Antihypertensive Drugs Cardiovascular System Course William B. Jeffries, Ph.D. Room 463 Criss III

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 disease Nephropathy Peripheral artery disease Retinopathy

Ways of Lowering Blood Pressure Reduce cardiac output (ß- blockers, Ca 2+ 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 Ca 2+ 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.

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:

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 selective Prototype: Propranolol (others: nadolol, timolol, pindolol, labetolol) Cardioselective Prototype: Metoprolol (others: atenolol, esmolol, betaxolol) EQUALLY Non selective and cardioselective ß-blockers are EQUALLY 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 – Ca 2+ 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 ) blockers Monotherapy Adjunctive therapy

Side effects of  1 -adrenoceptor blockers First dose phenomenon Tachycardia GI effects (rare) ALLHAT Data

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 Captopril Prodrugs: 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, Dysgeusia Skin rash Proteinuria Neutropenia

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 AT 1 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

Ca 2+ 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 Ca 2+ 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)