Anti-hypertension - -.pdf

C.V.S Antihypertensive Drugs Dr/ Mohammad Al-Ghazali Learning Objectives • The risk factors of hypertension • Types of hypertension • Mechanism of controlling • Guidelines in nonpharmacological therapy • Classification of pharmacological therapy • Pharmacokinetics and pharmacodynamics • Contraindi...

C.V.S Antihypertensive Drugs Dr/ Mohammad Al-Ghazali Learning Objectives • The risk factors of hypertension • Types of hypertension • Mechanism of controlling • Guidelines in nonpharmacological therapy • Classification of pharmacological therapy • Pharmacokinetics and pharmacodynamics • Contraindications and side effects Hypertension Blood pressure It is the force of the blood against the walls of the arteries. Hypertension It is an increase in blood pressure and usually defined as a systolic pressure above 140 mm Hg and a diastolic pressure above 90 mm Hg. Types ✓ Essential hypertension ✓ Secondary hypertension Hypertension is serious because: ➢ It causes the heart to work too hard and contributes to atherosclerosis. ➢ It increases the risk of heart disease, congestive heart failure, kidney disease, blindness, and stroke. Risk Factors….. Factors affecting blood pressure BP = CO x PR Cardiac output Peripheral resistance CO is the amount of blood pumped by each ventricle in one minute CO is the product of heart rate (HR) and stroke volume (SV) HR is the number of heart beats per minute SV is the amount of blood pumped out by a ventricle with each beat Cardiac Output (ml/min) = Heart Rate (75 beats/min) x Stroke Volume (70 ml/beat) Cardiac Output = 5250 ml/min (5.25 L/min) Mechanisms for controlling blood pressure Mechanisms Controlling CO and PR Artery Vein Ways of Lowering Blood Pressure 1- Reduce cardiac output (ß-blockers, Ca2+ channel blockers) 2-Reduce plasma volume (diuretics) 3- Reduce peripheral vascular resistance (vasodilators) THERAPY OF HYPERTENSION Guidelines for management of hypertension A. Non-pharmacological - lifestyle - Decrease of salt intake - Reduction of body weight - Restriction of smoking and restriction drinking alcohol - Regular physical activity and relaxation, lack of stress B- Pharmacological Treatment of hypertension 1. DIURITICS 2. β-ADRENOCEPTOR BLOCKING AGENTS 3. ACE INHIBITORS 4. ANGIOTENSIN II ANTAGONISTS 5. CALCIUM CHANNEL BLOCKERS 6. α- ADRENERGIC BLOCKING AGENTS 7. CENTRALLY-ACTING ADRENERGIC DRUGS 8. VASODILATORS DIURITICS 1- Diuretics Diuretics are currently recommended as the first-line drug therapy for hypertension ▪ Thiazides Chlorothiazide Hydrochlorothiazide Chlorthalidone Indapamid Methyclothiazide Clopamide Metipamid Metolazone Pharmacokinetics ➢ Absorption • Chlorothiazide: PO and IV • Hydrochlorothiazide, chlorthalidone, indapamid, Methyclothiazide, metolazone: PO ➢ indapamid metabolszed in liver and excreted in urine ➢ Chlorothiazide, Hydrochlorothiazide, chlorthalidone, Methyclothiazide, metolazone: Excreted unchanged in urine Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70% of patients, hypercalcemia and hyperglycemia in 10% of patients. ▪ Loop diuretics Bumetanide Furosemide Torsemide Ethacrynic acid Eplerenone Triamterene Amiloride Mechanism of action: ➢ Loop diuretics inhibit the Na+ /K+/CI- cotransport of the luminal membrane in the ascending limb of the loop of Henle. Therefore, reabsorption of Na +, K +, and CI- is decreased. ➢ The loop diuretics cause decreased renal vascular resistance and increased renal blood flow. (Note: Loop diuretics increase the Ca ++ content of urine, whereas thiazide diuretics decrease the Ca ++ concentration of the urine) Pharmacokinetics Absorption: The loop diuretics are rapidly absorbed • Furosemide, Bumetanide, (IV, IM, and PO). • Torsemide, Ethacrynic acid, (IV, and PO). • Eplerenone, Triamterene and Amiloride (PO). Metabolism in liver (P450) Excretion in urine and feces ➢ Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours). ➢ The duration of effect for furosemide is usually 2–3 hours. ➢ The effect of torsemide lasts 4–6 hours. ▪ Potassium sparing diuretics Spironolactone, eplerenone, triamterene and amiloride. • They depress the reabsorption of sodium in the kidney tubules, therefore increasing sodium and water excretion Pharmacokinetics ➢ All absorbed orally ➢ Metabolized by liver ➢ Excreted through urine and feces except triamterene excreted in urine 2- β-BLOCKING AGENTS diuretics are as first-line drug therapy for hypertension. e.g: Propranolol (?) Metoprolol (?) and atenolol (?) ➢ β non-selective antagonist: Carteolol – Nadolol – Propranolol – Penbutolol – Pindolol – Sotalol – Timolol ➢ β1 selective antagonist: Acebutolol – Atenolol – Esmolol – Metoprolol – Bisoprolol – Betaxolol ➢ β non-selective with intrinsic mimetic activity (IMA): Pindolol – Carteolol – Acebutolol ➢ α and β antagonist: Carvedilol - labetalol Pharmacokinetics Acebutolol, Atenolol, Betaxolol, Bisoprolol, Nebivolol, Carvedilol, nadolol, penbutolol, pindolol and timolol absorbed orally and most of them metabolized in liver & excreted in urine. Except o Acebutolol, atenolol, nebivolol, pindolol are excreted in urine and feces o Carvedilol excreted primary in feces o Nadolol excreted unchanged in urine • Metoprolol, labetalol and propranolol absorbed orally and IV , metabolized by liver 450 and excreted in urine. • Esmolol used only as IV, metabolized by esterase in blood and excreted in urine. Side effect: • Fatigue • Insomnia • Impotence • Hallucinations • Bronchospasm 3- ACE INHIBITORS E.g: Captopril ,Enalapril and Lisinopril Pharmacokinetics ➢ Captopril, moexipril, benazepril, perindopril, ramipril, fosinopril, trandolapril and quinapril are absorbed orally, metabolized by intestinal wall and liver and excreted in urine and feces. ➢ Lisinopril: Absorbed orally and excreted unchanged in urine. ➢ Enalapril: Used orally and IV, metabolized in liver and excreted in urine and feces. (ACE) inhibitors are recommended when the preferred first-line agents (diuretics or β-blockers) are contraindicated or ineffective. Side effect: Dry cough, rash, fever, altered taste, renal failure, neutropenia, hypotension and hyperkalemia 4- ANGIOTENSIN II ANTAGONISTS Its pharmacologic effects are like ACE inhibitors in that it produces vasodilation and blocks aldosterone secretion. Losartan Valsartan Irbesartan Eprosartan Candesartan Azilsartan Pharmacokinetics ➢ Losartan, valsartan, irbesartan, eprosartan, candesartan and azilsartan: absorbed orally ➢ Losartan, irbesartan and azilsartan: metabolized in liver and excreted in urine and feces. ➢ Valsartan, eprosartan: metabolized in liver and primarily excreted in feces. ➢ Candesartan: metabolized in liver and excreted in urine Adverse effects • Hyperkalemia • Fatigue • Inhibit P450 enzymes: ➢ Losartan ➢ Irbesartan ➢ candesartan ➢ eprosartan Renin inhibitor Aliskirin • It lowers BP effectively(directly inhibits renin) and used alone or in combination. Pharmacokinetics ➢ Absorbed orally ➢ Metabolized in liver ➢ Excreted in urine and feces Side effects: ▪ Diarrhea (especially at high doses) ▪ Cough ▪ Hyperkalemia 5- CALCIUM CHANNEL BLOCKERS Verapamil, Diltiazem, Nifedipine, Amlodipine. Actions: The intracellular concentration of calcium plays an important role in maintaining the tone of smooth-muscle and in the contraction of the myocardium. - • Calcium channel antagonists block the inward movement of calcium in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. Adverse effects: • Constipation in 10% of patients • Dizziness • Headache • Feeling of fatigue caused by a decrease in blood pressure. 6) α1- ADRENERGIC BLOCKING AGENTS • Prazosin, oxazosin and terazosin produce a competitive block of α1-adrenoceptors. • They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. They used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Side Effect: Reflex tachycardia and first dose syncope are almost universal adverse effects. Concomitant use of a β-blocker may be necessary to blunt the shortterm effect of reflex tachycardia. 7) CENTRALLY-ACTING ADRENERGIC DRUGS A. Clonidine • This α2-agonist diminishes central adrenergic outflow. • Clonidine is used primarily for the treatment of mild to moderate hypertension that has not responded adequately to treatment with diuretics alone. • Clonidine does not decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension complicated by renal disease. SE: sedation and drying of nasal mucosa B. α-Methyldopa • This α2 adrenergic agonist is converted diminish the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. • Because blood flow to the kidney is not diminished by its use, α-methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. SE: sedation and drowsiness 8- VASODILATORS E.g: Hydralazine, nitroprusside, diazoxide and minoxidil Vasodilators act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure. These agents produce reflex stimulation of the heart, resulting in the competing symptoms of increased myocardial contractility, heart rate, and oxygen consumption. Vasodilators also increase plasma renin concentration, resulting in sodium and water retention. These undesirable side effects can be blocked by concomitant use of a diuretic and a β-blocker. SE: Tachycardia, headache, nausea, sweeting, arrhythmia, lupus like syndrome with hydralazine, hair growth with minoxidel, and methemoglobin with nitroprusside. HYPERTENSIVE EMERGENCY A. Sodium nitroprusside • Nitroprusside is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. It is capable of reducing blood pressure in all patients, regardless of the cause of hypertension. • Nitroprusside is metabolized rapidly and requires continuous infusion to maintain its hypotensive action. • Nitroprusside metabolism results in cyanide ion production, cyanide toxicity can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys B. Diazoxide • Diazoxide is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine. • Diazoxide is administered intravenously with a β-blocker, which diminishes reflex activation of the heart. Excessive hypotension is the most serious toxicity. C. Labetalol • Labetalol is both an α- and β-blocker that has been successfully used in hypertensive emergencies. • Labetalol does not cause the reflex tachycardia. Pregnancy: (a) Mild HT  no need for ttt (b) Severe HT : • Acutely treated with labetalol • Chronically treated with-methyldopa