PHARMACOLOGY Chapter 11: Anti-hypertensive Agents

Hypertension the most common cardiovascular disease. HYPERTENSION & REGULATION OF BLOOD PRESSURE Diagnosis The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure and not on symptoms reported by the patients. Classification of Hypertension (based on blood pressure) Normal <120/80 Prehypertension 120-135/80-89 Hypertension 140/90 Stage 1 140-159/90-99 Stage 2 160/100 Etiology (Cause) of Hypertension 1. Primary or Essential Hypertension - Patients in whom no specific cause of hypertension can be found 2. Secondary Hypertension Patients with specific cause of hypertension (e.g. renal abnormalities, pheochromocytoma) Normal Regulation of Blood Pressure Arterial blood pressure (BP) = CO x PVR Blood pressure is maintained by: 1. Arterioles 2. Capacitance vessels (veins) 3. Heart 4. Kidneys ( by regulating the volume of intravascular fluid) *Barorecepters (SANS), including the renin-angiotensin-aldosterone system (RAAS), coordinate and function at these 4 control sites and maintain normal BP. *Local release of vasoactive substances like: - endothelin-1 = constricts blood vessels - nitric oxide = dilates blood vessels may be also involved in the regulation of vascular resistance. A) Postural baroreflex = responsible for rapid, moment-to-moment adjustments in blood pressure (e.g. transition from a reclining to an upward position) = carotid baroreceptor activation inhibits central sympathetic discharge Renal response to Decrease Blood Pressure = kidneys -> responsible for the long-term blood pressure control by controlling blood volume = a renal arteriole pressure causes: 1. Intrarenal distribution of blood flow 2. reabsorption of salt and water 3. Stimulates production of renin production of angiotensin II

BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS y All antihypertensive agents act at one or more of the four anatomic control sites. 1. Diuretics - BP by depleting the body of sodium; blood volume 2. Sympathoplegic agents - BP by reducing PVR, inhibits cardiac function, venous pooling in capacitance vessels (reduction in CO) 3. Direct vasodilators - BP by relaxing vascular smooth muscle, capacitance 4. Agents that lock production or action of Angiotensin thereby reduce PVR and (potentially) blood volume DRUGS THAT ALTER SODIUM & WATER BALANCE Mechanism of Action y Diuretics lower BP by depleting body sodium stores and by reducing blood volume and cardiac output. y Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural activity. y These effects are reversed by diuretics or sodium restriction. y Diuretics are effective in lowering BP by 10-15 mmHg. y Used in combination with sympathoplegic and vasodilator drugs to control the tendency of sodium retention. (severe cases) Use of Diuretics y Kidneys = site of action y Thiazide diuretics = appropriate for mild or moderate hypertension = e.g. Chlorothiazide, Hydrochlorothiazide (most used diuretic, given in combination w/ Telmisartan), Chlorthalidone, Polythiazide y Loop diuretics (acting on the loop of Henle) = more powerful acting diuretics = e.g. Furosemide necessary in severe hypertension, Torsemide, Bumetanide, Ethancrynic acid y Potassium-sparing diuretics (acting on the collecting tubule) = useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics = e.g. Spironolactone, Eplerenone, Amiloride, Triamterene = ADR: hyperkalemia Toxicity of Diuretics y Most common ADR: Hypokalemia (except in PSD) y Some are: hyperuricemia, hyperlipidemia, hyperglycemia y Spironolactone is associated w/ gynecomastia DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUCNTION Drugs in this group are classified according to the site at which they impair the sympathetic reflex arc.  Drugs that lower BP by actions on the CNS tend to cause sedation and depression, disturbance in sleep.  Drugs that act by inhibiting transmission through autonomic ganglia (ganglion blockers) produce toxicity from inhibition of parasympathetic regulation (no longer used)  Drugs that reduce the release of norepinephrine inhibits ejaculation, causes postural hypotension  Drugs that block postsynaptic adrenoceptors more selective spectrum of effects depending on the class of receptor to which they bind Sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic.

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*Angiotensin II causes: (1) direct constriction of resistance vessels (2) stimulation of aldosterone synthesis renal sodium absorption and intravascular blood volume *Vasopressin released from the posterior pituitary gland; regulates water absorption by the kidneys

A) Centrally Acting Sympathoplegic Drugs Mechanism & Sites of Action y Reduce sympathetic outflow from vasomotor centers but allow these centers to retain or even increase in sensitivity to baroreceptor control. y METHYLDOPA = an analog of L-dopa = given orally = its action appear to be due to stimulation of central adrenoceptors by -methylnorepinephrine or -methyldopamine y CLONIDINE = a 2-imidazoline derivative = given sublingually = direct stimulation of adrenoceptors in arterioles = reduces sympathetic and increases parasympathetic tone lowering BP and bradycardia = also binds to imidazoline receptor, a nonadrenoceptor site, which may also mediate antihypertensive effects *these 2 drugs are classified under 2-selective agonist y GUANABENZ & GUANFACINE = centrally active antihypertensive drugs 1. Methydopa - used primarily for hypertension during pregnancy - lowers BP by PVR - ADR: postural hypotension, sedation, vertigo, depression, nightmares 2. Clonidine - lowers BP by reduction of cardiac output and PVR due to decreased heart rate and relaxation of capacitance vessels - lipid-soluble (enters the blood-brain barrier like methyldopa) - ADR: dry mouth, sedation, tachycardia B) Ganglion-Blocking Agents y Drugs that block activation of postganglionic autonomic neurons by st acetylcholine were among the 1 agents used in the treatment of hypertension. y Competitively block nicotinic cholinoceptors on postganglionic neurons in both sympa and parasympa ganglia. y ADR: postural hypotension, impotence, constipation, urinary retention, glaucoma, blurred vision, dry mouth, etc. C) Adrenergic Neuron-Blocking Agents y These drugs lower BP by inhibiting the release of norepinephrine. 1. Guanethidine - in high doses, can produce profound sympathoplegia - used in the pharmacologic sympathectomy - too polar to enter the CNS; has a long half-life - inhibits the release of NE from sympathetic nerve endings by entering the vesicular monoamine transporter (VMAT) and displacing NE - ADR: postural hypotension (orally), impotence, diarrhea 2. Reserpine - an alkaloid from Rauwolfia serpentina - inhibits VMAT; VMAT blocker depletion in NE, dopamine, and serotonin - can cross the blood-brain barrier - used for the treatment of mild hypertension - ADR: sedation, depression, parkinsonism, diarrhea, gastric acid secretion D) Adrenoceptor Antagonists y Blockers Phenoxybenzamine, Phentolamine - these agents reduce arterial pressure by dilating both resistance and capacitance vessels; retention of salt and water occurs (more effective in combination w/ diuretics) - useful in the diagnosis and treatment of pheochromocytoma y 1-selective Prazocin(shortest acting), Terazocin, Doxazocin (longest acting), Tamsulosin

E) Beta-Adrenoceptor-Blocking Agents y Useful for lowering BP in mild to moderate hypertension. y Especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. y Have been shown to reduce mortality after a myocardial infarction and patients with heart failure. 1. Propranolol st - 1 Beta-blocker shown to be effective in hypertension and ischemic heart disease - non-selective beta-blocker - decrease BP by cardiac output - inhibits the stimulation of renin production by catecholamines 2. Metoprolol & Atenolol - 1-selective blockers st - M: extensively metabolized by CYP2D6 with high 1 -pass metabolism; short half-life - M: equipotent with propranolol but causes less bronchial constriction than propranolol - A: not extensively metabolized and is excreted through the urine 3. Nadolol, Carteolol, Betaxolol, & Bisoprolol - Nadolol (longest acting) and Carteolol non-selective beta blockers = not appreciably metabolized and excreted in the urine - Betaxolol and Bisoprolol 1-selective blockers = metabolized in the liver but have long half-lives 4. Pindolol, Acebutolol, & Penbutolol - lowers BP by vascular resistance and appear to depress cardiac output or heart rate - Pindolol & Penbutolol can cross the blood-brain barrier (can cause vivid dreams, nightmares, insomnia, drowsiness) 5. Labetalol, Carvedilol, & Nebivolol - these drugs have both beta-blocking and vasodilating effects - L: BP is lowered by reduction of systemic vascular resistance w/o significant alteration in heart rate/CO - L: effective in the treatment of pheochromocytomo and hypertensive emergencies - C: a non-selective beta-blocker, useful in patients w/ both heart failure and hypertension - N: is the most 1-selective blocker with vasodilating properties that are not mediated by blockade 6. Esmolol - a 1-selective blocker; rapidly metabolized via hydrolysis by RBC esterases - generally administered as a loading dose followed by constant infusion; shortest-acting - used in the management of intraoperative and postoperative hypertension VASODILATORS  The oral vasodilators, HYDRALAZINE and MINOXIDIL, which are used for long-term outpatient therapy of hypertension.  The parenteral vasodilators, NITROPRUSSIDE, DIAZOXIDE, and FENOLDOPAM, used to treat hypertensive emergencies 2+  The Ca channel blockers, NICARDIPINE and NIFEDIPINE.  The nitrate, used mainly in angina. Mechanism of Action y Relaxes the smooth muscle of arterioles, thereby systemic vascular resistance. y Does not cause postural hypotension or impotence. y Work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. 1. Hydralazine - dilates arterioles but not the veins - No potassium efflux - ADR: lupus-like symptoms (arthritis, nephritis, vasculatis, etc.), headache, nausea, anorexia, palpitations, sweating, flushing

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Minoxidil - very efficacious orally active vasodilator - dilates arterioles but not the veins - potassium efflux is present - topical Minoxidil (Rogaine) is used as a stimulant to hair growth (hypertrichosis) Sodium Nitroprusside - a powerful parenterally administered vasodilator - dilates both arterioles and venioles - no potassium efflux - liberates cyanide thiocyanate eliminated by the kidney - given by IV infusion and should be protected from light - can develop cyanide toxicity Diazoxide - effective and relatively-long acting parenterally administered arteriolar dilator - potassium efflux is present - inhibits insulin release in the pancreas - ADR: renal salt and water retention, hypotension, can provoke angina Fenoldopam - a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension - acts as an agonist of dopamine D1 receptors - short-acting -ADR: intraocular pressure Calcium Channel Blockers = MOA: inhibition of Calcium influx into arterial smooth muscle cells = well absorbed orally = Verapamil, Diltiazem, and the Dihydropyridine family (Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, and Nisoldipine) are all equally effective in lowering BP. = Clevidipine is a newer member of this group (for IV use only). Nifedipine - more selective as vasodilators and have less cardiac depressant effect than Verapamil and Diltiazem - short-acting - in long term use, the chance of stroke Verapamil - has the greatest depressant effect in the heart - cardio-selective (same as Diltiazem); Class IV anti-arrhythmics Nimodipine - dilate cerebral blood vessel

DRUGS AFFECTING RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM Three classes of drugs act specifically on the renin-angiotensin system: ACE inhibitors; the Angiotensin II-receptor blockers, and Aliskiren, an orally active renin antagonist.

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Renin = produced in the kidneys (responsible for the 21% CO) = capable of converting angiotensinogen (pro-enzyme in the blood) Angiotensin I Angiotensin II (converted by ACE produced in the lungs) Angiotensin II =(1) Na reabsorption in the kidneys (through the activity of =(2) vasoconstriction BP

O2 =

renin release

aldosterone)

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A) ACE INHIBITORS y Inhibit ACE (which degrades bradykinin) y Inhibits peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II y Effective in treating patients w/ kidney disease, heart failure, and after myocardial infarction y ADR: cough, hypertension, hyperkalemia, FDA category: C/D, teratogenic 1. Captopril - works at least in part by releasing nitric oxide and prostacyclin - icatibant, a bradykinin receptor antagonist, blunts the BP lowering effect of Captopril. Enalapril - an oral prodrug enalaprilat (active metabolite) - available only for IV use Lisinopril - a lysine derivative of enalaprilat

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Other examples: Benazepril, Fosinopril & Moexipril (eliminated primarily in the kidneys), Perindopril, Quinapril, Ramipril, Trandolapril, and Imidapril B) ANGIOTENSIN RECEPTOR-BLOCKING AGENTS y Orally administered, more selective y They have no effect on bradykinin metabolism y ADR: hypotension, hyperkalemia, angioedema y CIND: bilateral renal artery stenosis constriction of the 2 renal arteries 1. Losartan 2. Valsartan st *were the 1 marketed blockers of angiotensin II receptor 3. Candesartan 4. Eprosartan 5. Irbesartan 6. Telmisartan 7. Olmesartan C) RENIN INHIBITOR (from the book) 1. Aliskiren - inhibits the enzyme activity of renin - reduces angiotensin I and II and aldosterone - for hypertension - ADR: hyperkalemia, renal impairment, potential teratogen

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