Dr. Sasan Zaeri PharmD, PhD (Department of Pharmacology)

1. Antihypertensive Drugs Dr. Sasan Zaeri PharmD, PhD (Department of Pharmacology)

2. ≥ 140 mmHg ≥ 90 mmHg Introduction ****************************************************

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4. Treatment – Why? • To prevent target organ damage: • Eye (retinopathy) • Brain (stroke) • Kidney (chronic renal disease) • Heart (coronary artery disease, CHF) • Peripheral arteries (atherosclerosis) • Even asymptomatic hypertension needs to be treated

5. Blood Pressure = Cardiac output (CO) X Resistance to passage of blood through precapillary arterioles (PVR) CO is maintained by Heart (3) and postcapillaryvenules (2) PVR is maintained by arterioles (1) Kidney (4) controls BP by affecting volume of intravascular fluid in long term Baroreflex and renin-angiotensin- aldosterone system regulate the above 4 sites Local agents like Nitric oxide cause vasodilation and decreases BP All antihypertensives act via interfering with normal mechanisms Normal Blood Pressure Regulation

6. Baroreceptor Reflex Pathway

7. Antihypertensive Drugs • Diuretics • Thiazides, loop diuretics, K-sparing diuretics • Sympathoplegic drugs • ß-adrenergic blockers, α -adrenergic blockers, Centrally acting drugs • Direct vasodilators • Calcium channel blockers, Minoxidil, Hydralazine, Sodium nitroprusside • Angiotensin antagonists • Angiotensin-converting Enzyme (ACE) inhibitors, Angiotensin receptor 1(AT1) blockers

8. Diuretics • Mechanism of antihypertensive action: • Initially: diuresis – depletion of Na+ and body fluid volume – decrease in cardiac output • Subsequently after 4 - 6 weeks, reduction in total peripheral resistance (TPR) • Thiazides: Hydrochlorothiazide • Loop diuretics: Furosemide • K+ sparing diuretics: Spironolactone, triamterene and amiloride

9. Diuretics

10. Diuretics • Thiazide diuretic is the first-choice drug in mild hypertension • Thiazide diuretic can be used with a potassium sparing diuretic • Example: Triamterene-H • Loop diuretics are used only in complicated cases • CRF, CHF marked fluid retention cases

11. Thiazide diuretics • Adverse Effects (mostly seen in higher doses): • Hypokalaemia • Hyperglycemia: precipitation of diabetes • Hyperlipidemia: rise in total LDL level – risk of stroke • Hyperurecaemia: inhibition of uric acid excretion • Hypercalcemia • Thiazide diuretics reduce mortality and morbidity in patients with BP

12. Beta-adrenergic blockers • Mechanism of action: • Reduction in CO • Decrease in renin release from kidney (beta-1 mediated) • Non-selective:Propranolol (others: nadolol, timolol, pindolol, labetolol) • Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol) • Advantages: • Prevention of sudden cardiac death in post MI patients • Prevention of CHF progression

13. Beta-adrenergic blockers • Advantages of cardio-selective over non-selective: • In asthma • In diabetes mellitus • In peripheral vascular disease • Current status in treatment of BP: • First line along with diuretics and ACEIs • Preferred in angina pectoris • Preferred in Post MI patients – useful in preventing progression to CHF and mortality

14. Αlpha-adrenergic blockers • Mechanism of action: • Vasodilatation by blocking of alpha adrenergic receptors in smooth muscles: Reduction in PVR, reduction in CO by reduction in venomotor tone • Specific alpha-1 blockers: prazosin, terazosin and doxazosine • Non selective alpha blockers (phenoxybenzamine, phentolamine) are not used in chronic essential hypertension • Only used in pheochromocytoma

15. Αlpha-adrenergic blockers • Adverse effects: • Prazosin causes postural hypotension • First-dose effect • Fluid retention in monotherapy • Advantages: • Improvement of carbohydrate metabolism (diabetics) • Improvement of lipid profile (↓ LDL, ↑ HDL) • Treatment of benign prostatic hyperplasia (BPH) • Current status in treatment of PB: • Not used as first line agent, used in addition with other conventional drugs which are failing – diuretic or beta blocker

16. Centrally-Acting Drugs • Mechanism of action: • Inhibition of adrenergic discharge in brain by agonizing alpha-2 receptors: fall in PVR and CO • Methyldopa • Various adverse effects – cognitive impairement, postural hypotension, hemolytic anemia • Not used therapeutically now except in Hypertension during pregnancy • Clonidine • Not frequently used now because of tolerance and withdrawal hypertension

17. Calcium Channel Blockers - Classification

18. Calcium Channel Blockers (CCBs) • Mechanism of action: • Blockade of L-type voltage-gated calcium channels in heart and vessels: vascular smooth muscle relaxation (↓ PVR), negative chronotropic and ionotropic effects in heart (↓CO) • DHPs (amlodipine and nifedipine) have highest smooth muscle relaxation followed by diltiazem and verapamil

19. Calcium Channel Blockers • Advantages: • Can be given to patients with • Asthma with BP • Angina with/without BP • Peripheral vascular disease • Prophylaxis of migraine • Immediate acting Nifedipine is not encouraged anymore • Not first line of antihypertensive unless indicated

20. Vasodilators - Hydralazine • Mechanism of action: • Hydralazine molecules combine with receptors in the endothelium of arterioles and causes Nitric oxide release – relaxation of vascular smooth muscle – fall in PVR • Adverse effects: • Reflex tachycardia • Salt and water retention • Drug-induced lupus erythematosus • Uses: • Moderate hypertension when 1st line fails – with beta-blockers and diuretics • Hypertension in pregnancy

21. Vasodilators-Sodium Nitroprusside • Mechanism of action: • Rapidly produces nitric oxide to relax both resistance and capacitance vessels (↓PVR and CO) • Uses: Hypertensive Emergencies • (slow infusion)

22. Vasodilators – Minoxidil • Mechanism of action: • Hyperpolarization of smooth muscles by opening potassium channels and thereby relaxation of vascular smooth muscles • mainly 2 major uses – antihypertensive and alopecia • Rarely indicated in hypertension • Only in life threatening chronic hypertensions e.g. in chronic renal failure • More often in alopecia to promote hair growth

23. Angiotensin Converting Enzyme (ACE) Inhibitors What is Renin – Angiotensin System (RAS)?

24. RAS • Reninis produced by juxtaglomerular cells of kidney • Renin is secreted in response to: • Decrease in arterial blood pressure • Decrease in Na+ in tubular fluid • Increased sympathetic nervous activity • Renin acts on a plasma protein, Angiotensinogen, and cleaves it to produce Angiotensin-I • Angiotensin-I is rapidly converted to Angiotensin-II by ACE (present in luminal surface of vascular endothelium) • Angiotensin-II stimulates Aldosterone secretion from Adrenal Cortex

25. RAS Increased Blood Vol. Rise in BP Vasoconstriction Na+ & water retention Kidney (Adrenal cortex)

26. RAS – Actions of Angiotensin-II • Powerful vasoconstrictor particularly arteriolar • It increases myocardial force of contraction (CA++ influx promotion) • Mitogenic effect – cell proliferation • Aldosterone secretion stimulation – retention of Na++ and water in body • Vasoconstriction of renal arterioles – rise in IGP – glomerular damage

27. Angiotensin-II • What are the chronic ill effects? • Volume overload and increased PVR • Hypertension – long standing will cause ventricular hypertrophy • Cardiac hypertrophy and remodeling • Renal damage • Risk of increased CVS related morbidity and mortality • ACE inhibitors reverse actions of Ang II

28. ACE Inhibitors • Captopril, Enalapril, Ramipril, Fosinopril etc.

29. ACEIs – Antihypertensive action • RAS is overactive in 80% of hypertensive cases and contributes to the maintenance of vascular tone and volume overload • RAS inhibition by ACEIs causes Lower PVR and volume overload hence lower BP

30. ACEIs – Adverse effects • Cough – persistent cough in 20% cases induced by inhibition of bradykinin breakdown in lungs • Hyperkalemia (routine check of K+ level) • Acute renal failure (bilateral renal artery stenosis) • Angioedema: swelling of lips, mouth, nose etc. • Foetopathic: hypoplasia of organs, growth retardation etc • Contraindications: Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia

31. Place of ACE inhibitors in HTN • Drug of choice in: • HTN with diabetes (nephroprotective) • HTN with chronic renal disease • HTN with CHF • HTN with MI • Minimal worsening of quality of life – general wellbeing, sleep and work performance etc.

32. ACE inhibitors – other uses • Congestive Heart Failure (CHF) • Myocardial Infarction (MI) • Diabetic Nephropathy

33. Angiotensin Receptor Blockers (ARBs) Angiotensin Receptors: Most of the physiological actions of angiotensin are mediated via AT1 receptor ARBs block the actions of A-II: vasoconstriction, aldosterone release No inhibition of ACE, therefore no accumulation of bradykinin Cough is rare with ARBs Indications of ARBs are similar to those of ACEIs. Examples: Losartan, candesartan, valsartan and telmisartan