Antihypertensive Drugs

Secondary hypertension is hypertension due to an identifiable cause Hypertension or arterial hypertension is a chronic medical condition in which the blood pressure in the arteries is persistently elevated. Hypertension is present if the blood pressure is persistently at or above 140/90 mmHg  Hypertension is classified as either primary (essential) hypertension (90–95%) or secondary hypertension (5–10%). Primary hypertension is high blood pressure with no obvious underlying cause. Secondary hypertension is hypertension due to an identifiable cause

Complications of Hypertension

Hypertensive crisis -severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110). Hypertensive crisis is categorized as : Hypertensive urgency There is no evidence of end organ damage resulting from the elevated blood pressure. In these cases, oral medications are used to lower the BP gradually over 24 to 48 hours. Hypertensive emergency There is evidence of direct damage to one or more organs.The most affected organs include the brain, kidney, heart and lungs, producing symptoms which may include confusion, drowsiness, chest pain and breathlessness. In hypertensive emergency, the blood pressure must be reduced rapidly to stop ongoing organ damage.

CLASSIFICATION 1. Diuretics Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide High ceiling: Furosemide, etc. K+ Sparing: Spironolactone, Amiloride 2. ACE inhibitors Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc. 3. Angiotensin (AT1 receptor) blockers Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan 4. Direct renin inhibitor Aliskiren 5. Calcium channel blockers Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc. 6. β Adrenergic blockers Propranolol, Metoprolol, Atenolol, etc. 7. β + α Adrenergic blockers Labetalol, Carvedilol 8. α Adrenergic blockers Prazosin, Terazosin, Doxazosin, Phentolamine, Phenoxybenzamine 9. Central α2 Adrenomimetics Clonidine 10. Vasodilators Arteriolar: Hydralazine, Minoxidil, Diazoxide Arteriolar + venous: Sodium nitroprusside Sympatholytics (Reserpine, Guanethidine, etc.) and ganglion blockers (Pentolinium, etc.) are only of historical importance.

DIURETICS Only the thiazide and thiazide-like diuretics should usually be the first choice when selecting a diuretic to treat hypertension. The reason why thiazide-type diuretics are better than the others is (at least in part) thought to be because of their vasodilating properties. Loop diuretics should be used only in case of severely elevated blood pressure (hypertensive crisis). Potassium sparing diuretics are used only in conjunction with a thiazide diuretic to prevent K+ loss.

ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS inhibit the activity of angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor.

ACE-INHIBITORS

ACE-INHIBITORS Captopril Enalapril Lisinopril Ramipril Perindopril Clinical use: Hypertension Cardiac conditions such as congestive heart failure Myocardial infarction Adverse effects: Hypotension Cough: a persistent brassy cough is caused by inhibition of bradykinin breakdown in the lungs Hyperkalemia Teratogenicity Acute renal failure

Angiotensin II receptor antagonists Angiotensin II receptor antagonists  also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans Work by antagonizing the activation of angiotensin receptors. Losartan Telmisartan Irbesartan Valsartan

Mechanism of action Blockage of AT1 receptors directly causes: Vasodilation Reduce production and secretion of aldosterone Medical uses primarily for the treatment of patients that is intolerant of ACE inhibitor therapy They do not inhibit the breakdown of bradykinin ⇒ there are no the persistent dry cough or angioedema that limit ACE inhibitor therapy. Adverse effects: Hypotension Hyperkalemia Headache Dizziness

Calcium channel blockers (CCB) Block the entry of Ca2+ into: Smooth muscle cells in artery walls SA, A-V node, atrial and ventricular cardiac fibres Classes of calcium channel blockers: Dihydropyridines : Amlodipine Felodipine Isradipine Nicardipine Nifedipine Nimodipine Non-dihydropyridines: Verapamil ⇒ Diltiazem ⇒ Act only on arteries ⇒reduce systemic vascular resistance and arterial pressure   selective for myocardium Act both on arteries and heart

Comparative properties of representative calcium channel blockers Nifedipine Verapamil Diltiazem Vascular smooth muscle relaxation ++++ - ++ Cardiac effects : Heart rate ↓ AV conduction velocity↓ Contractility↓ Clinical use in Hypertension Angina Arrhythmia Angina (Hypertension) Arrhythmia ADR Hypotension Tachycardia Edema Bradycardia A-V block CHF Cardiac arrest

β-ADRENERGIC BLOCKERS Nonselective (β1 and β2) a. Without intrinsic sympathomimetic activity: Propranolol Sotalol Timolol b. With intrinsic sympathomimetic activity: Pindolol Cardioselective (β1): Metoprolol Atenolol Acebutolol Bisoprolol Esmolol Betaxolol Nebivolol α and β blockers (with additional vasodilator property): Labetalol Carvedilol

αβ ADRENERGIC BLOCKERS Labetalol acts faster than pure β blockers. It has been used i.v. for rapid BP reduction in hyperadrenergic states, cheese reaction, clonidine withdrawal, eclampsia, etc. Oral labetalol therapy is restricted to moderately severe hypertension not responding to a pure β blocker. Carvedilol produces vasodilatation and has additional antioxidant/free radical scavenging properties. Carvedilol is a frequently selected drug for long-term treatment of CHF, and is approved as an antihypertensive as well.

α-ADRENERGIC BLOCKERS A. Nonselective Phentolamine Phenoxybenzamine B. α1 selective— Prazosin, Terazosin, Doxazosin, Alfuzosin

Central α2 Adrenomimetics Clonidine Use Clonidine was a popular antihypertensive in the late 1960s and 1970s, but frequent side effects, risk of withdrawal hypertension and development of tolerance have relegated it to a 3rd or 4th choice drug. There is no data on prognostic benefits, if any, of clonidine. At present, it is occasionally used in combination with a diuretic. Clonidine has also facilitated alcohol withdrawal and smoking cessation. ADR: Orthostatic hypotension Sedation Rebound effect

VASODILATORS Vasodilators act directly on the smooth muscle of arteries and veins to relax their walls They are only used in hypertensive emergencies or when other drugs have failed. Arteriolar: Hydralazine, Minoxidil, Diazoxide Hydralazine and its derivatives are used in the treatment of severe hypertension, although they should be avoided in emergencies. They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns. Arteriolar + venous: Sodium nitroprusside Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection).

VASODILATORS

Adverse effects of vasodilators Facial flushing, throbbing headache, dizziness, palpitation, nasal stuffiness, edema, CHF, weakness, disorientation Angina and MI may be precipitated in patients with coronary artery disease. Postural hypotension Paresthesias, tremor, muscle cramps, rarely peripheral neuritis.

TREATMENT OF HYPERTENSION 4 groups of first choice antihypertensive drugs: A—ACE inhibitor/ARB B—β-blocker C—CCB D—diuretic A and B are preferred in younger patients (<55 years), C and D are preferred in the older (> 55 years)

Combination therapy Though guidelines emphasise on single drug therapy, the addition of a second (and third or even fourth) drug is also highlighted when monotherapy fails. In practice, a large majority of hypertensives ultimately require 2 or more drugs (70% patients who achieved target BP were being treated with 2 or more drugs)

The preferred combinations Thiazide diuretic and ACE inhibitor Thiazide diuretic and angiotensin receptor antagonist Calcium antagonist and ACE inhibitor Calcium antagonist and angiotensin receptor antagonist Calcium antagonist and thiazide diuretic β-blocker and calcium antagonist (dihydropiridine)

Combinations to be avoided 1. An α adrenergic blocker with clonidine: apparent antagonism of clonidine action has been observed. 2. Hydralazine with a DHP or prazosin; because of similar pattern of haemodynamic action (huge risk of orthostatic hypotension and collapse). 3. Verapamil or diltiazem with β blocker, because marked bradycardia, A-V block can occur. 4. Any two drugs of the same class.

Hypertensive emergencies and urgencies Oral therapy Nifedipine (10 mg orally or s.l. every 30 min). Adverse consequences - abrupt fall in BP. Captopril (25 mg oral every 1–2 hours) - risk of excessive hypotension. Clonidine (100 mg every 1–2 hours oral) acts mostly in 30–60 min, but produces sedation and rebound rise in BP on stopping the drug.

Parenteral therapy 1. Sodium nitroprusside (slow i.v. injection) is the drug of choice for most hypertensive emergencies. 2. Hydralazine (i.m. or slow i.v. injection) acts in 20–30 min and keeps BP low for 4–8 hours, but is less predictable, and not a first line drug. It has been especially used in eclampsia. It causes tachycardia and should be avoided in patients with myocardial ischaemia. 3. Phentolamine .This nonselective α1 + α2 blocker is the drug of choice for hyperadrenergic states, e.g. hypertensive episodes in pheochromocytoma, cheese reaction or clonidine withdrawal. Injected i.v. 4.Furosemide (oral or i.v.) Nicardipine and clevidipine (parenteral DHPs), Enalaprilat (a parenteral ACE inhibitor) Trimethaphan (a ganglion blocker)