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Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
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Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
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Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
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Antihypertensive agents
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Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
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Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
Antihypertensive agents
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Antihypertensive agents

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  • 1. Antihypertensive Agents By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
  • 2. Antihypertensive Agents  Introduction  Classification  Diuretics  Sympathoplegic agents  Direct vasodilators  Angiotensin Blockers  Clinical Pharmacology  Hypertensive Emergencies  Drug PicturesM.H.Farjoo
  • 3. Introduction  Hypertension is the most common cardiovascular disease.  Even mild hypertension (blood pressure 140/90 mm Hg) increases the risk of organ damage.  Hypertension is asymptomatic until overt organ damage is imminent or has already occurred.  Starting at 115/75 mm Hg cardiovascular disease risk doubles with each increment of 20/10 mm Hg.M.H.Farjoo
  • 4. Introduction (cont’d)  A specific cause of hypertension is established in only 10-15% of patients.  Inheritance, stress, increased salt and decreased potassium or calcium intake are all involved.  The heritability of hypertension is 30%.M.H.Farjoo
  • 5. Classification  Drugs are categorized according to their mechanism.  Drugs within each category tend to produce similar toxicities.M.H.Farjoo
  • 6. Diuretics  Diuretics lower blood pressure by 10-15 mm Hg.  Diuretics alone provide adequate treatment for mild to moderate hypertension.  Indapamide has also direct vasodilating effects.  Amiloride inhibits smooth muscle responses to contractile stimuli.M.H.Farjoo
  • 7. Diuretics (cont’d)  Thiazide diuretics are appropriate for patients with normal renal and cardiac function.  Potassium-sparing diuretics are useful to avoid potassium depletion in patients taking digitalis.  Loop diuretics are used in emergency.M.H.Farjoo
  • 8. Diuretics (cont’d)  The most common adverse effect of diuretics (except potassium-sparing) is hypokalemia.  Hypokalemia is hazardous in persons taking digitalis, arrhythmias, MI or left ventricular dysfunction.  Potassium loss is coupled to reabsorption of sodium so restriction of sodium minimizes potassium loss.M.H.Farjoo
  • 9. Diuretics (cont’d)  Diuretics may increase serum lipids.  Diuretics increase uric acid concentrations and may precipitate gout.  Potassium-sparing diuretics may produce hyperkalemia in those taking ACE inhibitors or angiotension receptor blockers.  Spironolactone is associated with gynecomastia.M.H.Farjoo
  • 10. Sympathoplegic agents  In moderate to severe hypertension, inhibitors of sympathetic nervous system should be included.  All of the agents that alter sympathetic function elicit compensatory effects.  Sympathoplegic drugs are most effective when used concomitantly with a diuretic.M.H.Farjoo
  • 11. Sympathoplegic agents (cont’d)  Drugs are classified according to the site at which they impair the sympathetic reflex arc:  Act on the CNS May cause  Ganglion blockers sedation, depression, sleep Produce autonomic disturbances (nightmares).  Reduce norepinephrine release instability.  Block adrenoceptors of ejaculation, Cause inhibition and orthostatic hypotension. is according to Side effects the receptor to which they bind.M.H.Farjoo
  • 12. Centrally Acting Sympathoplegics  Their antihypertensive and toxic actions are less dependent on posture.  Two drugs are in this group:  Methyldopa  ClonidineM.H.Farjoo
  • 13. Methyldopa  Methyldopa is useful in the treatment of mild to moderately severe hypertension.  Its antihypertensive action is due to stimulation of central α adrenoceptors.  Most cardiovascular reflexes remain intact after administration of methyldopa.  Postural hypotension may occur in volume- depleted patients.M.H.Farjoo
  • 14. Methyldopa (cont’d)  One advantage of methyldopa is reduction in renal vascular resistance.  Because the effect depends on storage of a metabolite, the action persists after stopping the drug.M.H.Farjoo
  • 15. Methyldopa (cont’d)  Lactation, associated with increased prolactin secretion, can occur both in men and in women.  This is mediated by inhibition of dopaminergic mechanisms in the hypothalamus.  Positive Coombs test occurs in 10-20% of patients undergoing therapy for longer than 12 months.  Discontinuation of the drug results in prompt reversal of these abnormalities.M.H.Farjoo
  • 16. Clonidine  Clonidine is an α2 (and less powerful α1) agonist.  After IV injection, clonidine produces a brief rise in blood pressure followed by hypotension.  The pressor response is due to direct stimulation of α adrenoceptors in arterioles.  Severe hypertension can complicate a massive overdose.  Clonidine reduces norepinephrine release resulting in hypotension and bradycardia.M.H.Farjoo
  • 17. Clonidine (cont’d)  Withdrawal of clonidine after protracted use can result in life-threatening hypertensive crisis.  Patients exhibit nervousness and tachycardia after omitting one or two doses of the drug.  Stopping the drug should be done gradually while other antihypertensive agents are being substituted.  Treatment consists of reinstitution of clonidine or administration of α and β adrenoceptor-blockers.M.H.Farjoo
  • 18. Clonidine (cont’d)  Clonidine decreases renal vascular resistance and maintains renal blood flow.  Dry mouth and sedation are frequent.  The drug should be withdrawn if depression occurs.M.H.Farjoo
  • 19. Ganglion-blocking Agents  Ganglion blockers block both parasympathetic and sympathetic ganglia.  Their adverse effects are extensions of their pharmacologic effects and include:  Sympathoplegia Orthostatic hypotension, sexual  Parasympathoplegia dysfunction. Constipation, urinary retention, glaucoma, blurred vision, dry mouth.M.H.Farjoo
  • 20. Adrenergic Neuron-blocking Agents  The most important drug is reserpine.  Reserpine is effective for mild to moderate hypertension.  Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines.  This results in depletion of norepinephrine, dopamine, and serotonin in central and peripheral neurons.M.H.Farjoo
  • 21. Adrenergic Neuron-blocking Agents (cont’d)  In low doses sympathetic reflexes remain intact and postural hypotension is mild.  Reserpine depletes amine stores in brain resulting in sedation, mental depression, and parkinsonism.  This may occur even after months of uneventful treatment.M.H.Farjoo
  • 22. Adrenoceptor Antagonists  All β blockers are very useful for mild to moderate hypertension.  In severe hypertension, β blockers prevent the reflex tachycardia due to vasodilators.  Propranolol inhibits the stimulation of renin production mediated by β1.  Propranolol reduces blood pressure without prominent postural hypotension.M.H.Farjoo
  • 23. Adrenoceptor Antagonists (cont’d)  Side effects occur in asthma, diabetes, cardiac conduction disease and peripheral vascular diseases.  Propranolol may cause a withdrawal syndrome: nervousness, tachycardia, angina, or hypertension. Propranolol should not be discontinued abruptly.M.H.Farjoo
  • 24. Alpha1 Blockers  Prazosin, terazosin, and doxazosin selectively block α1 receptors in arterioles and venules.  These agents produce less reflex tachycardia and little postural hypotension.  Alpha1 selectivity allows norepinephrine to exert unopposed negative feedback.  A precipitous drop in standing blood pressure develops after the first dose (first-dose phenomenon). The first dose should be small andM.H.Farjoo should be administered at bedtime.
  • 25. Direct Vasodilators  Vasodilators do not cause sexual dysfunction or orthostatic hypotension.  Vasodilators work best in combination with other antihypertensive drugs.M.H.Farjoo
  • 26. Direct Vasodilators (cont’d)  They consist of:  Oral: hydralazine and minoxidil.  Parenteral : nitroprusside, for long-term Used diazoxide, and fenoldopam. outpatient therapy Used to treat hypertensive  The calcium channel blockers. emergencies.  All of the vasodilators relax arterioles, sodium Used in both circumstances. nitroprusside also relaxes veins.M.H.Farjoo
  • 27. Hydralazine  Hydralazine is metabolized by acetylation at a bimodal rate in the population: rapid & slow.  Rapid acetylators have greater first-pass metabolism, and less effect than slow acetylators.  In slow acetylators, there is a 10-20% incidence of a lupus erythematosus like syndrome.  The adverse effects of hydralazine are: headache, nausea, anorexia, palpitations, sweating, and flushing.M.H.Farjoo
  • 28. Minoxidil  Minoxidil opens potassium channels and makes contraction less likely.  Minoxidil must be used in combination with a β blocker and a loop diuretic.  Topical minoxidil (Rogaine) is used for hair growth for correction of baldness.M.H.Farjoo
  • 29. Sodium Nitroprusside  It activates guanylyl cyclase, either via release of nitric oxide or direct stimulation of the enzyme.  The result is increased intracellular cGMP, which relaxes vessels.  It rapidly lowers blood pressure, and its effects disappear within 1-10 minutes after discontinuation.  It is sensitive to light and must be made up fresh and covered with opaque foil.M.H.Farjoo
  • 30. Sodium Nitroprusside (cont’d)  The most serious toxicity is accumulation of cyanide; metabolic acidosis, arrhythmias, and death.  Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide.  Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin.  Both agents are used for cyanide poisoning during nitroprusside infusion.M.H.Farjoo
  • 31. Diazoxide  Diazoxide opens potassium channels and stabilizes the membrane at resting potential.  Its effect after a rapid injection appears within 5 minutes and lasts 4-12 hours.  Diazoxide should be avoided in ischemic heart disease.  It inhibits insulin release from the pancreas (opens K+ channels) and is used for insulinoma.M.H.Farjoo
  • 32. Fenoldopam  Fenoldopam is agonist of D1 receptors causing peripheral artery dilatation and natriuresis.  Its half-life is 10 min. it is administered by continuous IV infusion.  The toxicities are: tachycardia, headache, and flushing.  Fenoldopam increases IOP and should be avoided in patients with glaucoma.M.H.Farjoo
  • 33. Calcium Channel Blockers  Nifedipine is more selective as a vasodilator and have less cardiac depressant effect.  Verapamil has the greatest depressant effect on the heart.  Diltiazem has intermediate actions.  Risk of MI or mortality is increased in patients receiving short-acting nifedipine.M.H.Farjoo
  • 34. Calcium Channel Blockers (cont’d)  It is recommended that nifedipine not be used for hypertension.  Calcium blockers with long half-lives are more appropriate for chronic hypertension.  Oral nifedipine is used in emergency treatment of severe hypertension.M.H.Farjoo
  • 35. Inhibitors of Angiotensin  Renin acts upon angiotensinogen to produce angiotensin I.  ACE converts angiotensin I to angiotensin II.  Angiotensin II has vasoconstrictor and sodium-retaining activity.  It also stimulates aldosterone release.M.H.Farjoo
  • 36. Inhibitors of Angiotensin (cont’d)  Even in low-renin hypertensive states, these drugs can lower blood pressure.  Two classes of drugs act on the renin- angiotensin system:  The ACE inhibitors  The inhibitors of angiotensin at its receptors.M.H.Farjoo
  • 37. ACE Inhibitors  They consist of: Captopril  Captopril inhibits the renin-angiotensin system Enalapril Lisinopril and stimulats the kallikrein-kinin system. Benazepril  Fosinopril Most of them are prodrugs, and are converted Moexipril to the active agents Perindopril by hydrolysis. Quinapril Ramipril TrandolaprilM.H.Farjoo
  • 38. ACE Inhibitors (cont’d)  ACE inhibitors do not result in reflex tachycardia and can be used safely in ischemic heart disease.  ACE inhibitors diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure).  ACE inhibitors are extremely useful in heart failure, and after MI.  ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk.M.H.Farjoo
  • 39. ACE Inhibitors (cont’d)  Severe hypotension can occur after initial doses of any ACE inhibitor.  ACE inhibitor can causes renal failure in patients with bilateral renal artery stenosis.  Other side effects are: hyperkalemia and dry cough.  ACE inhibitors are contraindicated in pregnancy (fetal hypotension, renal failure, malformations or death).M.H.Farjoo
  • 40. ACE Inhibitors (cont’d)  Potassium supplements or potassium-sparing diuretics with ACE Inhibitors can result in hyperkalemia.  NSAIDs antagonize effects of ACE inhibitors (block bradykinin-mediated vasodilation by prostaglandins).M.H.Farjoo
  • 41. Angiotensin Receptor Blockers  They consist of: Losartan  They block angiotensin II type 1 (AT1) Valsartan receptor. Candesartan Eprosartan Irbesartan  They have no effect on bradykinin Telmisartan metabolism.  The adverse effects are similar to ACE inhibitors, but cough and angioedema are less common.M.H.Farjoo
  • 42. Clinical Pharmacology  The physician must establish with certainty that hypertension is persistent and requires treatment.  Hypertension is established by finding an elevated blood pressure on at least three different office visits.  Secondary causes that might be treated by surgery must be excluded.  Patients have had elevated blood pressure for months or years, and therapy is best initiated gradually.M.H.Farjoo
  • 43. Clinical Pharmacology (cont’d)  Dietary control of blood pressure is a nontoxic therapeutic measure and may even be preventive.  Even modest dietary sodium restriction lowers blood pressure in mild hypertension.  Weight reduction normalizes blood pressure in 75% of overweight patients with mild to moderate hypertension.  Thiazide diuretics, β blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers may be used for initial drug therapy.M.H.Farjoo
  • 44. Clinical Pharmacology (cont’d)  ACE inhibitors are particularly useful in patients with evidence of chronic kidney disease.  Beta blockers or calcium channel blockers are useful in angina.  Diuretics, ACE inhibitors, angiotension receptor blockers, or β blockers are useful in heart failure.  α1 blockers are helpful in prostatic hyperplasia.M.H.Farjoo
  • 45. Clinical Pharmacology (cont’d)  If a diuretic is not used initially, it is often selected as the second drug.  If three drugs are required, a sympathoplegic agent, a diuretic, or an ACE inhibitor, and a direct vasodilator (hydralazine or a calcium channel blocker) is effective.  An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient.M.H.Farjoo
  • 46. Clinical Pharmacology (cont’d)  The optimal blood pressure end point is 138/83 mm Hg.  Lowering blood pressure below this level produces no further benefit.  In diabetics, there is a continued reduction of risk with lower blood pressures.  Systolic hypertension (>140 mm Hg with normal diastolic blood pressure) is a strong risk factor in patients >50 years.M.H.Farjoo
  • 47. Clinical Pharmacology (cont’d)  Causes of failure to drug therapy include:  Excessive sodium intake and inadequate diuretic therapy.  Drugs: TCAs, NSAIDs, sympathomimetics, amphetamine, cocaine, excessive doses of caffeine and OCPs.M.H.Farjoo
  • 48. Hypertensive Emergencies  They occur in poorly controlled patients or those who suddenly discontinue the drug.  Hypertensive emergencies include hypertension with vascular damage (malignant hypertension).  Hypertensive encephalopathy is a classic feature of malignant hypertension.  It consists of: severe headache, mental confusion, blurred vision, vomiting, and focal neurologic deficits.  If untreated, the syndrome progresses in 12-48 hours to convulsions, coma, and death.M.H.Farjoo
  • 49. Hypertensive Emergencies (cont’d)  Parenteral drugs are used to lower blood pressure rapidly (within a few hours).  The drug most commonly used is sodium nitroprusside.  Esmolol is used for intra- and postoperative hypertension.  As soon as reasonable blood pressure is achieved, oral therapy should be substituted.M.H.Farjoo
  • 50. Hypertensive Emergencies (cont’d)  The goal of treatment in the first few hours or days is not complete normalization of blood pressure.  Chronic hypertension is associated with autoregulatory changes in cerebral blood flow.  Rapid normalization of blood pressure may lead to brain hypoperfusion and injury.M.H.Farjoo
  • 51. Hypertensive Emergencies (cont’d)  Blood pressure should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100-110 mm Hg.  Blood pressure can be reduced to normal levels using oral medications over several weeks.M.H.Farjoo
  • 52. Summary In English
  • 53. Thank you Any question?

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