diarrheal which acts on intestinal musclcs to inhibit p€ristrlsis.2. Is a member ofthe opioid family. It does not penetrate the cenffal nervous system like the opi-oids such as codeiner thus it can b€ sold ov€r the counter.

J. IIas no €vidence of drug abus€ or dependence (utllike other opioicls such os codeine, morphine

dnri neperidine).- Diphenoxt-late is an anti-dianh€al and inhibits excessive GI tract motiliry and Gl propulsion. Com-mercial prcparations contain a sub-therapeutic amount ofatropine to discourage abus€. Diphenoxylat€

and. atropine (Lomatil), unlike loperamide flrrodiu,rr, rcquires a prescription.

. Antisecretory:bismuth st$sahcylate ( P epto-B is mo I )

. Adsorbents: attapulgile (Kaopectate)

R€member: Laxatives act in the revene manner ofthe anti-diarrheals and increase the motility of the CI..aci. Tle] are used to trcat constipation. Examples include: magnesium hydroxide (Milt ry'Magnesid), c s-

ror oil. \letamucil and methylcellulose.

Antiemetics:actonthc'vomitingcenter"inthemedulla-Thiscenterhasfourdifferentsourcesofstimuli.Thc.hemoreceplor rrigger zone (CTz) is located outside the blood-brain barrier near the vomiting center in the

medulla. It communicares with th€ vomiting center after input is received from drugs and hormones. The

classes of antiemetics are:

. Antidopaminergic:. Phenothiazines: prochlorpcrazine (Conqazi ne) a'nd prcmelhazioe (Phenerydn). Benzamidesi metoclopramide /Re8/dnl and fiimcthobenzamide HCL flgdnl

. Anticholinergics:. Antihistamines: meclizine (Antivert), dimenhydrln te (Dramamine), and scopolamine A/arrderTrt-Scop)

. Serotonin 5-HT3 receptor antagonists: ond ^t\sgtron

HCL (Zotan), dolasetron (Anzemer, granisetron

HCL fj$,t/i, and palonosetron (,4/orl)

Page 187: Pharmacology

. Initability

. Xerostomia

. Loosened teeth

. Gum disorders

. Sluned speech

. Tremors

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Of the amino acid neurotransmitters listed belowwhich one is an excitatory neurotransmitter?

. Glycine

. Glutamate

. GABA (y -eminobutyric acid)

. None ofthe above

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Page 188: Pharmacology

*** Excessive saliva is a prominent toxic effect ofmercury not xerostomia

These symptoms are all of the chronic form, which results from the inhalation of thevapors ofdust ofmercurial compounds or from repeated ingestion ofvery small amounts.The presence of mercury in the body is determined by a urine test. Treatment may includegastric lavage with milk and egg white or sodium bicarbonate, chelation with British anti-lewisite (BlI), and fluid therapy.

Not€: British Anti-Lewisite (BAL) or Dimerc prol and p€nicillamin€ are two drugs cur-rently marketed for promoting the excretion of mercury, lead, and several other agents. A fewadditional agents are available for the treatment of poisoning by metals other than mercuryk.9., edetote colciunt disodium for lead and deferoxamine for iron).

Mercury that is absorbed into the circulatory system may be deposited in any tissue.Higher-than-average accumulations occur in the brain, livel and kidney. Mercury doesnot collect irreversibly in human tissues. There is an average half-life of 55 days fortransport through the body to the point of excretion. Thus, mercury that came into thebodl years ago is no longer present in the body.

l. Children and adults wbo are to be treated for lead poisoning should only befoftr' given the Edetate Calcium Disodium (Calcium Disodium Versenate) form of.., ,._ :, "EDTA."

2. Penicillamine is also a highly effective chelator ofcopper and is ofprimary im-portance in the management of Wilson's drsease Thepatolenticulqr degeneratiotr).

3. Deferoxamine is a drug that chelates to absorbed iron very well and is elimi-nated in urine.4. For carbon monoxide poisoning the fteatment is 100%o oxygen therapy fz-volves breathing oxygen thxtugh a tight-ftting uask).5. Cyanide poisoning can be treated with rapid oxygen administration and the an-

tidotes sodium nitrite and sodium thiosulfate.

Chemicals that ransmit the signal from one neuron to the next are called neurotransmitlers They are synthe-

sizcd in the ccll body or nen'e terminal of the pr€synaptic neuron. Neuroffansmitters are rcleased from thc

s\napse and cross the synaptic cleft. The d€ndrite on the nerve cell body receives the signal. Various receptors

on the posts!naptic membrane ofthe dendrite accept only certain neurotransmitte$.

h the brain. 30 differcn! neurotrarlsmitters have been classified as amino acids, amines, and neuropeptides.

. Amino acid neutofransmitters:- Glutamate, GABA, and glycine. Glutamate is an excit|tory neurctransmitter. GABA and glycine are

inhibitort neurotransmitters. GABA is the major inhibitory neurotransmitter within the CNS.

- Include the catecholamin€s -dopamine,

norepinephrin€, and epinephrine -as

well as serotonin,histamine, and acetylcholin€,

. \europeptides -most

are also hormones; these include vasopressin, oxytocin, insulin, somatostatin, gas_

trin. substance P, endoryhin, and enkephalin.

Remember:. Acetltcholin€: effects in CNS generated by interaction with a mixture ofnicotinic and muscarinic recep_

lors. Dopamine: a catecholamine which acts thrcugh at least two subt?es D7 (activates aden![ c\'c|ot"r,r,(inhibits adenyl cjclase). serotonin: is s-hydroxytryptamine which works through at lcast 14 subreceptor "trtPtominergic" OTe

1. Biosynthetic pathway ofACH: Step (l) Choline (taken up into nenevia action ofpermease)St€p (2) Choline acetylcholinesterase catalyzes the synthesis ofAch liom acetyl CoA and choline

2.Biosynthesis of NE and E: Step (1) Tyrosine to DOPA (enzyme is tvrosine hvdrorylaseStep (2) DOPAto Dopamine (enzlme is aromatic L-amino acid de-

carborylase)Step (3) Dopamine to NE (enz-vme is dopamine bela h)dro\lase)Step (4) fnorlb in the ddrenal nedulla): NE ro E lenzvme isphen ethanolamine N-meth translbrase)

Page 189: Pharmacology

Oral contraceptives block ovulation by inhibitingwhich ?TrlO ant€rior pituitary hormones below?

. Follicle stimulating hormone (FS11)

. Growth hormone (GII)

. Th).roid stimulating hormone (TSll)

. Luteinizing hormone (I11)

. Adrenocorticotrophic horrnone (ACTH)

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. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

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Page 190: Pharmacology

In addition to the above effects, oml contraceptives produce altemtions in the genital trac! including changesin cervical mucus, rcndering it unfavomble for sperm penetration even if owlation occurs. Changes in the en-dometrium may also occur .endering it unfavorable for nidation (lnrp lantotion of the -fertili.ed owm). Estto-gens and progesterone-like compounds (p/ogertrrs) are used for oml contraception.. Estrogens: are a group of chemically similar steroid hornones. In humans, estrogens are made pri-marily in the female ovaries and in small amounts in the male testes and the adrenal glands, brain, andfat ofboth sexes. Estradiol is the most abundant and potent natural estrogen in humans. Other gstrogens

inlcude ethinyl estradiol and mestranol.. Progestins: ar€ a gloup of chemically similar steroid homones as well. In humans, progestins aremade primarily in the female ovaries and male testes. Progesterone is the most abundant and potentprogestin in humans. Other progestins include levonorgestrel, rorethindrone, medroxyprogesterone,norgestimate and norgestrel.

Types of oral contrac€ptives:. Combination: oml contraceptive agents usually contain both an estrogen agent and a progestin agent.

Combination drugs include:. ethinyf estradiol and norethindrone fovcor 50, Brevicon 21, and Modicon 28). ethinyl estradiol and fevonorgestrel fPolria 0.15/30, Alesse 28 and Aviane 21). thinyf estradiol and norgestrel (Cryselle, Ovral, and Oryestrel)

. Progestin-onfy: nor€ fiindrone (Micronor)

. Emergency contrrception: levonorgestrol (P/dn B)

\\'ernings/Prccautions with OIal Contraceptives:. Tle risk of cardiovascular side effects increases inwomenwho smoke cigarettes, especially those who are>.15 .veaN ofage.. May increase the risk ofthromboembolism. Women with h)?ertension shouldbe encouraged to use anon-hormonal folm of contraception.

\ote: Antibiotics have the potential to diminish the effectiveness oforal contraceptives. Advise patients touse additional method ofbirth control when taking antibiotics and oral contmceptives concunently.

*** Most drugs travel though the blood stream by binding to albumin protein, which is abun-

dant in plasma. In this way, drugs can be carried to all the tissues and organs.

A dmg which is bound to plasma albumin always has some fraction which is not bound. The un-

bound portion is free to leave the blood compartment to be taken up by tissues where the drug willelicit its pharmacological ellect. The remaining bound fraction of drug then aontinuously releases

more free drug to be taken up by tissues. Eventually all drug in the blood compartment will be

taken up by this process.

lmportant: Interactions betw€en two or more drugs can occur ifthey compete for binding on the

plasma albumin. If drug A is bound to albumin prior to the patient taking drug B, and drug B has

a geater binding affinity to albumin than drug A, then when drug B is taken, it will displace drugA from albumin to result in large amounts ofunbound drugAwhich could lead to adverse reactions

due to the sudden large amounts gaining access to the tissues.

One ofthe most fundamental aspects of drug action is the relationship between dose adminis-

tered and the effect obtained (drugs are dose dependent), Dose and response are related and can be

represented by a dose-response curve. There are two basic types ofdose-response curves:

. The graded dose-response (Dn, curve plots the degree ofa given response against the con-centration ofthe drug. These curves are useful for determining characteristics ofagonists and an-

tagonists.. The quantal dose-elTect curve: In this case, a given quantal eIlect is chosen (e.9., .t certain

degree of cough suppression), and the concentntion ofthe drug is plotted against the percent-

age of a specific population in which the drug produces the effect. The median effective dose

(8D50 or the dose at which 50%o of the individuals exhibit the specifed quantal effecr) and the

median lethal dose (2D50 or the dose at which death is produced in 50'% oJ the expelimental an-

imals in preclinical sludies) canbe estimated from quantal dose-eIlect curves. With this tlpe ofcurve, the relative effectiveness ofvarious drugs for producing a desired or undesired effect, as

well as the relative safety between various drugs, can be determined.

Page 191: Pharmacology

What are four criteri| to consider when selecting atranalgesic agent for a patient?

. Type ofpain

. Location ofpain

. Age ofpatient

. Sex ofpatient

. Patient's weight

. Concurrent medication

. Pregnancy

t 9{)

Coplrighr O 20ll 2012 - DentalDecks

. Heparin

. Warfarin (Coumadin)

. Aspirin

. Anagrelide

t 9.t

Coplriehr O 201l'201? - Dental Decks

Z'\Which of the following competitively blocks vitamin K-binding sites .ndinhibits the synthesis of vitamin Kdependent coagulation factors VII,

lX,X, andll (prothrombin) and anticoagulant proteins C and S?

Page 192: Pharmacology

Criteria considered when selecting an analgesic agent:

l. Type ofpain:. Severe. Mild. Moderate

2. Ag€ ofthe patient:. Infant ) When calculating dosage, the height, weight, body surface area and renal hepatic. Child .f function must be taken into account. Adult. Elderly: drug response is affected by age-related changes in physiology and pharmo-

kinetics3. Corcurrent medications: Consider unwanted interactions, especially with the elderly.4. Pregnancy: Because virtually any drug a pregnant womar takes can cross th€ placenta

and enter the fetal circulation, drug use in pregnant patients is a source of special concem(clrcck with patient s OB/GYN).

FDA Rating System for the T€ratog€nic Eff€cts of Drugs: The FDA, the govemm€nt agency

that ovemees the safety ofdrugs, provides the most widely used system to grade the teratogenic

effects ofmedications. The FDA assigns a safety category for medications by using a sleftersystem: A, B, C, D, and X, with A being considered the most safe. X category medications:

Studies in animals or humans have demonstrated fetal abnormalities or there is positive evi-dence of fetal risk based on adveme teaction reports from investigational or marketing expe-

rience, or both, and the risk ofthe use ofthe drug in a pregnant woman clearly outweighs any

possible benefit (/or example, safer tlrugs or otherfotms of therapy are available).

At therapeutic levels, warfarin decreases liver synthesis of vitamin K-dependent clottingfactors by 30o% to 50olo. These clotting factors have different half-lives. Factor WI has the

shortest halfJife {6- t hr) vs. factor lI andx (up to 72 hr). Oral anticoagulants do not re-

verse ischemic damage or lyse an established thrombus but rather prevent extension oftheexisting thrombus and the formation ofnew thrombi by blocking synthesis of clouingfactors.

Oral anticogulants are used after a myocardial infarction to prevent coronary occlusion,in the treatment ofpulmonary embolism, and in the treatment ofvenous thrombosis.

l{ote: Enhanced anticoagulant effects are seen when these drugs are combined with as-

pirin. For this reason, use acetaminophen (Tylenol) for pain control.

Patients on anticoagulant therapy may have excess bleeding after dental treatment. Al-ways check medical history. If patient is on anticoagulants, his/her physician shouldhave documentation of INR values to assess anticoagulant effects. INR stands for Inter-national Normalized Ratio and essentially is the ratio of the prothrombin time meas-

ured in the patient divided by a standard prothombin time value, and multiplied by a

constant. An INR value of I means normal prothrombin times of approximately 12 sec-

onds; normal blood clotting would be present. INR values greater thar I indicate that

there is an anticoagulant effect. The higher the INR value, the greater the anticoagulant

effect. Many patients taking anticoagulants have INR values of2, 3 and even up through6.

Page 193: Pharmacology

. Immune globulins

. Immunosuppressants

. Keratinoc),te growth factor

. Interferons

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Grunisetron (Klttil) rnd ondansetron (Zofran) *e selective5-IIT3 receptor antagonists used to treat what condition?

)

. Breast cancer

. Osteoporosis

. Emesis caused by cancer chemotherapy

. Mucositis caused by radiation therapy

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Interferons are used for a variety ofconditions including: hairy cell leukemia (intederon

alpha-2a) chronic hepatitis B (interferon alpha-2b), recurring genital warts (interferon

alpha-n3) and treatment of multiple s clerosis (interferon beta- I a) .

Immune globulins provide passive immunity by increasing antibody titers.

Immunosuppressants are drugs such as cyclosporin which prevent organ transplant re-jection.

Growth factors such as keratinocle growth factor promote cell proliferation and angio-genesis.

The 5-HT3 receptor is a serotonin receptor which when activated during chemotherapy

for cancer, causes emesis (nausea and vomiting). Both granisetron and ondansetron are

indicated for prophylaxis of chemotherapy-related emesis, prophylaxis of nausea and

vomiting associated with radiation therapy, and prophylaxis and treatment ofpostopera-tive nausea and vomiting (PONV).

Other s€rotonin 5-HT3 receptor antagonists include: dolasetron (Anzemet) andpalonosetron @/oxr)

\ote: 5-HT3 stands for 5-hydroxytryptamine type 3 receptor.

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. Irnmune modulators

. Monoclonal antibodies

. Immunosuppressants

. Interferons

. Colony stimulating factors

. Immune modulators

. Monoclonal antibodies

. Immunosuppressants

. Interferons

. Colony stimulating factors

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t95CoplriSh O 201l-2012 - Dental Decks

The following drugs belong to what pharmrceuticsl class of agents:

. Adrlimumab

. Alefacept

. Inflixim|b

. Trastuzumab

Page 196: Pharmacology

Pimecrolimus (Elidel) is an immunosuppressant agent used for treatment of mild tomoderale atopic dermatitis.

Sirolimus (Rapamune) is an immunosuppressant agent used for prophylaxis of organrejection in patients receiving renal transplants.

Tacrolimus (Protopic) is an immunosuppressant agent used to treat moderate to severe

atopic dermatitis in patients not responsive to conventional therapy.

Adalimumab (Humira) rs arecombinant monoclonal antibody that binds to human tumornecrosis factor alpha (TNF-alpha) receptor sites. It is used to treat active rheumatoidanhritis.

Afefacept (Amevive) is a monoclonal antibody used to treat moderate to severe plaque

psoriasis.

Infliximab (Remicade) is a monoclonal antibody used to treat ankylosing spondylitis,

Crohn's disease, and rheumatoid arthritis. Like adalimumab, infliximab works by bind-ing to TNF-alpha receptor sites.

Trastuzumab (Herceptin) is a monoclonal antibody which binds to the extracellulardomain of the human epidermal growth factor receptor 2 protein (HER-2) ' It is used forthe treatment of patients with metastatic breast cancer whos€ tumors overexpress the

HER-2 protein and who have not received chemotherapy for their metastatic disease.

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.Improve walefi ness during daytime sleepiness

. Improve salivary flow in dry mouth disorders

. Manage psychotic disorder

. Treat mental depression

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Which herbal supplement below is known to be somewhrt€ffective in treating rnild forms ofmental depression?

. Ginkgo biloba

. St Johls Wort

. Garlic

. Echinacea

. Ginseng

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Modafinil (Provigil) represents a class of central nervous system stimulants used to

improve wakefuhess in patients with excessive daytime sleepiness associated with nar-

colepsy and shift work sleep disorder. It also has an unlabeled use to treat attentiondefi cit/hyperactivity disofier (ADHD).

The exact mechanism of modafinil is unclear; however part of its action may be do to

decreased GABA-mediated neurotransmission.

Some studies have shown the St Johns Wort can inhibit the re-uptake of serotonin at neurcnalsynapses resulting in the elevation of serctonin within the CNS. This effect is similar to those antide-pressants u'ithin the flnoxetine (Plozac) fatrily. Of all the herbal supplements available to the consumer,

St Johns Wort is associated with use as a mild antidepressant.

Ginkgo biloba is a herbal supplement used as a peripheral anery vasodilator

Garlic is a herbal supplement used to lower cholesterol and to inhibit platelet aggregation resulting in a

decrease in blood clotting.

Echinacea is a herbal supplement and immune stimulator used to minimize the severity ofthe commoncold and seasonal flu.

Ginseng is a herbal supplement used to stimulate the immune system.

Chamomile has a long history of use in Europe for digestive ailments. The active constiuents ofchamomile have anti-inflammatory properties, and ease spasm and discomfort in the digcstive tract.

\ote: Chamomile contains coumarin, a natumlly-occurring compound with anticoagulant or blood-rhinning effects. It should not be combined with warfarin or other anticogulants-

S.li palmetto has long been used in Europe to treat an enlarged prcstate or benign prostatic hyperpla-

sia (BPH).

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. Increase the effectiveness ofmedications

. Decrease the effectiveness ofmedications

. Increase the toxicity ofmedications

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AII ofthe following drugs are serotonin 5-HT1a receptor agonists us€d to trertmigraines EXCEPT one.Whrch ow is the EXCEPTION?

. Sumalliptan (Imitre,

. Frcyatiptan (Froya)

. Naratriptan (Amerge)

. Donepezil (Aricept)

. Kzatiptan (Mamlt)

. Aknolnplan (Axert)

. Zolmrtrrptan (Zomig)

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St Johns Wort may induce the cytochrome P450 enzyme system to result in a more rapid metabolism ofmanydrugs in rhis pathway. More rapid metabolism of a drug equates to less active drug available and less fde-c/edre4 effectiveness. Specifically, data indicates probable intcractions betwe€n St Johns Wort and iis effectin decreasing the actions ofihe following drugs:

. The HIV-l protease inhibitor indinavir

. The antirejection medication cyclosponn

. The sedative midazolam

. The antihypertensive nifedipine

Drug-drug interactions can involve prescription or nonprcscription fo),er-the-counter) drrJgs. Dnrgs interactby acting at lhe same receptor or signal transduction paihway, or more commonly, a drug may af]'ect the phar-

macokinetics ofanother dnrg. The most common form ofdrug-drug inleraction is one drug affecting the me-

tabolism ofanother drug, involving eifier induction or inhibition ofmetabolizing enzymes.. I nd uction of metabolism : is a reaction to certain drugs in *,hich the number of liver enzymes increases,

resulting in a reduction in the €flic! ofthe other drug.. Inhibition ol metabolism: is a process by which one drug either competes for metabolism ofanolher or

directly inhibits drug-metabolizing enzymes.

l. Herbal medicines such as g.rlic, ginseng, and ginkgo /gir,(go 6i1o6., are thought to interact

-\otee: *ith anticoagulant or antiplatelet th€rapy. Remember: Chamomile contains coumarin and

should not be used in patients taking warfarin for fear ofan additivc affect.'' 2. St. John's wort is the herbal product most often reported !o be involved in drug-herb interac-

l. Echinac€a has potential interactions with immunosuppressants.4. Many herbal weight loss and "herbal speed" products rely on the pharmacodynamic interaction

between ephedra and caffeine. Two primary alkaloids containcd in ephedra -ephedrine

and pseu-

doepbedrine -have

rdditive cardiovascular effects when taken with caf]eine. At higher doses,

the ephedra-caffcine interaction has been cited as a cause ofdcath.

Important:The rate ofdrug metabolism can vary greatly. depending on the cytochrome p450 isozyme profile

ola patient. Over the next few years, genetic screening ofthc c)'tochrome p450 system will be able to iden-

riry $hich patients are likely to develop toxicity or drug-drug interactions, and with which drugs. Ultimately,metabolic screening based on studies using highly-specific probcs could bclp decide whether or not a drug is

prescribed.

*** Donepeztl (Aricep, is a cholinesterase inhibitor used in the treatment ofAlzheimer'sdisease.

Migraine medications:. The most commonly used migraine medications are the serotonint f5-11fl receptoragonists, commonly known as the "triptans." All 5-HTl receptor agonrsts (triptans)

have a similar chemical structure and a comparable mechanism of action. 5-HTl s and

5-HTtD receptors located on the extracerebral, intracranial blood vessels that become

di)ated during a migraine attack and on nerve terminals in the trigeminal system. Ther-apeutic activity is caused by activation ofthese receptors, which results in cranial ves-

sel constriction, inhibition of neuropeptide release, and reduced transmission intrigeminal pain pathways.

. Ergotamine derivatives demonstrate partial agonist and/or antagonist activity against

dopamine. tryptaminergic, and alpha-adrenergic receptors, depending on their site. Er-gotamine derivatives have three primary actions. They (1) depress central vasomotorcentel (2) constrict peripheral and cranial blood vessels, and (3) reduce extracranialblood florv and decrease hyperfusion ofthe basilar artery area. Examples include: ero-

tamine tartrate (C aferyo t) and dihydroergotamrne (D H E - 4 5 ). Combination drugs: Midrin is a combination capsule that contains 65 mg ofisometheptene mucale (an ergotamine derivative), 325 mg of acetaminophen, whichexerts an analgesic effect, and 100 mg ofdichloralphenazone, a mild sedative that acts

centrally to allay an"riety. Note: Caffeine, which is added to many migraine combina-tions. helps to promote constrictive properties, and enhances absorption.

Note: Methylsergide (Sansert) blocks 5-HT2 receptors fs erotonin antagotrist) and is used

for prophylaxis against migraines.

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. Levothyroxine sodirtm (Synthroid)

. Liotbyr onine (Cytome l)

. Liotrrx (Thyrolar)

. Methimazole (Tapazo le)

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Nlcotine is rapidly absorbed across the pulrnonary caplllary membrane and isdelivered to the brain in high concentration within seconds of inhalstion.

The nasal spray bas the fastest delivery of the NRTs and more closely resemblesthe ons€t ofthe nicotine effects ofsmoking.

. The first statement is true; the second statement is false

. The first statement is false; the second statement is true

. Both statements are true

. Both statements are false

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Thyroid medications:. Thyroid supplements: used to treat hypothyroidism

. Levothyroxine sodi|dm (synthetic T4)

. Liothyronine (synthetic Tj)' Liotrix (T4;73= 4 l)Note: These drugs are usually taken orally in a single daily dose. preferably before

breakfast- The treatment of choice for hypothyroidism is T4. lt has a relativelyslow onset of action, and its effects are cumulative over several weeks. T3 has a

more rapid onset ofaction and dissipation ofaction. Adverse side effects includenervousness, nausea, dianhea, tachycardia, tremoq weight loss and heat intoler-ance.

. Thyroid suppressants: used to treat hyperthl,roidism

. Methimazole (Tapazole)

. Propylthiouracil (PIUI\ote: These drugs inhibit thyroid peroxidase, which is an enzyme expressed mainlyin the thyroid that liberates iodine for addition onto tyrosine residues on thyroglob-ulin for the production of the thyroid hormones - thyroxine (I4.; or triiodothyro-nrne (Tj). Through reduced absorption of iodine, thyroid hormone synthesis is

diminished. Adverse effects include rash, nausea, and agranulocytosis.

\ote: Thyrogen is a recombinant DNA source ofhuman TSH useful in the management

and lreatment of thvroid cancer oatients.

\fan) phannacologic approachcs havc bccn uscd to hclp pcoplc stop smoking. h current usc arc thc nicotinc rc-placcnlcnt thcrapy l\'Rl products, bupropion r'4'han ll/elbutriD zt\d \arcnicline (Cha tn).

\icotine rcplaccmcnt producls are meant to help palients stop smoking. They arc not mcant to belp gct a paticnt

rhrough a long flight or an all-day mccting in a nonsmoking building.

Class Generic Name Tr.de Name Formulation

Nicorine replacement lherapy Nicotine polacrilex Nicorette Gum

Nicotine Nicodem CQHabitrolNicoholProStepNicotrol NSNicotrol inhalerCo1nmit

TransdemalTransdemalTransdermalTransdermalNasal sprayOral inhaler

Anridepressant Bupropion Zyban, Wellbutrin Tablet

N icotine rcceptor agonist Varenicline Chanlix Tablct

).'lhcp^tch (trunsdamdl) is thc most commonly used tvpe ofNRT' Patchcs arc availablc in l5 and

2l mg strcngths for trcatmcnt inilialion.2. Thc gum dclivcrs nicotinc faster than thc patch and can be uscd for incidcncc ofcraving. Thc gum

is availablc in two strcngths: 2 mg and 4 mg.3. Thc lozenge also comcs in 2 mg and 4 mg doscs and dclivcrs about 25% morc nicotinc than gum..1. Thc nasal spray has thc fastest delivery ofnicotinc ofthc NRTs.

5. Inhaled nicotine (xslng the nirctine ifihaler) is absorbcd in lhc mouth not in the lungs. Each car-tridgc contains l0 mg nicotinc and dclivers 4 mg. It also contains I ng mcnthol.6. Bupropion as a systcmic medication sccms to rcducc thc craving forcigarcttes orlhc urgc !o smokc.Its mcchanism ofaction is unclcar7. !arenicline is thc ncwcst dmg in thc smoking ccssation arscnai. Note: Thc FDA has issucd an alcrtto providcrs to monitor patients taking this medication for dcpressior, scvcrc mood swings, abnormal

drcam statcs. and thoughls ofsuicidc.

\ote_q

Page 203: Pharmacology

. Analgesics

. Anti-inflammatories

. Antitussives

. Antidiarrheals

. Preanesthetic medications

. Codeine

. Oxycodone

. Hydrocodone

. Meperidine

. Morphine

. Fentanyl

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Page 204: Pharmacology

Opiates are very effective analgesics, They suppress the cotgh reflex (tntitussive). Theycause constipation and thus are effective antidiarrheal agents. When used as preanes-thetic medications, opiates permit a reduction in the amount of general anesthetic re-quired for surgical anesthesia.

Some common side effects ofopiates (narcotics) include: sedation/drowsiness, dizzinessand nausea. Other less common adverse effects are vomiting, h)?otension, irregular/la-bored breathing /dyspnea), lightheadedness, nightmares and insomnia.

: - - ... l. Respiratory d€pression is dose related and is the cause of death in nar-, i\oq: cotic drug overdose. It can happen with any of the narcotics.

'.td;a 2. Abuse can and does occur with all the narcotics. They are all controlleddrugs falling under DEA Schedule II or DEA Schedule III ofthe schedules ofcontrolled substances.

3. A DEA number is required in order to prescribe narcotics.

Opioid analgesics are thought to inhibit paintul stimuli in the substantia gelatinosa ofthe spinal cord, bmin-stcm. rcticular activating system, thalamus, and limbic system. Opiate rcccptors in each of thcse areas inter-

act with neurotransmittcn ofthe autonomic nervous system, producing alteralions in reaction to painful stimuli.fhc opioid action ofthc drug manil-e\1. as:

. Dro\\'siness

. Euphoria

. \fentalcloudrng

. Decreased peristaltic motility

. Nausea and vomiting

. Respiratory depression

. Depression ofthe cough reflcx. \lrosts @upillan, constriction) . Orthostatic hypotension

\Iorphine is a narurally occurring opiate tha! is metaboliTed chiefly through glucuronidation by uridineciphLriphare glucuronosyl transferase fUG4 €nzymes in the liver These enzymes produce an active analgesic

meiaboltle ( m o rp h i n e- 6 - E: lucuron id e ).

Srgri and s]mptoms ofacute opioid intoxication:!he intoxicaled person is stuporous or asleep and has con-

s-icied pupils /pir-poi t p?./plls/ and depressed respimtion- As the severity ofintoxication increases, coma en-

sucs. \ote: Death from acute intoxication by an opioid analgesic is the result ofpmfound, direct respiratorydepression.

Remember:L Codeine is weaker f/e.rr pol€r, than morphine and less addictiv€. 11 is converted to morphine by cy-rochrome p,l50 2D6. Note: It diffcrs from morphine in that a methoxy (-OXIIj) substitution replaces thehi dro\yl (-OH) group on the aromatic ring ofthe molecule. This relatively minor structural change pro-\ldes codeine with significant oral effectiveness.:. ox]codone has a similar potency as morphine. ln combination with acetaminophen it is known as P€r-cocet or Tylox.3. HJ''drocodone has a similar potency as morphine. In combination with acetaminophen it is known as

vicodin and Lorcet.4. Meperidline (Denero, is more potent than codeine but less potent than morphine butjust as addictive.It has a shorter duration ofaction. It is the only narcotic agent tbat does not cause miosis lPupillary con-

5. Methadone (Doloprl,e) is an opioid agonist used in maintenance for treating opioid addiction.6. Buprenorphine fsrrrle, is an opioid partial agonist uscd to treat opioid dependence.

Page 205: Pharmacology

Which sdverse effect is associated with opioid anNlgesicsand not non-narcotic pain relievers?

. Allergic response

. Nausea

. Vomiting

. Respiratory depression

20tCoplright C 20ll 2012 - DenlalD€cks

PIIARMACOLOGY

All ofthe folfowing are opium alkaloids, EXCEPT oae.Which one is the,EXCZ'PZ1O1V?

. Meperidine

. Morphine

. Codeine

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Page 206: Pharmacology

The most significant and well-known adverse reaction to opioids is respiratory depr€s-sion. Death secondary to opioid overdose is nearly always due to respiratory depression.When opioids are appropriately used, the risk of severe respiratory depression is gener-ally small as tolerance rapidly develops to this effect.

Drug Length ol Effcctivcness Other Information

Morphine lV or lM: 2-3 hoursBy rnouth: 3-4 hoursSustaincd relcase: 8-12 hours

Starts to work quickly. Oral form can bc vcryeffective for cancer pain.

Codeine By mouth: 3-4 hoursTaken \lith aspirin or acetaminophen

Less potent than morphine

Meperidine IV or IM: about 3 hoursBy mouth: not very effective

Can cause seizurcs, tremors, and muscle spasms

Methadone Bv mouth:4-h hours. somelimes longcr Also used for treatins heroin withdmwal

Propoxyphene By mouth: 3-4 hours Gererally taken \ri!h aspidn or acetaminophen totreat mild pain

Le\'olphano! lV or IM: 4 hourstsy mouih: 4 hours

oral form is strong. Can be used instead ofmorphine

Hr"drocodone By moulh: 4-6 hours Usuallv combined wirh acetaminophen

Oxr codone Bv mouth: 3-4 hours Usually combined with aspirin or acetaminophen

Pentazocine By mouthr up to 4 hours Can block painkilling action of other opioids.Aboul as strong a codeine. Can cause confirstonand arlxiety. especially in the elderly.

Chernical classihcation of opioid analgesics:Opium alkaloids:

. Morphine

. CodeineSl nthetic deriYatives:

. )Iorphine group:. Hydromorphone (Dilaudid). Oxymorphone (l'l umorphan). Nalbuphine /?fuDaif

. Codeine group:. Hydrocodone (in Vicodin). Oxycodone (in Percodan, Percocet and Tylox)

Synthetic narcotics:. Meperidine group:

. Meperidine (Demerol)

. Alphaprodine (Nisentil)

. Alfentanil (Alfenta)

. Fentanyl (Sublimaze)

. Sufentanil (&r&rta)

. Diphenoxylate (in Lomotil)

. Loperamide (in Imodium). Methadone group:

. Methadone (Dolophine)

. Propoxyphene (Darvott)

Page 207: Pharmacology

. Morphine

. Naloxone

. Propranolol

. Ibuprofen

. Beta-endorphins

. Morphine

. Enkephalins

. Dynorphins

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Page 208: Pharmacology

Naloxone (Narcaz) is a narcotic antagonist and is used in medical emergencies to teverse

narcotic overdose. Overdose of narcotics results in respiratory depression and death due

to respiratory shut down. Naloxone will reverse the respiratory depressant effects ofthenarcotics thus counteracting the lethal effects of these agents. Naloxone is given intra-venously, intramuscularly or subcutaneously. Note: Naloxone does not have agonist ac-tivity at any opioid receptors.

Nalmefene (Revex) and naltrexone (ReWa) are the other two narcotic reversal agents

used to reverse the respiratory depressive effects olthe narcotic analgesics.

Typical narcotic analgesic drugs which are reversed by naloxone (Narcan), nalmefene(Revex), and naltrexone (Rena) Lnclude:

. Codeine

. Morphine

. Hydrocodone

' Oxycodone. \{eperidine (Demextl). Fentanyl

\ote: Naltrexone (Rel/ia) is also used to treat alcohol dependence.

opiate receptors in the CNS mediate analgesic activity. Opioid agonists occupy the same receptors as en_

dogcnous opioid peptides, and both alterthe central release ofueurotransmitters ilom afferentrerves sensitiveto no\ious stimuli. They decrease presyraptic release ofneurotranmitters and incrcasc postslnaptic potential.

The opioid reccplors all have a common general strucfur€. They are characleristically G protein-linked re-

ceptors enrbedded in thc plasma nrembrane ofneurons. Once the receptors are bound, a portion ofthe G pro-

rein /Gtl is activated, allowing i! !o diffxse within the plasmn menbmne. The G protein moves within the

membrane until it rcaches ils larget -cithcr

an cnzyme or an ion channel.

Opi[)id receplors in lhe centml nervous system are thought to be activated by endogenous chemicals under

Fh\ iiologic condirions. fie body coniains three types ofthese chemicals that produce morphine-like effects

. Beta+ndorpbins bind to opioid receptors in the brain and have potent analgesic activity.

. Enkephalins bind to opioid reccptors in the brain and are more widely distributed in the brain than lhcbera-endorphins. Seem !o play a role in pain perception, movement. mood, and behavior. Dlnorphins are the most powerful ofthese cbemicals and are lbund throughout the central and periph-

eml nen ous syslems. Some research supports the theory that they regulate pain at the spinal cord level, in-fluence feeding behavior at the hlpothalamic levcl and function with other cndogenous opioids to regulatc

the cardiovascular systcm.

Opioid receptors:l. mu (!) mediate morphinelik€ supraspinal analgesia, mitosis, respiratory depression, €uphoria, phys-

ical dependence, and supression ofopiale withdrawal. Nolei The protot)?ical opioid agonist for this receptor

is morphine, and its analgesic activity is considered to depend on its binding to this reccptor2. della (6) mediate antagonist activity. Note: The €nkephalins are considered to be the q?ical agonist

tbr this rec€ptotL kappa (K) mediate spinal analgesia, respiratory depression, and sedation. \ote: The dynorphins are

thought to be the R?ical agonist for this receptor

Sites of analgesic action of opioids: The opioid drugs produce analgcsia by actions at several levels ofthencwous system, in particular, inhibition ofneurotransmitter rcleasc f.om the primrry alferent terminals in

the spinal cord and activrtion ofdescending inhibitory controls in the midbrain.*** Opioid analgesics (i.e., motphine. codeine, mepericline. propoxvp,ftcn€, eL..) mimic endogenous opioids

at CNS opiate recepiors, raising the pain threshold and increasing pain tolerance.

Page 209: Pharmacology

. Morphine

. Hydrocodone (component of Wcodin)

. Oxycodone (component of Percocet)

. Meperidine (Demerol)

. Codeine

. Fentanyl

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. Acetaminophen

. Ibuprofen (Motrin; Advil)

. Hydrocodone with acetaminophen

. Aspirin

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Therapeutic indication for opioids (narcotic analgesics) are the relief of moderate-to-severe pain, as preanesthetic medications, as analgesic adjuncts during anesthesia, as an-titussives, and as antidiarrheals. Note: They are administered with caution to patientswith head injury or those with a history ofdrug abuse and dependency.

l. Morphine is not used in dentistry because ofits high addictive liability.2. Hydrocodone in combination with acetaminophen is known as Vicodin,Lorcet, Lortab, Maxidone, and Zydone.3. Ilydrocodone in combination with ibuprofen is known as Vicoprofen,4. Oxycodone in combination with acetaminophen is known as Roxicet Per-cocet, and lllox.5. Oxycodone in combination with ibuprofen is known as Combunox.6. Oxycodone alone is klown as Oxycontin. It is more potent than codeine.

7. Meperidine (Demerol) in combination with promethazine is known as

Mepergan Fortis.8. Codeine in combination with acetaminophen is known as Tllenol #3.9. Fentanyl is available as a transmucosal preparation known as Actiq, a trars-dermal patch formulation known as Duragesic and as an intravenous prepa-

ration known as Sublimaze,

Among the opiates available for use in dentistry, hydrocodone products are commonlythe drues ofchoice.

Ibuprofen and other non-selective NSAIDs (inhibitors of both cyclo-oxygenase I andq clo-orygenase 2 enzymes) snch as naproxen (Anaprox) and flurbiprofen (Ansaid) in-hibit platelet aggregation. This action would enhance the anti-coagulant effect of war-fain (Coumodin) to increase the risk ofbleeding. Aspirin inhibits platelet aggregation topotentiate the anticoagulant effects of warfarin (Coumadin) and increase the risk ofbleed-lng.

Acetaminophen is a non-narcotic analgesic that do€s not affect platelet aggregation nordoes it affect the coagulation pathway. Thus, it will not affect the anticoagulant nature ofwarfartn (Coumadin). Acetaminophen can be given safely to patients taking warfarinlCoumadi .

Hyrocodone with acetaminophen is a combination ofa narcotic analgesic with aceta-

minophen. Common brand names for this combination are Vicodin, Lorcet and Lortab.Hydrocodone and the entire drug class ofnarcotic analgesics do not affect blood clottingand will not enlance the anticoagulant effects of warfarin (Coumadin). Narcotics withacetaminophen can be given safely to patients taking warfarin (Coumadin).

Page 211: Pharmacology

. Nausea

. Peptic ulcers

. Insomnia

. Constipation

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Which drug is r synthetic opioid analgesic used as an inkrvenoussedative and is more potent than morpbine?

. Meperidine (Demerol)

. Pentazocine (Talwin)

. Propoxyphene (Danon)

. Fentanyl

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The most common side effect of the narcotic (opiqte) analgesics is nausea. The mostserious side effect of the narcotic analgesics is respiratory depression. The cause ofdeath from overdose ofnarcotics is respiratory depression and shut down ofthe respira-

rory sysrem.

Narcotic analgesics do not cause peptic ulcers. Nor do they cause insomnia, but ratherwould cause drowsiness and sedation since narcotics depress the conscious centers ofthe brain.

Fentan!-l (Sublimaze)is a potent narcotic analgesic used primarily as an intravenous supplement

during conscious sedation procedures or proccdures requiring general anesthesia. Fcntanyl is 80-100 times more potent than morphine.

Fentanyl is also avaifable as a lollipop-type lozenge (brand name Actiq) for transmucosal absorp-

tion and as a transdcnnal patch (brand name Duragesic) for dclivcry thrcugh a patch applied to the

skin. Note: Fcntanyl congeners include Alfentanil, Sufentanil, and Remifentanil.

Meperidine (Denerol) is used as an intravenous supplement during conscious scdation proce-

dures. However, it is less potent than morphine and much less potent than fentanyl. Meperidine(Demerol) is also wed as an oral medication for pain control aftcr dental surgery. Note: A mctabo-

lite, normeperidine, is a CNS stimulant. lmportant; Contfaindicated with MAO inhibilors(e.g., phen;lzine ard tru llcypromine)

Pentazocine (Talwin) is chemically related to morphine and has weak analgesic properties. 1t is

a mixed agonist-antagonist drug, having agonist activity at some reccptom and antagonist activ-ity at other rcceptors. It is not used intravenously to produce conscious sedation. Pentazocine has

abuse liability. Note: Talwin Nx tablets contain naloxone which is added to deter misuse.

Propoxyphene fDanon) in the form ofpropoxyphene napsylate with acetaminophen is knownas Darvocet-N 100 and is useful tb. pain control after dental surgery. It is taken orally and notused inlravenously. Darvocct-N 100 has low abuse liability. l\-ote: lt is less potent than codeine

and a metabolite, norpropoxyphene, is a CNS stimulant.

Tramadol (Ultran) is an opioid partial agonist. It is not a scheduled drug. Use great caution in com-bination with MAOIs (e.g., phenylzine and tranylcypromine).

Page 213: Pharmacology

. Codeine

. Morphine

. Hydrocodone

. Meperidine (Demerol)

. Oxycodone

. Voltaren

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AII of the followitrg sites are generally accepted for IM injectionsEXCEPT one. Which one is the EXCEPTIOM

. The buttocks

. The biceps muscle

. The deltoid muscle

. The anterior thigh

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Page 214: Pharmacology

*** Voltaren is a NSAID which do not produce drug dependence and addiction.

The other analgesics belong to the opiate class of drugs. They are also klown as nar-cotic analgesics since the actions ofthis family is to cause drowsiness and sleep as a sideeffect.

The opiates produce drug dependence leading to addiction. Psychic dependence, phys-ical dependence, and tolerance can develop upon repealed administration. Psychic de-pendence is unlikely if an opiate is taken for a short period for pain relief. Physicaldependence is a condition in which continued administration of the drug is required toprevent unpleasant withdrawal symptoms. Tolerance occurs when increasingly large

doses ofopiate are required in order to produce the same degree ofanalgesia.

Opiate drugs used in dentistry to provide pain reliefafter dental surgery include:. Codeine. Hy drocodone O)icodin). Oxycodone (Percocet rylox). Meperidine (Demerol)

*** For young children, the anterior thigh is usually the place to give IM injections.

Absorption from an intrarnuscular injection is often faster and there is a higher bioavail-abilit]' than with oral administration.

Proper depth of needle in muscle: In big muscle (adult) go in one inch; in children go

in one-quarter of an inch. Never go beyond two-thirds ofthe needle length.

Page 215: Pharmacology

. Pharmacologic agonist

. Pharmacologic antagonist

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. Topical administration

. Oral ingestion

. Subcutaneous inj ection

. Intravenous injection

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Page 216: Pharmacology

Drugs that bind to physiologic receptors and mimic the regulatory effects ofendogenoussignaling compounds will produce a pharmacologic effect as a result of binding to the

receptor. A drug that elicits a full response through this process is referred to as a phar-macologic agonist.

A partial agonist is a drug which acts on the physiologic receptor but elicits an effect

which is only partly as effective as an agonist drug.

An antagonist is a drug which binds to the physiologic receptor but does not trigger an

effect. When artagonist is present, the agonist drug cannot reach the receptor site to pro-

duce an effect.

1. Competitiv€ antagonism occurs when a response can be achieved by increasingthe dose of agonist in the presence ofantagonist.2. Noncompetitive antagonism occurs when a response cannot be achieved with in-creasing doses of agonist in the presence ofantagonist.

Common routes of administration ofdrugs:

1. Parenteral administration (not by wa!" ofintestine or GI tract)

. Intravenous (lV) - diectly into the bloodstream. Acts very rapidly.

. Intramuscular |1M/ injected into a muscle area, where it is promptly absorbed

. Subcutaneous - injection beneath the skin. Absorption may be less rapid.

2. Enteraf administration @y v,q) ofthe intestine or GI tract)

. Buccal or sublingual a tablet is placed under the tongue or in the cheek

. Or^l- (most common route), the drrrg is swallowed. It is the most convenient forsafe drug administration. It is safe, painless and economical.. Rectal - the drug in solution (enema) or suppository form is inserted into the rec-

tum

3. Inhalation - the drug is given as an aerosol into the respiratory tract.

4. Topical administration the drug is placed on the skin for a local effect.

5. Transdermal - the drug is placed within a "patch" and placed on the skin to be ab-

sorbed into the systemic circulation.

Page 217: Pharmacology

. Lungs

. Liver

. Brain

. Kidneys

. Gastrointestinal tract

. Does; extrinsic

. Does not; extrinsic

. Does; intrinsic

. Does not; intrinsic

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Page 218: Pharmacology

Hepatic metabolism of drugs occurs in Phase I reactions catalyzed by a microsomalmixed-function oxidase system (a/so known es the P-450 system) and in Phase II reac-tions known as conjugation reactions.

Phase I reactions:. Occur in the liver microsomal enzyme system (mixed-lilnction oxidase system or P-450 system).In this system, drug metabolism occurs in three basic pattems. First, the

active parent drug can be converted to the inactive metabolite. Second, an active par-

ent drug may be converted to a second active compound which is subsequently con-verted to an inactive compound; and thirdly an inactive parent drug may be

transfonned to an active compound.

. The most common r€action in drug metabolism is an oxidation reaction in whichoxygen in the form ofhydroxyl group is attached to the drug molecule.. There are at least eight distinct groups of microsomal drug metabolizing enzymes:

These enzymes "families" are identified as a cytochrome (CYP preJix) followed bytheir numerical digestion (e.g., lA2).Thusrhe enzyme CYP lA2 is a distinct drug me-

tabolizing enzyme that converts a variety of drugs to the oxidized product.

Phas€ II reactions:. Conjugation reactions involve coupling the drug with an acid present in cells (rrsa-

alh glucuronic acid). \,,lhen coupled to glucuronic acid, the process is known as glu-

curonide conjugation with the resulting metabolite refened to as the "glucuronide.". Conjugations occur in the liver, kidney and to a lesser extent in other tissues.. Conjugation ofdrugs results in polar, water-soluble compounds that are rapidly ex-creted in urine. Thus, the parent drug is effectively rendered inactive and transport€d out

ofthe body by this process.

There are four major families ofphysiological receptors that drugs can bind to produce

effects:

. Receptors as enzymes 6.e., cell surface protein kinases): These kinases exert theirregulatory effects by phosphorylating proteins within the cell which alters the cellularbiochemical activities. By binding to these kinases, drugs can also cause the alterationin biochemical activities resulting in a drug effect.

. Ion channels: Drugs can bind to ion channels in cell membranes to cause opening orclosing. This alters the cell's membrane potential to result in a drug effect.

. G protein-coupled receptors: When drug binds to these receptors, second messen-

gers are produced such as cyclic AMP to produce an effect within the cell. This results

in a drug effect.

. Receptors in c€ll nucleus: Receptors for steroid hormones are soluble DNA-tran-scription factors within the nucleus that regulate the transcription of specific genes.

Modification ofthe transcriptions ofthese genes results in a drug effect.

Page 219: Pharmacology

. Oral

.IV

. Rectal

. Inhalation

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. Actlve transport

. Facilitated diffusion

. Filtration

. Simple diffirsion

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Page 220: Pharmacology

Howeveq it is also the most unpredictable and least effective route available. Drugstaken by mouth have to be absorbed (as ually fr om the small intestine) before they can be

transported to their site ofaction. Absorption may be slow, unpredictable and inegular due

to the presence of variable amounts of food in different stages of digestion and to thevarying degrees ofacidity and alkalinity ofthe digestive juices. Moreover, blood from the

intestinal tract passes first to the liv€r: some drugs are metabolized in the liver and oth-ers may be stored there to be released only slowly. These considerations make it clear thatoral administration is usually unsuitable in emergencies or on other occasions when a

rapid effect is needed.

Note: After oral administration, drugs will generally be absorbed best from the duode-num. The duodenum has a large surface area due to the presence of villi and n.ricrovilli.

Note: A major advantage of IV administration ofa drug is it allows for titration ofthedrug.

Other advantages of IV administration include:. Rapid onset. Drugs that cause irritation when administered subcutaneously can be given IV withno irritation. In case of emergency, there is an open line through which emergency drugs can be

injected

One major disadvantage of IV injection is that since it has such a rapid onset ofaction,overdosage may have effects so immediate that it is impossible to reverse them.

The mechanism of drug transfer across biological membranes is by:

L Passive transfer -is essential to various processes of metaboltsm. Simple diffusion: Iipid-soluble substances move across the lipoprotein membrane

by.' this process. The majority of drugs penetrate biomembranes by this process

through membrane phospholipids. The amount of drug dissolving in the membrane

at any time is directly proportional to the concentration gradient and its degree oflipid solubility (Note: Only nonionized drugs are soluble in lipid).. Filtration: water-soluble molecules small enough to pass through membrane chan-

nels may be carried through the pores by the bulk flow of water. Drugs ofmolecu-lar u eights of 60,000 or less can "filter" through capillary membranes.

3. Specialized transport. Active transport: lipid-insoluble substances (for example gluco.re) are shuttled

across plasma membranes by forming complexes with specific membrane con-

stituents called carriers. These carrier molecules within a cell fumish energy forransportation ofthe drug to regions ofhigher concentration. Facilitated diffusionis the term given to carrier-based transfer when the driving force is simply the con-

centration difference ofthe drug across the membrane.

Note: Osmosis is the movement of a pure solvent, as water, througl't a semipermeable

membrane from a solution that has a lower solute concentration to one that has a higher

concentration. The membrane is impermeable to the solute but is permeable to the sol-vent.

Remember: The physiochemical properties ofdrugs that influence their passage across

biologic membranes are: lipid solubility, degree of ionization, and molecular size and

shaoe.

Page 221: Pharmacology

. 5 milliliters

. l0 milliliters

. l5 milliliters

. 20 milliliters

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. Levodopa (Larodopa, Dopar)

. Prazosin (Minipress)

. Indomethacin (Indocin)

. Morphine

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Page 222: Pharmacology

*** lndomethacin (ndoclry' is an NSAID which may cause GI bleeding, ulcers and pos-sible stomach perforation.

Drugs that may produce orthostatic hypotension:. -{ntih} pertensiyes: for example prazosm (Minipress). Phenothiazines: for exanple chlorpromazine and thiondazine (Mellaril). Triclclic antidepressants: for example doxepin (Sinequan), amitriptyline (E/avll)and imipramine I Tolianil). \arcotics: for example meperidine (Demerol) and rnorphine. -Lntiparkinson drugs: for example levodopa (Larodopo. Dopur) and carbidopa *ler odopa /Slnenet)

Orthostatic h)'potension (also called postural hypotension) is abnormally lorv bloodpressure occuning when an individual assumes the standing posture.

Important: Following vasovagal syncope, orthostatic hypotension is the most likelycause of transient unconsciousness in the dental office. Many factors have been identi-fied that rnay be responsible for the development of orthostatic hypotension, includingseveral which are important to the practice of dentistry. They include the administrationand ingestion ofdrugs, prolonged recumbency and convalescence, an inadequate postural

reflex, pregnancy, various defects in the legs, Addison's disease, physical exhaustion andstarvation and chronic orthostatic hypotension (Shy-Drager sludrome).The incidence in-creases with age.

Page 223: Pharmacology

Pain that has no organic basis and is fixed uponsome portion ofthe anatomy is referred to as:

. Intractable pain

. Refened pain

. Psychogenic pain

. Phantom pain

222

Coplaighr C2011,2012 - Dental Decks

. Schedule I

. Schedule II

. Schedule III

. Schedule IV

. Schedule V

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Page 224: Pharmacology

*** For example, the sensation ofpain felt in a limb, although that limb has been am-putated.

Other terms to know:.Intractable pain: is pain that is resistant or refractory to ordinary analgesic agents. Referred pain: is pain felt in an area other than the site of odgin, such as pain near

the shoulder associated with biliary disease. Psychogenic pain: is pain produced or caused by psychic or mental factors ratherthan organic factors

Remember: Pain threshold refers to the lowest level ofpain a patient will detect.

Schedule I - a category ofdrugs not considered legitimate for medicinal use. Among the

substances so classified by the DEA are mescaline, LSD, heroin, and marijuana. Special

licensing procedures must be followed to use these or other Schedule I substances.

Schedule II a category ofdrugs considered to have a strong potential for abuse or ad-

diction. but which have legitimate medical use. Among the substances so classified by the

DEA are Morphine, Cocaine, Pentobarbital, Oxycodone, Methadone, and straightCodeine.

Schedule III - a category ofdrugs considered to have less potential for abuse or addic-tion than Schedule I or II drugs. Among the substances so classified by the DEA are var-ious analgesic combination compounds containing codeine fi.e., acetaminophen andcodeine - \'lenol #3) and various analgesic combination compounds containing hy-

drocodone (i.e., hydrocodone and acetaminophen -l'icodin;

Lorcet).

Schedule IV - a category of drugs that have less pot€ntial for abuse or addiction than

those of Schedules I to III. Among the substances so classified by the DEA are diazepam(Valiurn),lorazepam (Ativan), triazolam (Halcion), alprazolam (Xanax), and chloral hy-drate.

Schedule V a category of drugs that have a small potential for abuse or addiction.Among the substances so classified by the DEA are many commonly prescribed medica-

tions that contain a small amount ofCodeine.

Note: Schedule II and III must have a written prescription signed by the health profes-

sional (aws vary from stqte to state). The FDA determines which drugs are to be sold byprescription only. The prescription must have the address ofthe patient and dentist as wellas the DEA number olthe dentist.

Page 225: Pharmacology

. High therapeutic index and is, therefore, very dangerous

. High therapeutic index and is, therefore, relatively safe

. Low therapeutic index and is, therefore, very dangerous

. Low therapeutic index and is, therefore, relatively safe

224Cop,righr O 201l-2012 - Dental Decks

. Intramuscular

. Inhalation

. Sublingual

. Oral

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Page 226: Pharmacology

Explanation: The purpose ofan acute toxicity test is to determine the nature and extent

ofthe untoward reactions which might iollow the administration ofa single dose (or an

overdose) of a dntg. A quantitative aspect ofacute toxicity testing is the determination ofthe drug's lethal dose using mice. This is usually expressed as the LD59. Standing alone,

it conveys less information than does the ratio of the lethal to the effective doses

(LD5/ED50), a quantity which is often known as the therapeutic index (a measure ofdrug safety).The greater a drug's therapeutic index, the less lik€ly that fatalities will fol-low an accidental overdose.

..' --.,. 1. ED5g is the effective dose at which 50o% ofpeople will respond..:Noted.' 2. LD56 is the lethal dose at which, in theory 50% ofpeople will die..;g..4 *** Lethal doses are always determined in mice, not people

3. The concept oftherapeutic window is not the same as therapeutic index.The therapeutic window describes the range between the lowest therapeutic

concentration and the beginning of toxicity. Some drugs have a very nanowtherapeutic window, making patient monitoring especially important.4. Toxicity results when the dose ofthe drug is excessive for the particular pa-

tient.5. Side effect: an adverse effect that occurs within the therapeutic dose range

ofthe drug.6. Idiosyncratic reaction: a reaction to a medication that is unusual and un-predictable, specific to a particular person. Unlike allergy. it can occur on

first exposure to the medication, unlike a side effect, it affects only very few

individuals.

The oral administration of a drug is the one most acceptable to the patient. It is conven-

ient because drugs can be given in the form oftablets or capsules which contain an exact

dose. lt is easy and the patient can take the drug without help from anyone else.

One ofthe disadvantages of drugs taken by mouth is that they have to be absorbed (trsu-

ulh fiom the small intestine) before they can be transported to their site ofaction. Bloodfrom the intestinal ract passes first to the liver: some drugs are metabolized in the liver( "lirst-pass elfect") and others n.ray be stored there to be released slowly. This considera-

rion makes it clear that oral administration in usually unsuitable in emergencies or on

other occasions when a rapid effect is needed.

Intramuscular injection is an injection made into a large muscle. The advantages ofIM injection are that it results in uniform absorption and that it can be used for solutions

too iritant for subcutaneous injection. The speed ofabsorption of drugs given by IM in-jection depends on dre vehicle in which they are dissolved: absorption is rapid from aque-ous solutions and slow from oily solutions.

Page 227: Pharmacology

: . ... The term bioavailability ofa drug r€fers to:

. The movement of a drug into the body tissues over time

. The dissolution of a drug in the GI tract

. The measurement of the rate and amount of therapeutically active drug that reaches thesystemic circulation

. The relationship between the physical and chemical properties ofa drug and the systemicabsorption ofthe drug

. The amount ofdrug destroyed by the liverprior to syslemic absorption from the GI tract

226CoplriSht O 20ll-2012 - Dental Decks

Factors inlluencing hepatic drug metabolism include which ofthe followlng?

. Microsomal enzyme inhibition

. Microsomal enzyme induction

. Plasma protein binding

. Genetic factors

. Liver disease

. All of the above

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Page 228: Pharmacology

The bioavailability of a drug is allected by:. The dissolution ofa dnrg in thc Gl tract. The destnrction ofa drug by the liver

Phrrmrcokinetics focuscs on the proccsscs concemed with absorption, distribution, biotransfomation (metabo'

lisn), and cxcr.tlon (elim r'nalior) of drugs.

. Absorption: thcre are four prim.ry frctors that must be considered in evaluating drug absorption:

l. Drug chxncteristics:. Formulrtion ot the drug. Co[centration of the dru$ the higher the concentration, the more quickly the drug is absorbcd. Lipophilic drug formulrtions are morc rcadily rbsorbsble: nonionized drugs are more lipid soluble

and may readily difuse across cell membmn€s. Acidic drugs become nonionized in the acidiry ofthe stomach .nd then dilluse across mcmbranes:

basic drugs tend to ionize and arc not well absorbed in the stomach

2. Routes of edministration: the most common routcs for giving medications include oral, topical, subcuta-

ncous, infamlscular, intravenously, and rectal.

3. Blood flowi circulation at the sitc ofadministration is importrant in the drug absorption Foccss. Dc:crcased

circlJl^tion (as see'n fu congestiw heart fail rc) vtill result in dccrcascd drug absorptlon.

4. Cell membrrne chtractedstics: dtugs cross membranes via passivc diffusion or active tmnsport

. Distribution: is thc trrnsport ofa dnrg in body fluids from thc bloodstesm (at lhe sile ofabsorptiotr) to vai-ous tissues in thc body

. Biotranstormation a/n etabolism)t is the chemical inactivation of a drug lhrough convcrsion to a more waler-sol-

uble compoud that can be excreted from th€ body. It occurs primarily in the liver. Involves two major stcps:

Phas€ I makcs the drug morc hydrophilic through oxidation, reduclion, or hydrolysis. Phase lI is called glu'curonidrtion, it involves conjugrtion.. Eliminrtio[: is the proccss by which drugs and their metabolites are removcd from the body. The live. 8nd the

kidney are wo major organs responsible for elimination. Most climination occurs through excrction by thc kid-neys. Thc proc€sses involved in r€nal elimiDation consist ofglom€rular liltrution, tubuhr secretion' rdd par-tirl rerbsorDtion.

Factors Influencing Hepatic Drug Metabolism:

. Microsomal enyzne inhibition: many drugs and environmental agents can inhibitmany of the CYP isoforms of the P-450 microsomal drug metabolizing system. Thus

many drugs which ordinarily are metabolized by the particular CYP inhibited will notbe effectively metabolized and will achieve higher than expected blood levels.. Microsomal enzyme induction: agents which induce higher levels ofthe microso-mal drug metabolizing enzymes may cause a more rapid metabolism ofother drugsthus resulting in lower than expected blood levels ofa drug.. Plasma protein binding: drugs highly bound to plasma proteins will not enter theliver to be metabolized, thus resulting in a longer plasma halfJife ofthe drug.. Genetic factors: there is individual variance through genetic factors which contributeto differing rates of drug metabolism in the hepatic microsomal enzyme system.. Liver disease: hepatic impairment and liver disease most often will result in impair-ment ofthe microsomal drug metabolizing system. This most often results in elevated

levels of unmetabolized drug. Note: Mos! drugs are given at lower doses in hepatically impaired individuals.

Page 229: Pharmacology

. Glomerular filtration

. Microsomal enzyme induction

. Renal tubular reabsorption

. Active hansport tbrough renal tubular cells

Coplright C 201l-2012 Dental Decks

The average time for ths onset of drug effect aftersubcutaneous rdministration is:

. Immediate

. 5 minutes

. 15 minutes

. 30 minutes

229CoDright O 20ll-2012 - Detrtal Decls

Page 230: Pharmacology

. Glomerular liltration: all drugs are filtered through the glomerulus to enter the renal

tubules. The amount of drug varies according to the degree of plasma protein binding,and bound drugs are not subjected to filtration.

. Tirbular reabsorption: once they enter the renal tubules, drugs may be reabsorbed back

into the blood stream through the renal tubular cells. Reabsorption favors the highly lipidsoluble agents; the converse is that highly polar compounds are not effectively reabsorbed

and are effectively excreted from the renal tubules.

. Active transport through renal tubular cells: the rate of renal elimination also de-

pends on whether active transport into or out ofthe tubular fluid occurs.

Other excretory pathways for drugs:. The gastrointestinal tract excretes some drugs through the feces. This is not as preva-

lent as urinary excretion.. Most drugs can be detected in saliva after administration, but the salivary glands are

not considered a route ofdrug excretion since the drug is re-swallowed along with the

saliva.. Lungs excrete volatile compounds that were originally inhaled into the system. Ni-trous oxide and the volatile general anesthetics are excreted by this route.. Some drugs are excreted in the sweat' but this route accounts for only a small per-

centage of drug excreiion.

Routes of Drug Administration:

. Oral route: It takes approximately 30 minutes for onset of drug effect after drug isswallowed. Oral route allows for use ofmany different dosage forms including tablets,

capsules and liquids.

. Intramuscular injection: Onset of action of drugs injected into muscle occurs rap-idly (approximately 5 minutes) because ofhigh blood flow lhrough the muscles.

. Subcutaneous injection: Onset ofaction ofdrugs injected under the skin takes about

l5 rninutes.

. Inhalation: Gases such as nitrous oxide are absorbed rapidly though the lungs and

gain access to the general circulation within 5 minutes.

. Topical: This route includes ointments and creams applied to the skin and mucous

membranes. It is not intended for syslemic drug administration.

. Patch delivery: Onset ofaction ofdrugs in skin patches is about 15 minutes and sim-ilar to subcutaneous injection. Skin patches release drug into the blood stream over al2 to 24 hour Deriod.

Page 231: Pharmacology

. Habituation

. Tolerance

. Addiction

. None ofthe above

230Coplaight e 20ll'2012, Dental Decks

. Oral administration

. Subcutaneous injection

. Intravenous injection

. Intramuscular injection

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Page 232: Pharmacology

Habituation is an acquired tolerance from repeated exposure to a particular stimulus.Psychological and emotional dependence on a drug, tobacco or alcohol result from therepeated use of the substance but without the addictive, physiological need to increase

dosage.

Tolerance is the phenomenon ofdecreased responsiveness to a drug following chronicadministration.

Note: Physiological dependence is common to all forms ofdrug dependence and abuse.

These drugs ofabuse all have the ability lo change one's mood and sensory perception.

trrhen a drug is given intravenously, it is placed directly into the systemic circulation. The

drug is delivered rapidly to all tissues, including the drug receptor sites. For all other

routes of drug adminrstralion (v)ith the exception of intra-arterial inj ection), the drug must

be systemically absorbed prior to distribution to the drug receptor sites, and therefore the

onset of pharmacological effects is slower.

.A.lso. rvhen a drug is given by IV injection there is a complete (100o/') bio^v^ilabilif.The entire dose is placed into the systemic circulation. With other routes of administra-tion. the drug may be lost prior to reaching the systemic circulation. For example, withfirst-pass effects, a portion ofar orally administered drug is eliminated, usually through

degradation by liver enzymes, before the drug reaches its receptor sites.

Remember: The initial distribution ofa drug into the tissues is determined chiefly by

the rate of blood flow to the tissue, whereas drug affinity for the tissue will determine

s hether the drug will concentrate at that site.

l\,lote: Gastric emptying time and degree of plasma protein binding also have an effect

on drug distribution but are less important than the rate ofblood flow to the tissues.

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When a drug is administered repeatedly, a higher coneentntion ofthe drug than is desired may be achieved. The effect ofthis

excessive accumulation is knorvn as:

. Additive effect

. Synergistic response

. Cumulative action

. Idiosyncrasy

232Coplrighr O 201 1-2012 - Denial Decks

. Potential for abuse

. Medical usefulness

. Degree to which it produces physiological dependence

. Degree to which it produces physical dependence

. All ofthe above

233Coptrighr @ 2011-2012 , Denbl Deck

The Controlled Substsnce Act of 1970 uses which criteriofor inclusion of a drug into one ofthe five schedules?

Page 234: Pharmacology

An additive effect occurs when additive drugs are administered. The response is nogreater than that which would be expected had the drugs been given one at a time. Thereis no enhancement ofpotential ofthe individual drugs as a result ofbeing used in com-bination.

A synergistic r€sponse occurs when the combined action of two drugs is greater thanthe sum oftheir individual actions. Examples of synergism: Alcohol is synergistic withdiazepam (Valium), narcotics, barbiturates and phenothiazines. lt should be avoided iftaking these drugs.

Idiosyncrasy is a response to a drug that is unusual or abnormal or one that grossly de-

viates from the routine reaction.

Tle Controlled Substancc Acl of 1970 uses the following critcria fbr inclusion of a drug into onc ofthc fivc schcd-

1 . PorcntiaL for abuse r'', oi inportan,:. \tcdicaluscfulnessL Degfcc to which it produces physiological dcpcndcncc.1. Dclrcc to *hich it produccs physical dcpcndcncc

Remember: Schedule I d gs (LSD, hercin, etc.)@nnot be prescribed and a.c made availablc only for specific ap-

prored research pro.jccts. Schedule II drxgs fdmphetanines, noryhirc, cotleine, oxycodone elc.)$n be prescribed

but can not be refilled. A ne\\ prcscription mustbcwritten forrefills. Prescriptions lor Schedule II drugs can not bc

called into the pharmacy ovcr thc telephone. Schedule III drugs (,,,)d/ocodotie *'ith acetaninophe , cotleine \\'itharctaninophen, etc.) may be called in to thc pharmacy over the telephonc. Thc prcscribcrcan authorizc rcfills with-out need ofa new writlcn prcscriplion.

*** Thc prcscribcr must hsve a Drug Enforcement Agency ruthorization nnmber (DEA #) in ordcr lo prcscribc

schcdulcd drugs.

Clinical testing ofdrugsr Bcfore a drug can be approvcd for salc lo thc public there is a set ofclinical tests that must

be pcrformcd. Thcrc is thc Pre-Clinical Research Stage. Here the drug is s),nthcsizcd and purified. Animal tcsts arc

Dcrformed. and institutional rcvicw boards asscss thc studies and make recommcndations on how to procccd. Ifthcrccommcndations are positivc, thcn an application to the FDA occurs and clinical tesls bcgtn.

'Phase t: clinical studics in this phase represent thc first time that an investigational ncw drug is tested on hu-

mans cithcrhealthy voluntccrs or somctimcs patierts. The purposc ofthcsc studics is study in a clin;cal sctting thc

metabolism, structurc-reactivity rclationships. mcchanism ofaction, and side ellccts ofthe drug in humans. lfpos-siblc, phasc 1 studies arc uscd to determinc how ellcctivc thc drug is. Phasc I studics are usually conducted on 20

to E0 subiccts.. The purpose of phrse 2 clinical trials is to dctcrminc thc cfficacy ofa drug to trcat patients with a spccific dis-

casc or condition. as well as lcam about common short{crm sidc cffccts or risks. These studics are conducted on

a la.gcr scale than phasc I sodics and tlpically involvc scvcml hundrcd patients.. Phase 3 cLinical trials provide morc information about the effects a d safcty ofthe drug and they allow scicn-

tists to cxtrapolate thc rcsults ofclinical studies to thc gcncral population. Phasc 3 studics gcrcrally involvc scv-

cral hundrcd to scvcral thousand pcoplc.*** After a succcssful phasc III, thc drug company submiis to the Food and Drug Administration 1FD,r/ a Ne\r'

Drug Application fND,4/ to markct thc dru8.

Page 235: Pharmacology

' Which ofthe following refers to the efficacy ofa drug?

. The relative concentrations of two or more drugs that produce the same drug effect

. The ability ofa drug to produce a desired therapeutic effect regardless ofdosage

. The dose ofa drug that will kill a patient

234Coplri8ht @ 2011,2012, Denral Decks

. An additive effect

. A synergistic response

. An antagonistic effect

. Cumulative action

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Page 236: Pharmacology

*** Efficacy refers to the number of receptors that must be activated to yield a maximalresponse. A drug with high efficacy needs to stimulate only a small percentage ofreceptors,whereas a drug with lesser efficacy (but still considered to be a full agonist) has to activatea larger proportion of receptors.

Factors Goyerning Drug Action: Two factors that determine the effect of a drug on physio-logic processes are aflinity and intrinsic activity. Affinity is a measure ofthe tightness thata drug binds to the receptor. Intrinsic activity is a measue ofthe ability ofa drug once boundto the receptor to generate an effect activating stimulus and producing a change in cellular ac-

tivity.

Potency is the relative concentrations of two or more drugs that produce the same drugeffect. The effect usually chosen is 50% ofthe maximal effect and the dose causing this effectis called the EC56. Potency is determined mainly by the affinity of the receptor for the drug.Note: The smaller the 8C56, the greater the potency of the drug. Potency is a comparativeterm (o e drug is more polent than another drug).

Exampl€: Drug #l in a dose of l0 mg produces the same magnitude ofresponse as Drug #2

in a dose of 50 mg. The following is true: Drug #l is flrve times as potent as Drug #2.

Also: tf Drug #l has a great€r eflicacy than Drug #2, then Drug #l is capable ofproducinga greater maximum effect than Drug #2.

When comparing drugs with respect to intensity of response, the drug that produces the

greatest maximum effect is the one with the highest ellicacy.

An additive effect occurs when additive drugs are administered. The response is nogreater than the sum ofthe individual actions ofeach drug when given alone. There is noenhancement ofpotential ofthe individual drugs as a result ofbeing used in combination.

A synergistic response occurs when the combined action of two drugs having similarpharmacological effects is greater than th€ sum of the individual actions. Alcohol iss).nergistic with the Valium family ofdrugs fi.e., Valium, Xanax, Halcion, etc), narcoticsand barbiturates. Alcohol should be avoided when takins these medications.