1. Antihypertensive Drugs

2. Diuretics Sympathoplegic drugs Vasodilators Inhibitors and antagonists of the renin- angiotensin system ACE inhibitors ARBs Renin inhibitors Hydrochloro- thiazide ClonidineHydralazineCaptoprilLosartanAliskiren IndapamideMethyldopaNitroprussideEnalapril FurosemidePrazosinMinoxidilEnalaprilat SpironolactonePropranololDiazoxide LabetalolFenoldopam EsmololCCBs Drug List * * More drugs have been mentioned in other slides

3. Classification of Antihypertensive Drugs 1) Diuretics Thiazides Loop diuretics. Potassium-sparing diuretics. 2) Sympatholytic drugs 1.Centrally acting antiadrenergic agents. 2.Alpha adrenergic blockers. 3.Beta adrenergic blockers. 4.Alpha-beta adrenergic blockers.

4. 3) Vasodilators A.Nitric oxide releasers. B.Potassium channel openers. C.D1-dopamine receptor agonists. 4) Calcium channel blockers 5) Drugs acting on renin angiotensin system A.Renin inhibitors B.Angiotensin Converting Enzyme (ACE) inhibitors. C.Angiotensin receptor antagonists. (ARB)

5. 1. Diuretics Diuretics lower blood pressure but there is no strict correlation between diuretic efficacy and antihypertensive efficacy. The fact points out that diuretics do not reduce blood pressure only by increasing diuresis. The initial hypotensive effects of diuretics is associated with a reduction in plasma volume and cardiac output. Peripheral vascular resistance is usually unaffected (or sometimes increased).

6. After 4-8 weeks of continuous therapy intravascular volume and cardiac output return towards normal while peripheral vascular resistance decreases, due to arteriolar vasodilation Mechanisms of this vasodilation are still poorly understood, but are probably related to: a.Depletion of body Na+ stores (likely the main mechanism) which leads to a fall in smooth muscle Na+ concentration. This in turn decreases intracellular Ca++ concentration by activating the Ca/Na exchanger. b.Induction of renal prostaglandin biosynthesis. c.Opening of K channels.

7.  Thiazides and thiazide-like drugs are first choice antihypertensive agents. They are the most effective diuretics to reduce blood pressure in patients with normal renal function.  The antihypertensive doses are lower that those required for diuretic effect.  Loop diuretics are preferable to thiazides only in some well recognized clinical situations (malignant hypertension, concomitant chronic kidney disease etc.)  Potassium sparing diuretics are only used in combination with thiazides to counteract hypokalemia. Spironolactone is used in hypertension due to hyperaldosteronism.  Diuretics can enhance the hypotensive effects of many antihypertensive agents.

8. 2. Sympatholytic drugs

9. A. Centrally acting sympathoplegic Drugs Drugs Alpha-2 receptor agonists: clonidine Indirect acting adrenergic drugs: methyldopa Imidazoline receptor agonists: clonidine, Mechanisms of antihypertensive action a) Alpha-2 receptor agonists: Activation of central alpha-2 receptors (the main mechanism).

10. b) Indirect acting adrenergic drugs: Methyldopa acts as a false neurotransmitter. It is taken up by the adrenergic neurons where it is transformed into methylnorepinephrine, the alpha-2 receptor agonist, which acts as described above. c) Imidazoline receptor agonists: These drugs activates non-adrenergic binding sites called imidazoline receptors located in medulla, which is the final common pathway for sympathetic outflow. The final effect common to all these drugs is a decreased of central adrenergic tone

11. Therapeutic uses in hypertension Clonidine and methyldopa (usually given together with a diuretic) are second choice drugs for therapy of hypertension. Methyldopa is often preferred for the treatment of hypertension in pregnancy (long experience has shown that it is not harmful to the fetus). Adverse effects: CNS: Sedation and drowsiness, Weakness, headache, nightmares Risk for depression

12. CVS: Clonidine (and rarely methyldopa) can cause a hypertensive crisis, when the drug is suddenly withdrawn. Bradycardia, A-V block (in risk patients). Others Sexual dysfunction Skin eruption (up to 20% with clonidine, when given transdermally). Methyldopa can cause positive Coombs’ test

13. B. Alpha Blockers Prazosin, doxazosin. Mechanism of action Selective blockade of alpha-1 receptors. They reduce blood pressure by dilating both resistance and capacitance vessels Uses in hypertension Hypertension (second choice drugs), often combined with other antihypertensive drugs.

14. Adverse effects 1. CVS Postural hypotension, mainly after the first dose "first-dose phenomenon". Tachycardia, palpitations, syncope Peripheral edema, after chronic treatment (due to sodium and water retention). 2) Central nervous system Fatigue, dizziness, vertigo, drowsiness 3) Others Urinary frequency, urinary incontinence. Sexual dysfunction

15. C. Beta-blockers (the “olols”) Mechanisms of action Decrease in cardiac output (blockade of cardiac beta-1 receptors) Inhibition of renin release (blockade of beta-1 receptors of juxtaglomerular cells) Classes of beta blockers 1.Selective (B1): Atenolol, Bisoprolol, Metoprolol 2.Non selective: Propranolol, Penbutolol, Timolol

16. Pharmacological effects: Decrease heart rate. Decrease cardiac output. Venous tone unchanged. Dose not cause postural hypotension

17. Therapeutic uses of beta blockers Supraventricular arrhythmias. Hypertrophic obstructive cardiomyopathy. Exertional angina. Post myocardial infarction. Hypertensive emergency (labetalol).

18. Adverse Effects CVS: Bradycardia, hypotension, rebound hypertension when withdrawn abruptly Nonselective compounds devoid of partial agonist activity are most prone to cause peripheral vascular disturbances (because of a decreased cardiac output and associated blockade of vasodilation in skeletal muscle). Respiratory: Bronchoconstriction CNS: Insomnia, depression, nightmares Hepatic: Impaired ability of the liver for gluconeogenesis and glycogenolysis causing hypoglycemia Sexual dysfunction

19. Beta blocker with partial agonist action Pindolol and acebutolol : They bound to beta 1 and 2 and cause partial stimulation of it but not the full effect and they inhibit the binding of more potent catecholamine. Thus these drugs are named blockers with ISA (intrinsic sympathomimetic action). It used for treatment of hypertension in patients with moderate bradycardia, because a further decrease in the heart rate is less pronounced with these drugs

20. D. Alpha and beta adrenoceptor blockers Labetalol and carvedilol They block both α and β receptors They cause vasodilation and reduction in the HR and contractility. Uses: – Treatment of hypertension in black and elderly patients. – Labetalol is used in treatment of hypertension with pregnancy. – IV labetalol is used for treatment of hypertensive emergencies – Carvidalol can be used in treatment of heart failure. Side effects: – Orthostatic hypotension and dizziness

21. 3. Vasodilators used in treatment of hypertension DrugSite of actionMechanism of action NitropurssideArterioles and veinsProduction of nitric oxide HydralazineArteriolesUncertain (Perhaps inhibition of Ca ++ release from sarcoplasmic reticulum, and stimulation of NO release) Minodoxil Diazoxide Arterioles K + channel opening FenoldopamArteriolesD1- receptor activation

22. A. Nitroprusside Pharmacokinetics Rapidly metabolized by red blood cells with liberation of cyanide, which in turn is metabolized to thiocyanate. The half life is about 2 minutes, so the drug must be given by continuous infusion to be effective. Adverse effects Excessive vasodilation, rebound hypertension, palpitations Nausea and vomiting, sub sternal pain Accumulation of: a) Cyanide (with too high doses) b) Thiocyanate (over prolonged administration)

23. Therapeutic uses Hypertensive emergencies. Severe heart failure. To induce a controlled hypotension, during surgery.

24. B. Hydralazine It directly relaxes small arteries and arterioles. It is absorbed from GIT, acetylated in the liver. Adverse effects a) Due to extension of pharmacological effects: Headache, dizziness. Palpitations, flushing. b) Due to immunological reactions Lupoid syndrome (up to 20% incidence, with very high doses). Fever, serum sickness, hemolytic anemia, vasculitis.

25. Contraindications and precautions Coronary artery disease Cerebrovascular disease Collagen disease Therapeutic uses Hypertension (second choice drug). Heart failure (combined with isosorbide mononitrate)

26. C. Minodoxil Minoxidil is a prodrug which is transformed by the liver into the active molecule. Therapeutic uses: (Not very commonly used because of its toxicity) Severe hypertension that responds poorly to other antihypertensive medications. Locally used to treat baldness. Adverse effects Salt and water retention. Tachycardia, palpitations, flushing Hypertrichosis

27. D. Diazoxide It is a potassium channel opener It is similar to thiazide diuretics, but it does not cause diuresis (apparently because it lacks a sulfonamide group). Adverse effects Salt and water retention, edema. Hyperglycemia Excessive hypotension, Flushing and headache Hypertrichosis (Hair growth in 20% of patients). Therapeutic uses Hypertensive emergencies.

28. E. Dopamine D1-Receptor Agonist Fenoldopam is the only drug on the market. Administration: IV infusion Mechanism of action: Vasodilation, mainly in renal and mesenteric vascular beds. Increased natriuresis (activation of D1 receptors causes an inhibition of NA+ reabsorption in the proximal tubule) Therapeutic uses Hypertensive emergencies. To induce a controlled hypotension, during surgery.

29. Adverse effects Reflex tachycardia, flushing Dose-dependent increase in intraocular pressure Decrease in serum potassium levels (likely due to natriuresis-induced aldosterone release). Contraindications Angina (tachycardia can trigger an anginal attack) Glaucoma. Hypokalemic states.

30. 4. Calcium Channel Blockers All calcium channel blockers (dihydropyridines and non dihydropyridines ‘verapamil, diltiazem’) are equally effective in lowering blood pressure. Hemodynamic actions Heart rate: increased (dihydropyridines); unchanged or decreased (verapamil, diltiazem) Cardiac output: increased (dihydropyridines); unchanged (verapamil, diltiazem) Peripheral vascular resistance: decreased. Postural hypotension: negligible. Efficacy of antihypertensive effect: moderate.

31. Calcium Channel blockers Uses in hypertension Hypertension (first choice drugs, more effective in African patients). Hypertensive emergencies (nicardipine). Long term epidemiological studies have reported an increased risk of mortality when short-acting nifedipine is used in hypertension. Slow release formulations apparently do not increase this risk.

32. 5. Drug affecting renin angiotensin system A. Renin Inhibitors Aliskiren is the only drug on the market Mechanism of action Competitive inhibition of renin, the enzyme that converts angiotensinogen into angiotensin I (the rate limiting step in angiotensin II biosynthesis). The inhibition of renin activity causes a decrease of angiotensin I, II, and aldosterone and an increase renin.

33. Adverse effects (usually well tolerated) Dizziness, fatigue, Diarrhea Hyperkalemia (when given with ACE inhibitors or angiotensin antagonists)

34. B. ACE inhibitors Captopril, lisinopril and enalaprilat are active drugs. All other compound (enalapril, benazepril, fosinopril, etc.) are prodrugs. Mechanism of action The converting enzyme hydrolyzes angiotensin one to angiotensin II and inactivates bradykinin. By inhibiting this enzyme, ACE-inhibitors lead to: 1.Inhibition of the renin-angiotensin system 2.Increased plasma levels of bradykinin Both actions lead to a relaxation of vascular smooth muscle, but the first action is the most important.

35. By inhibiting angiotensin II formation ACE inhibitors decrease the negative feed-back so causing an increase in renin release. This may attenuate the antihypertensive effect of these drugs). Pharmacokinetics All compounds that are prodrugs are transformed by the liver into active metabolites. All compounds, except enalaprilat (IV), are administered by oral route only.

36. Adverse effects Cardiovascular system Hypotension and postural hypotension (mainly after the initial doses, in 3-5% of patients who are salt and water depleted, or who have congestive heart failure). Respiratory system Dry and disturbing cough (it may be mediated by accumulation in the lungs of bradykinin and prostaglandins or, more likely, substance P).

37. Urinary system Renal insufficiency (in patients with bilateral renal artery stenosis or with stenosis of the renal artery of a solitary kidney) Other systems Hyperkalemia Angioneurotic edema. It is rare (up to 0.3%), but may be fatal (inhibition of bradykinin metabolism can be involved). Pregnancy: ACE inhibitors are pregnancy category D

38. Therapeutic uses Hypertension (first choice drugs) Hypertensive emergencies (enalaprilat IV) Myocardial infarction (overall mortality is reduced when treatment is begun during peri- infarction period). Chronic congestive heart failure (they decrease the progression of heart failure, the incidence of sudden death and myocardial infarction, and they improve the quality of life)

39. Diabetic glomerulopathy, hypertensive nephroangiosclerosis (they decrease the progression of the disease by preventing the angiotensin II induced vasoconstriction on the efferent glomerular arteriole). Primary or secondary hyperaldosteronism (when resistant to conventional therapy).

40. C. Angiotensin II Receptor antagonists Losartan, eprosartan, irbesartan, All compounds are administered by oral route only. Mechanism of action Competitive antagonism at angiotensin II receptors (these drugs selectively block AT1 receptors)

41. Pharmacodynamics They can prevent and reverse most known actions of angiotensin II, including: 1.Rapid and slow hypertensive responses 2.Stimulant effect on the peripheral sympathetic nervous system. 3.All CNS effects (thirst, vasopressin release, etc.) 4.Release of adrenal catecholamines 5.Secretion of aldosterone 6.All growth-promoting actions

42. They exert a more complete inhibition of angiotensin actions compared with ACE inhibitors (enzymes other than ACE are capable of generating angiotensin II) They have no effect on bradykinin and leukotriene metabolism. Main actions are: Vasodilation Increased salt and water secretion

43. Adverse effects [all adverse effects that result from inhibiting angiotensin II related functions should be expected] Contraindications Bilateral renal artery stenosis, severe stenosis of abdominal aorta. Pregnancy [these drugs are classified by FDA in the pregnancy risk category D because of their substantial teratogenic risk]. Therapeutic uses Hypertension (first choice drugs)

44. Good luck