ANTI HYPERTENSIVES DRUGS WITH THEIR MODE OF ACTION

ANTIHYPERTENSIVES

1. Dr. A. L. Yiaile PHARMACOLOGY ANTIHYPERTENSIVE DRUGS

2. Hypertension

3. Introduction Hypertension is defined by persistent elevation of arterial blood pressure (BP). Patients with diastolic blood pressure (DBP) values ≥ 90 mm Hg and systolic blood pressure (SBP) values ≥140 mm Hg have isolated systolic hypertension.

4. Gradations of blood pressure and hypertension

5. Introduction … Diastolic or systolic? Most attempts to distinguish high blood pressure from the normal range definitions of hypertension allow for the greater proportional rise in SBP than DBP and include intermediate classifications to recognize the continuous variation.

6. Introduction … Because increased risk is associated with pressures sometimes regarded as normal, an ‘optimal’ grade has been proposed. SBP is inversely proportional to arterial compliance , which declines with age owing to smooth muscle fibrosis and calcification (arteriosclerosis). DBP by contrast reflects the peripheral resistance , a measure of the average size of blood vessel lumens throughout the body, against which the heart has to develop and maintain a pressure.

7. Gradations of blood pressure and hypertension

8. Introduction …. A hypertensive crisis (BP >180/120 mm Hg) may be categorized as either a hypertensive emergency (extreme BP elevation with acute or progressing target organ damage) or a hypertensive urgency (severe BP elevation without acute or progressing target organ injury).

9. Pathophysiology Primary or essential hypertension Hypertension is a heterogeneous disorder that may result either from a specific cause (secondary hypertension) or from an underlying pathophysiologic mechanism of unknown etiology (primary or essential hypertension).

10. Pathophysiology… Secondary hypertension accounts for fewer than 10% of cases, and most of these are caused by chronic kidney disease or renovascular disease . Other conditions causing secondary hypertension include pheochromocytoma , Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, primary aldosteronism , pregnancy, obstructive sleep apnea, and coarctation of the aorta.

11. Secondary Causes of Hypertension

12. Pathophysiology… The main causes of death in hypertensive subjects are cerebrovascular accidents , cardiovascular (CV) events , and renal failure. The probability of premature death correlates with the severity of BP elevation.

13. Potential Mechanisms of Pathogenesis Blood pressure is the mathematical product of cardiac output and peripheral resistance . Increased blood pressure can result from increased cardiac output and/or increased total peripheral resistance. Increased cardiac output Increased cardiac preload: Increased fluid volume from excess sodium intake or renal sodium retention (from reduced number of nephrons or decreased glomerular filtration) Venous constriction: Excess stimulation of the RAAS Sympathetic nervous system overactivity

14. Potential Mechanisms of Pathogenesis… Increased peripheral resistance Functional vascular constriction: Excess stimulation of the RAAS Sympathetic nervous system overactivity Genetic alterations of cell membranes Endothelial-derived factors Structural vascular hypertrophy: Excess stimulation of the RAAS Sympathetic nervous system over activity Genetic alterations of cell membranes Endothelial-derived factors Hyperinsulinemia resulting from obesity or the metabolic syndrome

15. Possible pathways in the pathogenesis of hypertension

16. Risk factors and etiological influences in hypertension

17. Complications of untreated hypertension

18. Clinical Presentation Patients with uncomplicated primary hypertension are usually asymptomatic initially. Patients with secondary hypertension may complain of symptoms suggestive of the underlying disorder. Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, palpitations, and orthostatic hypotension .

19. Clinical Presentation… In primary aldosteronism , hypokalemic symptoms of muscle cramps and weakness may be present. Patients with hypertension secondary to Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscular weakness.

20. Diagnosis

21. Treatment Desired Outcome The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality .

22. Treatment Desired Outcome … Most patients < 140/90 mm Hg Patients with diabetes < 130/80 mm Hg Patients with chronic kidney disease < 130/80 mm Hg (estimated GFR < 60 mL/min, serum creatinine > 1.3 mg/ dL in women or > 1.5 mg/ dL in men, or albuminuria > 300 mg/ day or ≥ 200 mg/g creatinine)

23. Treatment Desired Outcome … SBP is a better predictor of CV risk than DBP and must be used as the primary clinical marker of disease control in hypertension.

24. Non Pharmacologic treatment All patients with prehypertension and hypertension should be prescribed lifestyle modifications. provide small to moderate reductions in SBP. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with prehypertension BP values.

25. Non Pharmacologic treatment …. DASH eating plan is a diet that is rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat. Dietary approaches to stop hypertension

26. Algorithm for treatment of hypertension when patients are not at their goal blood pressure PHARMACOLOGIC THERAPY

27. Recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8)

28. Principles of drug therapy in hypertension As few drugs as possible As few daily doses as possible Start with most suitable initial drug(a) Increase the dose gradually until adequate effect achieved If primary failure, substitute another suitable drug from different group If effectiveness declines, add another agent rather than substitute Combine agents acting by different mechanisms Combine agents tending to reduce each other’s adverse actions Monitor adverse reactions and patient compliance regularly

29. Antihypertensive Drugs Beta blockers Calcium channel blockers Angiotensin Converting inhibitors (ACIs) Angiotensin receptor blockers (ARBs) Alpha blockers Vasodilators Centrally acting sympathoplegics Diuretics Others – Renin inhibitors

30. Alpha blockers They are divided into : Selective alpha 1 blockers eg prazosin , terazosin, doxazosin Nonselective alpha blockers eg phentolamine , phenoxybenzamine

31. Selective Alpha 1 blockers Mode of action : selectively blocks alpha 1 receptors and thus decrease vasoconstriction and reduce peripheral resistance and thus decrease in BP. Clinical applications : Hypertension Benign prostatic hyperplasia esp. subtype selective like tamsulosin and alfuzosin

32. Selective Alpha 1 blockers Side effects: orthostatic hypotension, Reflex tachycardia nasal stuffiness, dizziness, headache, Palpitations Edema

33. Non-selective Alpha blockers Mode of action: block both alpha 1 and 2 receptors Clinical applications: Phaechromocytoma Side effects : same as alpha 1 blockers

34. Vasodilators - A. Hydralazine Mode of action: causes nitric oxide release leading to vasodilation especially arterioles Clinical applications: hypertension and hypertensive emergencies

35. Vasodilators - A. Hydralazine Side effects: tachycardia, edema, angina, headache, nausea, palpitations, sweating and flushing hypotension

36. Vasodilators - B. Minoxidil Mode of action: metabolite opens K channels leading to vasodilation Clinical applications: hypertension, hair loss Side effects: same as hydralazine hypertrichosis

37. Vasodilators - C. Nitroprusside Mode of action: releases nitric oxide and thus leads to vasodilation of both arterioles and veins Clinical applications: Hypertensive emergencies, Side effects: Excessive hypotension, Shock, Arrhythmias

38. Centrally acting sympathoplegics Examples: Methyldopa, clonidine Mode of action: activates alpha 2 receptors which are presynaptic and thus reduce central sympathetic outflow Clinical applications: hypertension in pregnancy esp. methyldopa Resistant hypertension esp. clonidine Clonidine may also be used in drug rehabilitation programs

39. Centrally acting sympathoplegics Side effects: Sedation, Hemolytic anemia, nightmares, depression, vertigo, drug fever esp methyldopa

40. Diuretics Diuretics used in hypertension: Thiazide diuretics Potassium sparing diuretics Loop diuretics Other diuretics include Carbonic anhydrase inhibitors Osmotic diuretics Vasopressin inhibitors We’ll focus on those used in hypertension .

41. Diuretics

42. Diuretics

43. Thiazide diuretics Examples : Hydrochlorothiazide, indapamide , chlorthalidone , metolazone , bendroflumethiazide

44. Thiazide diuretics

45. Thiazide diuretics Mode of action : Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na +/Cl − transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. They also facilitate arteriolar vasodilation

46. Thiazide diuretics Clinical applications : Hypertension, Heart failure, Nephrolithiasis due to idiopathic hypercalciuria , Nephrogenic diabetes insipidus

47. Thiazide diuretics Side effects : Hypokalemic Metabolic Alkalosis Hyperuricemia Impaired Carbohydrate Tolerance (hyperglycemia) Hyperlipidemia Hyponatremia Allergic Reactions Weakness, fatigability, and paresthesias Impotence

48. Potassium-sparing diuretics Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone ) or by inhibition of Na influx through ion channels in the luminal membrane ( amiloride , triamterene)

49. Potassium-sparing diuretics

50. Potassium-sparing diuretics Clinical Applications States of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism ), due either to Primary hypersecretion (Conn’s syndrome, Ectopic adrenocorticotropic hormone production) or Secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume or Use of diuretics such as thiazides or loop agents )

51. Potassium-sparing diuretics Other Clinical Applications Hypertension Ascites Heart failure

52. Potassium-sparing diuretics Side effects Hyperkalemia Metabolic Acidosis Gynecomastia esp spironolactone Acute Renal Failure esp triamterene Kidney Stones

53. Loop diuretics Examples: Furosemide, bumetanide, torsemide , ethacrynic acid

54. Loop diuretics

55. Loop diuretics Mode of action: They inhibit NKCC2, the luminal Na + /K + /2Cl transporter in the TAL of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K recycling thus inhibiting reabsorption of Mg and Ca.

56. Loop diuretics Clinical applications: Acute pulmonary edema, Other edematous conditions, Acute hypercalcemia Heart failure Hyperkalemia Acute renal failure Anion overdose Hypertension

57. Loop diuretics Side effects: Hypokalemic Metabolic Alkalosis Ototoxicity Hyperuricemia Hypomagnesemia Allergic reactions eg skin rash, eosinophilia, interstitial nephritis Severe dehydration Hyponatremia Hypercalciuria

58. Other antihypertensive drugs Renin inhibitors eg aliskiren Ganglion blockers eg reserpine, trimethaphan camsylate