AntihypertensivesAntihypertensives

oror

How not to blow your corkHow not to blow your cork

BackgroundBackground Cardiovascular pharmacology must always deal with two problemsCardiovascular pharmacology must always deal with two problems

1. Treating the disease state (e.g. reducing elevated blood 1. Treating the disease state (e.g. reducing elevated blood pressure)pressure)

2. Accounting for the body’s homeostatic response to the 2. Accounting for the body’s homeostatic response to the treatmenttreatment

Individual variation in response, and probable drug interactions, Individual variation in response, and probable drug interactions, will dictate the correct regimen of drugs to be administeredwill dictate the correct regimen of drugs to be administered

Goal is to develop regimen using fewest drugs at lowest Goal is to develop regimen using fewest drugs at lowest effective doseseffective doses Reduces number and severity of side effectsReduces number and severity of side effects Increases patient complianceIncreases patient compliance

HypertensionHypertension

Defined as elevation of arterial blood pressure above a Defined as elevation of arterial blood pressure above a normal value (120/80 mmHg).normal value (120/80 mmHg).

Highest risk factor associated with cardiovascular Highest risk factor associated with cardiovascular disease disease risk doubles with each 20 mm Hg increase in risk doubles with each 20 mm Hg increase in systolic bp over 140 mm Hgsystolic bp over 140 mm Hg

Most cases of hypertension (90%) are due to unknown Most cases of hypertension (90%) are due to unknown etiology etiology called called essential hypertensionessential hypertension

Normal increase in bp with age (most cases diagnosed in Normal increase in bp with age (most cases diagnosed in middle age)middle age)

Note: for this class BP = APNote: for this class BP = AP

Hypertension is asymptomatic Hypertension is asymptomatic but may increase risk of other but may increase risk of other pathologies:pathologies:

AtherosclerosisAtherosclerosis Coronary artery diseaseCoronary artery disease Congestive heart failureCongestive heart failure DiabetesDiabetes Insulin resistanceInsulin resistance StrokeStroke Renal diseaseRenal disease Retinal disease (easiest condition to diagnose)Retinal disease (easiest condition to diagnose)

Recall: Regulation of blood Recall: Regulation of blood pressure due to pressure due to combination ofcombination of

Renin-angiotensin-aldosterone systemRenin-angiotensin-aldosterone system Sympathetic nervous systemSympathetic nervous system Vasopressin (ADH) systemVasopressin (ADH) system Fluid retention/excretion by the kidney Fluid retention/excretion by the kidney

Note: the most effective antihypertensive Note: the most effective antihypertensive drug regimens will impair the function of drug regimens will impair the function of one or more of the above systemsone or more of the above systems

Compensatory mechanisms Compensatory mechanisms counteracting decreased blood pressurecounteracting decreased blood pressure

Classes of Antihypertensive Classes of Antihypertensive DrugsDrugs

1.1. ββ blockersblockers

2.2. Peripherally acting sympatholyticsPeripherally acting sympatholytics

3.3. Centrally acting sympatholyticsCentrally acting sympatholytics

4.4. (Diuretics)(Diuretics)

5.5. Angiotensin inhibitorsAngiotensin inhibitors

6.6. Calcium channel blockersCalcium channel blockers

7.7. Direct vasodilatorsDirect vasodilators

Figure 12-2 Summary of sites and mechanisms of action Figure 12-2 Summary of sites and mechanisms of action antihypertensivesantihypertensives

Stages of HypertensionStages of Hypertension

Heart failure

Angina

Post-myocardial infarction

Extensive coronary artery disease

Diabetes

Chronic kidney failure

Recurrent stroke prevention

Mechanisms of Action: Mechanisms of Action: DiureticsDiuretics

Will talk about specifics later but Will talk about specifics later but generally reduce blood volume by generally reduce blood volume by decreasing electrolyte, and thus water, decreasing electrolyte, and thus water, reabsorption in the kidney (increase urine reabsorption in the kidney (increase urine excretion)excretion)

Causes reduced plasma volume which Causes reduced plasma volume which decreases CO, which lowers BPdecreases CO, which lowers BP

DiureticsDiuretics

amilorideamiloride Thiazides*Thiazides* burnetanideburnetanide chlorthalidonechlorthalidone eplerenoneeplerenone furosemide (also used in race horses, altitude sickness)furosemide (also used in race horses, altitude sickness) indapamideindapamide metolazonemetolazone spironolactonespironolactone triamterenetriamterene

Mechanisms of Action: Mechanisms of Action: Angiotensin InhibitorsAngiotensin Inhibitors Angiotensin converting enzyme (ACE) inhibitor Angiotensin converting enzyme (ACE) inhibitor

blocks conversion of angiotensin I to angiotensin IIblocks conversion of angiotensin I to angiotensin II

Angiotensin receptor blockersAngiotensin receptor blockers Reversibly bind to the Ang. I subtype of Ang. II Reversibly bind to the Ang. I subtype of Ang. II

receptors in blood vessels receptors in blood vessels reduce physiological reduce physiological effect of Ang. IIeffect of Ang. II

Note: both above have similar antihypertensive effectNote: both above have similar antihypertensive effect

Angiotensin InhibitorsAngiotensin Inhibitors

ACEsACEs captoprilcaptopril enalaprilenalapril lisinoprillisinopril benazeprilbenazepril ramiprilramipril

Angiotensin receptor blockersAngiotensin receptor blockers losartanlosartan valsartanvalsartan candesartancandesartan telmisartantelmisartan

Mechanisms of Action: Drugs Mechanisms of Action: Drugs affecting the SNS – Adrenergic affecting the SNS – Adrenergic ββ, , αα receptor antagonistsreceptor antagonists

Many types of Many types of ββ blockers blockers All competitively antagonize the effects of All competitively antagonize the effects of

epinephrine and norepinephrine on epinephrine and norepinephrine on ββ11 –adrenergic –adrenergic

receptors in the heart, and renin-secreting cells of receptors in the heart, and renin-secreting cells of the kidneythe kidney

αα receptor antagonists work only by blocking receptor antagonists work only by blocking αα11

receptors on vascular smooth musclereceptors on vascular smooth muscle

Mechanisms of Action: Drugs Mechanisms of Action: Drugs affecting the SNS – Sympatholyticsaffecting the SNS – Sympatholytics

CNS activeCNS active Work by reducing the firing rate of sympathetic nervesWork by reducing the firing rate of sympathetic nerves Mediated by activation of Mediated by activation of αα22-adrenergic receptors in the -adrenergic receptors in the

CNS but exact site is unclearCNS but exact site is unclear Enter brain after absorption into bloodstreamEnter brain after absorption into bloodstream

Peripherally actingPeripherally acting Interfere with norepinephrine release from sympathetic Interfere with norepinephrine release from sympathetic

nerve terminalsnerve terminals May inhibit formation of catecholaminesMay inhibit formation of catecholamines

Adrenergic receptor Adrenergic receptor antagonistsantagonists

ββ-blockers-blockers propanololpropanolol atenololatenolol sotalolsotalol pindololpindolol labetalollabetalol CarvedilolCarvedilol

αα11 receptor antagonists receptor antagonists clonidineclonidine αα-methyldopa-methyldopa guanfacineguanfacine guanabenzguanabenz Reserpine – 1Reserpine – 1stst widely used antihypertensive widely used antihypertensive

Mechanisms of Action: Mechanisms of Action: CaCa2+2+ Channel Blockers Channel Blockers

All excitable tissue contains voltage-dependent All excitable tissue contains voltage-dependent CaCa2+2+ channels channels

Inhibit inward movement of CaInhibit inward movement of Ca2+ 2+ through through specific (L-type) voltage-dependent Caspecific (L-type) voltage-dependent Ca2+ 2+

channelschannels This type of channel prevalent in cardiac and This type of channel prevalent in cardiac and

vascular smooth musclevascular smooth muscle When CaWhen Ca2+ 2+ channels are inactivated, Cachannels are inactivated, Ca2+ 2+ is is

pumped out of cell, actin dissociates from pumped out of cell, actin dissociates from myosin and muscle relaxes, opening vascular myosin and muscle relaxes, opening vascular lumen and decreasing resistance, which lumen and decreasing resistance, which decreases BPdecreases BP

Major effect is on coronary and peripheral Major effect is on coronary and peripheral arteriolesarterioles

CaCa2+2+ channel blockers channel blockers

Verapamil (1Verapamil (1stst one used to treat one used to treat hypertension)hypertension)

nifedipinenifedipine diltiazemdiltiazem

Mechanisms of Action: Mechanisms of Action: Direct vasodilatorsDirect vasodilators

Most powerful antihypertensive drugsMost powerful antihypertensive drugs May cause strong compensatory reactions to May cause strong compensatory reactions to

bring BP back upbring BP back up Fluid retentionFluid retention Increase in Increase in

renin-releaserenin-release heart rateheart rate contractilitycontractility

Usually used only in severe hypertension or for Usually used only in severe hypertension or for patients not responding to other patients not responding to other antihypertensivesantihypertensives

Direct vasodilatorsDirect vasodilators

HydralazineHydralazine MinoxidilMinoxidil PinacidilPinacidil DiazoxideDiazoxide

Clinical considerations: Clinical considerations: diureticsdiuretics

Usually well tolerated, relatively cheap, Usually well tolerated, relatively cheap, and work as well as other methodsand work as well as other methods

They are especially effective in African-They are especially effective in African-AmericansAmericans

At initial treatment urinary excretion At initial treatment urinary excretion increase significantly but after several increase significantly but after several days returns close to normal, and BP days returns close to normal, and BP remains depressedremains depressed

Clinical considerations: Clinical considerations: angiotensin inhibitorsangiotensin inhibitors

Most effective in patients with elevated plasma Most effective in patients with elevated plasma renin levels (but this condition is rare)renin levels (but this condition is rare)

Still effective in hypertensive patients with Still effective in hypertensive patients with normal or even low levels of reninnormal or even low levels of renin

Useful for treating hypertension associated Useful for treating hypertension associated with other cardiovascular risk factors, like heart with other cardiovascular risk factors, like heart failure, stroke, myocardial infarctions, diabetes, failure, stroke, myocardial infarctions, diabetes, and kidney diseaseand kidney disease

Clinical considerations: SNS Clinical considerations: SNS drugsdrugs

The long-term decrease in CO is usually most The long-term decrease in CO is usually most responsible for lowering BPresponsible for lowering BP

For some patients CO returns to normal as TPR For some patients CO returns to normal as TPR decreases decreases decreased BP continues decreased BP continues

ββ–blockers also inhibit renin release which contributes –blockers also inhibit renin release which contributes significantly to decreased BP, especially if renin levels significantly to decreased BP, especially if renin levels are elevatedare elevated

Effect on two different systems causes Effect on two different systems causes ββ–blockers to –blockers to often be used in combination with other often be used in combination with other antihypertensives (direct vasodilators, antihypertensives (direct vasodilators, αα11 adrenergic adrenergic receptor blockers) because get three types of effects receptor blockers) because get three types of effects with only two drugswith only two drugs

ββ–blockers may also counteract reflex compensatory –blockers may also counteract reflex compensatory responses (that increase CO) caused by these other responses (that increase CO) caused by these other drugsdrugs

Clinical considerations: SNS Clinical considerations: SNS drugs (con’t)drugs (con’t)

Peripheral Peripheral αα11 adrenergic receptor adrenergic receptor

blockers (prazosin, doxazosin) reduce blockers (prazosin, doxazosin) reduce TPR TPR may cause fluid retention may cause fluid retention may may then need to give diuretics to counteractthen need to give diuretics to counteract

Clinical considerations: CaClinical considerations: Ca2+2+ channel blockerschannel blockers

All excitable tissue contains receptors for CaAll excitable tissue contains receptors for Ca2+2+ channel blockers but not all tissue affected channel blockers but not all tissue affected equallyequally Dependence of tissue on exogenous CaDependence of tissue on exogenous Ca2+2+ dictates dictates

sensitivity to blockerssensitivity to blockers High in cardiac tissue (especially AV node), lower in High in cardiac tissue (especially AV node), lower in

skeletal muscleskeletal muscle Some may be contraindicated due to other disease Some may be contraindicated due to other disease

states or if using specific drugs states or if using specific drugs Example - do not use verapamil in cases of heart failure Example - do not use verapamil in cases of heart failure

associated with increased TPR associated with increased TPR will slow down an will slow down an already poorly pumping heart already poorly pumping heart

Example - do not use certain Example - do not use certain ββ-blockers in combination -blockers in combination withwith Ca Ca2+2+ channel blockers in heart failure channel blockers in heart failure

Drugs for hypertensive Drugs for hypertensive emergenciesemergencies

May have to reduce BP quickly but temporarilyMay have to reduce BP quickly but temporarily Unexpected side effects of other drugsUnexpected side effects of other drugs Side effects of illegal drugsSide effects of illegal drugs Accidental poisoning Accidental poisoning

Above may cause severe tachycardia Above may cause severe tachycardia can can reduce BP (and HR) by i.v. infusion of reduce BP (and HR) by i.v. infusion of nitroprussidenitroprusside Full effect in secondsFull effect in seconds Recovery from effect within a few minutesRecovery from effect within a few minutes

Or repeated low-dose i.v. injections of Or repeated low-dose i.v. injections of diazoxidediazoxide Full effect in 1 to 5 minutesFull effect in 1 to 5 minutes Recovery within a dayRecovery within a day

Treatment of HypertensionTreatment of Hypertension

and see Table 12-1