Antihypertensive drugs and diuretics.pptx

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1. ANTIHYPERTENSIVE DRUGS PREPARED BY MR. ANTHONY MATU Drugs acting on the Cardiovascular System

2. Classes of antihypertensive drugs Sympathoplegic agents , which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance.

3. Direct vasodilators which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well. Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms. Classes of antihypertensive drugs

4. Sympathoplegic Agents Centrally-acting sympathoplegics Methyldopa Clonidine Alpha adrenoceptor blockers Prazosin Terazosin Doxazosin Classes of antihypertensive drugs

5. Sympathoplegic Agents Beta- adrenoceptor blockers Propranolol Metoprolol Atenolol Nadolol Labetalol Carvedilol Nebivolol Betaxolol Bisoprolol Carteolol Classes of antihypertensive drugs

6. Classes of antihypertensive drugs Vasodilators Calcium-channel blockers Verapamil Diltiazem Amlodipine Felodipine Isradipine Nicardipine Nifedipine Nisoldipine

7. Classes of antihypertensive drugs Inhibitors of Angiotensin Angiotensin-Converting Enzyme Inhibitors Captopril Enalapril Linisinopril Benazepril Fosinopril Moexipril Perindopril Quinapril Ramipril Trandolapril

8. Classes of antihypertensive drugs Inhibitors of Angiotensin Angiotensin Receptor Blockers Losartan Valsartan Azilsartan Candesartan Eprosartan Irbesartan Olmesartan Telmisartan

9. Classes of antihypertensive drugs Diuretics Loop Diuretics Furosemide Thiazide diuretics Hydrochlorothiazide, Chlorthalidone Potassium-sparing diuretics Spironolactone Eplerenone

10. Alpha- adrenoceptor antagonists Prazosin , terazosin , and doxazosin produce most of their antihypertensive effects by selectively blocking a1-receptors in arterioles and venules . These agents produce less reflex tachycardia when lowering blood pressure than do nonselective a- antagonists such as phentolamine .  

11. The drugs are more effective when used in combination with other agents, such as a b-blocker and a diuretic, than when used alone. Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia. Alpha- adrenoceptor antagonists

12. Beta- adrenoceptor antagonists These are commonly used agents in control of hypertension The prototype drug is propranolol

13. Propranolol Propranolol was the first beta blocker shown to be effective in hypertension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective beta blockers such as metoprolol and atenolol. All b- adrenoceptor -blocking agents are useful for lowering blood pressure in mild to moderate hypertension.

14. In severe hypertension, b-blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators.   Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions Propranolol

15. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by b1 receptors). In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension. The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial b-receptors Propranolol

16. Metoprolol and atenolol Metoprolol and atenolol, which are cardioselective , are the most widely used b-blockers in the treatment of hypertension.  Relative cardioselectivity is advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease.   Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours; it is usually dosed once daily.

17. Labetalol, Carvedilol & Nebivolol These drugs have both b-blocking and vasodilating effects. Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output. Because of its combined a and b-blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies.   Nebivolol is a b1-selective blocker with vasodilating properties

18. Esmolol Esmolol is administered by intravenous infusion. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure, in which case a drug with a short duration of action that can be discontinued quickly is advantageous.

19. Sympathoplegic agents These agents reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Examples are methyldopa and clonidine

20. Methyldopa Methyldopa was widely used in the past but is now used primarily for hypertension during pregnancy. It lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output. The most common undesirable effect of methyldopa is sedation, particularly at the onset of treatment.

21. Methyldopa With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa.

22. Clonidine Blood pressure lowering by clonidine results from reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance. Clonidine is lipid-soluble and rapidly enters the brain from the circulation

23. Dry mouth and sedation are common. Clonidine should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy. Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine. Clonidine

24. Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity. Patients exhibit nervousness, tachycardia, headache, and sweating after omitting one or two doses of the drug. If the drug must be stopped, it should be done gradually while other antihypertensive agents are being substituted. Clonidine

25. Vasodilators Direct vasodilators which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well

26. Hydralazine Hydralazine, a hydrazine derivative, dilates arterioles but not veins. In Kenya, its only mainstream use is to treat hypertensive emergencies in pregnancy.   Toxicity The most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing.

27. Sodium nitroprusside Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation.

28. Sodium Nitroprusside The drug is given by intravenous infusion. Because of its efficacy and rapid onset of effect, nitroprusside should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording. Toxicity Other than excessive blood pressure lowering, the most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted.

29. Calcium channel blockers Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine , isradipine , nicardipine , nifedipine , nisoldipine , and nitrendipine are all equally effective in lowering blood pressure,   Clevidipine is a newer member of this group that is formulated for intravenous use only.

30. Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients given dihydropyridines . Calcium channel blockers

31. Inhibitors of angiotensin Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule  Renin acts upon angiotensinogen to yield the inactive precursor decapeptide angiotensin I.

32. Angiotensin I is then converted, primarily by endothelial Angiotensin-Converting Enzyme, to the arterial vasoconstrictor octapeptide angiotensin II which is in turn converted in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor and sodium-retaining activity. Inhibitors of angiotensin

33. Angiotensin II and III both stimulate aldosterone release. Angiotensin may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity, such as renal arterial stenosis, some types of intrinsic renal disease, and malignant hypertension, as well as in essential hypertension after treatment with sodium restriction, diuretics, or vasodilators.  The converting enzyme involved in tissue angiotensin II synthesis is also inhibited by ACE inhibitors. Inhibitors of angiotensin

34. The classes of drugs that act specifically on the renin-angiotensin system are: ACE inhibitors The competitive inhibitors of angiotensin at its receptors, including losartan and other nonpeptide antagonists; Aliskiren , an orally active renin antagonist The aldosterone receptor inhibitors ( eg , spironolactone, eplerenone ), Inhibitors of angiotensin

35. Angiotensin-converting enzyme (ACE) inhibitors Captopril and other drugs in this class inhibit the converting enzyme that hydrolyzes angiotensin I to angiotensin II   Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat , with effects similar to those of captopril. Benazepril, fosinopril , moexipril , perindopril, quinapril, ramipril , and trandolapril are other long-acting members of the class.

36. All are prodrugs, like enalapril , and are converted to the active agents by hydrolysis, primarily in the liver Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease.   Angiotensin-converting enzyme (ACE) inhibitors

37. Toxicity: ACE inhibitors Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure, hyperkalemia, dry cough sometime accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes.  

38. ACE inhibitors are contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. First-trimester exposure to ACE inhibitors appear to have increased teratogenic risk. Captopril, particularly when given in high doses to patients with renal insufficiency, may cause neutropenia or proteinuria. Toxicity: ACE inhibitors

39. Angiotensin-receptor antagonists Examples include Losartan, valsartan, Azilsartan , candesartan, eprosartan , irbesartan , olmesartan , and telmisartan They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II.

40. Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease. The adverse effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and angioedema can occur but are uncommon. Angiotensin-receptor antagonists

41. Angiotensin receptor-blocking drugs are most commonly used in patients who have had adverse reactions to ACE inhibitors. Combinations of ACE inhibitors and angiotensin receptor blockers or aliskiren , which had once been considered useful for more complete inhibition of the renin-angiotensin system, are not recommended due to toxicity Angiotensin-receptor antagonists

42. Diuretics Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6–8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines.

43. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or dietary sodium restriction. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function Diuretics

44. The initial step in treating hypertension may be non-pharmacologic. Sodium restriction Eating a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Moderation of alcohol intake (no more than two drinks per day) also lower blood pressure. Weight reduction Regular exercise Antihypertensive therapy

45. For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug. Most patients with moderate to severe hypertension require two or more antihypertensive medications  The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. Antihypertensive therapy

46. For example, drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. Beta blockers or calcium channel blockers are useful in patients who also have angina; Diuretics, ACE inhibitors, angiotensin receptor blockers, b-blockers, or hydralazine combined with nitrates in patients who also have heart failure Antihypertensive therapy

47. a1-blockers in men who have benign prostatic hyperplasia. If a single drug does not adequately control blood pressure, drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity (“stepped care”). If three drugs are required, combining a diuretic, an ACE inhibitor or angiotensin receptor blocker, and a calcium channel blocker is often effective. If a fourth drug is needed, a sympathoplegic agent such as a b-blocker or clonidine should be considered. Antihypertensive therapy

48. Hypertensive emergency Despite the large number of patients with chronic hypertension, hypertensive emergencies are relatively rare. Marked or sudden elevation of blood pressure may be a serious threat to life, however, and prompt control of blood pressure is indicated. The general management of hypertensive emergencies requires monitoring the patient in an intensive care unit with continuous recording of arterial blood pressure.

49. Fluid intake and output must be monitored carefully Body weight measured daily as an indicator of total body fluid volume during the course of therapy. Parenteral antihypertensive medications are used to lower blood pressure rapidly (within a few hours); Oral antihypertensive therapy then substitutes parenteral drugs after achieving control of BPs. Hypertensive emergency

50. The goal of treatment in the first few hours or days is not complete normalization of blood pressure because chronic hypertension is associated with autoregulatory changes in cerebral blood flow. Thus, rapid normalization of blood pressure may lead to cerebral hypoperfusion and brain injury. Rather, blood pressure should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100–110 mm Hg. Hypertensive emergency

51. Subsequently, blood pressure can be reduced to normal levels using oral medications over several weeks. The parenteral drugs used to treat hypertensive emergencies include sodium nitroprusside, nitroglycerin, labetalol, calcium channel blockers, fenoldopam , and hydralazine. Hypertensive emergency

52. Esmolol is often used to manage intraoperative and postoperative hypertension. Diuretics such as furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators. Hypertensive emergency

53. End of presentation