Antihypertensive Drugs

Cardiovascular System Course

William B. Jeffries, Ph.D.

Room 463 Criss III

280-3600

Email: wbjeff@creighton.edu

Treatment Rationale

Short-term goal of antihypertensive therapy:

Reduce blood pressure

• Primary (essential) hypertension• Secondary hypertension

Treatment Rationale

Long-term goal of antihypertensive therapy:Reduce mortality due to hypertension-induced disease

Stroke Congestive heart failure Coronary artery diseaseNephropathyPeripheral artery diseaseRetinopathy

Ways of Lowering Blood Pressure

Reduce cardiac output (ß-blockers, Ca2+ channel blockers)

Reduce plasma volume (diuretics)

Reduce peripheral vascular resistance (vasodilators)

MAP = CO X TPR

Classes of Antihypertensives Diuretics Peripherally acting sympatholytics

– Beta adrenergic antagonists– 1 adrenergic antagonists

Centrally acting sympatholytics– 2 adrenergic agonists– Reserpine

Other sympatholytics: – guanethidine, ganglionic blockers,

Renin angiotensin system blockers– ACE Inhibitors– AT II antagonists

Ca2+ entry blockers Vasodilators

– Chronic use: minoxidil, hydralazine– Emergency use: sodium nitroprusside, diazoxide

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

42,418 participants, greater than 55 years of age, plus at least one other cardiovascular risk factor.

Findings: Chlorthalidone is superior to an ACE inhibitor, a calcium channel blocker and an 1-adrenergic antagonist in preventing one or more CVD events.

Recommendations for antihypertensive treatment:– Use Thiazide-type diuretics as first treatment in stage I and II HTN

prevent cardiovascular disease better than other classes lower cost drugs of choice for first-step antihypertensive therapy.

– Diuretic intolerant patients: consider CEB’s and ACE inhibitors – Most hypertensive patients require more than one drug. Diuretics should

generally be part of the antihypertensive regimen. – Lifestyle advice should also be provided.

http://www.nhlbi.nih.gov/health/allhat/index.htm

Principles of Therapeutics: JNC VII

Thiazide diuretics should be used in most patients w/ uncomplicated hypertension

High risk conditions: initial use of other drug classes– Beta adrenergic blockers– ACE Inhibitors and ARB’s– Calcium channel blockers

MOST patients will require more than one drug to achieve blood pressure reduction to normotensive range.

JNC VII Guidelines: http://allhat.sph.uth.tmc.edu/publications/jnc7.pdf http://jama.ama-assn.org/cgi/content/full/289/19/2560

Thiazide Diuretics

Mechanism of action Indications

– Monotherapy for mild-moderate HTN

– ALLHAT: reduction of CVD risk superior to other agents

– Adjunct agent– Usually necessary in severe

HTN

Hydrochlorothiazide

Thiazide diuretics: considerations

Long-term hypokalemia increases mortality. K-sparing diuretics are superior to K

supplementation when diuretics used. Most efficacious in “low renin” or volume-

expanded forms of hypertension

ß-Adrenoceptor blockers

Mechanism of Action:ß-adrenoceptor antagonism

Why blood pressure reduction?

– Reduction of cardiac output– Reduction of renin release– Central nervous system -

reduction of sympathetic outflow

Types of ß-blockers (*olol):

Non selectivePrototype: Propranolol (others: nadolol, timolol, pindolol,

labetolol)

CardioselectivePrototype: Metoprolol (others: atenolol, esmolol, betaxolol)

Non selective and cardioselective ß-blockers are EQUALLYEQUALLY effective in reducing blood pressure

Other Properties Relevant to Antihypertensive Effect:

Intrinsic sympathomimetic activity. – Partial beta-2 agonism– Pindolol, acebutolol, penbutolol

Mixed antagonism.– Labetalol– Carvedilol

Therapeutic Use in Hypertension

Monotherapy Initially most effective in high renin

hypertension Hypertension with coronary

insufficiency Low cost to patient – increased

compliance

Adverse Effects

Bradycardia Bronchospasm Coldness of extremities Withdrawal effects Heart failure Glucose metabolism:

– prevention of catecholamine-induced rise in glucose metabolism and lipolysis

– Contraindicated in insulin-dependent diabetes

Adverse Effects (Cont)

CNS effects Use in Pregnancy: propranolol Rise in plasma triglyceride concentration; decrease

in HDL cholesterol Drug interactions:

– NSAID'S - can blunt effect of ß-blockers – Epinephrine - causes severe hypertension in presence

of ß-blockade – Ca2+channel blockers Conduction effects on heart are

additive w/ ß blockers.

-Adrenoceptor Blockers

Mechanism of action: blockade of vascular adrenoceptors

Non-selective (1 and 2) blockers: Phentolamine, phenoxybenzamine and dibenamine

Selective (1) prototype: prazosin (others: terazosin, doxazosin, trimazosin)

Therapeutic Use in Hypertension

Non selective (1 and 2) blockers: used for treatment of hypertensive crises in pheochromocytoma

Selective (1) blockersMonotherapyAdjunctive therapy

Side effects of 1-adrenoceptor blockers

First dose phenomenon Tachycardia GI effects (rare) ALLHAT Data

http://allhat.sph.uth.tmc.edu/http://www.nhlbi.nih.gov/health/allhat/

Adverse Effects of Non Specific -Adrenoceptor Blockers

Postural hypotension Reflex tachycardia Fluid retention

Other Sympatholytics

Guanethidine Ganglionic blockers

Drugs Interacting With the Renin-angiotensin System

ACE inhibitors ATII antagonists

Renin-Angiotensin System

Details: Katzung, Chapter 17

Angiotensin Converting Enzyme (ACE) Inhibitors

Mechanism of Action: Inhibition of angiotensin II formation

Competitive inhibition of angiotensin converting enzyme reduces circulating ang II, reducing vascular tone.

Systemic Effects of ACE Inhibitors

Reduction in systemic arteriolar resistance, systolic, diastolic and mean arterial pressure.

Regional hemodynamic effects: – Increased regional blood flow in proportion to

ang II sensitivity of the vascular bed – Increased large artery compliance– Cardiac output and heart rate unchanged

Aldosterone secretion reduced Reduction of Remodeling

Types of ACE Inhibitors

Active molecules: Captopril, Lisinopril, Enalaprilat

Prodrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril

Therapeutic Uses in Hypertension

One of the initial choices for monotherapy of mild to moderate hypertension

Well tolerated as monotherapy. Drugs of choice in diabetes mellitus with hypertension

Most effective in high renin hypertension More effective in white vs. black patients Excellent for patients with concomitant congestive

heart failure, LVH, cardiac arrhythmias or diabetes mellitus, consider in asthma instead of ß-blockers

Efficacy enhanced by diuretics

Administration

CaptoprilProdrugs: inactive prodrug is hydrolyzed

in vivo to active compound, e.g., enalapril to enalaprilat

Lisinopril

ACE Inhibitor Adverse Reactions

Hypotension Cough Hyperkalemia Angioedema Renal insufficiency Hyperreninemia Teratogenicity: All three trimesters

AHA recomends women who are taking ACE inhibitors for high blood pressure not become pregnant while on this class of drugs

ACE Inhibitor-Induced Angioedema

Minor Adverse Effects of ACE Inhibitors

Ageusia, DysgeusiaSkin rashProteinuriaNeutropenia

Pharmacology of AT-Receptor Antagonists

Losartan: competitive antagonist Valsartan: non-competitive antagonist Candesartan: non-competitive antagonist Irbesartan: non-competitive antagonist *sartan

Mechanism of Action of ATII Antagonists

Molecular: Competitive or non-competitive inhibition of AT1 receptors. Block ability of angiotensins II and III to stimulate pressor and cell proliferative effects

Antihypertensive effects Cell growth effects Lack of “bradykinin” effects

Clinical Indications for ATII Antagonists

Hypertension Heart failure Prevention of re-stenosis following angioplasty

Adverse Reactions Hypotension Hyperkalemia Renal insufficiency Hyperreninemia Teratogenicity

Ca2+ Channel Blockers

One of the initial choices for monotherapy of mild to moderate hypertension

all CEB's are equally effective when used as monotherapy for Stage 1 hypertension

Verapamil and diltiazem are vasodilators that do not cause reflex tachycardia due to direct inhibition of cardiac automaticity

Best in low renin hypertension: Blacks and elderly do not cause fluid retention

Hydralazine

Direct acting vasodilator: liberates NO from vascular endothelium which stimulates the production of cGMP in vascular smooth muscle, resulting in relaxation (arterioles > veins)

Can NOT be used for monotherapy Bioavailability dependent on genetic factors (fast or slow

acetylators) Tachycardia with palpitations, hypotension OFTEN Fluid retention Lupus-like syndrome may occur with chronic use that is reversible

upon continuation Never use as first choice; Try in refractory hypertension as part of

a multidrug regimen

Minoxidil

Prodrug of minoxidil N-O sulfate, which is a direct acting vasodilator.

Mechanism: K+ channel opener, causes membrane hyperpolarization, reducing ability of smooth muscle to contract.

Other K channel openers: pinacidil, diazoxide.

refractory hypertension only. Long duration of action (>24 hours).

Minoxidil Adverse Effects

Fluid and water retention: can lead to pulmonary hypertension

Tachycardia and increased cardiac output: can progress to congestive heart failure

Hypertrichosis: Occurs in all patients who take therapeutic doses of minoxidil for a prolonged time

Centrally Acting Sympatholytics: 2-Adrenoceptor Agonists

Methyldopa Clonidine Guanabenz Guanfacine

2-Adrenoceptor Agonists Mechanisms of Action

Central Action: Stimulation of 2 adrenoceptors in the brainstem reduces sympathetic tone, causing a centrally mediated vasodilatation and reduction in heart rate

Prejunctional action: Stimulation of 2 adrenoceptors located prejunctionally on peripheral neurons reduces norepinephrine release

Vascular smooth muscle: 2 adrenoceptors located on vascular smooth muscle open Ca2+ channels and cause vasoconstriction. Not evident clinically unless given intravenously

Mechanisms of Action (cont.)

Clonidine, guanabenz and guanfacine: Direct acting 2 adrenoceptor agonists.

-methyldopa: Prodrug taken up by central adrenergic neurons and converted to the 2 adrenoceptor agonist -methylnorepinephrine.

Therapeutic Uses in Hypertension

Not generally used for monotherapy of mild to moderate hypertension

Considerations– fluid retention: must use diuretic– Direct acting 2 adrenoceptor agonists: effective

in lowering blood pressure in ALL patients. – Direct acting 2 adrenoceptor agonists are equally

efficacious but more efficacious than -methyldopa

Other Use

Clonidine is useful in diagnosis of pheochromocytoma. Clonidine (single 0.3 mg dose) will reduce plasma norepinephrine concentration to below 500 pg/ml in tumor-free patients.

Administration: Methyldopa

Short plasma half life (2 hours) but longer action (peak at 6-8 hours, duration 24 hours

Once or twice daily dosing due to long action

Action prolonged in patients with renal insufficiency

Administration: Clonidine, Guanabenz and Guanfacine

Orally active, good absorption, usually given twice daily

Clonidine: available as a sustained release transdermal patch (avoids withdrawal syndrome)

Adverse Effects of 2-Adrenoceptor Agonists

Hypotension especially in volume depleted patients

Sedation: more prominent for direct acting 2 adrenoceptor agonists - 50% of patients

Withdrawal syndrome: hypertension, tachycardia, nervousness and excitement.

Adverse Effects Unique to Methyldopa:

Heart block (methyldopa) Immunological changes: positive Coombs test

(20% after 1 year), lupus like syndrome, leukopenia, red-cell aplasia

Altered liver function 5% Hyperthermia Reduced mental acuity

Adverse Effects of Clonidine, et al:

Dry mouth, nasal stuffiness Contact dermatitis with clonidine patch: 20% Vivid dreams Restlessness Depression (infrequent)