pharmacology jeopardy block 2 part ii peter o. beaumont, m.sc. (pharm) st. vinnie’s fall 2000

PharmacologyPharmacology

JeopardyJeopardyBlock 2 Part IIBlock 2 Part II

Peter O. Beaumont, Peter O. Beaumont, M.Sc. (Pharm)M.Sc. (Pharm)

St. Vinnie’s Fall 2000St. Vinnie’s Fall 2000

Local and General Local and General AnaesthesiaAnaesthesia

The Five Goals of The Five Goals of General General

AnaesthesiaAnaesthesia

What are…What are…Analgesia, amnesia, Analgesia, amnesia,

muscle relaxation, LOC muscle relaxation, LOC and Loss of somatic & and Loss of somatic &

visceral reflexesvisceral reflexes–The first three are universal, the last

two are somewhat secondary

The Surgical Stage The Surgical Stage of Anaesthesia,and of Anaesthesia,and the easiest test to the easiest test to

determine itdetermine it

What are…What are…

Stage III, and the Stage III, and the eyelash reflex testeyelash reflex test

The greatest medical The greatest medical concern in concern in

Guedel’s stage II of Guedel’s stage II of anaesthesiaanaesthesia

What is…What is…

Aspiration of vomitAspiration of vomit

–During this stage, delirium and excitement are often accompanied by retching,vomiting and incontinence.

– Intubation must unfortunately wait until the patient loses gag reflexes

The earliest feature The earliest feature of Guedel’s stage Iof Guedel’s stage I

analgesiaanalgesia

– this is soon accompanied by amnesia, but consciousness is not lost.–Remember, not all anaesthetics show

all stages, and further, not all agents are good analgesics e.g. halothane

The only true The only true anaesthetic ‘gas’ anaesthetic ‘gas’

Nitrous OxideNitrous Oxide

–The others are all volatile liquids

The rate of onset of The rate of onset of an excellently an excellently

soluble anaestheticsoluble anaesthetic

Very slowlyVery slowly

–The sooner the point of saturation is reached, the sooner the blood is willing to give up the agent to the brain tissues

The rate of onset of The rate of onset of anaesthesia in a anaesthesia in a

patient with heart patient with heart failurefailure

Faster than normalFaster than normal

–This is is a tough concept

–slowly flowing blood will reach its saturation sooner than fast flowing blood

–A greater fraction of the CO goes to the brain in failure

Once you stop the Once you stop the flow of Nitrous and flow of Nitrous and oxygen, this may oxygen, this may

happen to the happen to the patient post-oppatient post-op

Diffusion HypoxiaDiffusion Hypoxia

– A high partial pressure of gas coming out of solution dilutes oxygen in the lungs in the post-op patient

– Only happens with nitrous oxide, others are used a too low partial pressure

When 1/2 your When 1/2 your patients do not patients do not

jump off the table jump off the table following induction, following induction,

this point is this point is reachedreached

MACMAC

–By definition… when 50% of patients do not respond to a painful stimulus–highly dependent on degree of

stimulation–Elderly and children have lower MAC

This prototypic GA This prototypic GA has good effect, but has good effect, but

high metabolism high metabolism makes it makes it

undesirable these undesirable these daysdays

HalothaneHalothane

–Release of halogens can cause hepatotoxicity (methoxyflurane does this as well, so it is rarely used)

If you use halothane If you use halothane for a D&C, you for a D&C, you must also use must also use

these these twotwo adjuncts adjuncts

Opiods and oxytocinOpiods and oxytocin

–Halothane has virtually no analgesic effect

–oxytocin causes uterine contraction to counteract the relaxant effect of halothane

Were it not for Were it not for concurrent muscle concurrent muscle paralysis, patients paralysis, patients induced with this induced with this agent might hurt agent might hurt

themselvesthemselves

EnfluraneEnflurane

–Seizure complexes on EEG

–EEG goes with Enflurane

This GA is great for This GA is great for maintenance, but maintenance, but

rarely used for rarely used for inductioninduction

DesfluraneDesflurane

–Extreme sympathetic stimulation during induction. Also has a sharp irritating odour

–Rapid post-op recovery

Some consider this Some consider this GA to be the GA to be the

‘Cadillac’ inhalation ‘Cadillac’ inhalation agent for short agent for short

proceduresprocedures

SevofluraneSevoflurane

– rapid onset and recovery

– little airway irritation

–2-5% hepatic metabolism makes it less desirable for long procedures

–Sevo is the “Seville”

Were it not for a Were it not for a high MAC, this high MAC, this

agent would be a agent would be a nearly ideal GAnearly ideal GA

Nitrous OxideNitrous Oxide

–No CV depression, excellent analgesia

–Must be used with a second GA and paralytic agent

This class of IV GA’s This class of IV GA’s are the prototypical are the prototypical

induction agentsinduction agents

BarbituratesBarbiturates

–Thiopental was the first - Still used widely today

–Onset in 1 minute

While inhalation While inhalation agents terminate agents terminate

their effect by their effect by exhalation, this is exhalation, this is the mechanism for the mechanism for

barbituratesbarbiturates

RedistributionRedistribution

–Also known as gamma phase redistribution

–99% hepatic metabolism to inactive compound AFTER termination of sedation effect

Incapable or Incapable or reaching stage III reaching stage III themselves, these themselves, these

agents provide agents provide sedation and sedation and

amnesiaamnesia

benzodiazepinesbenzodiazepines

–Diazepam, lorazepam and midazolam are short acting agents

–Slower onset than barbiturates

–used as part of “balanced anaesthesia”

Occasionally used Occasionally used alone in Cardiac Sx, alone in Cardiac Sx,

these agents these agents typically support typically support GA agents with GA agents with

analgesiaanalgesia

OpiodsOpiods

–patient may be ‘aware’ of or recall the Sx

–Chest tightness impairing ventilation may occur

Opiod + neuroleptic Opiod + neuroleptic + Nitrous Oxide =+ Nitrous Oxide =

NeuroleptanesthesiaNeuroleptanesthesia

– Important for painful, invasive procedures requiring patient cooperation

Dr’s and patients Dr’s and patients agree, this drug is agree, this drug is the ‘real the ‘real Pro’Pro’ of the of the induction agentsinduction agents

PropafolPropafol

–Similar induction to barbiturates, but faster recovery

–Patients feel much better post-op

–May even have anti-emetic properties

–much much more expensive than thiopental

Catatonia, amnesia Catatonia, amnesia and analgesia and analgesia without LOCwithout LOC

dissociative dissociative anesthesiaanesthesia

–Produced by ketamine alone–Similar to PCP–only CVS stimulant–good for Sx on patients in shock

This untoward effect This untoward effect of ketamine is of ketamine is

obviated by pre-obviated by pre-medication with medication with

diazepam or diazepam or fentanylfentanyl

Emergence Emergence PhenomenonPhenomenon

–hallucinations and perceptual illusions

This iv induction This iv induction agents shares one agents shares one shortcoming with shortcoming with halothane and one halothane and one with nitrous oxidewith nitrous oxide

EtomidateEtomidate

–No analgesia (halothane), no muscle relaxant effect (nitrous)

This effect makes This effect makes Etomidate Etomidate

unsuitable for long unsuitable for long Sx and ICU Sx and ICU

sedationsedation

inhibition of adrenal inhibition of adrenal steroid synthesissteroid synthesis

–produces hypotension, electrolyte imbalance and oliguria

The two chemical The two chemical groups required for groups required for

effect as a local effect as a local anaestheticanaesthetic

lipophilic group and lipophilic group and ionizable groupionizable group

–Must be able to readily pass through lipid bilayer, yet interact with ion channel

Relative Relative effectiveness of effectiveness of

locals on locals on infectedinfected tissuetissue

DecreasedDecreased

– lower pH of tissue causes more ionized agent, which is unable to enter the cell

Major benefit of Major benefit of cocaine as a Local cocaine as a Local

anaestheticanaesthetic

vasoconstrictionvasoconstriction

–All other agents are vasodilators

– functions through blocked NE reuptake

–prolongs anaesthetic effect

–used in URT and ear

CocaineCocaine

TetracaineTetracaine

BenzocaineBenzocaine

The ‘ester’ localsThe ‘ester’ locals

–Typically shorter T1/2 due to hydrolysis by plasma cholinesterase

Mechanism of action Mechanism of action of the local of the local

anaestheticsanaesthetics

blockade of voltage-blockade of voltage-dependent Na dependent Na

channelschannels

–Use-dependent

–blocks from inside

Characteristics of Characteristics of the earliest blocked the earliest blocked

nerve fibresnerve fibres

What are…What are…small, myelinated, rapidly small, myelinated, rapidly

firing, peripherally firing, peripherally located on the bundlelocated on the bundle

–why myelinated first - I don’t know!–Use-dependent means rapidly firing

sensory fibres blocked before motor fibres

CNS sedation, CNS sedation, restlessness, restlessness, nystagmus, nystagmus,

seizuresseizures

Toxic effects of local Toxic effects of local anaestheticsanaesthetics

–Premedication with benzos, and hyperoxemia are prophylactic for these symptoms

Local that does not Local that does not permeate the skin permeate the skin

when applied when applied topicallytopically

benzocainebenzocaine

Three LA agents that Three LA agents that cross mucous cross mucous membranes in membranes in

therapeutic therapeutic amountsamounts

tetracaine, lidocaine tetracaine, lidocaine and cocaineand cocaine

– tetracaine suitable for ophthalmic use - no irritation (cocaine too?)–epinephrine cannot be used in topical

preps.

Rationale for use of Rationale for use of nerve blocksnerve blocks

Covers larger area, Covers larger area, with smaller amount with smaller amount

of drugof drug

–prevents systemic toxicity– (also, prevents distortion of wound

when suturing!)

Three techniques to Three techniques to prevent cephalad prevent cephalad diffusion of spinal diffusion of spinal

anaesthesiaanaesthesia

Tilt the patients, use Tilt the patients, use small amount, use small amount, use

‘heavy’ diluent‘heavy’ diluent

–Specific gravity determines whether agent will rise, sink or remain static

Small muscles, Small muscles, trunk muscles, trunk muscles,

diaphragmdiaphragm

Order of effect of Order of effect of NMJ blockersNMJ blockers

Effect of pre-Effect of pre-synaptic NMJ synaptic NMJ blockade of blockade of

nicotinic receptorsnicotinic receptors

‘‘Fade’Fade’

–These receptors normally cause increased release of ACh required to maintain repetitive firing

AChE inhibitors AChE inhibitors have this effect on have this effect on non-depolarising non-depolarising

NMJ blockersNMJ blockers

antagonismantagonism

–non-depol agents are essentially pharmacological antagonists. AChE inhibitors increase the amount of ACh–On the other hand, they would

enhance depolarising blockade

Primary use of Primary use of depolarising NMJ depolarising NMJ

blockersblockers

temporary paralysis to temporary paralysis to allow intubationallow intubation

–Succinylcholine is the only agent in use

–onset < 1 min, duration 5-10 min - rapid metab by plasma cholinesterase

These two classes These two classes of agents are of agents are

known to cause known to cause malignant malignant

hyperthermiahyperthermia

volatile anaesthetics volatile anaesthetics and succinylcholineand succinylcholine

–Causes over-release of Ca from SR - Tx with Dantrolene–Genetic susceptibility

Basis for emesis Basis for emesis due to due to

succinylcholinesuccinylcholine

What is…What is…Increased intragastric Increased intragastric psi due to abdominal psi due to abdominal muscle contractionmuscle contraction

–Not triggered by CTZ

inhalation, local and inhalation, local and IV anaesthetics, IV anaesthetics,

and and aminoglycosidesaminoglycosides

agents that agents that potentiate NMJ potentiate NMJ

blockadeblockade

Goal of Tx with Goal of Tx with spasmolyticsspasmolytics

reduction in tone, reduction in tone, without reduction without reduction

in strengthin strength

–Useful in CP, MS and stroke

Facilitates GABA-Facilitates GABA-mediated pre-syn mediated pre-syn

inhibitioninhibition

benzodiazepines benzodiazepines (diazepem)(diazepem)

–muscle spasms of any origin

–marked sedation

GABA-mimetic at GABA-mimetic at GABAGABABB receptors receptors

baclofenbaclofen

–hyper-polarises pre-syn afferent of reflex arch

–decreases transmitter release

–works in brainstem

–equally effective as diazepam - less sedation

spasmolytic with 3 spasmolytic with 3 month duration of month duration of

actionaction

botulinum toxinbotulinum toxin

–effective in blepharospasm, dystonia and achalasia

–admin by local injection

Tuberculosis Tuberculosis and Leprosyand Leprosy

Guess the first-line Guess the first-line drugs for Tx of TB drugs for Tx of TB

and win the and win the P.R.I.S.E.P.R.I.S.E.

Pyrazinamide, Pyrazinamide, Rifampin, Isoniazid, Rifampin, Isoniazid,

Streptomycin & Streptomycin & EthambutolEthambutol

Slow growth, Slow growth, intracellular, intracellular, resistanceresistance

Three reasons for Three reasons for difficulty in Tx TBdifficulty in Tx TB

–Combination Tx is often used to ovecome these problems

Mechanism of action Mechanism of action of the most import of the most import

drug in the Tx of TBdrug in the Tx of TB

inhibition of mycolic inhibition of mycolic acid synthesis by acid synthesis by

INHINH

–Pyridoxine congener

The dose-limiting The dose-limiting toxicity of INHtoxicity of INH

hepatotoxicityhepatotoxicity

–“INH: Injures Neurons and Hepatocytes

–peripheral neuritis is easily Tx with B6 - so, technically, not ‘dose-limiting’

–significant (1%) incidence of severe hepatitis; even greater in alcoholics

This TB agent is an This TB agent is an inhibitor of DNA-inhibitor of DNA-

dep-RNA - dep-RNA - polymerasepolymerase

RifampinRifampin

–Effective in all mycobacteria and many other agents

–good CSF penetration - exposure/carrier prophylaxis in meningococci and H.flu

Rifampin and Rifampin and phenazopyridine phenazopyridine

have this in have this in commoncommon

(think back to UTI)(think back to UTI)

colours body fluids colours body fluids REDRED

–4 R’s

–RNA-poly, Reves P450, Red fluid, Rapid Resistance used alone

If you took this TB If you took this TB drug, you may not drug, you may not

know that your know that your urine was red from urine was red from

rifampinrifampin

EthambutolEthambutol

–Causes loss of red-green discrimination

– relative contraindication in children

–2nd TB agent that causes hepatitis

This TB agent may This TB agent may precipitate gout in precipitate gout in

susceptible susceptible individualsindividuals

pyrazinamidepyrazinamide

–Hyperuricemia occurs in all patients, but only some are symptomatic

INH, rifampin, INH, rifampin, pyrazinamide, but pyrazinamide, but not ethambutol or not ethambutol or

streptomycinstreptomycin

First-line TB agents First-line TB agents that cause that cause

hepatotoxicityhepatotoxicity

–Ethambutol does, not… as may have been stated in class

This quasi-first line This quasi-first line agent is still used agent is still used for life-threatening for life-threatening

StreptomycinStreptomycin

–Especially useful in meningitis and milliary TB

–some do not consider it 1st-line for TB anymore

Mech of act of this Mech of act of this primary Tx for primary Tx for

LeprosyLeprosy

What is…What is…Inhibition of Inhibition of

dihydropteroate dihydropteroate synthase by Dapsonesynthase by Dapsone

–Just like all of the other PABA analogues

This dapsone ADR This dapsone ADR is similar to that is similar to that seen in the Tx of seen in the Tx of

spirochete infectionspirochete infection

the Lepra Reactionthe Lepra Reaction

–somewhat like Jarisch-Herxheimer reaction (erythema nodosum leprosum)

–Tx with thalidomide, chloroquine and clofazime (not in G&G)

Perhaps the most Perhaps the most effective drug in effective drug in leprosy, it can leprosy, it can never be used never be used

alonealone

RifampinRifampin

–Resistance is a major concern

The main ADR of the The main ADR of the main Dapsone main Dapsone alternative in alternative in

resistant Leprosyresistant Leprosy

Skin discolourationSkin discolouration

–Clofazime is an ‘azo’ dye that discolours the skin

Malarial parasites Malarial parasites with more than one with more than one

exoerythrocytic exoerythrocytic cyclecycle

Vivax and OvaleVivax and Ovale

–Falciparum and Malariae have only one cycle before proceeding to RBCs

–Basis for dormant infection in V & O

Stages of the Stages of the lifecycle taken up lifecycle taken up by the mosquito, by the mosquito, and later injected, and later injected,

respectivelyrespectively

Gametocytes and Gametocytes and sporozoitessporozoites

DOC for Tx and DOC for Tx and prophylaxis of P. prophylaxis of P. falciparum (area falciparum (area

without resistance)without resistance)

ChloroquineChloroquine

–often used in combo with pyrimethamine

DOC for prophylaxis DOC for prophylaxis of P. falciparum, in of P. falciparum, in

resistant areasresistant areas

What is…What is…Melfoquine Melfoquine oror

Chloroquine + pyrimethamineChloroquine + pyrimethamine(Depending on your source)(Depending on your source)

–2nd choice doxycycline, 3rd chloroquine + proguanil (Katzung and G&G agreee)–Can also be used for the other plasmodia too

DOC for Tx ofDOC for Tx of

chloroquine-resistant chloroquine-resistant P. falciparumP. falciparum

QuinineQuinine

–given with a tetracycline or antifolate

–Mefloquine is used in some geographic areas

Drug that would Drug that would have made Dr. have made Dr. McPhearson a McPhearson a millionare, and millionare, and which was not which was not

covered in class!covered in class!

ArtemisininArtemisinin

–Effective blood schizontacide in all types of malaria, including resistant P.f.

–Not good for prophylaxis

–Not available in US… yet.

Only drug for Only drug for eradication of eradication of

tissue schizontstissue schizonts

PrimaquinePrimaquine

–One of the few indications that is absolute

–only required in Ovale and Vivax

Enzyme deficiency Enzyme deficiency associated with associated with

ADRs in ADRs in primaquine and primaquine and

quininequinine

Glucose-6-Glucose-6-phosphate DeHasephosphate DeHase

–Produces hemolysis and methmoglobin - toxic to kidneys

Antiviral Antiviral PharmacologyPharmacology

Amantadine is used Amantadine is used in the Tx of: in the Tx of:

Influenza A, and...Influenza A, and...

Parkinson’s Disease Parkinson’s Disease

– I hope you didn’t guess Influenza B or C!

This drug….This drug….

Is an excellent Is an excellent prophylactic for the prophylactic for the Flu, but won’t make Flu, but won’t make you feel any better you feel any better

once you get itonce you get it

amantadine or amantadine or rimantadinerimantadine

– these agents block uncoating of the viral particle in the cytosol, but by the time you feel sick, you already have lots of viral particle in your system

These agents limit These agents limit the abilitiy of the abilitiy of

viruses to enter viruses to enter cellscells

Gamma-globulinsGamma-globulins

–Temporary, passive immunity

–duration about 3 wks

Mech of Act of Mech of Act of amantadine amantadine (for viruses)(for viruses)

blocks uncoating of blocks uncoating of the virusthe virus

–Raises pH of endosome to alkaline levels–SE are all neuro related (increased

release of DA)

Agents that require Agents that require HSV viral thymidine HSV viral thymidine

kinase to be kinase to be effectiveeffective

All of the “__ciclovirs”All of the “__ciclovirs”

–Applies to Tx of HSV 1, 2, and 3 (VCV)–acyclovir, famciclovir, ganciclovir,

valaciclovir, etc.

Key difference in Key difference in phosphorylation of phosphorylation of

GanciclovirGanciclovir

phosphorylated by phosphorylated by CMV-specific kinaseCMV-specific kinase

–uses regular thymidine kinase for HSV, but a different one in CMV

Mech of Act of Mech of Act of acycloviracyclovir

comp inhibit viral comp inhibit viral DNA polymerase & DNA polymerase &

causes chain causes chain terminationtermination

–May cause some renaldysfxn, but generally well tolerated

Key indication for Key indication for use of Gancicloviruse of Ganciclovir

What are…What are…CMV retinitis, CMV retinitis, pneumonitis, pneumonitis,

esophagitis, and colitisesophagitis, and colitis

–SE: reversible neutropenia and renal dysfxn

Spectrum of action Spectrum of action of inhaled Ribavirinof inhaled Ribavirin

RSV, Influenza A & BRSV, Influenza A & B

Spectrum of action Spectrum of action of oral/IV Ribavirinof oral/IV Ribavirin

Lassa feverLassa fever

–HCV effects are debatable

–many more SE when given systemically - cytopenias and suppressoin

Mech of Act of Mech of Act of RibavirinRibavirin

Inibits RNA-dep-RNA Inibits RNA-dep-RNA polymerasepolymerase

–May interfere with GTP synthesis and the cap on mRNA as well–effective in BOTH DNA and RNA

viruses

Phosphorylated by Phosphorylated by Host cell kinasesHost cell kinases

What are…What are…Idoxuridine, cytarabine, Idoxuridine, cytarabine, Vidarabine, TrifluridineVidarabine, Trifluridine

– Inhibit viral DNA poly

– too toxic for systemic use, except Vidara for neonatal herpes in immunocompromised

HSV /VCV drug HSV /VCV drug requiring no host or requiring no host or viral kinase activityviral kinase activity

FoscarnetFoscarnet

– Inhibits viral DNA & RNA poly AND HIV reverse transcriptase

Key uses of Key uses of FoscarnetFoscarnet

What are…What are…• AIDS-related CMVAIDS-related CMV

• Acyclovir resistant / Acyclovir resistant / thymidine kinase def HSVthymidine kinase def HSV

• Gancicovir-resistant CMVGancicovir-resistant CMV

–Limited resistance has been observed

3 mechanisms of 3 mechanisms of action of action of

interferonsinterferons

What are…What are…• synth of protein kinases to synth of protein kinases to

inhibit further protein synthinhibit further protein synth

• oligoadenylate synthase oligoadenylate synthase activates RNAaseactivates RNAase

• PDE degrades tRNAPDE degrades tRNA

Major indications for Major indications for interferon Txinterferon Tx

What are…What are…• Pv disseminated HSC, Pv disseminated HSC,

relapse CMV, and relapse CMV, and trigeminal HSV trigeminal HSV

• Hep B & CHep B & C

• Kaposi’s and wartsKaposi’s and warts

...to name a few...to name a few

Major SE of Major SE of interferon Txinterferon Tx

Constitutional Constitutional symptomssymptoms

–Fever, malaise, chills, etc.

Type of kinases Type of kinases used on 5 out of 6 used on 5 out of 6

HIV reverse HIV reverse transcriptase transcriptase

inhibitorsinhibitors

Host cell kinasesHost cell kinases

–All 3 phosphorylation steps, c.f. just the last two step for antiherpes drugs

Primary means of Primary means of resistance to AZT, resistance to AZT,

et alet al

mutation of RT genemutation of RT gene

–Much more common in mono Tx and in advanced disease

Basis for selective Basis for selective toxicity of the RT toxicity of the RT

inhibitorsinhibitors

our cells do not our cells do not have RT!have RT!

–Simple point, but commonly overlooked

Indications for AZTIndications for AZT

What are…What are…• CD4 count < 200 (500 w CD4 count < 200 (500 w

symptoms)symptoms)

• 3rd trimester (with 3TC)3rd trimester (with 3TC)

• Prophylaxis for needle Prophylaxis for needle stickstick

Major toxicity of AZTMajor toxicity of AZT

Bone marrow Bone marrow suppressionsuppression

– increased by Rx that undergo glucuronidation, and decerased by rifampin

Two RTI’s that cause Two RTI’s that cause pancreatitispancreatitis

ddIddI and ddC and ddC

–More common in alcoholics

–also cause peripheral neuropathy

Claim to fame of Claim to fame of NevirpapineNevirpapine

NNOONN--nnucleoside RTIucleoside RTI

–potentiallife threatening rash

The function of HIV The function of HIV aspartate proteaseaspartate protease

Final protein cleavage Final protein cleavage into mature, into mature,

infectious particlesinfectious particles

–SE: kidney stones and unconjugated hypernilirubinemia

General formulae for General formulae for HIV TxHIV Tx

AZT + 2nd RTI + AZT + 2nd RTI + Protease inhibitorProtease inhibitor

HypertensionHypertension

Long term Mech of Long term Mech of Act of diureticsAct of diuretics

Reduction in Na Reduction in Na altering vascular altering vascular

tonetone

–Volume reduction occurs early, but is abated over 6-8 weks in mild essential HTN

Location and Location and Mechanism of Mechanism of

Action of ClonidineAction of Clonidine

Central and peripheral Central and peripheral alpha-2 alpha-2

sympathomimeticsympathomimetic

–blocks NE release–SE: sedation and dry mouth

Major caution in Major caution in clonidine useclonidine use

What is…What is…withdrawal syndromewithdrawal syndrome

–Rebound HTN, tachcardia, sweating

–As little as one or two missed doses

–Tx with alpha and beta blockers

Direct vasodilators Direct vasodilators must be used with must be used with

these drugsthese drugs

Beta blockersBeta blockers

–No sympathoplegia, so reflex response to a decreased BP is still present

Orally active direct Orally active direct vasodilatorsvasodilators

Hydralazine and Hydralazine and minoxidilminoxidil

–work through opening K channels and hyperpolarises arteriolar SMCs

Fast acting, IV Fast acting, IV arteriolar and arteriolar and venous dilatorvenous dilator

Na NitroprussideNa Nitroprusside

–high dose > 1 hr assoc w cyanide toxicity

–onset in 1-10 minutes

–activate guanylyl cyclase - not a K channel agent

The other IV only The other IV only direct vasodilatordirect vasodilator

DiazoxideDiazoxide

–much longer acting means less precise control

– inhibits insulin release

1st-line Tx in an 1st-line Tx in an elderly, black elderly, black

patient with CHF patient with CHF and CRFand CRF

A loop diureticA loop diuretic

–Without the RF (GFR < 30 ml/min) a thiazide would be first choice

–beta blockers have little efficacy in black patients

Anti-HTN agent Anti-HTN agent contraindicated in contraindicated in

pregnancypregnancy

ACE-I and AgII ACE-I and AgII receptor blockersreceptor blockers

– fetal hypotension and risk of malformation

Rationale not to use Rationale not to use direct dilators or direct dilators or alpha blockers in alpha blockers in coronary artery coronary artery

diseasedisease

Coronary stealCoronary steal

–provokation of angine

Patients in who you Patients in who you should not use should not use

amiloride or ACE-I amiloride or ACE-I for HTNfor HTN

Whe are…Whe are…

Patients in renal Patients in renal failurefailure

–both tend to exacerbate hyperkalemia

Drugs not to be Drugs not to be used for HTN in used for HTN in

diabetesdiabetes

thiazides and non-thiazides and non-selective beta selective beta

blockersblockers

Tx of HTN assoc Tx of HTN assoc with kidney stoneswith kidney stones

Analgesia and Analgesia and hydrationhydration

–Different stories in different small groups–Texts indicate no benefit of diuretics

or anti-spasmodics

Management of HTN Management of HTN crisiscrisis

decrease psi by < decrease psi by < 25%, and diastolic 25%, and diastolic not less than 100-not less than 100-

110110

–according to Katzung

BP at which to BP at which to initiate Drug Txinitiate Drug Tx

140/90140/90(open for discussion)(open for discussion)

–For stage I patients, after 6-12 months of lifestyle change

Why Why hydrochlorothiazide hydrochlorothiazide

and alpha-and alpha-methyldopa are used methyldopa are used

in preg assoc HTNin preg assoc HTN

““fetal friendly”fetal friendly”

–May not be the best agents, but there are proven safe.

–Hard to test new Rx on mothers.

Basis for pulmonary Basis for pulmonary edema in our case edema in our case

studystudy

What is…What is…Albuterol activates RAS via Albuterol activates RAS via

beta-2 receptors & the beta-2 receptors & the ‘infusion’ may have volume ‘infusion’ may have volume

overloaded the patientoverloaded the patient –Discussion….–MgSO4 may have been better, but

fetus old enough to deliver

Two causes for red Two causes for red urine in our case urine in our case

studystudy

Hemorrhagic cystitis Hemorrhagic cystitis & doxorubcin die & doxorubcin die

effecteffect

Two causes of the Two causes of the erythematous erythematous

response at the response at the injection siteinjection site

What are…What are…extravasation of extravasation of

vesicant vesicant antineoplastics & the antineoplastics & the

“Adriamycin-flare”“Adriamycin-flare”

Best of LuckBest of Luck to you All! to you All!

Slides available atSlides available at

sguweb.tripod.comsguweb.tripod.com

pharmacology jeopardy block 2 part ii peter o. beaumont, m.sc. (pharm) st. vinnie’s fall 2000

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