Cardiovascular+pharmacology+drug+therapy+of+hypertension

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Cardiovascular+pharmacology+drug+therapy+of+hypertension

  1. 1. بسم الله الرحمن الرحيم<br />
  2. 2. Cardiovascular PharmacologyManagement of Hypertension Dr. Mohamed saad<br />
  3. 3. Cardiovascular PharmacologyManagement of hypertension<br /> Hypertension is a major health problem with <br /> prevalence rate of 25% among adults, <br /> increasing to 50% among those above 60 <br /> years.<br />Hypertension causes dangerous complications <br /> (Target Organ Damage [TOD]) such as <br /> myocardial infarction, heart failure, aortic <br /> aneurysm, stroke and renal failure. These <br /> complications occur commonly in high risk <br /> patients as males, elderly, smokers, diabetics, <br /> and those with high cholesterol levels.<br />
  4. 4. The cause of hypertension is unknown and only less than 5% of cases are secondary to renal diseases, pheochromocytoma, hyperaldosteronism, aortic coarctation, or secondary to drugs (drug-induced hypertension) such as:<br /><ul><li>Vasoconstrictors, e.g. phenylephrine or flu medicine
  5. 5. Volume expanders, e.g. glucocorticoids, NSAIDs and oral contraceptives.</li></li></ul><li>Classification and Management of High Blood Pressure<br />
  6. 6. Target Blood Pressure<br /><140/90 in low-risk group<br /> <130/85 in high-risk group<br />
  7. 7. Lifestyle Modification (Nonpharmacological Management of Hypertension)<br />Beneficial in reducing high blood pressure and its complications.<br />Reduces the dose requirement of antihypertensive drugs.<br />Recommended in all hypertensives initially and with drug therapy.<br />
  8. 8. Lifestyle modification includes :-<br />(1). Reduced dietary intake of Na+ and fat, increased Ca2+ and K+ intake, together with diet rich in fruits and vegetables and low-fat dairy products.<br />(2). Weight reduction for overweight patients.<br />(3). Regular physical exercise.<br />(4). Stopping smoking and reducing alcohol <br /> intake<br />
  9. 9. 3. Sympatholytics<br />2. b Blockers<br />NE <br />early<br />late<br />Vasospasm<br />Angiotensin II<br />Vasodilators<br />4. Angiotensin Converting Enzyme<br />Inhibitors (ACEIs)<br />1. Diuretics<br />5. Angiotensin Receptor Blockers (ARBs)<br />6. Calcium Channel Blockers<br />7. Direct Vasodilators<br />Classification of Antihypertensive Drugs<br />Centrally-acting<br /><br />a1-blockers<br /><br /><br /><br />BP<br />COP<br />TPR<br /> =<br />×<br /><br /><br />
  10. 10. NB:<br />Hypertensive patients can be classified into salt-sensitive and salt-resistant patients.<br />Salt-sensitive hypertension is more common in elderly, obese, black, and patients with renal disease. These patients have impaired renal Na+ excretion leading to Na+ retention with increased Na+-Ca2+ exchange and vasoconstriction and low renin status.<br />Hypertension in these patients gives better response to diuretics and calcium channel blockers with poor response to B-blockers and ACEIs which act mainly in high-renin status.<br />
  11. 11. I. Diuretics<br />Mechanism of Action<br />Initially, they act by reducing plasma volume and COP, followed by vasodilation and reduction in peripheral vascular resistance.<br />Advantages<br />Reduce mortality, stroke and cardiovascular complications of hypertension.<br />The least expensive antihypertensives.<br />
  12. 12. Indications<br />1st choice in uncomplicated hypertension.<br />Specially indicated in:<br />1. Systolic hypertension.<br />2. Hypertension in elderly, black and obese patients (salt-sensitive).<br />3. Hypertension complicated with heart failure.<br />Combined with other antihypertensives to potentiate their effect:<br />1. Control edema of vasodilators.<br />2. Reduce plasma volume -> increase renin and potentiate the hypotensive action of ACEIs and b blockers, especially in black old patients.<br />
  13. 13. Thiazides are the preferred diuretics for hypertension because in single daily dose they cause persistent volume depletion which is required to lower BP; whereas once daily dose of frusemide is inadequate as it causes temporary Na+ loss.<br />Thiazides tend to retain Ca2+ -> ↓ risk of bone fracture in the elderly.<br />
  14. 14. Preparations and Dosage<br />Hydrochlorothiazide: low (12.5 mg) or lower (6.25 mg) dose combined with an ACEI or a b blocker has adequate antihypertensive effect with fewer side effects.<br />Indapamide: a thiazide-like agent with more vasodilator effect and less side effects especially in low-dose (1.25 mg) slow-release preparations. <br />Frusemide: orally 2-3 times daily in hypertension with renal impairment in which case thiazide diuretics are not effective due to decreased GFR.<br />
  15. 15. Side Effects-:<br />1. Metabolic Side Effects<br />Hyperuricemia - hyperglycemia -hyperlipidemia.<br />2. Electrolyte Disturbances<br />Hypokalemia - hyponatremia -hypomagnesemia.<br />
  16. 16. These side effects can be minimized by:-<br />a. Low-sodium and high-potassium diet.<br />b. Using low dose of thiazide especially when combined with b blockers to avoid unfavorable additive metabolic effects.<br />c. Combination with spironolactone in cardiac patients to avoid the dangerous effects of hypokalemia and hypomagnesemia.<br />d. Combination with ACEIs which may neutralize these effects.<br />
  17. 17. 3. Impotence (common).<br />4. Sulfonamide hypersensitivity reactions (rare) as jaundice, pancreatitis and blood disorders.<br />
  18. 18. II. B-Adrenergic Blockers<br />Mechanism of Action-: <br />Initially, they decrease COP without effective drop in BP due to reflex vasospasm with early increase in TPR.<br />Later, they decrease TPR and BP through:<br />a. ↓ Renin release.<br />b. ↓ NE release by central and peripheral effects.<br />c. ↑ PG causing VD.<br />
  19. 19. Advantages<br />Decrease cardiovascular mortality & morbidity and protect against coronary heart disease.<br /> Relatively not expensive.<br />Indications<br />Alternative to diuretics as 1st line treatment of uncomplicated hypertension.<br />Used in young hypertensives where COP is high.<br />Hypertension associated with coronary heart disease.<br />
  20. 20. Preparations and Dosage<br />The ideal antihypertensive B-blocker would be long-acting (once-daily) and b1-selective.<br />It is best to start with low dose to lessen the initial side effects as fatigue and bradycardia due to ↓ COP.<br />If the ordinary dose is inadequate, it is better to combine with another drug rather than to increase the dose.<br />Atenolol 25-100 mg<br />Bisoprolol 2.5-10 mg.<br />Metoprolol 50-200 mg.<br />
  21. 21. B-Blocker Combinations in Hypertension<br />1. b Blockers plus Diuretics<br />Diuretics acting by Na+ loss increase renin secretion -> VC by angiotensin II thus offsetting their hypotensive effect. b Blockers inhibit renin release -> potentiate the hypotensive effect of diuretics. On the other hand, diuretics, by increasing renin level, potentiate the hypotensive effect of b blockers in low-renin hypertensives as black elderly patients.<br />For initial therapy of hypertension, the lowest effective dose of both drugs [bisoprolol (2.5 mg) and hydrochlorothiazide (6.25 mg)] is recommended to avoid possible additive metabolic side effects such as hyperglycemia and hyperlipidemia.<br />
  22. 22. 2. B-Blockers plus Dihydropyridine (DHP) Ca2+ Channel Blockers<br />DHP Ca2+ channel blockers induce vasodilator effect and reflex tachycardia, offsetting a possible vasospasm and bradycardia induced by b blockers.<br />
  23. 23. Side Effects (Less with B1-selective):<br />1. Bronchospasm, cold extremities.<br />2. Metabolic: glucose intolerance, dyslipidemia.<br />3. Bradycardia, heart block.<br />4. CNS depression, sense of fatigue.<br />5. Impotence.<br />
  24. 24. III. Calcium Channel Blockers<br />There are two main types of voltage-dependent Ca2+ channels:-<br />1. L-type (Long-lasting) with slow inactivation and high conductivity.<br />2. T-type (Transient) with fast inactivation and low conductivity.<br />Ca2+ channel blockers act on α1 subunit of L-type channel that is located in conductive tissues (SAN & AVN) cardiac myocytes and vascular smooth muscle including coronaries.<br />
  25. 25. Classification, Actions, Uses and Adverse Reactions of Calcium Channel Blockers<br />
  26. 26. Calcium Channel Blockers for Hypertension<br />Mechanism of Action<br />Peripheral VD and ↓ TPR.<br />Diuretic action secondary to ↑ renal blood flow.<br />↓ Aldosterone secretion.<br />Advantages<br />No metabolic side effects (no changes in glucose, lipid or uric acid levels).<br />No affection of sexual activity.<br />May improve renal function.<br />
  27. 27. Indications : <br />2nd Choice after diuretics in elderly hypertensives or in isolated systolic hypertension.<br />2nd Choice after b blockers in hypertensives with coronary heart disease.<br />Hypertension with peripheral vascular disease (PVD).<br />Hypertension with renal impairment.<br />Preparations and Dosage: <br />Amlodipine 5 mg once daily.<br />Verapamil 240 mg SR once daily. <br />
  28. 28. IV. Angiotensin-Converting Enzyme (ACE) Inhibitors<br />Angiotensinogen<br />Renin<br />Bradykinin<br />Angiotensin I<br />ACE<br />Angiotensin II<br /> Inactive peptide<br />AT2 Receptors<br /><ul><li>Protective VD.
  29. 29. Anti-proliferative.</li></ul>AT1 Receptors<br /><ul><li>Direct VC.
  30. 30.  Sympathetic (central + peripheral).
  31. 31. ↑ Aldosterone (Na+ retention).
  32. 32. ↑ ADH (water retention).
  33. 33.  Proliferation of myocytes in heart and vessel wall.</li></ul>AT4 Receptors?<br /><ul><li>Prothrombotic:</li></ul>↑ Fibrinogen.<br />↑ Plasminogen activator inhibitor I (PAI1)<br />
  34. 34. Mechanism of Action of ACEIs: ACEIs have dual vasodilator action by:<br />1. ↓ Angiotensin II formation which mediates most of its effects through activation of AT1 receptors (inhibits vasospasm, salt & water retention & cardiac & vascular remodeling induced by angiotensin II).<br />↓ Activity of angiotensin II at AT2 receptors -> minimizes vasodilator effect of ACEIs (a disadvantage compared to ARBs). <br />↓ Activity of angiotensin II at AT4 receptors -> ↓its prothrombotic effect mediated by ↑ fibrinogen & PAI1 (an advantage over ARBs).<br />2. ↑ Bradykinin through inhibition of its deactivation -> direct VD & release of potent vasodilator PGs and NO from vascular endothelium.<br />
  35. 35. Therapeutic Uses of ACEIs<br />I. Cardiovascular Uses<br />ACE inhibitors have unique effects in preventing and treating cardiovascular diseases. They act on sequential events from risk factors to left ventricular failure.<br />
  36. 36. The main cardiovascular indications of ACEIs are:<br />Major risk factors<br />1. Hypertension: ↓ BP, } Major risk factors<br /> ↓ LV hypertrophy<br />2. Ischemic heart disease: inhibits atherogenesis and thrombogenesis.<br />3. Myocardial infarction:<br />Early administration during acute attacks prevents sudden death by preventing arrhythmia induced by hypokalemia and sympathetic overactivity.<br />Decrease postinfarction remodeling caused by aldosterone and prevent heart failure.<br />4. Heart failure: used in all stages of heart failure.<br />Major risk factors<br />
  37. 37. II. Nephropathy (diabetic or nondiabetic)<br />ACEIs decrease intraglomerular pressure, progressive glomerulosclerosis, and proteinuria and delay the onset of renal failure.<br />
  38. 38. ADVERSE REACTIONS<br />Related to<br />↑ Bradykinin<br />Related to <br />↓ Angiotensin II<br />Related to <br />High DoseCaptopril (immune-base)<br /><ul><li>Acute angioedema (early)
  39. 39. Chronic dry cough (late).</li></ul>Hypotension<br />Renal impairment<br />Hyperkalemia (↓ aldosterone)<br /><ul><li>Skin allergy
  40. 40. Neutropenia
  41. 41. Proteinuria
  42. 42. Loss of taste.</li></li></ul><li>1. Cough <br /> Common side effect which may disappear after 4 months. Addition of low dose of nifedipine may decrease cough. If not, shift to angiotensin receptor blockers (ARBs).<br />2. Angioedema<br /> Rare but may be fatal. Epinephrine and intubation may be needed.<br />3. Hypotension and reversible renal failure<br /> More common in high renin states such as in patients on diuretics, or those with heart failure or renal artery stenosis.<br />4. Hyperkalemia<br /> Occurs with co-administration of b blockers, aldosterone antagonist or renal impairment.<br />
  43. 43. Class I<br />Captopril (SH)<br />Class II<br />Enalapril - Perindopril<br />Ramipril - Fosinopril<br />Class III<br />Lisinopril<br />Classification of ACEIs<br />
  44. 44. Class I (Captopril) :<br />Not a prodrug.<br /> Rapid onset & short duration (t½ 4-6 h), can be given sublingually in severe hypertension<br />↓ Nitrate tolerance (due to its SH group).<br />Class II (Enalapril - Perindopril - Ramipril - Fosinopril):<br />Prodrugs (activated first in liver).<br /> Slow onset & long duration (given once/day).<br />Have carboxyl group not SH group with absence of immune base side effects of captopril.<br />Fosinopril has phosphoryl group instead of carboxyl group with dual route of excretion (hepatic & renal) -> no dose adjustment in renal failure.<br />
  45. 45. Classification (contin)<br />Class III (lisinopril) :<br />Not a prodrug.<br />Long duration.<br />Water soluble, not metabolized in liver and excreted unchanged by the kidney -> given in liver disease.<br />
  46. 46. ACE Inhibitors in Hypertension<br />Mechanism of Action<br />1. Vasodilation due to ↓ angiotensin II & ↑ vasodilator BK, PGs & NO.<br />2. Anti-adrenergic effect by blocking central & peripheral adrenergic activity of angiotensin II (thus ACEIs decrease BP without reflex tachycardia).<br />3. Inhibition of aldosterone -> Na+ loss.<br />
  47. 47. Advantages<br />1. ↓ Cardiovascular mortality and morbidity.<br />2. Protect renal function especially in diabetics.<br />3. No metabolic side effects (no effect on glucose, lipid or uric acid).<br />4. May improve glucose intolerance in insulin resistance.<br />5. No changes in heart rate. <br />Indications<br />1. Diabetic hypertensives.<br />2. Hypertension with nephropathy in diabetics or nondiabetics.<br />3. Hypertension in HF or after myocardial infarction.<br />
  48. 48. V. Angiotensin II Receptor Blockers (ARBs)(Losartan - Valsartan - Telmisartan)<br />They block angiotensin II receptor type I (AT1) responsible for most of the damaging effects of angiotensin II (see figure p. 179).<br />Advantages of ARBs over ACEIs<br />1. Antagonize AG II formed by both ACE & non-ACE pathway (e.g. chymase).<br />2. They are able to avoid hormonal "escape" (↑ renin & angiotensin II) which may occur during prolonged administration of ACEIs.<br />3. They block the hypersensitivity of AT1 receptor caused by insulin or LDL.<br />4. Blocking AT1 receptor directs angiotensin II to AT2 receptor which has vasodilator action and antiproliferative effect.<br />5. No production of bradykinin which may be responsible for angioedema and cough seen with ACEIs.<br />
  49. 49. Disadvantages of ARBs<br />1. Lack of protective effect of bradykinin due to NO & PGs formation.<br />2. Activation of AT4 receptor responsible for prothrombotic effect with increased fibrinogen, plasminogen activator inhibitor I.<br />
  50. 50. VI. Direct VasodilatorsHydralazine<br />Mechanism of Action<br />It is an arteriolar vasodilator that may act as a K+ channel opener with hyperpolarization of vascular membrane which prevents Ca2+ influx into the wall of blood vessels.<br />Pharmacokinetics<br />It is rapidly absorbed from the gut.<br />It is metabolized in the liver by acetylation. Fast acetylators need large dose, while slow acetylators may develop lupus syndrome.<br />It is excreted by the kidney and the dose should be reduced in renal disease.<br />
  51. 51. Indications :-<br />1. Hypertension<br />a. IV hydralazine is the drug of choice in severe hypertension with pregnancy.<br />b. The chronic use of hydralazine in hypertension is associated with rapid tolerance due to reflex activation of the sympathetic and renin-angiotensin systems resulting in salt retention and reflex tachycardia. So it is often used with diuretics and b blockers.<br />2. Congestive Heart Failure<br />It is not used alone but usually combined with nitrates.<br />It potentiates the effect of nitrates by reducing afterload and by reducing nitrate tolerance by decreasing free radical formation.<br />
  52. 52. 3. Mitral Regurge<br />Hydralazine, by decreasing peripheral resistance, increases forward stroke volume and decreases regurgitant volume.<br />Adverse Effects<br />Salt retention and edema.<br />Reflex tachycardia.<br />Lupus syndrome.<br />
  53. 53. Sodium Nitroprusside<br />Mechanism of Action<br />It is a donor of nitric oxide (NO) that increases the level of cGMP which induces vasodilation by inhibiting Ca2+ influx into the wall of blood vessels.<br />Pharmacological Properties<br />It has a potent direct vasodilator (arteriolar and venular) effect decreasing both preload and afterload.<br />It has an immediate effect and very short duration of action (2 minutes).<br />It is converted in the body into cyanomethemoglobin and free cyanide which is metabolized into thiocyanate in liver and excreted by the kidney.<br />
  54. 54. Indications :-<br />1. Hypertensive Emergencies<br />It is useful in most hypertensive emergencies as hypertensive encephalopathy, severe hypertension with acute HF and dissecting aortic aneurysm.<br />2. Severe Acute Heart Failure<br />It is useful in severe acute HF especially with mitral and aortic regurgitation provided the arterial pressure is reasonable.<br />It may be used in acute HF complicating myocardial infarction, cardiac surgery or acute exacerbation of chronic HF.<br />Nitroprusside is now replaced by safer drugs as nitroglycerin or milrinone (an inotropodilator).<br />
  55. 55. Toxicity<br />1. Cyanide Toxicity<br />Occurs especially when it is given at high doses for long periods, particularly in liver and renal diseases which limit cyanide clearance.<br />It varies from mild abdominal pain & vomiting to neurological symptoms as headache, confusion and convulsions up to unexplained death.<br />Treatment<br />Sodium nitrate 3% solution 2.5 ml/min for 5 min, followed by sodium thiosulfate 12.5 g in solution of 5% D/W over 10 minutes.<br />Overdose may cause severe hypotension and myocardial ischemia.<br />Dosage: 0.5-10 mg/kg/min IV infusion.<br />
  56. 56. Precautions :-<br />a. Infusion rate needs careful titration against BP, which must be continuously monitored to avoid excessive hypotension (potentially fatal).<br />b. Avoid extravasation.<br />c. Solution in normal saline should be freshly prepared and then protected from light during infusion.<br />d. Solution should be discarded when it is 4 hours old or if it is discolored.<br />
  57. 57. VII. Sympatholytics<br />They include centrally-acting drugs and a1-adrenoceptor blockers.<br />Mechanism of Action of Centrally-Acting Drugs<br />Relmenidine<br />Moxonidine<br />Clonidine<br />Methyldopa<br />Imidazoline Receptor<br />Rostral ventrolateral medulla (RVLM)<br />α2 Receptor<br />Nucleus tractus solitarius (NTS)<br /><br /><br /><br />Salivary gland<br />(Dryness)<br />Locus ceruleus<br />(Sedation)<br />Central Sympathetic Discharge<br />
  58. 58. Sympatholytics used in Hypertension<br />
  59. 59. Hypertension in the elderly<br />Benefit from antihypetensive therapy is evident up to at least 80 years of age.<br />The thresholds for treatment are diastolic pressure averaging 90 mmHg and systolic pressure averaging 160 mmHg.<br />A low dose of a thiazide is the drug of first choice, with addition of another antihypertensive when necessary.<br />
  60. 60. Isolated Systolic Hypertension<br />ISH (systolic > or = 160, diastolic <90mmHg, should be lowered, even if diastolic hypertension is absent.<br />Treatment with a low dose of a thiazide, with addition of a B-blocker when necessary is effective.<br />A long-acting dihydropyridine CCB is given when a thiazide is contraindicated or not tolerated.<br />Patients with severe postural Hypotension should not receive BP lowering drugs.<br />
  61. 61. Hypertension in Diabetes<br />The aim should be to maintain SBP<130 and DBP<80 mmHg.<br />HTN is common in type 2 DM and treatment of HTN prevents macrovascular and microvascular complications.<br />In type I DM, HTN usually indicates diabetic nephropathy.<br />An ACEI or ARB may have a specific role in the management of diabetic nephropathy.<br />In type 2, an ACEI or ARB can delay progression of microalbuminuria to nephropathy.<br />
  62. 62. Hypertension in renal disease<br />The thresholds for treatment in are diastolic pressure averaging 90 mmHg and systolic pressure averaging 140 mmHg.<br />Optimal BP is a SBP <130 and a DBP<80 mmHg if proteinuria exeeds 1 g in 24 h.<br />Thiazides may be ineffective and high doses of loop diuretics may be required.<br />Specific cautions apply to the use of ACEI in renal impairment, but ACEIs may be effective.<br />DHP CCBs may be added.<br />
  63. 63. Hypertension in Pregnancy<br />High BP in pregnancy may usually be due to pre-existing essential HTN or to pre-eclampsia.<br />Methyldopa is safe in pregnancy.<br />B-blockers are effective and safe in the third trimester.<br />Modified release preparations of nifedipine are also used in HTN in pregnancy.<br />IV labetalol or hydralazine can be used to control hypertensive crisis.<br />Magnesium sulphate is the drug of choice to prevent seizures in pre-eclampsia and eclampsia<br />
  64. 64. Hypertensive Crisis<br />Hypertensive crisis is defined as severe elevation in BP usually a systolic BP exceeding 220 mmHg and/or a diastolic BP greater than 120 mmHg.<br />It includes hypertensive emergencies and hypertensive urgencies.<br />Hypertensive Urgencies<br />It is severe elevation of BP in absence of progressive target-organ damage.<br />Immediate reduction in BP is not indicated and can be managed as outpatient case using combination of oral antihypertensives.<br />Hypertensive Emergencies<br />It is severe elevation in BP with acute progressive target-organ damage.<br />It represents an acute life-threatening situation which requires ICU admission for immediate controlled reduction in BP using IV drug therapy to avoid death or irreversible organ damage.<br />
  65. 65. Clinical Conditions Associated with HypertensiveEmergencies & their Drug Therapy :-<br />1. Malignant Hypertension<br />It is associated with bilateral retinal hemorrhage and/or exudates with or without papilledema.<br />Fenoldopam D1 agonist is the preferred drug, as it ↑ renal blood flow.<br />Other drugs: labetalol, enalaprilat.<br />2. Hypertensive Encephalopathy<br /> It is associated with neurological manifestations as headache, vomiting, visual disturbance, confusion or convulsions.<br />BP should be reduced gradually not to normal level to avoid brain ischemia.<br />Preferred drugs: labetalol, nitroprusside.<br />Nimodipine is used in subarachnoid hemorrhage -> ↓ cerebral vasospasm.<br />
  66. 66. 3. Acute Coronary Syndrome (unstable angina & myocardial infarction)<br />Nitroglycerin, esmolol are preferred drugs.<br />Nitroprusside is preserved for resistant cases as it may ↓ coronary BF.<br />4. Acute Left Ventricular Failure<br />Enalaprilat, nitroglycerin and nitroprusside are preferred. <br />b Blockers are avoided.<br />5. Dissecting Aortic Aneurysm<br />Drugs used: esmolol and nitroprusside.<br />
  67. 67. 6. Excessive Circulating Catecholamines<br />Occurs in pheochromocytoma, clonidine withdrawal and food interaction with MAO inhibitors.<br />Drugs used: phentolamine (plus b blockers) or labetalol (without b Bs)<br />7. Eclampsia <br />Hydralazine, nitroglycerin, labetalol may be used.<br />8. Perioperative <br />Includes severe hypertension in patient requiring immediate surgery or postoperative hypertension (↑ risk of myocardial infarction). <br />Drugs used: nitroglycerin, esmolol, labetalol, nitroprusside.<br />
  68. 68. Parenteral Agents for Hypertensive Emergencies<br />

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