Cardiovascular Pharmacology - Antihypertensive AgentsCardiovascular Pharmacology - Antihypertensive Agents

8/18/2019 Cardiovascular Pharmacology - Antihypertensive AgentsCardiovascular Pharmacology - Antihypertensive Agents

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Cardiovascular Pharmacology - Antihypertensive Agents

Edward JN Ishac. Ph.D.Professor, Dept. Pharmacology & Toxicology

Office: Smith Bldg, Room 74!mail: eishac"#c$.ed$ Tel: %'4( )7

O!ectives"

Demo*strate a* $*dersta*di*g of a*tihyperte*si#e age*ts +ith respect to:). S$categories %dr$g classes( a*d the specific mecha*isms. -aor pharmaco/i*etic characteristics of each dr$g class0. Primary ad#erse effects of each dr$g class4. 1*i2$e characteristics of i*di#id$al age*ts3. Similarities a*d differe*ces i* the hemody*amic effects of the dr$g classes. Differe*ces amo*g pop$latio*s i* respo*se to dr$g classes7. 5d#a*tages or disad#a*tages of $si*g comi*atio*s from differe*t dr$g classes

#. $lood Pressure %egulation" Physiology

&ran'(s )ormula* $P regulation" BP 6 O x TPR O 6 8R x S9$aroreceptor re)le+: oppose cha*ges i* BP, rapid, mome*ttomome*t BP ad$stme*ts

%enal system: o*trol of ;a a*d 8O ala*ce, respo*sile for lo*gterm BP co*trol

&igure #. %egulation o) lood pressure

,. Non-drug treatment i)e-style changes/

↓salt i*ta/e %.3g


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Dr. ?shac 5*tihyperte*si#e 5ge*ts

0. Pharmacotherapy"

#. Diuretics . %enin 1 A-II system ACEI* A%$s/0. Calcium antagonists 4. $eta-receptor antagonists3. 5lphaa*tago*ists . Potassi$mspari*g di$retics7. 9asodilators . e*tral acti*g alphaago*ists@. Re*i* i*hiitor )'. Dopami*e ago*ist)). Red$ce ;! release ). Aa*glio*ic loc/ers

2. Drugs which lower lood pressure act through three 3eneral 4echanisms:

). 5lter sympathetic acti#ity. Relax #asc$lar smooth m$scle0. 5lter sodi$m a*d +ater ala*ce

5.#. Diuretics

A. 6hia7ides &rontline* #st o) e8uals/" 8ydrochlorothiaide, -etolao*e

early distal t$$le, i*hiit ;al cotra*sporter to i*hiit +ater lood #ol$me %B9(


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Dr. ?shac 5*tihyperte*si#e 5ge*ts 0

Adverse e))ects"

hypo/alemia, hypercalcemia G $ric acid rete*tio* = go$t ca* ca$se hyperglycemia


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5.,. %enin Angiotensin A6/ - Aldosterone ;ystem"

A. Converting En7yme Inhiitors ACEI/aptopril, Jisi*opril, !*alapril %prodr$g(, Be*aepril, Kosi*opril


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Adverse e))ects" se#ere hypote*sio* i* hypo#olemic patie*ts a*gioedema, hyper/alemia

dry co$gh %associated +ith↑ rady/i*i*( glossitis, oral $lceratio*, rash altered se*se of taste %loss of i*c(

co*trai*dicated i* preg*a*cy %tetroge*ic, category D( co*trai*dicated i* ilateral re*al artery ste*osis

dr$g i*teractio* +ith spari*g di$retics %↑C(, ;S5?Ds %↓ effect(

$. Angiotensin II 6ype # %eceptor $loc'ers A%$s/" Josarta*, 9alsarta*, ?resarta* Esarta*F

competiti#e a*tago*ists of 5*giote*si* ?? Type ? receptors

Type ? receptors mediate: ↑aldostero*e, ↑5D8, ↑TPR, ↑sympathetic ;S Type ?? receptors mediate: #asodilatio* %↓TPR(, ↑ ;O $se i*creasi*g, *o ge*eric, $sed if ca**ot tolerate 5!?

actio*s similar to 5!? $t *ot associated +ith dry co$gh %*o ↑ rady/i*i*( less li/ely to ca$se a*gioedema, glossitis, oral $lceratio*, rash also co*trai*dicated i* preg*a*cy a*d ilateral re*al a. ste*osis i*creasi*g $se, most li/ely +ill o#erta/e 5!?s +ith ge*eric a#ailaility

C. %enin Inhiitor" 5lis/ire* *e+est age*t, i*trod$ced ''3, expe*si#e

direct re*i* i*hiitor = ↓ prod$ctio* of a*giote*si* ? actio*s similar to 5!? $t *ot associated +ith dry co$gh %*o ↑ rady/i*i*( less li/ely to ca$se a*gioedema, glossitis, oral $lceratio*, rash ad#erse effects a*d co*trai*dicatio*s similar to 5!?s


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Dr. ?shac 5*tihyperte*si#e 5ge*ts

Cardiovascular ? renal actions"

Diltiaem 9erapamil ;ifedipi*e %D8Ps(

8eart rate ↓ ↓↓ ↑ %reflex(-yocardial co*tractility ↓ ↓↓ ↓ or G %reflex( ;odal co*d$ctio* ↓ ↓↓ G %reflex(

Peripheral resista*ce ↓ ↓ ↓↓Re*al lood flo+ ↑ ↑ ↑

Adverse e))ects" co*stipatio* %more li/ely +ith *o*D8Ps(

*o*D8Ps: cardiac depressio*, radycardia, 59 loc/

*o*D8Ps are co*trai*dicated +ith etaloc/ers

mostly D8Ps: hypote*sio*, reflex tachycardia, fl$shi*g, headache, edema

hypote*sio* %more li/ely +ith D8Ps(

ca* ca$se gi*gi#al hyperplasia %more li/ely +ith *ifedipi*e, )'M(

*o*D8Ps co*trai*dicated i* 8K, D8Ps *ot recomme*ded P054 i*hiitors: grapefr$it, #erapamil, diltiaem

P054 s$strates: amlodipi*e, #erapamil

&igure @. Calcium loc'ers and nitrates

>asodilators"

5. a cha**el loc/ers: ?*hiit mo#eme*t of a thro$gh Jtype cha**els %ie. 9erapamil(

B. Ope* cha**els: -i*oxidil %Rogai*e(, Diaoxide %ac$te 8T(

. Direct #asodilator: mai*ly arterioles, 8ydralai*e, may i*hiit calci$m release

D. o$pled to ;O


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5.,.2. $eta-Adrenoceptor $loc'ing Agents" EololF, lol Q $*i2$e, 5- Q )

Kro*tli*e class, high cli*ical #al$e as a*tihyperte*si#e age*ts delayed hypote*si#e actio* actio*s dimi*ished i* elderly, 5fro5merica*s, smo/ers

-$ltiple possile mecha*isms of actio*:

i. ;S effect to decrease sympathetic ;S to*eii. i*hiitio* of re*i* secretio*: eta)receptors mediate re*i* release

iii. loc/ cardiac eta)receptors: ↓ 8R → ↓ O → ↓ BP

&eatures o) eta-adrenoceptor antagonists

Selecti#e #s *o*selecti#e ie. ate*olol %)( #s propra*olol %*o( Partial ago*ist acti#ity %?S5( ie. pi*dolol %yes( #s propra*olol %*o( -emra*e stailii*g actio* %J5actio*( ie. metoprolol %yes( #s ate*olol %*o( Jipid sol$ility %;S a#ailaility(: ate*olol %lo+(, propra*olol %high(


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Dr. ?shac 5*tihyperte*si#e 5ge*ts ))

5.,.. 3anglion-$loc'ing Agents

!arliest effecti#e class $sed to treat hyperte*sio* competiti#ely loc/ ga*glio*ic *icoti*ic receptors %S;S, P;S( rarely $sed, cli*ical #al$e as a*tihyperte*si#e dr$g is #ery lo+.

a. 6rimethaphan

i.#. i*ectio*, rapid effect, short half life %precise titratio*( hyperte*si#e crisis, co*trolled hypote*sio*, $s$ally d$ri*g s$rgery

. 4ecamylamine" orally acti#e

;erious adverse e))ects oth agents/"

sympathoplegia: excessi#e orthostatic hypote*sio* sex$al dysf$*ctio*

parasympathoplegia: co*stipatio*, $ri*ary rete*tio* gla$coma, l$rred #isio*, dry mo$th

5.,.. Adrenergic Neuron-$loc'ing Agents

5*tihyperte*si#e cli*ical #al$e is lo+, effecti#e $t age*ts of last resort

3uanethidine* % Bretylium $sed as a*tidysrhythmic, sa#ed !T(

i*hiits release of ;! from *er#e termi*als = grad$al depletio* of ;! stores *e$ro*al $pta/e %$pta/e )( is esse*tial for actio* %T5s or cocai*e > effect(5d#erse effects: mar/ed post$ral hypote*sio*,

diarrhea, impaired eac$latio*

%eserpine %sig*ifica*t ad#erse effects(

5*tihyperte*si#e cli*ical #al$e is lo+, effecti#e $t age*t of last resort i*hiit $pta/e of ;! i*to storage #esicle %also D5, 38T( leads to depletio* of tra*smitter stores %peripheral & ;S actio*(

5d#erse effects: se#ere sedatio*, me*tal depressio*, Par/i*so*ism i*creases gastric acid secretio*

&igure .


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Dr. ?shac 5*tihyperte*si#e 5ge*ts )

@. 6reatment o) Bypertension

@.#. 3eneral considerations- Age Q Betaloc/er a*d 5!?


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Dr. ?shac 5*tihyperte*si#e 5ge*ts )0

@.@. 6reatment strategy" Se#e*th Report of the oi*t ;atio*al ommittee o* Pre#e*tio*,Detectio*, !#al$atio*, a*d Treatme*t of 8igh Blood Press$re %; 7(

&igure #. ;trategy o) hypertension pharmacotherapy

@.. Bypertension and Compelling Indication )or Fse"

Bigh %is' Condition %ecommended Drugs

6hia7ide $-loc'er ACEI A%$ CC$ 9-sparing

Beart )ailure G G G G G

Post 4I GG G G

CAD %is' G G G G

Diaetes G GG G G

9idney Disease G G

;tro'e Prevention G G

; 9??: ''0. U: ?*dicates compelli*g i*dicatio* for $seH 5RB: 5*giote*si* ?? Type )receptor loc/er, B: alci$m cha**el loc/er, 5D: oro*ary artery disease


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Dr. ?shac 5*tihyperte*si#e 5ge*ts )4

. Bypertension Pharmacotherapy ;ummary"

&igure ##.

NO6E: Betaloc/ers $sed i* the treatme*t of co*gesti#e heart fail$re. o*trai*dicatio*i*cl$de: ro*chospasm, sig*ifica*t radycardia, decompe*sated heart fail$re a*ddepressio*.

. %e)erences

Basic a*d li*ical Pharmacology, B.A. at$*g, ))th ed., ''@, pp. )7)@.

Aoodma* a*d Ailma*s The Pharmacological Basis of Therape$tics, 8ardma* a*dJimird, ))th ed., ''3, pp. 7@@0.

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Cardiovascular Pharmacology - Antihypertensive AgentsCardiovascular Pharmacology - Antihypertensive Agents