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www.PharmacyPrep.Com Nervous System Drugs

1 - 1Copyright © 2000-2009 TIPS Inc. Unauthorized reproduction of this manual is strictly prohibited and it is

illegal to reproduce without permission. This manual is being used during review sessions conducted by

PharmacyPrep.

Functions of ANS

The functioning of the organs of the human body is controlled by the endocrine system and the ner-

vous system. The endocrine system is controlled by hormones that act as messengers. Circulating

hormones of the endocrine system exert a slowly developing and long lasting control compared to

the control exerted by the nervous system. The autonomic nervous system (ANS) controls involun-

tary body functions. The ANS is composed of two divisions, the sympathetic (adregenic) system and

the parasympathetic (cholinergic) system.

Central Nervous System (CNS)

Spinal cord and brainPeripheral Nervous System (PNS)

Autonomic Nervous System (ANS) Sensory somatic nervous System

12 pairs of cranial nerves

31 pairs of spinal nerves

Cholinergic Adrenergic

Nervous System

▼ ▼

▼ ▼

▼ ▼

1 Autonomic Nervous System Drugs

Types of Neurons in ANS

• Efferent neurons (motor neurons)à deliver message from brain to organs

• Afferent neuronsà Collects message from organs to the brain

Efferent neurons divided into the

• Sympathetic (Adrenergic) nervous system

• Parasympathetic (cholinergic) nervous system

Responsible for regulation of

• Internal metabolic activity

• Myocardium

• Smooth muscle of the viscera

• Glandular activity

• Hormonal activity

• Ensure that the body operates in optimum range

There are four types of adrenergic receptors. These are αlpha-1 and αlpha-2 and βeta-1 andβeta-2. Alpha-receptors are located mainly in the blood vessels and pupils. Βeta-1 receptors

are in the heart and βeta-2 receptors are mainly in the lungs, skeletal muscles and uterus.

Afferent

Efferent


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Sympathetic (adrenergic) Parasympathetic (Cholinergic)

• Originate in the thoracic and lumbar region • Originate in sacral and cranial region

• Post ganglionic nerve fbre very long • Post ganglionic nerve fbre very short

• Preganglionic nerve fbre very short • Preganglionic nerve fbre very long

• Ganglia is near spinal cord • Ganglia is near innervated organs Neurotransmitters

• Norepinephrine (NE)

• Epinephrine (epi)

• Dopamine (D)

• ACh

Neurotransmitters

• ACh

Receptors:

• Norepinephrine (NE)à α1,α

2, b

1 (Not on b

2)

• Epinephrine (epi)àα1, α

2, b

1, b

2

• DopamineàD1 > b > α

• AChà M1

Receptors

• AChàM1, M

2, M

3, M

4 and M5

Functions

• Increase heart rate

• Increase blood pressure

• Increase blood ow to skeletal muscle and heart• Dilation of pupil and bronchioles

• Adjust in response to stressful situation (trauma,

cold, fear, hypoglycemia, exercise)

• Changes in emergencies (Fight or ight response)

Functions

• Maintains essential body functions

(Digestive, waste elimination).

• Oppose or balance the action ofsympathetic.

• Dominant over sympathetic in rest and

digest situation

Receptor Site Effectα

1Vessels Strong vasoconstriction

α1 Brain (postsynaptic) NeurotransmissionContraction

α2

α2

Presynaptic

Membrane

Penis

Auto inhibition of norepinephrine

release

Ejaculationβ

1Heart Stimulation

β1

Kidney

Juxtamedullary apparatus

Renin release

β1

Cerebral vessels Dilation (?)β

2Bladder (including Longitudinal muscle) Relaxation

β1

Fat cells Lipolysisβ

2Bronchial muscles Bronchodilation

β2

Vessels (Venules) Weak vasodilationβ

2Pancreas Relaxation

Insulin releaseβ

2Liver, fat cells Gluconeogenesis,

Glycogenolysis,

LipolysisD

1,D

2 Nigrostriatal pathway Motor coordination

D1,

D2

Median eminence, anterior pituitary Inhibition of prolactin releaseD

1 Nucleus accumbens, limbic system Control of emotions

D1

Renal and mesenteric vessels DilationD

1Chemoreceptive trigger zone Nausea

D2 Ganglia presynaptic membrane Auto inhibition of dopamine release

Both the sympathetic and parasympathetic nerves innervate the same structures. Their actions are opposing

but not equal in scope.

Anatomic Distribution and Main Effects of Catecholamine Receptors

cAMP = cyclic adenosine monophosphate


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Effector Organ Sympathetic ParasympatheticAdipose ↑ Lipolysis (β3)

Metabolise fatty acidsArterioles Skin and mucosa Skeletal Muscle

Constriction (α1)

Usually relaxation (β2,

M) Some relaxation (M)

Some relaxation (M)

Bladder

Detrusor Sphincter

Relaxation (β2)Contraction (α

1)

Contraction (M)Relaxation (M)

Eye Radial Muscle, iris

Sphincter muscle, iris Ciliary muscle

Mydriasis (contraction, α1)

-

Accommodation(Relaxation, β

2)

-

Miosis (M)Contraction for nearvision (M)

Heart Sinoatrial node Atrioventricular node Atria

Ventricles

↑Heart rate (β1)àChronotropic

↑ Conduction (β1)àDromotropic

↑ Contractility (β1)àInotropic

?

↓ Heart rate (M)

↓ Conduction (M)

↓ Contractility (M)

?Kidney Renin secretion (β

1) -

Lacrimal glands - ↑ Tear secretion (M)Liver Glycogen breakdown (β2) Glycogen synthesis (M)Lung (bronchial muscle) Relaxation (β

2) Contraction (M)

Male sex organs Ejaculation (α2) Erection (M) Nasopharyngeal glands - Mucus secretionPancreas ↑ Insulin secretion (β

2) ↑ Fluid secretion (M)

Salivary Glands Viscous secretion (α1) Marked water secretion

(M)

Stomach & intestine

Motility Sphincters Secretion

Decrease (β2)à

PeristalisisContraction (α1)àSpincter

-

Increase (M)Relaxation (M)

Stimulation (M)

Sweat glands ↑ Secretion (M) ↑ Secretion (M)Uterus ↑ Contraction (α

1)à Relaxes detrusor

muscles

Relaxation (β2)

-

Veins (systemic) ↑ Dilation (β2) -Spleen Contraction (α1) -

(a=alpha, β =beta, M=cholinergic-muscarinic)

Abbrevation and Terminology

ANS Automic Nervous System

CNS Central Nervous System

EPI EpinephrineM Cholinergic-muscarinicACh AcetylcholineD DopaminecAMP Cyclic Adenosine Monophosphate

NE Norepinephrine


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Generic and Brand

Epinephrine Epipen, Anapen


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www.PharmacyPrep.Com Adrenergic Drugs



PharmacyPrep.

a1agonists

a1 agonists • Phenylephrine

• Pseudoephridine• Methoxamine

Pharmacologicalactions

• Bronchodilation• ↑ Blood Pressure• ↑ Peripheral Resistance

• ↑ Closure Sphincter bladder• Mydriasis• Vasoconstriction

Therapeutic use • Dimetapp Cold (Night time) extra strength containsà Phenylephrine + chlorpheniramine + acetaminophen

• Dimetapp Daytime Cold extra strength containsà Pseudoephedrine + Acetaminophen

a2 agonist – Centrally acting antihypertensive

a2agonists • Methyldopa• Clonidine• Guanabenz

Adrenergic agonists

Alpha agonist • Alpha 1 agonist

• Alpha 2 agonist

Beta agonist • Beta 1 agonist

• Beta 2 agonist

• Mixed alpha and beta agonist

Adrenergic antagonists

Alpha antagonists

(a-blockers)

• Alpha1 antagonists (a1-blockers)

• Alpha 2 antagonists (a2-

blockers)

• Alpha 1 and 2 antagonistBeta antagonists

(b-blockers)• Beta antagonists (b-blockers)• Non selective b-blockers• Cardioselective b-blockersPartial alpha and beta blockers

• Partial agonist and antagonist

2Adrenergic Drugs

(Sympathetic Drugs)

Adrenergic agonist (Sympathomimetics)

Epinephrine

(in blood)

Adrenergic

ReceptorAdrenergic

Receptor

Norepinephrine

Ach


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Mechanism • Decrease Central adrenergic outow• a

2 receptors located on perineuronal membrane

• a2 receptors have inhibitory action on epinephrine and NE

• Increase alpha2 receptors increase inhibitory action on epi and NE

• ↓ Blood Pressure• ↓ Release of insulin• ↓ NE• Bradycardia

Therapeutic use • Centrally acting antihypertensive• Hypertension with renal disease (no decrease blood ow to kidney)

Common side effects • Rebound hypertensionà clonidine

b-agonists pharmacological actions

b-agonists non selective • Dobutamine (b1>b

2)

• Isoproterenol (b1= b

2)

Mechanism • Tachycardia

• Increase lipolysis• +ve Inotropic effect (increase force of contraction of heart)• Increase Cardiac output (CO)• Increase Heart rate (HR)• Bronchodilation

Therapeutic use • Dobutamine (Dobutrex)à the treatment of adults with cardiacdecompensation due to depressed contractility resulting fromorganic heart disease or following cardiac surgical procedures inwhich parenteral therapy is necessary for inotropic support.

Contraindication Tachycardia and ventricular brillation

Beta 2 agonist

Beta2 agonist Short acting beta

2 agonist

• Albuterol (Salbutamol)• Terbutaline• Metaproterenol• Pirbuterol

Long acting beta2 agonist

• Salmeterol• Formeterol

Mechanism • Bronchodilation• Vasodilation• Slightly decrease peripheral resistance• Increase muscle and liver glycogenolysis• Relax uterine muscles• Increase release of glucagon

Therapeutic use • Treat Asthma and COPD

Short acting beta2

agonist• Rapid onset of action and provide relief for 4 to 6 hours.• Indicated in symptomatic treatments, rescue agents, combat acute broncho-

constriction• Albuterol, terbutaline, pirbuterol has little alpha-1 and beta-1 effects.

• Does not effect by COMT enzymes because these are activated by nonCOMT (Catechol Amine O-Methyl Transferase)


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• Inhalation route has less toxic side effects than systemic routes.• Have less tachycardia, hyperglycemia, and hypokalemia effects with

inhalations routes.• Short acting are best reserved for treatment of acute exacerbations and

prophylaxis of exercise induce asthma

Long acting beta2

agonist

• Salmeterol has long duration of action, providing bronchodilation for at

least 12 hours, and slow onset of action.• Indicated in maintenance treatment in combination with corticosteroidsespecially for nocturnal asthma, EIA, and COPD

• Not indicated in acute asthmatic attacks

Mixed a and b agonist

Mixed a and b agonist • Dopamine• Epinephrine• Norepinephrine

Norepinephrine • a1, a2, b1 agonistMajor affects • Vasoconstriction

• ↑ Cardiac contractility• ↑ Systolic Blood Pressure (SBP)• ↑ Diastolic Blood Pressure (DBP)• ↑ Peripheral Resistance (PR)• Reex bradycardia• Vasoconstriction à causes peripheral resistance• Baroreceptor reexà stimulates cardiac contractility

Epinephrine (Adrenaline)

Action • a 1, a

2 at higher doses and b

1 and b

2 at lower doses

Cardiovascular • At low doses beta effectsà vasodilation• At high doses alpha effectsà vasoconstriction predominates.• ↑ oxygen demand• ↑ the rate of contraction (+ve chronotropic effect, b

1action)

• ↑ the contractility of myocardium (+ve inotropic effect, b1 action)

• ↑ systolic (SBP) and slight decrease diastolic (DBP)à reex bradycardia

Respiratory • Intense bronchodilatorà used for allergic and histamine induced bronchoconstriction

Hyperglycemia • Has signicant hyperglycemic effect (↑ glycogenolysis),• ↓ Release of insulin.• Causes lipolysis

Therapeutic use • Acute asthma• Anaphylactic shock (Type1 hypersensitivity)• Glaucoma (2% epinephrine solution)• In local anesthesia (1:100,000)à Due to vasoconstrictor

Side effects • CNSà Anxiety, fear, tension, headache, and tremor • Hemorrhageà Elevation of BP may cause hemorrhage• Arrhythmiasà Can trigger arrhythmias in patient using digitoxin• Pulmonary edemaà Can cause pulmonary edema


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Dopamine (Inotropin)

Mechanism • Act on D1, D

2, D

3, D

4, D

5, and Mixed a and b agonist

Major affects • Has +ve inotropic and +ve chronotropic effects

• Dilates renal arterioles by increasing blood ow to kidney

• Dopamine is drug of choice for shock given by continuous infusion.• Same as adrenergic agonist

• Metabolizes to homovanillic acid

Adrenergic Blockers

a1-antagonists

a1-antagonists • Prazosin

• Terazosin

• Doxazosin

• Tamsulosin (a 1A

)

• Alfuzosin (a 1A

)

Mechanism • ↓ BPà orthostatic hypotension

• ↓Total Peripheral Resistance

• No Reex tachycardia

• Vasodilations

• First dose effect (syncope)à Fainting

• Miosis

Therapeutics use • Antihypertensive

• Symptomatic Benign Prostate Hyperplasia

Side effects • Postural (Orthostatic) hypotension

• Headache, drowsiness, palpitation

Comments • Starting dose for doxazocin 1mg once daily and titrate slowly• Tamsulosin has no postural hypotension

• Tamsulosin is a selective a 1A receptor blocker

Adrenergic antagonists

Alpha-blockers

(Adrenergic blockers)

Beta blockers Neuronal blockers

Selective (α1

Doxazocin (α1)

Terazocin (α1)

Tamsulosin (α1a

)

Nonselective(α

1 and β

2

blockade)

blockade)ββ

1, 2 , &α1 blockade

Carvedelol

Labetelol

Selective (β1

EsmololMetoprolol

Atenolol

Acebutolol

Nonselective

(β1 and β

2 blockade)Propanolol

Pindalol

Nadolol

Timolol

Levobutalol

Reversible

Phentolamine

Irreversible

Phenoxybenzamine


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a2-antagonist

Yohimbine • Yocon and odan

Pharmacological

actions

• Blocks presynaptic a2

• ↑HR

• ↑BPTherapeutic use • For impotency treatment

Side effects • Postural hypotension

Contraindications • Renal and hepatic diseases

• Cardiovascular disease

Mirtazepine • Used as antidepressant

a1

& a2 antagonists

a1& a

2 antagonist

Phentolamine

(Reversible)

• Competitive, short acting agent

• a blockade

• ↓BP

• ↓Total Peripheral Resistance

• Reex tachycardia.

Therapeutic use • Used occasionally in patients to ↓BP

• Pheochromocytoma

Phenoxybenzamine

(Irreversible)

• Non-competitive long acting blocker

• NE release is enhanced due to blockade of presynaptic a receptors-causes excessive response.

• Used occasionally in patients to ↓BP

Pheochromocytoma • Type of adrenal gland cancer

• Can cause uncontrolled blood pressure

• Can cause uncontrolled tachycardia

• Increase heart rate and palpitation

b-blockers

Mixed b1 and b2-antagonists (non

selective)

• Propranolol ProPiNaTionaLe• Pindolol

• Nadolol

• Timolol

• Levobutolol

Mechanism • Reduce intra ocular pressureà Decrease secretion of aqueous humor

• Bradycardia

• Bronchoconstriction (Bronchospasm)

b1 antagonists

(cardioselective or

selective)

• Esmolol Selective EMAA

• Metoprolol

• Acebutolol• Atenolol


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Mechanism • Vasoconstriction

• No bronchoconstrictionMixed a and

b-antagonists

• Labetalol: acts a1, b

1 and b

2 receptor (Non-ISA/alpha)

• Carvedilol: acts a1, b

1 and b

2 receptors (Non-ISA/alpha)

Mechanism • Produce vasodilationà ↓ BP

• Peripheral vasoconstriction

• Does not alter serum lipid levelsPartial agonist andantagonist

• Acebutolol

• Pindolol

• Oxprenolol

Mechanism • Intrinsic sympathomimetic activity (ISA)

• Minimized disturbances of lipid and carbohydrate metabolism.

ISA: Intrinsic

Sympathomimetic

Activity:

• The partial agonist stimulates the beta-receptors to which they

are bound; yet inhibit stimulation by the more potent endogenous

catecholamines, epinephrine and norepinephrine.

Summary of the side effects of adrenergic Drugs(Sympathetic drugs)

Adrenergic agonists

Alpha agonist • a 1 agonist

• Phenylephrine• Pseudoephridine

Increase BPInrease TPR • Vasoconstriction• Mydriasis

• a 2 agonist

• Clonidine• Methyl dopa

• Decrease lipolysis

• Decrease insulin secretions• Sexual dysfunction

Beta agonist • b1 agonist

• b2 agonist • Tremors

• Palpitations• Hyperglycemia• Tachycardia

• Mixed a and b agonist

AdrenergicantagonistsAlpha antagonists

(a-blockers)

• a1 antagonists (a

1-blockers)

• Doxazocin• Prazocin• Terazocin• Tamsulosin

• Orthostatic hypotension

• Tachycardia (No reex tachycardia)• Vertigo• Sexual dysfunction• First dose effects (syncope)

• a 2 antagonists (a

2-blockers) • Hypotension

• a 1 and 2 antagonist • Orthostatic hypotension

• Reex tachycardia

Beta antagonists(b-blockers)

• Non selective b-blockers• Propranolol• Pindolol

• Nadolol• Levobutalol• Timolol

• CNSà insomnia, fatigue,hallucinations, impotency (libido)

• CVSàDecrease HDL and increase

TG, bradycardia, orthostatichypotension


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• Cardioselective b-blockers• Esmolol• Metaprolol• Atenolol• Acebutalol

• Partial alpha and beta blockers• Carvedilol

• Labetelol• Partial agonist and antagonist

• Acebutalol• Pindolol• Oxyprenolol

Adrenergic Drugs Tips

• Drugs that have +ve inotropic and +ve chronotropic effect is: dopamine.

• Inotropic is: force of contraction (+ve increase in force of contraction)• Chronotropic is: heart rate (+ve increase in heart rate)

• Drugs that have +ve inotropic and –ve chronotropics is: Digoxin

• Drugs that have +ve inotropic are: ACE Inhibitors.

• Epinephrine is used for: Anophylactic reaction or hypersensitive reactions.

• Epinephrine is: a1, a2, b

1 and b2 agonist

• Xylometazoline action is on alpha-adrenergic receptors.

• Salbutamol is b2 agonist

• Summary of b2 agonist:

• b2 agonist drugs have no anti-inammatory effect and act as branchodilators

• SABA always used as prn and tolerance can occur with regular use and also mask the symptoms

of inammation.• SABA has additive effect with anticholinergic drugs (Ipratropium)

• LABA always used as daily dose.

• LABA has same effect as SABA but long duration of action.

• LABA has synergistic effect with corticosteroids. (Products available: Fluticosone + Salmeterol

= Advair)

• SABA and LABA are branchodilators.

• Beta-blockers are drug of choice for uncomplicated hypertension in patient age under 65 years

old.

• Beta-blockers are used cautiously in: Asthma, CHF, Diabetes and sever peripheral vascular

diseases.

• Diabetic patient taking beta-blockers monitor? Blood sugar levels

• Digoxin, non-DHP CCB may cause additive Bradycardia with beta blockers.

• b-blockers are drug of choice for orthostatic hypotension.

• What adrenergic blockers are useful in treating Tachycardia? b blockers (Propranolol)

• The longest acting beta-blockers is? Nadolol

• Example of irreversible and noncompetitive a1 and a2 blocker isà Phenoxybenzamine

• Examples of drugs that reverse effect of epinephrine associated vasocontriction à a1 blockers.

• Examples of sympathomimetic that should be avoided in Glaucomaà Phenylephrine,

pseudoephridines.


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Generic and Brand

NE Norepinephrine

CNS Central Nervous System

CO Cardiac Output

HR Heart RateCOPD Catechol Amine O-Methyl TransferaseEIA Exercise Induce AsthmaSBP Systolic Blood PressureDBP Diastolic Blood PressurePR Peripheral ResistanceTPR Total Peripheral ResistanceBPH Benign Prostate HyperplasiaIOP Intra Ocular PressureBP Blood PressureEMAA Esmalot, Metopralol, Acebutalot, AtenalolISA Intrinsic Sympathomimetic Activity

HDL High density LipoperteinsACE Angiotism Converting EnzymesSABA Short Acting b

2 Agonist

LABA Long Acting b2 Agonist

CHF Congestive Heart FailureDHP DihydropyridineCCB Calcium Channel Blockers

Xylometazoline Otrivin

Fluticasonet + Salmeterol Advair


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3 Cholinergic Drugs

(Parasympathetic Drugs)

Acetylcholine is not reuptaken, it is terminted by enzyme Acetylcholine esterase. This enzyme

hydrolyse Acetylcholine into choline and acetate. This Acetylcholine esterase only found in synaspe.

• Choline can be recycled but not ACh

• Muscuranic innervation

Hearts have too kiond of tissue, muscle tissue such as atrial tissue and ventricle tissue also

specialized cells called Nodal cells. Node cells are highly innervated by parasympathetic system.

There is no innervations of the parasympathetic system in ventricle and purkinje bre.

Only sympathetic system can innervate the blood vessels.(Smooth muscle)

Blood vessels (endothelium) - Muscuranic Receptors present

This endothelium Muscuranic receptor stimulation result in NO release.

This endothelium derived NO release.

This endothelium derived NO diffuses into smooth muscle and mediates relaxation of smooth

muscle by ↑cAMP

So the only true Muscuranic agonist have the above action.

Nicotinic receptors (N N, NM)

• NN → Adrenal medulla, autonomic ganglia

• NM→ Neuromuscular junction

Cholinergic

agonists

Antiacetylcholinesterases

Choline

estere

Pilocarpine

Cevimeline

Bethanechol

Carbachol

Quarternary

alcoholsCarbamate Organo-

phosphate

Edrophonium

TacrineDonepezil

Physostigmone

NeostigmineDemecarium

Pyridostigmine

Echothiophate

MalathionParathion

Sarin

Soman

Acetylcholine

agonists

Direct

cholinergic

agonist

Indirect

cholinergic

agonists

Classication of Choliinergic Agonist


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Direct acting muscuranic agonist recluse (Braolyeardia)

The heart rate directly affectin on M3 receptors. Also their effect on endothelial blood vessel release

NO, which dialte, the smooth blood vessels. This will cause reux Tachycardia.

Atropine overdose

Atropine is lipid soluble only physostigmine can enter CNS, so it will be used as Atropine antidote.

Summary of Cholinergic receptors effects:

Muscarinic Receptor EffectEye –sphincter muscle M

3Contraction- causes miosis

Heart – SA node AV node

M2

M2

Decrease HR (-ve chronotropy)-vagal arrestDecrease conduction velocity (-ve dromotrophy)

Lung- branchioles Glands

M3

M3

BranchospasmIncrease secretions

GI tract M3

Stomach-increase motility causes crampsIntestine-increase motility causes diarrhea

Blood vessels M3

Vasodilation but no innervation (to stimulate for action)

Nicotinic NAdrenal medullaGanglia

Neuromuscular junction

N Increase secretion of epi and norepinephrine

Stimulation causes muscle hyperactivity

Side Effects

Cholinergic drugs AnticholinergicMyopic accommodation

Bradycardia

SalivationLacrimation

Flushing

Diarrhea

Hypotension

Tremors

Hyper optic

accommodation and

increased intraocular pressure

Tachycardia

Dry mouth

Blurred vision and

mydriasis

Constipation

Urinary retention

Dizziness and

drowsiness

Direct acting cholinergic drugs

Direct acting

Cholinergics

• Acetylcholine

• Pilocarpine

• Bethanechol

• Carbachol• Methacholine

Acetylcholine

Synaptic

vesicle

Choline

Choline

Acetate

Choline

Presynaptic

receptor

Acetylcholine

INTRACELLULAR

RESPONSE

Acetylcholine

CoA


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Muscarinic antagonists

Nicotinic Blockers (Ganglionic blockers)

Nicotine: Depolarizes ganglia, resulting rst in stimulation and followed by paralysis of all ganglia,

increase in BP, HR, inceased peristalsis, and secretion.

a-Bungarotoxin

a -Bungarotoxin is a postsynaptic neurotoxin found in the venom of the Braided Krait snake

(Bungarus Multictus). Like other neurotoxins it blocks neuromuscular transmission.

α-Bungarotoxin (α Bgtx) is a toxin known to interact with muscle nicotinic receptors and with some

neuronal nicotinic receptors.

NMJ blockers

These agents are used for surgical patients to relax the muscles during surgery. .Pharmacological actions:

• Blocks the cholinergic transmission between motor nerve and nicotinic receptors.

• Antagonizes (non depolarizing type) and agonist (polarizing) the effect of acetycholine.

Classied as two categories of NMJ blockers:

Depolarizing: Succinylcholine

• Depolarizing drug attaches to nicotinic receptors and act like acetylcholine to depolarize the

junction.

• Causes opening of sodium channel associated with nicotinic receptors, which results in

depolarization of receptors.

Non-depolarizing:

• Prevents the binding of acetylcholine.

• Inhibits muscular contraction

Anticholinergic

drugs

• Atropine

• Ipratropium

• Scopolamine

• Benztropine• Tropicamide

• Glycopyrrolate

• TrihexyphenidylPharmacological

actions• ↓ in salivationà cause

dry mouth (xerostomia)

• ↓ intestinal secretionà Constipation

• Increase HRà Tachycardia

• Mydriasisà Pupil dilatation

• Relaxation of detrussor muscleà Urinary retention

• Blurred visionAnticholinergic

side effects

• Dry mouth

• Blurred vision

• Tachycardia

• Constipation

• Urinary retention

Tertiary amines

Atropine

Scopalamine

Muscarinic antagonist

Quarternary amine

Ipratropium

Tiotropium


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• Antagonist for non depolarizing agents are: neostigmine, edrophoniuum (cholinesterase

inhibitors)

• At higher doses, these (non depolarizing) drugs block the ion channels of end plate and

reduced the ability of antagonists.

• Indicated in anesthesia during surgery to relax skeletal muscles.

• Side effects: Decrease the BP, paralysis of diaphragm


Generic and Brand

Depolarizing NMJ Blockers

Depolarizing – Noncompetitive

• Succinylcholine

Mechanism • Blocks the cholinergic transmission between motor nerve and nicotinicreceptors.

• Antagonizes (non depolarizing type) effect of acetylcholine.Therapeutic use • Clinically used in surgery to produce complete muscle relaxation.

SA Sinoatrial Node

AV Atroventricular Node

PR Peripheral Resistancea -BgTx a -BungarotoxinACh Acetyl Choline

NMJ Neuro Muscular JunctionBP Blood PressureHR Heart Rate

Non-depolarizing NMJ Blockers

Non Depolarizing -competitive • Atracurium• Tubocurarine• Doxacurium• Pancuronium• Vecuronium• Mivacurium

Mechanism • Prevents the binding of acetylcholine• Inhibits muscular contraction.• At higher doses, these (non depolarizing) drugs block the ion channels

of end plate and reduced the ability of antagonists

Therapeutic uses • Indicated in anesthesia during surgery to relax skeletal muscles.

Side effects • Decrease BP• Paralysis of diaphragm

Antagonist for nondepolarizing agents

• Neostigmine, edrophonium (cholinesterase inhibitors)

Pilocarpine IsotoCarpine

Atropine Atreza, AtroPen, Atropine Care, AtropisolIpratropium Atrovent, Atrovent HFAScopolamine Isopto Hyoscine, Maldemar, ScopaceBenztropine Cogentin


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4 Antihypertensive Drugs

Blood Pressure is caused by Cardiac Contraction

• Systole (contraction)

o When the heart beats (systole) the pressure in the arteries leaving the heart

rises to about 120 mm Hg.

• Diastole (relaxation)

o Between beats (diastole) the arterial pressure drops to about 80 mm Hgo The 80 mm Hg DBP keeps the blood owing between beats

• Blood pressure is reported as SBP over DBP

o Example: 120/80

• Optimal BP is 120/80

• Normal BP is 130/85

• High normal BP is 130-139/85-89

• Grade 1 (mild hypertension) 140-159/90-99

• Grade 2 (moderate hypertension) 160-179/100-109

• Grade 3 (severe hypertension) >180/>110

• Isolate systolic hypertension >140 / 130/>80

Laplace’s Law

Laplace’s law describes how tension in the vessel wall increases with transmural pressure.

According to Laplace’s law, the PRESSURE GRADIENT ACROSS THE VESSEL WALL is given

by: tiwhere Pout and Pin are the pressures outside and inside the vessel, respectively. T is the vessel

wall tension, and r is the vessel radius. If the vessel wall is completely attened against a smooth

sensor surface (r→∞), the measured pressure will be equal to the intra-luminal blood pressure

(DP→0).

Systemic Blood Pressure Depends Upon1-Cardiac Output and Resistance to Flow (TPR): CO = HR X SV

2-Kidney provide long term control of BP

X Total Peripheral Resistance (TPR)= Cardiac Output (CO)Blood Pressure

Angiotensin

antagonistAlpha

2

agonists

Alpha1

Blocker

Calcium

Channel

Blockers

Beta

Blockers Diuretics

AT1 Receptor

Blocker ACE inhibitors


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Nonselective (β

1 & β

2)

Cardioselective

(β 1

only)

Beta & Alpha blockers

Partial agonist &

antagonist

• Propranolol• Pindolol• Nadolol• Timolol• Levobutolol

• Esmolol• Metoprolol• Acebutolol• Atenolol• Bisoprolol

Betoxalol

• Labetalol• Carvedilol

• Acebutolol• Pindolol• Oxprenolol

VasoconstrictionReduce intra

ocular pressure

(IOP) = ↓ secretion of

aqueous humor

Bradycardia

Alpha receptorsProduce

vasodilatation =

↓BPBeta blocker

cause Peripheral

vasoconstriction

Does not alter

serum lipid

levels

Intrinsicsympathomimetic

activity (ISA)

Minimized

disturbances

of lipid and

carbohydrate

metabolism

By altering blood volume: Sympathetic stimulation releases the enzyme renin. Angiotensinogen and

angiotensin I & angiotensin II.

Angiotensin II is the bodies most potent circulating vasoconstrictor causing increases BP.

Angiotensin II stimulates aldosterone (ADH) secretion leading to increase kidney sodium reabsorption

and increase in blood volume, which contributes to increase in BP.

Systemic blood pressure depends upon cardiac output and resistance to ow

β-blockersBeta-blockers are used to treat hypertension and angina. These drugs act by slowing the heartbeat,

which results in lowered blood pressure since blood pressure is affected by the heart rate and

peripheral resistance. Because of its action on the lining of arteries, propranolol is also used to treat

migraines.

Nonselective (β1

& β2)

CardioSelective

(β 1

only)

Beta & Alpha blockers

Partial agonist

& antagonist

Beta Blockers

►

►

►

►

• The more blood pumped into the arteriesthe higher the pressure

• Pressure also goes up if there is moreresistance to ow- this occurs when largenumbers of arterioles constrict

• The body changes both CO and resistanceto adjust blood pressure, the higher the

blood pressure the more work the heartmust do to pump blood.

Renin

Angiotensin I

Angiotensin II

Aldosterone

Na/H2O retension

PR

BP

Blood

Volume

ACE


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Mixed β1 and β

2-

antagonists (non

selective)

• PropranololProPiNaTionaLe

• Pindolol• Nadolol• Timolol• Levobutolol

Mechanism • Reduce intra ocular pressureà Decrease

secretion of aqueous humor • Bradycardia• Bronchoconstriction (Bronchospasm)

β1 antagonists

(cardioselective)• Esmolol• EMAA Selective• Metoprolol• Acebutolol• Atenolol

Mechanism • Vasoconstriction• No bronchoconstriction

Mixed a and

β-antagonists

• Labetalol

• CarvedilolMechanism • Produce vasodilationà ↓ BP

• Peripheral vasoconstriction• Does not alter serum lipid levels

Partial agonist andantagonist

• Acebutolol• Pindolol• Oxprenolol

Mechanism • Intrinsic sympathomimetic activity• Minimized disturbances of lipid and

carbohydrate metabolism.

ISA: Intrinsic

SympathomimeticActivity:

• The partial agonist stimulates the beta-

receptors to which they are bound; yetinhibit stimulation by the more potentendogenous catecholamines, epinephrine andnorepinephrine.

• The result of opposing actions is a much-diminished effect on cardiac rate and cardiacoutput.

• Compared to β-blocker without ISA.Side effects

Slowed heartbeat (bradycardia), profound low

blood pressure (orthostatic hypotension), dizziness,depression, drowsiness and some stomach upset andhypoglycemia. Because of the effect of βeta-blockeron the βeta-receptor of smooth muscle, the lining ofthe bronchioles may be affected. These drugs canaggravate asthma, breathing difculty or shortnessof breath in some sensitive patients. These drugsshould not be given to asthma patients unless noother class of drug can be used. However, esmalol,acebutol, atenolol, bisoprolol, betaxolol andmetoprolol are selective β-blockers and generally,have less or no bronchospasm side effects. Theselective β-blockers may be given to lower doses to

patients sensitive to these drugs if no other class ofmedication can be used.

Mechanism of action of beta-blockers

β1 receptors

↑ CO

↑ HR

↑ Force

blood

β receptors

peripheral

vasodilation

Effect of B receptor

on heartCardiac output

Renin Angiotensin II Preripheral

resistant

Aldosterones

Na, H2O levelsBlood volume

Cardiac output

BP


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Contraindications

• Bradycardia• Heart blockage• Asthma and bronchospasm (avoid non selective)• Peripheral vascular diseases such as Raynaud’s

phenomenon and intermittent claudication except

carvedilol and labetelol can be tried.• Caution in congestive heart failure.• Left ventricular dysfunction

Drug and food interactions

• Propranolol is best absorbed with food butconsistency is the most important factor

• Metoprolol is best taken with meals• These drugs should be taken at about same

time every day

• Beta blocekers that have Ist pass metabolism; propranolol, timolol

• Beta blocekers that have no biotransformation;atenolol

• Beta blocekers that have α blockadeeffect:labetalol, carvedilol

• Beta blocekers that act as membrane stabilizer;

propranolol

Alpha-blockers are the drug of choice in

Decrease in contractility of heart and decrease

in oxygen consumption

Propranolol Used for hypertension, angina, post MI, migraine, essential

tremor, performance anxiety,

Hyperthyroidism (acute-

thyroid storm)

Timolol Used for hypertension, postMI, migraine. Chronic

treatment of Open angle

glaucoma

Pindolol Used for hypertension

Metaprolol Cardioselective, used forhypertension, angina

Atenolol Cardioselective, used forhypertension

Esmolol Cardioselective used forhypertension, tachycardias

Acebutolol Cardioselective, used forhypertension, angina

Beta-blockers therapeutic uses:

In addition to being used for hypertension, terazosin, doxazosin, tamsulosin and alfuzosin which are

chemically related to prozasin are often used to treat benign prostatic hypertrophy (BPH), the medical

term for enlarged prostate. These drugs cause the muscles of the bladder neck and prostate to relax,

thereby making it easier for patients to urinate. As Antihypertensives, they help control pressure by

relaxing blood vessels and permitting them to expand.

α1-antagonist α

2-agonist

Indication Hypertension

Benign Prostatic Hypertrophy

(BPH or enlarged prostate)

DOC for pheochromacytoma

hypertension

Hypertension

Treat withdrawal

symptoms in recovering

drug and alcohol abusers

(Clonidine)ContraindicationSide Effects Orthostatic hypotension

Tachycardia

Vertigo

Sexual dysfunction

Decrease lipolysis

Decrease insulin secretion

Sexual dysfunction

α-receptors

a1 antagonists

• Doxazosin mesylate

• Prazosin hydrochloride• Terazosin hydrochloride dehydrate

• Alfuzosin

• Tamsulosin


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pheochromacytoma hypertension.

Pharmacological actions of a 1 anatagonist:• ↓ BP

• ↓Total Peripheral Resistance (TPR)

• No Reex tachycardia

• Vasodilations• First dose effect (syncope)

• Miosis

Side effects: Orthostatic hypotension, Tachycardia (No reex tachycardia), Vertigo, Sexual dysfunction

to avoid the rst dose effect of hypotension and occasional syncope, the starting doses should be small

and given at bedtime.

a2 agonist – Centrally acting antihypertensive

a2 agonist used to treat hypertension are centrally acting agents, which act directly in the brain tochange the signals send to the heart and blood vessels. These drugs are not commonly used, as it is

difcult to achieve the proper dose with these agents. They are generally reserved for people who

fail to respond to other therapies.

Other uses have been found for clonidine. Clonidine is sometimes used to treat withdrawal

symptoms in recovering drug and alcohol abusers.

a2 agonists

• Methyldopa

• Clonidine• Guanabenz

Pharmacological actions a 2 agonist:• Decrease Central adrenergic outow

• a2 receptors have inhibitory action on epinephrine and NE• Increase a2 receptors increase inhibitory action on epi and NE• ↓ Blood Pressure

• ↓ insulin secretions

• ↓ NE

• Bradycardia

• Side effects: Decrease lipolysis, Decrease insulin secretions, Sexual dysfunction

Methyldopa (Aldomet)

Mechanism • a2 agonists

• Inhibit norepinephrine release

• Inhibit insulin releaseTherapeutic use • Indicated in moderate to sever hypertension

• Produced active metabolite (Methyl dopaà Alpha methyl

norepinephrine)

• Methyl dopa is prodrug• Drug of choice for hypertension in pregnancy.

cAMP

ATP

α

Norepinephrine


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Side effects • Cardiovascularà Bradycardia, orthostatic hypotension

• Blood relatedà Hemolytic anemia, thrombocytopenia

• Bone marrow depression

• GIà Dry mouth, nausea, diarrhea

Clonidine (Cataprex)

Chemistry • Clonidine contain imidazoline ring.

Therapeutic use • Used in non complicated hypertension to lower BP.

• Indicated in opioids and benzodiazepine withdrawal symptoms (CNS

symptom)Side effects • CVSà bradycardia orthostatic hypotension, severe rebound hypertension

• CNSà drowsiness, dizziness, agitation

Dosage • Transdermal patch

• Pruritus and rash at the site of transdermal• Patch (TT1 (release 0.1 mg/24 h), TT2 (0.2 mg 24/h). TT3 (0.3 mg/24 h)Precautions • Don’t discontinue abruptly, reduce dose over 2-3 days to reduce sever

hypertension

Counselling • Don’t miss any pill, Don’t stop suddenly

• Causes drowsiness

• Need gradual withdrawal

Diuretics

• Often called water-pills, diuretics increase urine production,

• Reducing the body of sodium and water, thereby reducing the volume of blood that the heart

must pump, and in this manner decreasing blood pressure.

• Side effects: stomach upset, frequent urination, potassium depletion, and dizziness.

• Potassium blood levels should be monitored.

• Foods rich in potassium may be ingested (eaten) daily. These are potatoes, bananas, cantaloupe,

and citrusfruit.

• If potassium levels are very low, potassium chloride or potassium oral liquids may be used.

• Mechanism of hypokalemia induced by CA inhibitors, loops and thiazide diuretics: Because of

upstream blockade of NaCl reabsorption there is ↑ Na+ consequently there is ↑ reuptake of Na+. ↑

+ve charge in the cell. The increase +ve charge then pushes out K + into the lumen.

Thiazide

DiureticsLoop

DiureticsK-sparing

diuretics

Carbonic acid

Inhibitor

Osmotic

diuretic

Chlorothiazide

Hydrochlorothiazide

Chlothalidone

Furosemide

Ethacrynic acid

Bemetanide

Spirolactone

Triamterene

Amiloride

Acetazolamide Mannitol

Classication of Diuretics


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• Nephritis (intestinal)

• Gout arthritis

• Sequence of ototoxicity (etharynic acid>furosemide>bumetanide)

Do not use • If patient has renal stones

• If patient has gout do not use loop and thiazides

Ethacrynic Acid • Does not contain sulfonamide functional groupà no sulfa allergy

Potassium sparing

Potassium sparing • Amiloride (Midamor)

• Triamterene (Dyrenium)

• Spironolactone (Aldactone)

• The K + STAys

• Spironolactone

• Triamtereneà blue color urine

• AmilorideMechanism • Act in the early collecting duct to

inhibit the electrogenic reabsorption

of Na+ by blocking the Na channels

and hence the exchange of sodium for potassium.

• After administration: ↑ Na+, Cl- elimination, ↓K+, Ca++ (amiloride).

• Increase Na, H2O, HCO

3 excretion (decrease levels in body)

• Decrease K +, H+ excretion

• Alkaline urinary pHà Increase excretion of HCO3

Aldosteroneantagonist

• Spironolactone (Aldactone): competitive inhibits aldosterone at minorAldocorticoid receptors. Decreases potassium excretion.

Non aldosterone

antagonist

• Amiloride and triamterene

• Act directly on late distal tubule and collecting duct. They disrupt

sodium exchange with Potassium and hydrogen by blocking sodium

channel

• Decrease in the driving force for secretion of potassium and hydrogen.• Used in nephrogenic diabetic insipidus

• Amiloride, spironolactone and trianterene act as competitive antagonists of aldosterone in the

kidney. Because they are weak diuretics when given alone, they are often used in combination

with hydrochlorthiazide, as in Aldactazide, Apo-Triazide, Apo-Amilzide.

• A side effect may be hyperkalemia, an increase in potassium levels, so that potassium

supplements are usually not taken with these drugs. If they are needed, the dose of potassium is

frequently administered three times a week instead of daily.

Osmotic Diuretics

Osmotic • Mannitol, and Urea

Mechanism • Increase excretion of H2O, Na, Cl and HCO

3 (decrease levels in body)

• Increase alkaline urinary pHàIncrease excretion of HCO3• Increase tubular osmolarityà Increase urine ow


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Carbonic anhydrase Inhibitors

• Acetazolamide

• Increase excretion of H2O, Na, K, and HCO

3 (Decrease levels in body)

• Increase alkaline pHà Inc. exc-HCO3

• Cause metabolic acidosis

Serum Electrolyte of Diuretics

In general, the opposite ndings of serum electrolytes are seen in urine

Diuretics Tips

• Diuretics that cause metabolic alkalosis:

• Diuretics that cuase intracellular alkalosis:

• Diuretics that act on distal convoluted tuble:

• Diuretic that cause metabolic acidosis:

• Diuretics that have greater vasodilation effect:

• Hyperlipidemia NOT generally siginicant at low doses, (


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Ramipril, Trandolapril

Pharmacological actions

• ↓ sympathetic output

• Vasodilation of smooth muscles• ↑ levels of bradykininàcauses dry cough

and vasodilation

• ↓ retention of Na and H2O

• Above combined effect produce ↓ in preload

and after load

• ↑ cardiac output (CO).

• Dilation of venous blood vessels leads to

decrease in cardiac preload by ↑ venous

capacitance.

• Arterial dilator reduces systemic arteriolar

resistance and ↓ after load.• Lower BP by reducing peripheral vascular

resistance with reexly increasing cardiac output rate.

• By reducing circulating angiotensin II levels ACE ↓ the secretion of aldosterone, resulting ↓

retention of Na and H2O.

• Little change in HR, or GFR.

Therapeutic use • 1ST LINE: Heart Failure

• Diabetes nephropathy

• Post MI

• Uncomplicated hypertension,and pre-hypertensive patient

• LVH (Left ventricularHeart failure)

• Prior CVA/TIA (CardiovascularAttacks/ Transient Ischemic attacks)& in renal disease

Side effects • Dry cough (5-15%)• Hypotension• Hyperkalemia• Renal insufciencies

• Angioedema (rare)• Reversible neutropenia• Proteinuria (presence of protein in urine)• Fatigue

ContraIndications:

• Pregnancy (absolute): Can produce hypotension in the fetus leading renal failureand death, skull hypoplasia and death.

• Documented angioedema-secondary angioedema,

• Bilateral renal artery stenosis.• Captopril should be taken one hour before meals.• High fat meals may reduce absorption of Accupril

• Food does not effect the other drugs in this class

Angiotensinogen

(alpha globulin in blood)

Na & H2O levels

Bradykinin

Sympathetic action

VasodilationRenin

(kidney)

BP

Angiotensin IIAngiotensin I

ACE I

Angiotensin II Formation

Angiotensinogen

Liver

Bloodstream

Renin

Angiotensin I

Angiotensinconverting

enzyme

Angiotensin II

Kidney Lung

Vasoconstriction

Aldosterone secretion

ADH secretion

Thirst


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Vasodilators cause the smooth muscle in

blood vessels to relax. Relaxed or dilated

blood vessels allow more blood to ow

through, causing a reduction in blood

pressure by decreasing peripheral resistance.

As vasodilators work, the blood vessels

become dilated causing a drop in pressure because there is less blood volume to ll

the vessel. The body can compensate for

this by retaining enough uid to ll the

blood vessel sufciently to raise the blood pressure again.

Hydralazine and minoxidil are direct vasolidators not usually used a sole therapy for high blood

pressure, as their effect is usually short-lived when administered alone. Minoxidil is available in

tablets and also as a topical lotion for treatment of male-pattern baldness).

Pharmacological action

Vasodilators reduce excessive preload and after load.Elevated after load causes the heart to work harder to pump blood into arterial system.

Dilation of venous blood vessels leads to decrease in cardiac preload by increasing venous

capacitance.

In arteries dilators reduce systemic arteriole resistance and decrease after load.

Minoxidil (Rogaine)

• A prodrug, which must be conjugated with a sulfate to form the activedrug.

Mechanism • Minoxidil is potent renal vasodilator and stimulator of renin release.Therapeutic use • Hypertension and alopecia treatment

Side effects • Salt and water retention (use a diuretic)• Reex tachycardia• Pulmonary hypertension• Blurred vision• Hypertrichosis - topical solution is now marketed for baldness.

For alopecia • Each mL of clear, colorless to slightly yellow solution contains:minoxidil 20 mg (2%), in alcohol (63%), propylene glycol (20%) andwater.

• For external use only. Store at controlled room temperature (15 to

30°C).• Hypertrichosis (excessive hair growth) occurs continued treatment over

4 weeks

Emergencey use drugs

Hydralazine (Apresoline)

Mechanism Acts directly relaxing arteriolar smooth muscle. Orthostatic hypotension is

not a problem.Therapeutic use • Indicated in pregnancy induced hypertension (PIH)

Vasodilators

Direct Vasodilators:

Hydralazine

Sodium NitroprussideMinoxidil

Indirect Vasodilators:

ACE inhibitors

Calcium channel blockers


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Side effects • Salt and water retention, which may lead to CHF (use a diuretic).

• Hematologic-neutropenia,

• Leucopenia,

• Agranulocytosis,

• Muscle cramps,• Orthostatic hypotension

• Tachycardia• Lupus like syndrome (Systemic Lupus Erythromatus)

Diazoxide (Hyperstat)

Mechanism • Dilates arterial smooth muscle.

• Used IV for the treatment of hypertensive emergenciesTherapeutic useSide effects • Salt and water retention

• Hyperglycemia (↓ release of insulin)

• Hypertrichosis

Sodium Nitroprusside

Mechanism • Dilates both resistance and capacitance vessels,

• Nitroprusside when come in contact with red blood cells (RBC) produces

nitric oxide (NO), which then stimulates guanylate cyclase.Therapeutic use • DOC for hypertensive crisisSide effects • Short term-excessive vasodilatation and hypotension. Long term-

accumulation of cyanide and thiocyanate (24-hours).• Concomitant administration of sodium thiosulfate decrease cyanide

accumulation by changing into thiocyanate.Thiocyanate

toxicity

• Nausea, disorientation and toxic psychoses

Antihypertensive Drugs Tips

• Targeted isolated systolic BP should beà

• Hypertension with diabetes DOC isà

• Hypertension with renal disease DOC isà

• Hypertension + pheochromacytoma which antihypertensive should be avoidedà

• Isolated systolic Hypertension which drugs should not useà

• Cardioselective beta-blockers areà

• What percent of patients diagnosed with high blood pressure have essential hypertension?à

• Name the cation most prevalent in the extracellular uid of the body.à

• Why is bedtime the best time to dose terazosin?à

• What is the recommended sodium intake for a patient diagnosed with hypertension?à

Summary of β - blockers

Pharmacological actions

• β1 = decrease heart rate

• β2 = bronchoconstriction


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• Peripheral vasoconstriction (Increase TPR )—β2

• ↓ Na/water retention

• ↓ glycogenolysis (glycogenà glucose)

• ↓ glucagon secretions

• Blocks the effect of isoproterenol

Antihypertensives Lowers blood pressure through reducing the PR or CO.

Diuretics

• Create a negative sodium balance, reduce blood volume, and decrease vasoconstriction.

Peripheral sympatholytics

• Blocks postganglionic adrenergic receptors, limiting release of neurotransmitters from

adrenergic receptors, or depleting intraneuronal catecholamine storage sites.

Central a2-sympathomimetics• Cause negative sympathetic outow and lowering peripheral resistance.

Calcium channel blockers

• Block voltage-gated calcium channels causes lower vascular resistance and blood pressure.

ACE inhibitors• Decrease Sodium retention by blocking the conversion of inactive Angiotensin I to

Angiotensin II.

Angiotensin II-receptor antagonist

• Produced vasodilation and causes loss of salt and water thus decreasing the plasma volume, and

myogenic activity.

Vasodilators

• Relaxes arterioles and veins, membrane hyperpolarization, decrease atrial resistance.


TPR Total Peripheral Resistance

DBP Diastolic Blood Pressure

SBP Systolic Blood PressureBP Blood PressureCHF Congestive Heart FailureCO Cardiac OutputADH Antidiuretic HormoneBPH Benign Prostate HyperplasiaACE Angiotensin-converting enzyme.HR Heart RateISA Intrinsic Sympathomimetic ActivityEMAA Esmalot, Metopralol, Acebutalot, Atenalol

NE NorepinephrineDHP Dihydropyridine

NDHP Non DihydropyridineGFJ Grape Fruit JuiceCA CalciumGFR Glomerular Filtration Rate.ARB Angiotensin Receptor Blocker

NO Nitric OxideRBC Red Blood CellsPIH Pregnancy induced hypertension

SV Stroke VolumeLVH Left Ventricular Heart FailureCVA Cardiovascular attacks


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www.PharmacyPrep.Com Antihyperlipidemics Drugs



PharmacyPrep.

5Antihyperlipedemic Drugs

Effects of Antihyperlipidemics on Lipoproteins

Drug class LDL HDL VLDL-TGBile acid sequesterants ↓ ↑ ↑

Nicotinic acid ↓ ↑ ↓HMG-CoA reductase inhibitors

↓ ↑ ↓ (TG)Fibric acid derivatives ↓

↑ ↓

Reference: Therapeutic Choices, 4th ed. page 242

Statins

Statins Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin

Mechanism HMG CoA reductase inhibitors (HMG = 3-hydroxy, 3-methyl glutaric acid)

Therapeutic use Decrease LDL receptors (18 – 55%)

Lower cholesterol synthesis (cholesterol pills)

Contraindicated In pregnancy and breast-feeding, children or teenagers.

Side Effects GI side effectsà GI upset, diarrhea, nausea and vomiting

Rhabdomyolysis (myopathy)àdisintegration and dissociation of muscles

Rhabdomyolysis is common in renal insufciency patients.

Drug interactions • Medication such as cyclosporine, itraconazole, erythromycin

(macrolide), gembrozil, niacin, brates and grapefruit juice increase

rhabdomyolysis, due to inhibition of CYP 34A enzyme, which isessential for metabolism of statins Niacin

Bile acid

sequeste-rants

Nicotinic

acid

HMG-CoA

reductase

inhibitors

Fibric acid

derivativesCholesterol

Absorption

inhibitors

Cholestyramine

Cholestipol

NiacinLovastatin

Simvastatin

Pravastatin

Fluvastatin

Atorvastatin

Cervastatin

Ezetimibe

Ezetrol

Classification of Antihyperlipidemic Drugs


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Management • Administration of aspirin prior to taking niacin decrease ush.

• Take with food

• Tolerance develops in 1 – 2 weeks

• Higher dose 2g/day may produce hepatic damage

No-ush prep • Contains Inositol + Niacin

Fibrates

Fibrates • Bezabrate

• Fenobrate

• Gembrozil

Mechanism • Decrease TG levels

• Increase HDL levels (moderately)

• Decrease LDL levels

• Inhibit cholesterol synthesis

• Fibric acid derivativesTherapeutic use • Treatment of choice in hypertriglyceridemia + diabetic patients.

• HDL increase 10 –20%

• TG decrease 20 – 50% (Effective for TG)

Side Effects • Mild GI disturbances.

• Lithiasis: because these drug increase bilary cholesterol excretionà

predispose gallstone formation.

Contraindication • Sever hepatic and renal dysfunction, potentiates warfarin activity.

Preexisting gall bladder disease.

Monitoring • Liver Function test

• Creatinin Kinase• Complete Blood Count

• Renal function test

• At 3, 6 and 12 mo, and yearly

Drug interactions • Combination with Statins may lead to rhabdomyolysis

Resins

Resins • Cholestyramine

• Colestipol

Mechanism • Prevents absorption of cholesterol.

• Anion-exchange resins bind with the enzymes in intestine and inhibit

the synthesis of cholesterol. Bile acids are synthesized from cholesterol.

• Decrease LDL 15 – 30%

• Increase HDL 3 – 10%

• No change or increase in TG (disadvantage)

Therapeutic use • Drug of choice in pregnancy

• Cholestyramine also relieves pruritis caused by accumulation of bile

acids in patients with biliary obstruction in cholestasis


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Side Effects • Decrease absorption of ADEK fat-soluble vitamins.

• High doses of folic acid and ascorbic acid absorption is reduced.

• Most common GI problem: constipation.

Drug-Drug

interactions

• These drug interfere with intestinal absorption of many drugs

(tetracycline, Phenobarbital, warfarin, pravastatin, uvastatin, aspirin,

and thiazide diuretics)

Ezetimibe (Zetia)

Mechanism • Selectively inhibit the intestinal absorption of cholesterol and related

phytosterol.

Therapeutic use • Used in combination with statins (increasing dose of statins only

does not decrease LDL levels, hence combination Ezetimibe is

recommended).

Side Effects • GI effects: Abdominal cramps,• Liver problems

• Sexual dysfunction

• Weight loss

Advantage • Does not affects fat soluble vitamins

• Low potential for drug interactions

Antihyperlipidemic Drugs Tips

• Goal of antihyperlipidemic therapy isà• FLS = only taken at night (at bedtime), for maximum effect.

• Pravastatin and rosuvastatin have no drug interactions

• Statins increase risk of arrhythmias at night

• HMG Co A inhibitors are mainly metabolized byà

• HMG Co A inhibitors side effect rhabdomyolysis patient may notice byà

• Which antihyperlipedemic have no effect or increase triglyceride levelsà

• Which antihyperlipidemics have equal proportion effect on LDL, HDL and TGà

• Resins act what part of GIà

• Hydrochlorothiazide effect on lipids includeà

• ACE inhibitors effect on lipids includeà

• CCB effects on lipidsà

• Lovastatin is given with food becauseà

• DOC for cholesterol in DM patientsà

• Normal levels of lipids: LDL = 0.9 mmol/L; TG =


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Generic and Brand

TGCBC Complete Blood CountHMG 3-hydroxy, 3-methyl glutaric acidLFT Liver Function TestCPK or CK Creatinin KinaseADEK Vitamin A, D, E and K DM Diabees Mellitue

HMG 3- Hydroxy, 3- Methylglutaric acid

Atorvastatin Lipitor

Fluvastatin Lescol

Lovastatin Mevacor Pravastatin PravacholRosuvastatin Crestor Simvastatin Zocor

Bezabrate BezalipFenobrate LipidilGembrozil LopidCholestyramine QuestranColestipol ColestidEzetimibe Zetia


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www.PharmacyPrep.Com Coronary Artery Disease



PharmacyPrep.

6Coronary Artery Diseases

Coronary artery Diseases

The most common complications associated with Coronary artery disease include: Angina pectoris,

Myocardial infarction, post Myocardial infarction,and Ischemic stroke. Insufcient supply of oxygen

to heart can lead to Ischemic conditions.

• Myocardial ischemia is usually caused by coronary vessel atherosclerosis (High LDL

and high cholesterol is the most common risk factor). As the vessel lumen narrows blood

ow is reduced.

• Other causes that limit coronary blood ow include: Arterial thrombi and Spasm

Angina Pectoris

Angina are those symptoms of myocardial ischemia that occur when myocardial oxygen availability

is insufcient to meet myocardial oxygen demand.

These symptoms include:

• Chest discomfort often described as heaviness, pressure, and squeezing. The sensation is

localized typically in the sternal region.

• Symptoms often last one to ve minutes. Angina can radiate to the left shoulder, to both arms(ulnar surfaces of the forearm and hand), and can radiate to the neck, jaw, teeth, epigastrium and

back.

Types of angina

Angina Pectoris • Severe chest pain because of inadequate coronary blood ow to supplyoxygen demand.

• Which is usually aggravated by exertion or stress and relieved bynitroglycerine.

• The most common form of IHD.

Types of angina

Stable angina Unstable angina Exercise-induced

Prinzmetal angina

Or

Vasospastic angina

Nocturnal Angina

Chronic angina


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Types of angina pectoris

• Stable angina/ Classic angina (most common-90%)• Unstable angina• Exercise induced angina• Exertion angina• Chronic angina• Prinzmetal angina• Nocturnal angina

Stable angina orclassical

• Mostly secondary to atherosclerosis (high LDL)• Due to obstruction in coronary arteries• More predictable• Precipitated by exertion or emotional stress or by heavy meal.• Relieved by rest or using nitroglycerine’s

Unstableangina/resting/Crescendo

• The most serious one (worsening pain)• Thrombosis in a branch• Caused by formation atherosclerotic (disease of arteries, in fatty plaques

develop in inner wall), occurs at rest• ACE inhibitors are used as single treatment• Decreased response to rest and nitroglycerine

Nocturnalangina (anginadecubitus)

• This angina occurs in the recumbent position and is not specically relatedto either rest or exertion

• Nitroglycerine may relieve the paroxysmal nocturnal dyspnea

Prinzmetalangina(vasospastic orvariant angina)

• Coronary artery spasm that reduces blood ow precipitates this angina.• Secondary to coronary artery spasm• Usually occurs at rest (pain may disrupt sleep)• Calcium channel blockers are most effective

Treatment of angina

• The following beta-blockers are used in treatment of angina:

• Beta-blockers with Selective Intrinsic Sympathomimetic Activity (ISA):

Acebutolol hydrochloride Beta-blockers with Non-ISA: Atenolol

and Metoprolol tartrate can be used.

• Beta-blockers with Nonselective, ISA: Pindolol

• Beta-blockers with Nonselective, Non-ISA: Nadolol, Propranolol hydrochloride,

Timolol maleate

• Calcium Channel Blockers are used in treatment of angina:• Amlodipine besylate, Diltiazem hydrochloride, Nifedipine, Verapamil hydrochloride

• The following Coronary Vasodilators, Nitrates are used in treatment of angina:

Vasodilators

Calcium blockers, and ACE inhibitors

Nifedipine,

Verapamil,

Diltiazem

Cardiac depressants

β-blockersProponolol

Nitrates

Short duration

Inhaled amyl nitrite

Sublingual

Nitroglycerine

Isosorbide dinitrite

Intermediate

Oral regular or sustained-

release Nitroglycerine

Isosorbide dinitrite

Long duration

Transdermal

Ntiroglycerine patch

Drugs Used In Angina Pectoris


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• Nitroglycerin, Isosorbide dinitrate, Isosorbide-5-mononitrate.

Nitrates• Organic nitrates act primarily by vasodilation (especially venodilation), which reduces

myocardial preload and therefore myocardial oxygen demand.

• Nitrates also promote redistribution of blood ow to relative ischemic areas.

Mechanism • Vascular smooth muscle relaxation

• Two major effects

• Dilation of the large veins (resulting of pooling blood in veinsà this

reduces preload and decrease work of heart.

• Dilates coronary vasculature, providing increased blood supply to the heart

muscles.

Side effects • The Most common side effect is headache.

• Higher doses: Postural hypotension, facial ushing and tachycardia.

• Toleranceàdevelops rapidly.

• This can be overcome by using “nitrate free period” and restore sensitivity

to drug.

Storage

Conditions

• Amber color, glass and metal capped

• Dispense in original container

• Discard cotton present on tablets in bottle.• Drug expires after 6 months from the day bottle open.

• Light sensitive, hygroscopic.

Drug

interactions

• Cause hypotension with Sildenal , Tadanal, Verdanal.

• Additive hypotension effectDosage forms • Nitroglycerine SLà Acute

• Nitroglycerine Pumpà Acute

• Nitroglycerine Patchà Maintenance

Nitrites

Therapeutic use • DOC for hypertensive crisis

Side effects • Cyanide toxicity (releases CN)

• Sodium thiosulte is an antidote

• (Cyanide (Intermediate) + Sodium thiosulteà Sodium thiocyanate

(water soluble)

• Photosensitive

Ca2+ channel Blockers

These agents are used to treat hypertension and are effective in treating angina as well. All muscles,

including the smooth muscle of the blood vessels, require calcium in order to contract. If the

Nitrates ↑ Nitrites ↑ Nitric oxide (NO) ↑ cGMP

↑ Dephosphorylation of

myosin light chain

Vascular smooth

muscle relaxation


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calcium-channel blocking agents block the entrance of calcium into the muscle, the muscle will not

contract. This will allow themuscle to relax and subsequently reduce the blood pressure. Other

therapeutic uses: angina, migraine, antiarrhythmic.

Non

dihydropyridines

• Diltiazem hydrochloride

• Verapamil hydrochloride

Mechanism • Verapamil is similar to Beta blockers in effect• Verapamil can cause bradycardia• The effect on Heart is graded from higher to lower: verapamil >

diltiazem > nifedipine

• Verapamilà avoid using in CHF (cause –ve inotropic effect) and

constipationDihydropyridine • Nifedipine

• Felodipine

• Amlodipine

• Nicardipine

Nifedipine is similar to Nitrate in effect (Peripheralà decrease afterload,

dihydropyridine can cause tachycardia.

Dihydropyridines Relax and dilating arteries. The effect on vascular smooth

muscles is high with dihydropyridine:

nifedipine > diltiazem > verapamil

Comparison of dihydropyridine and Non-dihydropyridine

DHP NDHP

Cause Reex tachycardia Cause Bradycardia

No heart blockade Cause Heart blockade

Peripheral vasodilation Myocardial vasodilation

Amlodipine long half-life Negative (-ve) inotropic(Only amlodipine does not cause effect (worsening CHF)

reex tachycardia)

Can be used in asthma

Avoid CYP3A4 Inhibitors/Inducers (GFJ)

Side effects: ushing, profound low blood pressure, swelling of legs and feet, constipation and

stomach upset. If edema (swelling) of the legs and feet occur, a diuretic may be added to the

regimen.

Nifedipine (Adalat)

Mechanism A calcium blocker which interfere with conduction of signals in the

muscles of the heart and vessels.Therapeutic use Given regularly to prevent Angina attacks.

Reduce high blood pressure and is often helpful in improving

circulation to the limbs in disorders such as Raynaud’s disease.Side Effects Blood pressure will fall too low’ and sometimes causes heart rhythm.

Tachycardia, ushing, headache, dizziness, Orthostatic hypotension,

and edema

Amlodipine (Norvasc)

Mechanism • A calcium blocker which interfere with conduction of signals in the

muscles of the heart and vessels.

Diltiazem

Coronary Dilatation

Veropamil

Av conductingdecrease


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Therapeutic use • Angina and Chest pain

• Can be safely used by asthmatic and non-insulin-dependent

diabetic.Side Effects • Blood pressure may fall too low

• Sometime may cause mild to moderate leg and ankle swelling

Diltiazem (Cardizem)

Mechanism • A calcium channel blocker that interfere with the conduction of

signals in the muscles of the heart and blood vessels.Therapeutic use • Angina

• Longer acting formulations are used to treat high blood pressureSide Effects • Usually well tolerated, occasional hypotension or orthostatic

hypotension, ushing, arrhythmia, and bradycardia. Use with

caution in patient with CHF

Myocardial Infarction (Heart attack)

Mechanism • Myocardial ischemia is usually caused by coronary vessel

atherosclerosis. As the vessel lumen narrows blood ow is reducedDrug of Choice

for Acute coronary

syndrome

• Acute MIà b-blockers, ACE, CCB,

• Prophylaxis (prevention)à ASA (60-81 mg/day), Nitroglycerine

• Severe chest painà Morphine

• AnticoagulantsàHeparins, LMWH,

Warfarin

• AntiplateletsàAspirin, clopidogrel,

ticlopidineASA • A = Analgesics

• A = Antipyretics

• A = Antiinammatory

• A = Antiplatelets (60-81 mg/day)

• Aspirin decrease morbidity and mortalityPost MI • No CCB

• Thrombolytic used for coronary perfusion, eg: streptokinase

• Also Glycoprotein IIB, IIIA inhibitors such Tiroban can be used

STEMI treatment: ASA, Beta-blockers, Nitrates, CCB, Thrombolytics NSTEMI treatment: ASA, Beta-blockers, Nitrates, Heparin

Coronary Artery Disease Tips

• Nitroglycerine spray storage and administrationà

• Nitroglycerine SL storage condition requireà

• Light sensitiveà

• Nitrates should be avoid taking withà

• What is active moiety of nitratesà • Nitroglycerine is chemically classied asà

• Nitroglycerine + seldanal can cause hypotension and this due to nitroglycerine and seldanal.

• The most common side effect of nitroglycerine is headache; therefore nitroglycerine should be

Coronary arteries

Zone 1: Necrosis

Zone 2: Injury

Zone 3: Ischemia


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taken while sitting position.

• Nitroglycerine patch can cause tolerance, to avoid tolerance use nitrate free period.

• What drugs effective in MI prevention and treatmentà

• What drugs should be avoided in MIà

• Severe chest pain associated with MI treated byà

• STEMIà

• NSTEMIà

• At what dose ASA act as Antiplateletà

• ASA act as irreversible Antiplatelet drug

• Nitratesà Increase nitritesàIncrease Nitric oxide (NO)à vascular smooth muscle relaxation


Generic and Brand

LDL Low-density Lipoprotein

IHD

SLCN

CCBMI

ACE Angiotensin-Converting EnzymeASA Acetyl SaliaylateSTEMI ST-Segment Elevation MI

NSTEMI non-ST-Segment Elevation MI

Verdanal Levitra

Sildenal Viagra

Tadanal Cialis Nitroprusside Nitropress


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