Antihypertensive Drugs

Antihypertensive Drugs PHR 242: Pharmacy Pharmacology William B. Jeffries, Ph.D Room 570A Criss III 280-4092 Email: wbjeff@creighton.edu flap.creighton.edu Definition Elevation of arterial blood pressure above 140/90 mm Hg. Can be caused by: • an underlying disease process (secondary hypertension) • Renal artery stenosis • Hyperaldosteronism • pheochromocytoma • idiopathic process (primary or essential hypertension) Mortality Is Related to Blood Pressure JNC VI Stages of Hypertension Stage High Normal Stage 1 Diastolic Range (mm Hg) 85-89 Systolic Range (mm Hg) 130-139 90-99 100-109 > 109 140-159 160-179 >179 Stage 2 Stage 3 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 (ßblockers, Ca2+ channel blockers) Reduce plasma volume (diuretics) Reduce peripheral vascular resistance (vasodilators)   MAP = CO X TPR Major Risk Factors That Increase Mortality in Hypertension       Smoking Dyslipidemias Diabetes Mellitus Age >60 Gender: men, postmenopausal women Family history "Individualized Care"  Risk factors considered  Monotherapy is instituted  Non pharmacological therapy tried first  Considerations for choice of initial monotherapy:  Renin status  Coexisting cardiovascular conditions  Other conditions Treatment Thresholds for Essential Hypertension Stages Risk group A (no major risk factors, no target organ damage) Risk Group B One or more major risk factors (except diabetes), no organ damage Lifestyle Modification Risk Group C Target organ damage and/or diabetes High Normal Lifestyle Modification Lifestyle Modification and Drug Therapy Stage 1 Lifestyle Modification (up to 12 months) Lifestyle Modification and Drug Therapy Lifestyle Modification and Drug Therapy Stages 2 and 3 Lifestyle Modification and Drug Therapy Lifestyle Modification and Drug Therapy Lifestyle Modification and Drug Therapy Monotherapy for Hypertension • • • • • ACE inhibitors and ATII antagonists Diuretics ß-adrenoceptor blockers a1-adrenoceptor blockers Ca2+ channel blockers Benzothiazide Diuretics   Mechanism of action Indications – – – Monotherapy for mild-moderate HTN Adjunct agent Usually necessary in severe HTN Thiazide diuretics: considerations    Long-term hypokalemia appears to increase mortality. K-sparing diuretics are superior to K supplementation when diuretics used. Most efficacious in “low renin” or volumeexpanded 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:  Non selective Prototype: Propranolol (others: nadolol, timolol, pindolol, labetolol)  Cardioselective Prototype: Metoprolol (others: atenolol, esmolol, betaxolol)  Non selective and cardioselective ß-blockers are EQUALLY effective in reducing blood pressure Other Properties Relevant to Antihypertensive Effect:   Intrinsic sympathomimetic activity. Mixed antagonism. Therapeutic Use in Hypertension     Monotherapy most effective in high renin hypertension hypertension with coronary insufficiency low cost to patient Administration    Blah Blah Blah Adverse Effects       Bradycardia Heart failure Bronchospasm Coldness of extremities Withdrawal effects Glucose metabolism 5.     Adverse Effects (Cont) CNS effects Pregnancy 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. a-Adrenoceptor Blockers    Mechanism of action: blockade of vascular aadrenoceptors Non selective (a1 and a2) blockers: Phentolamine, phenoxybenzamine and dibenamine Selective (a1) prototype: prazosin (others: terazosin, doxazosin, trimazosin) Therapeutic Use in Hypertension   Non selective (a and a ) blockers: used for treatment of hypertensive crises in pheochromocytoma Selective (a1) blockers 1 2  Monotherapy  Adjunctive therapy Administration of a1-Adrenoceptor Blockers    Read The Book Side effects of a1-adrenoceptor blockers    First dose phenomenon Tachycardia GI effects (rare) Adverse Effects of Non Specific aAdrenoceptor Blockers    Postural hypotension Reflex tachycardia Fluid retention Other Sympatholytics   Guanethidine Ganglionic blockers Guanethidine   Mechanism of action Therapeutic use Ganglionic Blockers (Trimethaphan)   Mechanism of action Therapeutic use Drugs Interacting With the Reninangiotensin System   ACE inhibitors ATII antagonists Physiology of Renin-Angiotensin System  Details: Katzung, Chapter 17 Receptor Subtypes for Angiotensin  AT1 – – – AT1A AT1B Prototype antagonist: Losartan  AT2 Primary antagonist available is PD123177  AT3?AT4 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 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  Renal insufficiency  Cough  Hyperkalemia  Hyperreninemia Minor Adverse Effects of ACE Inhibitors  Ageusia  Skin rash  Proteinuria  Neutropenia Pharmacology of AT-Receptor Antagonists     Losartan Valsartan Candesartan *sartan Mechanism of Action of ATII Antagonists  Molecular: Competitive inhibitor of AT1 receptors. Blocks 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 restenosis following angioplasty 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 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 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: a2-Adrenoceptor Agonists     a-Methyldopa Clonidine Guanabenz Guanfacine a2-Adrenoceptor Agonists Mechanisms of Action  Central Action: Stimulation of a2 adrenoceptors in the brainstem reduces sympathetic tone, causing a centrally mediated vasodilatation and reduction in heart rate Prejunctional action: Stimulation of a2 adrenoceptors located prejunctionally on peripheral neurons reduces norepinephrine release Vascular smooth muscle: a2 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 a2 adrenoceptor agonists.  a-methyldopa: Prodrug taken up by central adrenergic neurons and converted to the a2 adrenoceptor agonist a-methylnorepinephrine. Therapeutic Uses in Hypertension   Not generally used for monotherapy of mild to moderate hypertension Considerations – – – fluid retention: must use diuretic Direct acting a2 adrenoceptor agonists: effective in lowering blood pressure in ALL patients. Direct acting a2 adrenoceptor agonists are equally efficacious but more efficacious than a-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: a-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 a2-Adrenoceptor Agonists    Hypotension especially in volume depleted patients Sedation: more prominent for direct acting a2 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) a2-Adrenoceptor Agonist Drug Interactions   Diuretics enhance hypotensive action Tricyclic antidepressants inhibit clonidine's action Reserpine Molecular mechanism of action: Inhibition of noradrenergic function.    Reserpine binds to storage vesicles and releases norepinephrine and serotonin. Storage vesicles are destroyed and nerve ending loses capacity to store and release norepinephrine and serotonin Pharmacological consequences: reduction of cardiac output and TPR Reserpine    Extremely long acting Tolerated well (as well as diuretic plus propranolol in Veteran's cooperative study) CNS effects: – – Sedation, loss of concentration psychotic depression. Depression: insidious progression that can lead to suicide