Drugs used in the treatment of hypertension | Important drugs of the cardiovascular system | Pharmacology

Mechanism of action and adverse effects of antihypertensives

Drug	Mechanism of action	Adverse effects
Calcium channel blockers -dihydropyridines such as nifedipine, amlodipine, nicardipine, nimodipine, clevidipine	Block L type calcium channels of smooth muscles in blood vessels causing vasodilation	Reflex tachycardia, flushing, headache, edema, hypotension, not preferred in CAD/angina; Clevidipine formulation contains soy and egg so should be avoided in soy or egg allergies
Calcium channel blockers -non-dihydropyridines, diltiazem and verapamil	More cardio-specific, block L type calcium channels	Bradycardia, AV block, decreased contractility of the heart, do not combine with beta blockers, less preferred in heart failure
Alpha 1 blockers like prazosin, terazosin, doxazosin; Nonselective alpha blockers are phenoxybenzamine and phentolamine	Dilate arteries and veins by blocking alpha receptors on blood vessels	Dizziness, orthostatic hypotension, nasal congestion, headache, reflex tachycardia, fluid retention; Used along with beta blockers preoperatively in pheochromocytoma
ACE I or angiotensin inhibiting enzyme inhibitors such as captopril, enalapril, lisinopril, ramipril	Block the enzyme ACE that catalyzes the conversion of angiotensin I to angiotensin II; ACE also breaks down bradykinin, hence ACE I increase bradykinin levels; Dilate arteries and veins, decrease preload and afterload, natriuresis and diuresis, inhibit pathologic cardiac remodelling	Dry cough (from increased bradykinin), hypotension, angioedema (from increased bradykinin), hyperkalemia
Angiotensin receptor blockers or ARBs like losartan, valsartan, telmisartan, candesartan, irbesartan	Block angiotensin II receptors on blood vessels and heart, called AT 1; Do not increase bradykinin; (no cough, no angioedema); Dilate arteries and veins, decrease preload and afterload, natriuresis, diuresis, inhibit pathologic cardiac remodelling	Dizziness, hyperkalemia, headache (overall well tolerated drug)
Direct acting arterial dilators - hydralazine	Dilates arteries and arterioles, opening of vascular smooth muscle K channels, increase nitric oxide, increased cGMP; Short half-life	Reflex tachycardia, headache, flushing. Lupus-like syndrome; Used in the treatment of hypertensive emergencies, preeclampsia, pulmonary hypertension
Nitrates used in HT include nitroprusside and nitroglycerine	Sodium nitroprusside preferentially dilates arteries and arterioles, releases nitric oxide which dilates blood vessels; Nitroglycerine increases nitric oxide formation; Nitric oxide activates smooth muscle guanylyl cyclase to form cGMP which decreases intracellular calcium levels; it also opens K channels causing hyperpolarization	Headache, flushing, postural hypotension, reflex tachycardia, thiocyanate/cyanide toxicity (with nitroprusside); Tolerance to drug may develop;Used in hypertensive emergencies, pheochromocytoma, aortic dissection; Contraindicated with phosphodiesterase inhibitors like sildenafil
Ganglion blockers like mecamylamine and trimethaphan; These drugs are rarely used	Non competitive antagonist at nicotinic receptors of autonomic ganglions; Mecamylamine crosses the blood brain barrier while trimethaphan does not	Prolonged neuromuscular block with hypotension, impotence, constipation, urinary retention, dry mouth, stimulates histamine release, cycloplegia; Tremors, choreiform movements, mental status changes with mecamylamine
Potassium channel opener like Minoxidil	Open ATP sensitive K channels on vascular smooth muscle causing hyperpolarization and smooth muscle relaxation and vasodilation; Dilate arteries and arterioles	Reflex tachycardia, headache, flushing, edema, fluid retention, hypertrichosis (increases body hair- used to treat balding)
Renin inhibitors like aliskiren	Inhibits the renal enzyme renin which catalyzes the conversion of angiotensinogen to angiotensin I; Dilates arteries and veins	Diarrhea, cough, angioedema, hyperkalemia; Contraindicated in pregnancy
Diuretics	Thiazides are first line drugs for hypertension; potassium sparing diuretics are used in HT secondary to hyperaldosteronism or in addition to thiazides
Beta blockers like propranolol, atenolol, labetalol etc.	For antihypertensive effect, beta blockers block vascular beta 2 receptors , decrease intracellular cAMP in vascular smooth muscle causing vasodilation; Reduce blood pressure by decreasing cardiac output. Inhibit the release of renin by kidneys	Bradycardia, heart failure, hypotension, AV block, bronchoconstriction; Beta 1 selective blockers do not cause bronchoconstriction in usual doses
Centrally acting sympatholytics like clonidine, alpha methyldopa, guanabenz, guanfacine; Methyldopa/aldomet is a prodrug, structurally related to dopamine	Centrally acting alpha 2 agonist that stimulates adrenergic neurons in the rostral ventrolateral medulla and decrease sympathetic outflow to the cardiovascular system	Edema, sedation, dry mouth, depression, bradycardia, orthostatic hypotension, impotence, constipation, gastric upset, rebound hypertension on sudden discontinuation; Methyldopa can cause a Coombs positive hemolytic anemia and lupus-like syndrome. It may be used in pregnancy.

ACE inhibitors and ARBs are used in diabetes, diabetic nephropathy, chronic renal disorders with proteinuria and left ventricular failure. ARBs are preferred in patients who develop cough due to ACE inhibitor use. Both ACE inhibitors and ARBs are contraindicated in pregnancy and in bilateral renal artery stenosis. In African Americans with HT, a diuretic or calcium channel blocker should be added to ACE I or ARBs to decrease blood pressure.

In patients with cardiovascular risk factors or CAD, beta blockers, ACE inhibitors or ARBs, diuretics and calcium channel blockers are preferred for the treatment of HT.

Treatment of HT urgency and emergency: Patients with HT urgency do not need any specific anti HT therapy, in most cases. Any underlying causes of HT like pain, hyperaldosteronism etc. should be looked for. They should be followed up and treated if blood pressure does not normalize. However, HT emergency is a life threatening condition and should be treated. Blood pressure** **should be lowered by 25% in the first hour and then gradually decreased to 160/100 mmHg within the next 2 to 6 h, and then cautiously to normal over the next 24 to 48 h. However, in aortic dissection, the blood pressure should be decreased within 5-10 minutes to <120 mmHg systolic.

Preferred therapy of HT emergencies

Condition	Preferred drug
Aortic dissection	i.v esmolol, followed by i.v labetalol or nitroglycerine or nitroprusside
Pulmonary edema	i.v nitroglycerine, clevidipine or nitroprusside
AMI/CAD	i.v esmolol, followed by i.v nitroglycerine if needed; labetalol
Renal failure acute	Clevidipine, fenoldopam, nicardipine
Eclampsia/ pre eclampsia	Hydralazine, labetalol, nicardipine
Cocaine toxicity/pheochromocytoma	Phentolamine, nitroglycerine or nitroprusside; diazepam; Beta blockers should be given only after alpha blockers
Intracerebral hemorrhage	Clevidipine, labetalol, nicardipine and urapidil