Antihypertensive drugs

• Diuretics


  • Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide
  • High ceiling: Furosemide, etc.
  • Aldosterone antag.: Spironolactone, Eplerenone
• Renin-angiotensin system inhibitors


  • ACE inhibitors: Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc.
  • Angiotensin (AT1 receptor) blockers: Losartan, Candesartan, Irbesartan, Valsartan,Telmisartan
  • Direct renin inhibitor: Aliskiren
• Sympathetic inhibitors


  • Beta Adrenergic blockers: Propranolol, Metoprolol, Atenolol, etc.
  • Alpha+ Beta Adrenergic blockers: Labetalol, Carvedilol
  • Alpha Adrenergic blockers: Prazosin, Terazosin, Doxazosin Phentolamine, Phenoxybenzamine
  • Central sympatholytics: Clonidine, Methyldopa
• Calcium channel blockers


  • Phenyl-alkylamine: Verapamil
  • Benzothiazepine: Diltiazem
  • Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc
• Vasodilators


  • Arteriolar: Hydralazine, Minoxidil, Diazoxide
  • Arteriolar + venous: Sodium nitroprusside
• Thiazides


  Diuretic of choice in uncomplicated hypertension
• Mechanism of antihypertensive action of thiazides

  1. Initially, the diuresis reduces plasma & e.c.f. volume --- decreased c.o.

  2. Compensatory mechanisms operate to regain Na+ balance & plasma volume; c.o. is restored, but the fall in BP maintained by a slowly developing reduction t.p.r.

  3. Decrease in intracellular Na+ concentration in the vascular smooth muscles -- decrease stiffness of vessel wall -- Increase their compliance -- dampen responsiveness to constrictor stimuli (NA, All)

  4. Vasodilator action of thiazides due to opening of smooth muscle potassium channels and hyperpolarization
• Antihypertensive action of diuretics is lost when salt intake is high
• The fall in BP develops gradually over 2-4 weeks
• Postural hypotension is rare
• Diuretics potentiate all other antihypertensive (except DHPs) and prevent development of tolerance to these drugs (used in combination)
• Diuretics are more effective in the elderly
• Diuretics should be used at low doses only because by increasing the dose, antihypertensive effect does not increase but adverse effects tend to increase
• Hypertensive action of diuretics is attenuated by NSAIDs


  NSAIDs block the cyclo-oxygenase pathway of arachidonic acid metabolism, with a resultant decrease in prostaglandin formation. Prostaglandins are important in normal modulation of renal and systemic vascular dilatation, glomerular filtration, tubular secretion of salt and water, adrenergic neurotransmission, and the renin-angiotensin-aldosterone system. Blockade of salutary effects of prostaglandins by NSAIDs results in a complex series of events culminating in attenuation of the effects of thiazide as antihypertensive agents
• High ceiling diuretics (Loop diuretics) are not indicated for mild to moderate hypertension because of the brisk diuresis leading to severe reduction in blood volume and electrolyte imbalance
• High ceiling diuretics are indicated in severe hypertension with CHF and renal dysfunction
• Indacrinone (daily dose (2.5 mg)) can be used in patients of gout because it inhibits reabsorption of uric acid in the nephron (other loop diuretics and thiazides cause hyperuricemia)
• Side effects of diuretics

  • Hypokalaemia: muscle pain, fatigue and loss of energy
  • Erectile dysfunction in males
  • Carbohydrate intolerance
  • Dyslipidemia: rise in total and LDL cholesterol and triglycerides with lowering of HDL
  • Hyperuricaemia: by inhibiting urate excretion, increased incidence of gout
  • Increased incidence of sudden cardiac death
• Potassium sparing diuretics are used only in combination with thiazides or loop diuretics to decrease the risk of hypokalemia
• Spironolactone has hormonal side effects (gynecomastia, impotence, menstrual irregularities)
• JNC8 guidelines: Add andosterone antagonist to ACE inhibitor/ ARB+CCB+ thiazide (if target BP not achieved. But hyperkalemia should be watched when combined with ACE inhibitors/ ARBs
• ACE inhibitors


  Inhibit the enzyme kininase II or ACE, decrease the activity of RAAS, potentiate the vasodilatory action of bradykinin
• ACE inhibitors are one of the first choice drugs in all grades of essential as well as renovascular hypertension (except those with bilateral renal artery stenosis)
• Dry persistent cough is the most common side effect of ACE inhibitors (due to more kinin)
• ACE inhibitors are more effective in younger (< 55 year) hypertensives than elderly
• Angiotensin Receptor Blockers (ARBs)


  Act by antagonizing the action of angiotensin II at AT1 receptors
• ARBs can be combined with ACEI for various indications as ARBs act at a distal site, so these will inhibit the activity of RAAS even when angiotensin II is generated by non-ACE pathway
• In a dose of 50 mg/ day losartan is effective antihypertensive
• ARBs do not increase kinin level, no dry cough. Angioedema, urticaria and taste disturbance are also rare
• Beta adrenergic blockers


  1. Inhibition of cardiac beta 1 receptors leading to decreased cardiac output

  2. Decrease in renin due to inhibition of b1 receptors in JG cells of the kidney

  3. Inhibition of central and peripheral sympathetic outflow due to the inhibition of presynaptic stimulatory b1 receptors on adrenergic neurons

  4. Increased vasodilatory prostacyclin synthesis in the vascular beds
• Beta blockers are no longer considered first line antihypertensive drugs for monotherapy (JNC 8)
• Labetalol and carvedilol


  Combined alpha and beta blockers
• Labetalol is used i.v. for rapid BP reduction in cheese reaction, clonidine withdrawal, pheochromocytoma
• Carvedilol, due to its antioxidant and anti-mitogenic property is also useful in CHF
• Nonselective alpha blockers (Phentolamine, Phenoxybenzamine)

  Cause much greater tachycardia than selective α1blockers due to the inhibition of presynaptic α2 receptors (α2 decreases sympathetic outflow) in addition to reflex tachycardia due to vasodilation (caused by both non-selective as well as selective α1 blockers)
• Alpha-adrenergic blockers (Prazosin, Terazosin, and Doxazosin)


  1. Dilates both resistance (predominating) and capacitance vessels

  2. Reduction in t.p.r. and mean BP

  3. Postural hypotension & fainting may occur in the beginning or on dose increment -- called first dose effect. Disappears with continued therapy, but may persist in the elderly
• Alpha-adrenergic blockers improve carbohydrate metabolism, have favourable effect on lipid profile, and afford symptomatic improvement in coexisting PVD or benign prostatic hypertrophy and gout (do not affect uric acid)
• Side effects of alpha-adrenergic blockers

  • Postural hypotension

  Headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash

  Ejaculation impaired in males: especially with higher doses

  Fluid retention, prazosin monotherapy may precipitate CHF
• Clonidine


  Partial agonist with high affinity and high intrinsic activity at alpha 2 receptors (alpha2A) in brainstem. Stimulation of alpha2A receptors present mainly postjunctionally in vasomotor centre -- decrease sympathetic out flow -- fall in BP
• Clonidine causes sedation, increases HDL, decreases LDL