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

Introduction ≥ 140 mmHg≥ 90 mmHg ****************************************************

Types of Hypertension Essential A disorder of unknown origin affecting the Blood Pressure regulating mechanisms Secondary Secondary to other disease processes ****************************************************

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

Normal Blood Pressure Regulation Blood Pressure = Cardiac output (CO) X Resistance to passage of blood through precapillary arterioles (PVR) CO is maintained by Heart (3) and postcapillary venules (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

Baroreceptor Reflex Pathway

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

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

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

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

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

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

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

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

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

Calcium Channel Blockers - Classification

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

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

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 1 st line fails – with beta- blockers and diuretics Hypertension in pregnancy

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)

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

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

RAS Renin is 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

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

RAS – Actions of Angiotensin-II 1. Powerful vasoconstrictor particularly arteriolar 2. It increases myocardial force of contraction (CA++ influx promotion) 3. Mitogenic effect – cell proliferation 4. Aldosterone secretion stimulation – retention of Na++ and water in body 5. Vasoconstriction of renal arterioles – rise in IGP – glomerular damage

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

ACE Inhibitors Captopril, Enalapril, Ramipril, Fosinopril etc.

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

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

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.

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

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