Antihypertensive drugs

In this all drugs included except diuretics

1. Antihyper tensive Drugs Presented by Abhaya S S Roll no 59

2. Contents Introduction ACE Inhibitors ARBs Beta Adrenergic blockers Alpha Adrenergic blockers Calcium channel blockers Vasodilators Central Sympatholytics Beta + Alpha Adrenergic blockers Selection of drug 2

3. Introduction 3

4. Classification of Drugs Ace Inhibitors Captopril, enalapril , lisinopril , perindopril, ramipril . Angiotensin antagonists Losartan, irbesartan , candesartan Calcium channel blockers Verapamil, diltiazam , nifedipine , felodipine , amlodipine, lacidipine Diuretics Thiazide=hydrochlorothiazide, chlorthalidone . indapamide High ceiling = furosemide K+ sparing = spironolactone.amiloride , 4

5. Classification of Drugs ß - Adrenergic blockers Propranolol, metaprolol , atenolol.  +ß Adrenergic blockers Labetalol, carvedilol. sodium  - Adrenergic blockers prazosin., terazosin, phentolamine Central Sympatholytic Clonidine, methyldopa Vasodilators Hydralazine, minoxidil Renin inhibitors Aliskiren 5

6. ACE Inhibitors What is Renin - Angiotensin ? Physiology Angiotensin Converting Enzyme

7. ACE Inhibitors Captopril lisinopril enalapril ramipril fosinopril Angiotensin Converting Enzyme inhibitors 7

8. Mechanism of action This group of drugs inhibit the enzyme kininase II or ACE. So these drugs decreases the activity of RAAS and also potentiate the vasodilatory action of bradykinin . Angiotensin Converting Enzyme inhibitors 8

9. Adverse effects Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substanceP breakdown in lungs Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level) Hypotension (in hypovolemic states) – sharp fall may occur – 1st dose Acute renal failure - CHF and bilateral renal artery stenosis Angioedema - swelling of lips, mouth, nose etc. Rashes, urticaria etc Dysgeusia - loss or alteration of taste Angiotensin Converting Enzyme 9

10. Adverse effects Foetopathic - hypoplasia of organs, growth retardation etc Neutropenia Contraindications - Pregnancy , bilateral renal artery stenosis, hypersensitivity and hyperkalaemia 10

11. 2.ARBs Losartan Candesartan Irbesartan Valsartan Telmisartan Angiotension receptor blockers 11

12. Mechanism of action Angiotension receptor blockers 12 Angiotensiogen Angiotensiogen I Angiotensiogen II AT 2 receptor AT 1 receptor Renin ACE ARBS

13. Mechanism of action These drugs act by antagonizing the action of angiotensin II at AT1 receptors. Theses drugs do not increase bradykinin and thus have less chances for causing cough and angioedema Angiotensin receptor blockers 13

14. ADR Headache , hypotension, weakness, rashes, nausea, vomiting and teratogenic effects. They may cause hyperkalemia in patients with renal failure or in patients on potassium sparing diuretics. Angiotension receptor blockers 14

15. 3.Renin inhibitors Aliskiren , remikiren and enalkiren are the drugs that inhibit the enzyme renin. Thus these drugs decrease the activity of RAAS causing fall in BP . ADR Aliskerin can cause diarrhea at higher doses Aliskerin can also cause cough and angioedema but probably less often than ACE inhibitors. 15

16. 4.Beta-adrenergic blockers Selective  blockers (block only  1) Atenolol , metoprolol, esmolol , betaxolol etc Nonselective beta blockers (block both 1 and 2 ) propranolol and timolol . 16

17. Mechanism of action Inhibition of beta 1 receptors leading to decreased cardiac output . Decrease in renin release due to inhibition of  β1 receptors in JG cells of kidney , along with this inhibit AT-II and aldosterone production, and lower peripheral resistance 17

18. Contd. Inhibition of central and peripheral sympathetic outflow due to inhibition of presynaptic stimulatory β receptors on adrenergic neurons. 18

19. Advantages of cardio-selective over non-selective : In asthma In diabetes mellitus In peripheral vascular disease 19

20. ADR Fatigue, lethargy – decreased work capacity Loss of libido – impotence Cognitive defects – forgetfulness Difficult to stop suddenly- withdrawal syndrome. Can precipitate CHF and bronchospasm in susceptible individuals. Therefore cardio-selective drugs are preferred now 20

21. 5.- Adrenergic Blockers Prazosin Terazosin Doxazosin Phentolamine Phenoxybenzamine 21

22. Mechanism of action These drugs produce a competative block of alpha 1 adrenoceptors. They decrease PVR and lowers arterial BP by causing relaxation of both arterial and venous smooth muscle. Therefore long term tachycardia does not occur but salt and water retention does. - Adrenergic Blockers 22

23. - Adrenergic Blockers Non selective alpha blockers are not used in chronic essential hypertension ( phenoxybenzamine , phentolamine ), only used sometimes as in phaechromocytoma Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used 23

24. ADR Prazosin causes postural hypotension – start 0.5 mg at bed time with increasing dose and upto10 mg daily Fluid retention in monotherapy Headache , dry mouth, weakness, dry mouth, blurred vision, rash, drowsiness and failure of ejaculation in males. 24

25. 6. α-β Adrenoceptor blocking agents Labetalol and carvedilol are two drugs having antagonistic activity at both adrenergic receptors ( i.e block both α1 and  β1 and β2 receptors). They are mainly used for controlling hypertension in pheochromocytoma . Carvedilol due to its antioxidant and antimitogenic property is also useful in CHF. 25

26. 7 .Calcium Channel Blockers Classification 26

27. Mechanism of action CCBs block the inward movement of calcium by binding to L type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax ,dilating mainly arterioles . Calcium Channel Blockers 27

28. ADR Constipations occur in 10% of patients treated with Verapamil. Dizziness , headache, and feeling of fatigue caused by decrease in BP are most frequent with dihydropyridines . 28

29. 7. Vasodilators Arteriolar = Hydralazine, minoxidil , diazoxide . Arteriolar + Venous = Sodium nitroprusside. 29

30. Mechanism of action Hydralazine molecules combine with receptors in the endothelium of arterioles – NO release – relaxation of vascular smooth muscle – fall in BP Subsequent fall in BP – stimulation of adrenergic system leading to Cardiac stimulation producing palpitation and rise in CO even in IHD and patients – anginal attack Tachycardia Arteriolar vasodilators 30

31. Contd. 31 Increased Renin secretion – Na+ retention These effects are countered by administration of beta blockers and diuretics

32. Mechanism of action Minoxidil Powerful vasodilator, mainly 2 major uses – antihypertensive and alopecia Prodrug and converted to an active metabolite which acts by hyperpolarization of smooth muscles and thereby relaxation of SM – leading to hydralazine like effects Arteriolar vasodilators 32

33. ADR Hydralazine Headache , tachycardia, nausea, sweating, arrhythmia and precipitation of angina. A lupus like syndrome can occur with high dosage but it is reversible on discontinuation of the drug. Minoxidil This drug causes serious sodium and water retention leading to volume overload ,edema and CHF. 33

34. Sodium Nitroprusside Rapidly and consistently acting vasodilator Relaxes both resistance and capacitance vessels and reduces PVR and CO (decrease in venous return ) Unlike hydralazine it produces decrease in cardiac work and no reflex tachycardia . Improves ventricular function in heart failure by reducing preload 34

35. Mechanism of action In the body it functions as a prodrug, reacting with sulfhydryl groups on erythrocytes, albumin, and other proteins to release NO . NO , or endothelium derived relaxing factor, stimulates guanyl cyclase to produce cyclic GMP, sequestering calcium and inhibiting cellular contraction. Sodium Nitroprusside 35

36. Contd. Uses: Hypertensive Emergencies, 50 mg is added to 500 ml of saline/glucose and infused slowly with 0.02 mg/min initially and later on titrated with response (wrap with black paper) Adverse effects: ADRs are due to release of cyanides (“thiocyanate” which is a metabolic outcome of nitroprusside) – palpitation, pain abdomen, disorientation, psychosis, weakness and lactic acidosis. 36

37. 8. Centrally acting sympatholytics Clonidine Alpha methyldopa 37

38. Mechanism of action Clonidine binds α2-AR with higher affinity than α1-AR. The α2-agonistic activity contributes to its BP-lowering effect due to negative feedback at the presynaptic neurons. When given i.v. , clonidine induces a brief rise of BP, which is followed by prolonged hypotension. Clonidine 38

39. Mechanism of action The metabolite, α- methylnorepinephrine , is stored in neurosecretory vesicle in place of NE . When released, α-methyl-NE is a potent α-AR agonist and in PNS is a vasoconstrictor . Its CNS effect is mediated by α2-AR, resulting in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance. Alpha methyldopa 39

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41. ADR Clonidine Dryness of mouth and eyes, sedation ,depression, bradycardia, impotence, nausea, dizziness, parotid gland swelling, and pain. Postural hypotension may occur in some case. Sudden stoppage of clonidine after prolonged use may cause withdrawal syndrome- headache, nervousness, tachycardia, sweating, tremors, palpitation and rebound hypertension 41

42. ADR Alpha methyldopa Nasal stuffiness, headache, sedation, depression, dryness of mouth, bradycardia, impotence, gynaecomastia , hepatitis and rarely haemolytic anaemia . 42

43. Selection of Antihypertensive Drugs Selection of anti hypertensive drugs in individual patients depends on Comorbidity Associated complications Age Sex Cost of the drug Concomitant drugs 43

44. Selection of Antihypertensive Drugs Preferred drugs for initial treatment of hypertension: ACE inhibitors, ARBs, CCBs and thiazides . Therapy usually started with a single agent . Combination therapy is used in patients who do not respond to single drug, can be used as initial therapy in patients with high BP. 44

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48. References Lippincott’s illustrated reviews K D Tripathi essentials of medical pharmacology 48

49. Thank You