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Antihypertensive Drugs Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology
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Introduction Hypertension is characterized by the consistent elevation of arterial blood pressure. Failure to treat hypertension can lead to stroke, heart failure, or MI. The primary factors responsible for blood pressure are cardiac output, the resistance of small arteries and blood volume. Positive lifestyle changes can reduce blood pressure and lessen the need of medication Selection of specific antihypertensive drugs depends on the severity of the disease. Diuretics are often drugs of first choice for treating mild to moderate hypertension.
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Introduction Hypertension is the most common cardiovascular disease. Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 130 mm Hg or a sustained diastolic blood pressure (DBP) of greater than 80 mm Hg. Hypertension is asymptomatic until organ damage is already occurred (Silent Killer).
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Stages of hypertension
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Types of Hypertension Primary/Essential hypertension (no co-morbid cause), 90% Secondary hypertension ( with co-morbid cause ex. kidney disease)
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Arterial blood pressure is regulated within a narrow range Cardiac output and peripheral resistance are controlled mainly by: Baroreflexes (Sympathetic nervous system) Renin-angiotensin-aldosterone system Mechanisms for Controlling Blood Pressure
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Mechanisms for Controlling Blood Pressure Rapid, moment-to-moment regulation of blood pressure. ↓ BP --baroreceptors in the aortic arch and carotid sinuses, send fewer impulses to cardiovascular centers in the spinal cord. ↑ sympathetic and decreased parasympathetic output to the heart and vasculature----rise in blood pressure Renin-angiotensin- aldosterone system Baroreceptors and the sympathetic nervous system Renin converts angiotensinogen to angiotensin I, which is converted in turn to angiotensin II in the presence of angiotensin-converting enzyme (ACE) Angiotensin II is the body's most potent circulating vasoconstrictor Angiotensin II stimulate aldosterone secretion (vasocontraction – sodium retention) Renin release
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Antihypertensive drugs classifications Diuretics Centrally acting sympatholytic Adrenergic antagonists (alpha and Beta blockers) ACE Inhibitors Calcium Channel inhibitors Vasodilators Angiotensin receptor antagonists
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Antihypertensive drugs classifications (1) vasodilators, (2) β-adrenoceptor antagonists (β-blockers), (3) α-adrenoceptor antagonists (α-blockers), (4) angiotensin receptor antagonists, (5) centrally acting sympatholytic, (6) ACE inhibitors, and (7) diuretics.
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Diuretics Diuretics deplete body water and sodium stores. Initially reduce blood volume & cardiac output (CO). Used as initial single treatment In mild hypertension Diuretics lower blood pressure by 10-15 mm Hg. Diuretics alone provide adequate treatment for mild to moderate hypertension. In severe hypertension, diuretics + sympatholytic and vasodilators are used to control sodium retention.
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Uses of Diuretics Thiazide diuretics are appropriate for patients with normal renal and cardiac function with mild to moderate hypertension. Potassium-sparing diuretics are useful to avoid potassium depletion in patients taking other diuretics. Loop diuretics are used in emergency or in renal insufficiency or cardiac failure or cirrhosis Diuretics
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The most common adverse effect of diuretics (except potassium-sparing) is hypokalemia (avoid in digitalis, arrhythmias, MI or left ventricular dysfunction). Diuretics may increase serum lipids, magnesium depletion and impair glucose tolerance . Diuretics increase uric acid concentrations and may precipitate gout. Potassium-sparing diuretics may produce hyperkalemia. Spironolactone is associated with gynecomastia. ADR of Diuretics Diuretics
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Centrally acting sympatholytic Their antihypertensive and toxic actions are less dependent on posture. Two drugs are in this group: Methyldopa Clonidine
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Centrally acting sympatholytic Methyldopa is useful in the treatment of mild to moderately severe hypertension, Safe for pregnant women. It is α2 agonist, converted to α-methylnorepinephrine and α-methyldopamine Its antihypertensive action is due to stimulation of central α-2 adrenoceptors. One advantage of methyldopa is reduction in renal vascular resistance. Because the effect depends on storage of a metabolite, the action persists after stopping the drug. Methyldopa—PO; 250 mg bid or tid (max. 3 g/day) Methyldopa
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Centrally acting sympatholytic Lactation, associated with increased prolactin secretion, can occur both in men and in women (by inhibition of dopaminergic mechanisms in the hypothalamus). Most common ADR of methyldopa is sedation With long-term therapy: mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. ADR of Methyldopa
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Centrally acting sympatholytic Clonidine is an α2 (and less powerful α1) agonist. After IV injection, clonidine produces a brief rise in blood pressure followed by hypotension. The pressor response is due to direct stimulation of α adrenoceptors in arterioles. Severe hypertension can complicate a massive overdose. Clonidine reduces norepinephrine release resulting in hypotension and bradycardia. Clonidine decreases renal vascular resistance and maintains renal blood flow. Clonidine
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Centrally acting sympatholytic Withdrawal of clonidine after chronic use can result in life-threatening hypertensive crisis. Nervousness and tachycardia after omitting one or two doses of the drug. Stopping the drug should be done gradually while other antihypertensive agents are being substituted. Dry mouth and sedation are frequent. The drug should be withdrawn if depression occurs. ADR of Clonidine
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Adrenoceptor Antagonists All β blockers are very useful for mild to moderate hypertension. In severe hypertension, β blockers prevent the reflex tachycardia due to vasodilators. Propranolol inhibits the stimulation of renin production mediated by β1. Propranolol reduces blood pressure without prominent postural hypotension. β- Blockers
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Types: Selective β1-blockers Atenolol, Bisoprolol, Nebivolol, Metoprolol, Esmolol. Nonselective β-blockers (e.g., Nadolol, Propranolol, and Timolol) Esmolol is an IV administered, ultrashort-acting β1-blocker that is used to treat hypertension in surgical patients and in persons with hypertensive emergencies. Nebivolol is a selective blocker of β1 receptors, which also increases the production of nitric oxide, leading to vasodilation and has antioxidant effect Adrenoceptor Antagonists β- Blockers
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Uses: Hypertensive patients with concomitant heart disease, such as supraventricular tachyarrhythmia (for example, atrial fibrillation), previous myocardial infarction, angina pectoris, and chronic heart failure. Conditions that discourage the use of β-blockers include reversible bronchospastic disease such as asthma, second- and third-degree heart block, and severe peripheral vascular disease. Adrenoceptor Antagonists β- Blockers
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Adrenoceptor Antagonists ADR: Side effects occur in asthma, diabetes, cardiac conduction disease and peripheral vascular diseases. Propranolol may cause a withdrawal syndrome: nervousness, tachycardia, angina, or hypertension (should not be discontinued abruptly). β- Blockers
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Prazosin, Terazosin, and Doxazosin selectively block α1 receptors in arterioles and venules (vasodilation) These agents produce reflex tachycardia and postural hypotension. A quick drop in standing blood pressure develops after the first dose (first-dose phenomenon). The first dose should be small and should be administered at bedtime. Adrenoceptor Antagonists α1- Blockers
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ADR: May evoke reflex activation of the SNS and can increase the HR, contractile force, and circulating NE levels and thereby increase myocardial O2 requirements. Because they activate the RAAS and cause fluid retention, are often given with a diuretic Orthostatic hypotension First dose” syncope in some patients, particularly patients taking a diuretic Adrenoceptor Antagonists α1- Blockers
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Labetalol, Carvedilol MOA: block α1, β1, and β2 receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of HF. Carvedilol is a third-generation α- and β-blocker with antioxidant properties that can protect the vascular wall from free radicals Labetalol is used in the management of gestational hypertension, chronic hypertension and hypertensive emergencies Adrenoceptor Antagonists α-/β-adrenoceptor–blocking agents
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Direct Vasodilators Vasodilators work best in combination with other antihypertensive drugs. They consist of: Oral: hydralazine and minoxidil (Used for long-term outpatient therapy) Parenteral : nitroprusside, diazoxide, and fenoldopam (Used to treat hypertensive emergencies) The calcium channel blockers (Used in both circumstances). All of the vasodilators relax arterioles, sodium nitroprusside also relaxes veins.
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Direct Vasodilators
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Direct Vasodilators Hydralazine: The adverse effects of hydralazine are: headache, nausea, anorexia, palpitations, sweating, and flushing. Minoxidil: must be used in combination with a β blocker and a loop diuretic. Topical minoxidil is used for hair growth for correction of baldness.
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Direct Vasodilators It activates guanylyl cyclase, either via release of nitric oxide or direct stimulation of the enzyme → increased intracellular cGMP, which relaxes vessels. It rapidly lowers blood pressure, and its effects disappear within 1-10 minutes after discontinuation. It is sensitive to light and must be made up fresh and covered with opaque foil. The most serious toxicity is accumulation of cyanide; metabolic acidosis, arrhythmias, and death. Accumulation of cyanide can be treated with administration of sodium thiosulfate or hydroxocobalamin Sodium Nitroprusside
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Direct Vasodilators Diazoxide opens potassium channels and stabilizes the membrane at resting potential. Its effect after a rapid injection appears within 5 minutes and lasts 4-12 hours. Diazoxide should be avoided in ischemic heart disease. It inhibits insulin release from the pancreas (opens K+ channels) and is used for insulinoma. Diazoxide
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Direct Vasodilators Fenoldopam is agonist of D1 receptors causing peripheral artery dilatation and natriuresis. Its half-life is 10 min. it is administered by continuous IV infusion. The toxicities are: tachycardia, headache, and flushing. Fenoldopam increases IOP and should be avoided in patients with glaucoma. Fenoldopam
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Calcium Channel Blockers Nifedipine is more selective as a vasodilator and have less cardiac depressant effect. Verapamil has the greatest depressant effect on the heart. Diltiazem has intermediate actions. Risk of MI or mortality is increased in patients receiving short-acting nifedipine. It is recommended that nifedipine not be used for chronic hypertension. Calcium blockers with long half-lives are more appropriate for chronic hypertension. Oral nifedipine is used in emergency treatment of severe hypertension.
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Inhibitors of Angiotensin Renin acts upon angiotensinogen to produce angiotensin I. ACE converts angiotensin I to angiotensin II. Angiotensin II has vasoconstrictor and sodium-retaining activity. It also stimulates aldosterone release. Two classes of drugs act on the renin-angiotensin system: The ACE inhibitors The inhibitors of angiotensin at its receptors.
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Inhibitors of Angiotensin Examples: Captopril, Enalapril, Lisinopril, Benazepril, Fosinopril, Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril (-pril) MOA: Captopril inhibits the renin-angiotensin system and stimulates the kallikrein-kinin system. The ACE inhibitors
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Inhibitors of Angiotensin Pharmacokinetics: Most of them are prodrugs, and are converted to the active agents by hydrolysis. Uses: ACE inhibitors do not result in reflex tachycardia and can be used safely in ischemic heart disease. ACE inhibitors diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure). ACE inhibitors are extremely useful in heart failure, and after MI. ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk. The ACE inhibitors
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Inhibitors of Angiotensin Adverse effects: Severe hypotension can occur after initial doses of any ACE inhibitor. Renal failure in patients with bilateral renal artery stenosis. Hyperkalemia and dry cough. ACE inhibitors are contraindicated in pregnancy (fetal hypotension, renal failure, malformations or death). Drug interactions: Potassium supplements or potassium-sparing diuretics with ACE Inhibitors can result in hyperkalemia. NSAIDs antagonize effects of ACE inhibitors (block bradykinin-mediated vasodilation by prostaglandins). The ACE inhibitors
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Examples: :Losartan, Valsartan, Candesartan, Eprosartan, Telmisartan, and Olmisartan. (-sartan) MOA: They block angiotensin II type 1 (AT1) receptor. They have no effect on bradykinin metabolism. The adverse effects: similar to ACE inhibitors, but cough and angioedema are less common. Inhibitors of Angiotensin Angiotensin Receptor Blockers
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Life style modifications
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Hypertensive Emergencies They occur in poorly controlled patients or those who suddenly discontinue the drug. Hypertensive emergencies include hypertension with vascular damage (malignant hypertension). Hypertensive encephalopathy is a classic feature of malignant hypertension. It consists of: severe headache, mental confusion, blurred vision, vomiting, and focal neurologic deficits. If untreated, the syndrome progresses in 12-48 hours to convulsions, coma, and death.
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Hypertensive Emergencies Parenteral drugs are used to lower blood pressure rapidly (within a few hours). The drug most commonly used is sodium nitroprusside. Esmolol is used for intra- and postoperative hypertension. As soon as reasonable blood pressure is achieved, oral therapy should be substituted.
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REFERENCE: BASIC & CLINICAL PHARMACOLOGY. BERTRAM G. KATZUNG THANK YOU FOR YOUR ATTENTION
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