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Introductory Clinical Pharmacology Chapter 41 Antihypertensive Drugs Copyright © 2008 Lippincott Williams & Wilkins. Blood Pressure • Normal = sys<120 and diastolic <80 • Prehypertension 120-139/80-89 • Stage 1 hypertension 140-159/ 90-99 • Stage 2 hypertension >159 or >99 • For every 20mmgh increase in systolic BP from ages 4069, mortality from ischemic heart disease and stroke doubles. Copyright © 2008 Lippincott Williams & Wilkins. Blood Pressure • BP= CO x SVR Vascular resistance influenced by alpha1 receptors (norepinepherine), calcium channels, AT2 receptors (RAAs vasoconstriction and sodium and water retention w/potassium excreteion • CO= HR x SV Stroke volume=preload (aldosterone) – HR influenced by β1 receptors Copyright © 2008 Lippincott Williams & Wilkins. Copyright © 2008 Lippincott Williams & Wilkins. Blood Pressure • Force of blood against arterial walls • Normal: <120/<80 • Hypertension – Essential vs. secondary – Increases risk of heart disease, CHF, RF, blindness, stroke – African Americans twice as likely as Caucasians – Essential cannon be cured but can be controlled Copyright © 2008 Lippincott Williams & Wilkins. Non-Pharmacologic Control of HTN • Weight loss • Stress reduction • Smoking cessation • Regular aerobic exercise • Decrease sodium and sugar intake • Increase potassium intake • DASH diet Copyright © 2008 Lippincott Williams & Wilkins. Antihypertensive Drugs • ACE inhibitors: captopril, enalapril, lisinopril • ARBs: Losartan, valsartan • Nitrates: nitroglycerin, isosorbide dinitrate • Calcium channel blockers: verapamil, nifedipine, diltiazem • Alpha adrenergic blockers: phentolamine, phenoxybenzamine, prazosin, terazosin • Adrenergic neuron blockers: reserpine, guanethidine, guanadrel • Centrally acting agents: clonidine, guanabenz, methyldopa • Other: hydralazine, minoxidil, nitroprusside,diazoxide, nesiritide Copyright © 2008 Lippincott Williams & Wilkins. Pharmacologic control of BP • Diuretics decrease preload • Beta Blockers (-lols)decrease contractile state of the heart and heart rate (decrease cardiac output) • ACE inhibitors (-prils) Block AT2 via ACE inhibition • ARBs ( sartans) block AT2 receptors • Calcium Channel blockers (dipines and others) block calcium channels on peripheral vessels • Alpha 1 Blockers (-osins) are rarely used for HTN • Alpha 2 agonists (catapres) work in hypothalamus • Other: hydralazinie, nitroprusside, morphine, NTG: direct vasodilators for hypertensive crises Copyright © 2008 Lippincott Williams & Wilkins. Vasodilators • May dilate arterioles, veins or both • Uses: essential hypertension, hypertensive crisis, angina, heart failure, MI, production of controlled hypotension during surgery • Adverse effects: postural hypotension, reflex tachycardia, expansion of blood volume Copyright © 2008 Lippincott Williams & Wilkins. Hydralazine (Apresoline) • Selective dilation of arterioles peripheral resistance, BP, HR, myocardial contractility • Used for Essential HTN, usually in conjunction with a βblocker and a diuretic; hypertensive crisis, heart failure • Adverse effects: reflex tachycardia, Increased blood volume, SLE like syndrome, headache, dizziness, weakness, fatigue • Use with β-blocker prevents reflex tachycardia, diuretics prevent blood volume expansion Copyright © 2008 Lippincott Williams & Wilkins. Renin-Angiotension-Aldosterone System Copyright © 2008 Lippincott Williams & Wilkins. Ace Inhibitors • Benazepril, captopril, enalapril, lisinopril, ramipril, fosinopril • Prevent conversion of Angiotensin I to Angiotensin II • Use: hypertension, HF, diabetic neuropathy, MI. Prevention of adverse CV events in patients at risk • Excreted by the kidneys. Dosages must be reduced in patients with kidney disease. • SE: Hypotension, hyperkalemia, hypoglycemia, cough, angioedema Copyright © 2008 Lippincott Williams & Wilkins. Angiotensin Receptor Blockers • Losartan, valsartan, candesartan irbesartan telmisartan, olmesartan • Action of the angiotensin II receptor antagonists: Block the binding of angiotensin II at the receptor sites found in smooth muscle and adrenal gland; this stops renin angiotensin system and lowers blood pressure • Uses: Used for the treatment of hypertension; some drugs are used only in severe cases of hypertension; two antihypertensive drugs may be given together to achieve a better response Copyright © 2008 Lippincott Williams & Wilkins. Antihypertensive Drugs: Contraindications • Antihypertensive drugs are contraindicated in patients with known hypersensitivity to the individual drug • ACEIs: Contraindicated in patients with impaired renal function, congestive heart failure, salt or volume depletion, bilateral stenosis, or angioedema, also during pregnancy or lactation • Use of the ACEIs and the angiotensin II receptor blockers during the second and third trimester of pregnancy is contraindicated because use may cause fetal or neonatal injury or death Copyright © 2008 Lippincott Williams & Wilkins. Beta Blockers • Acebutolol, atenolol, carvedilol, esmolol, labetalol, bisoprolol, metoprolol, bisoprolol • Epinepherine stimulates β1 receptors on heart HR BP and increases strength of contraction • Β2 stimulation causes tremors, bronchodilation vasodilation of large arteries in legs. • Non-selective β-blockers affect heart, skeletal muscle, lungs and arteries (propranolol, nadolol, timolol, carvedilol, pindolol) • Β1 selective blockers block receptors on heart so that heart rate falls, blood pressure falls, cardiac workload decreases. (atenolol, metoprolol, betaxolol, bisoprolol) Copyright © 2008 Lippincott Williams & Wilkins. Uses of Beta-blockers • Decrease palpitations during panic attacks • Decrease essential tremors • Decrease situational anxiety Copyright © 2008 Lippincott Williams & Wilkins. Beta1 Agonists • Stimulate β1 receptors to increase HR and contractility – Dobutamine – Dopamine – Levophed Copyright © 2008 Lippincott Williams & Wilkins. Calcium Channel Blockers • Class 1: Verapamil – Blocks calcium channels primarily on the coronary vessels and AV node – Increases blood flow to heard and decreases impulses through AV node. Used to decrease workload of heart, slows rate, treat HTN, angina, afib • Class 2 Diltiazem – Dilates calcium channels on the coronary and peripheral vessels – Uses: a fib, HTN, angina, vasospasm Copyright © 2008 Lippincott Williams & Wilkins. Class 3 Calcium Channel Blockers • -dipines: amlodipine, felodipine, nifedipine, • Peripheral vessel calcium channel blockers • Uses: HTN, vasospasm (Prinzmetals’s angina, Reynaud’s) • SE: Verapamil causes significant consipation, diltiazem less – Dipines: headaches, hypotension, peripheral and pedal edema Copyright © 2008 Lippincott Williams & Wilkins. • True/False • 1. Blood pressure is the force of the blood against the walls of the arteries. • 2. A hypertensive emergency is a case of extremely high blood pressure in which blood pressure must be lowered immediately to prevent damage to the target organs. • 3. Risk factors for hypertension include diabetes, obesity, smoking and family history of CVD. • 4. A systolic pressure of less than 120 mmHg and a diastolic pressure of less than 80 mmHg (120/80) are considered abnormal. • 5. The hypotensive effects of most antihypertensive drugs are increased when administered with diuretics and other antihypertensives. • Fill-in-the-Blank • 1. ________________ is defined as a systolic pressure between 120 and 139 mmHg or a diastolic pressure between 80 and 89 mmHg. • 2. When a direct cause of the hypertension can be identified, the condition is described as ________________ hypertension. • 3. _________________ promotes the retention of sodium and water, which may contribute to a rise in blood pressure. • 4. _________________ hypotension occurs when the individual has a significant drop in blood pressure (usually 10 mmHg systolic or more) when assuming an upright position. • 5. Nitroprusside and diazoxide are drugs used to treat patients with a _________________ emergency. Copyright © 2008 Lippincott Williams & Wilkins.