Antihypertensive Drugs

1. Antihypertensive Drugs

2. Principles of blood pressure regulation • Regulated by the following: • Cardiac output • Peripheral vascular resistance • Volume of intravascular fluid (controlled at the kidney)

3. Baroreflexes: • Adjust moment-to-moment blood pressure. • Carotid baroreceptors respond to stretch, and their activation inhibits sympathetic discharge. • The renin—angiotensin system: • Provides longer-term regulation. • Decreased renal pressure stimulates renin production and leads to enhanced levels of angiotensin II. • Angiotensin II: • causes resistance vessels to constrict • stimulates aldosterone synthesis, which ultimately increases the absorption of sodium by the kidney.

5. Goal of therapy • The goal of therapy is to reduce elevated blood pressure, which would ultimately lead to end-organ damage. • This goal is achieved through: • Use of various drug classes • Treatment often involves a combination of agents

7. Diuretics Effects: • increase sodium excretion • lower blood volume. • Thiazide diuretics • Effective in lowering blood pressure 10—15 mm Hg. • When administered alone, thiazide diuretics can provide relief for mild-or-moderate hypertension. • Thiazide diuretics are used in combination with sympatholytic agents or vasodilators in severe hypertension.

8. Loop diuretics: • used in combination with sympatholytic agents and vasodilators for hypertension refractory to thiazide treatment. • Potassium-sparing diuretics: • used to avoid potassium depletion, especially when administered with cardiac glycosides.

10. Adrenoceptor antagonists • β-Adrenoceptor antagonists • Propranolol • Propranolol antagonizes catecholamine action at both β1- and β2-receptors. It produces sustained reduction in peripheral vascular resistance. • Blockade of cardiac β1-adrenoceptors reduces heart rate and contractility. β2-Adrenoceptor blockade increases airway resistance and decreases catecholamine-induced glycogenolysis and peripheral vasodilation. • Blockade of β-adrenoceptors in the CNS decreases sympathetic activity. • Propranolol also decreases renin release. • Propranolol is used in mild-to-moderate hypertension.

11. Nadolol, timolol, carteolol, pindolol, penbutolol • These drugs are similar in action to propranolol and block both β1- and β2-adrenoceptors. • Nadolol has an extended duration of action. • Pindolol, carteolol, and penbutolol have partial agonist activity (sympathomimetic). • Metoprolol, atenolol, acebutolol, bisprolol • These drugs are relatively selective for β1-adrenoceptors. • Acebutolol has partial agonist activity.

13. α-Adrenoceptor antagonists • Lower total peripheral resistance by preventing stimulation (and consequent vasoconstriction) of α-receptors, which are located predominantly in resistance vessels of the skin, mucosa, intestine, and kidney. • These drugs reduce pressure by dilating resistance and conductance vessels. • The effectiveness of these drugs diminishes in some patients because of tolerance.

14. Prazosin, terazosin, and doxazosin • α1-selective antagonists. • used in treating hypertension, especially in the presence of CHF. • often administered with a diuretic and a β-adrenoceptor antagonist. • Phentolamine and phenoxybenzamine • Antagonize α1- and α2-adrenoceptors. • Used primarily in treating hypertension in the presence of pheochromocytoma. • Phentolamine is administered parenterally • phenoxybenzamine is administered orally.

15. Labetalol and carvedilol • Labetalol is an α- and β-adrenoceptor antagonist. • Labetalol is available for both oral and IV administration. • Labetalol is useful for treating: • hypertensive emergencies • the treatment of hypertension of pheochromocytoma. • Labetalol does not cause reflex tachycardia. • Carvedilol has a significantly greater ratio of β to α antagonist activity than labetalol.

16. Agents that affect the renin-angiotensin system • ACE inhibitors • ACE inhibitors: reduce vascular resistance reduce blood volume • they lower blood pressure by decreasing total peripheral resistance. • ACE inhibitors include captopril, enalapril, lisinopril, ramipril, fosinopril , benazepril, moexipril, and quinapril, perindopril, spirapril, and trandolapril. • Useful in treating mild-to-severe hypertension.

17. Angiotensin II Receptor Blockers (ARBs) Losartan These drugs block angiotensin II type-1 (AT-1) receptors. • The effects of these drugs are similar to those seen with ACE inhibitors. • These drugs are effective as monotherapy for hypertension.

19. Renin Inhibitors: Aliskiren • Aliskiren directly inhibits renin. • It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. • It can also be combined other antihypertensives, such diuretics, ACE inhibitors, ARBs, or calcium-channel blockers. • Aliskiren can cause diarrhea, especially at the higher doses. • The drug is contraindicated during pregnancy. • Hyperkalemia was significantly more common in patients who received both valsartan and aliskiren.

20. Calcium channel-blocking agents • Calcium channel-blocking (CCBs) agents inhibit the entry of calcium into cardiac and smooth muscle cells by blocking the L-type Ca2+-channel; they lower blood pressure by reducing peripheral resistance. • CCBs used for treatment of hypertension includeverapamil, nifedipine, nicardipine, nisoldipine, isradipine, amlodipine, and felodipine, and diltiazem. • CCBs are effective in the treatment of mild-to-moderate hypertension.

21. Other drugs • Centrally acting sympathomimetic agents • reduce peripheral resistance • inhibit cardiac function • increase pooling in capacitance venules.

22. a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) a2 Receptors Sympathetic ganglion b1 Receptors • Decreased sympathetic tone • Decr. HR • Decr. Contractility • Decr. Renin release • Decr. Vasoconstriction Y Heart Y b1 Receptors Kidney a1 Receptors Y

23. Methyldopa • Used to treat mild-to-moderate hypertension • Adverse effects that include: • drowsiness • dry mouth • GI upset. • Sexual dysfunction may occur and reduce compliance.

24. Clonidine • Clonidine is frequently combined with a diuretic. • Clonidine commonly produces: • Drowsiness • dry mouth • constipation. • This drug is available as a transdermal patch that allows weekly dosing.

25. Guanabenz acetate • This drug is used in mild-to-moderate hypertension • most commonly in combination with a diuretic. • Adverse effects: • sedation and dry mouth

26. Adrenergic neuronal blocking drugs • Guanethidine monosulfate and guanadrel sulfate • They deplete norepinephrine concentrations to reduce norepinephrine release. • These drugs reduce: • cardiac output • total peripheral vascular resistance.

27. They do not cross the blood—brain barrier. • Guanadrel has a more rapid onset and a shorter duration of action than guanethidine. • These drugs are used for patients with severe refractory hypertension.

28. Reserpine • Reserpine eliminates norepinephrine release in response to nerve impulse by preventing vesicular uptake. It depletes norepinephrine from sympathetic nerve terminals in the periphery and in the adrenal medulla. • Reserpine is used in mild-to-moderate hypertension. • Reserpine most commonly produces GI disturbances. Mental depression, sometimes severe, may result, especially with high doses.

29. Vasodilators Relax smooth muscle lower total peripheral resistance lowering blood pressure.

30. Low blood pressure baroreceptor reflex increased myocardial contractility, heart rate, and oxygen consumption increase plasma renin concentration sodium and water retention. angina pectoris, myocardial infarction, or cardiac failure blocked by concomitant use of a diuretic and a β-blocker.

31. Hydralazine • Hydralazine reduces blood pressure directly by relaxing arteriolar muscle. • This drug is used to treat chronic hypertension and in hypertensive crises accompanying acute glomerular nephritis or eclampsia. • Hydralazine may cause a lupus-like syndrome.

32. Minoxidil • effects similar to hydralazine. • Minoxidil vasodilates predominantly arteriolar vessels. • Minoxidil is useful for long-term therapy of refractory hypertension. • Minoxidil produces hirsutism, an advantage in formulations that are now used to reduce hair loss in both males and females.

33. Sodium nitroprusside • is administered intravenously and causes prompt vasodilation with reflex tachycardia. • This drug is frequently used in hypertensive emergencies because of its rapid action. • Continuous infusion is necessary to maintain effects.

34. Diazoxide • Diazoxide is used intravenously to reduce blood pressure rapidly, usually in an emergency situation. • Diazoxide is administered with furosemide to prevent fluid overload. • This drug is declining in use because of its unpredictable action and adverse effects.

35. Specialized vasodilators • Phosphodiesterase type V inhibitors • sildenafil citrate [Viagra], • tadalafil • vardenafil hydrochloride • Viagra was originally developed as an antianginal and antihypertensive agent but proved very effective in treating erectile dysfunction.

36. These agents specifically inhibit phosphodiesterase type V, the class of enzymes that are responsible for the breakdown of cGMP. • The type V isoform is expressed in reproductive tissues and the lung. • Inhibition of the breakdown of cGMP enhances the vasodilatory action of NO in the corpus callosum and in the pulmonary vasculature.

37. These agents are useful in the treatment of erectile dysfunction, and sildenafil citrate is approved for treatment of pulmonary hypertension. • Adverse effects: headache, flushing, and abdominal pain. • The most serious adverse effects are cardiovascular: arrhythmias, heart block, cardiac arrest, stroke, and hypotension.