Antihypertensive Drugs

Thiazide and thiazide-like diuretics inhibit the sodium-chloride cotransporter in the distal convoluted tubule, producing natriuresis and mild potassium wasting. Their acute blood pressure-lowering effect is from volume depletion, but with chronic use, total peripheral resistance falls through mechanisms that are not fully understood — possibly involving reduced vascular smooth muscle sodium content. Blood pressure reduction is maintained despite normalization of volume over weeks.

A notable pharmacological feature is paradoxical calcium reabsorption enhancement in the distal convoluted tubule — the opposite of loop diuretics. This makes thiazides useful in calcium nephrolithiasis and potentially protective against osteoporotic fractures.

Among the available agents, chlorthalidone is preferred over hydrochlorothiazide. Chlorthalidone has a much longer half-life (40 to 60 hours versus 10 to 12 hours for hydrochlorothiazide), provides superior 24-hour blood pressure control, and has the strongest outcome trial evidence base — including the ALLHAT and Systolic Hypertension in the Elderly Program (SHEP) trials. Current guidelines favor chlorthalidone as the thiazide of choice for hypertension. Indapamide has additional vascular effects beyond sodium-chloride cotransporter inhibition and the most favorable metabolic profile of the three.

The metabolic consequences of thiazide diuretics are clinically important and require monitoring. Hypokalemia occurs in 10 to 30 percent of patients on standard doses. The mechanism is increased sodium delivery to the collecting duct, which stimulates aldosterone-mediated potassium secretion. Hypomagnesemia co-occurs with hypokalemia — magnesium depletion impairs renal potassium conservation, so correcting magnesium is often necessary to effectively correct potassium.

Hyperuricemia results from reduced uric acid excretion competing with thiazide for tubular secretion and from volume contraction increasing urate reabsorption. Asymptomatic hyperuricemia alone is not a contraindication, but when thiazide therapy coexists with gout, losartan is the preferred renin-angiotensin-aldosterone system inhibitor partner given its uricosuric effect.

Glucose intolerance and new-onset diabetes are dose-dependent, most prominent at hydrochlorothiazide doses above 25 mg per day. The mechanism involves hypokalemia impairing insulin secretion and angiotensin II upregulation reducing insulin sensitivity. Chlorthalidone at 12.5 to 25 mg has a more modest glucose effect. Hyponatremia occurs most often in elderly women through free water retention driven by volume depletion-stimulated antidiuretic hormone release — chlorthalidone carries higher risk than hydrochlorothiazide due to its longer half-life.

Loop diuretics inhibit the sodium-potassium-2-chloride cotransporter in the thick ascending limb of the loop of Henle, the nephron segment responsible for reabsorbing approximately 25 percent of filtered sodium. They are the most potent diuretics available. Unlike thiazides, loop diuretics increase urinary calcium excretion.

Loop diuretics are not first-line antihypertensive agents in patients with preserved renal function. Their antihypertensive role is primarily in stage 4 to 5 chronic kidney disease (estimated glomerular filtration rate below approximately 30 mL/min), where thiazide efficacy is markedly reduced, and in volume overload from heart failure. Furosemide has variable oral bioavailability and requires twice-daily dosing. Torsemide has more predictable oral pharmacokinetics and is suitable for once-daily dosing.

These agents act in the collecting duct to reduce potassium excretion while maintaining modest natriuresis. Spironolactone and eplerenone are competitive mineralocorticoid receptor antagonists that block aldosterone-mediated sodium reabsorption. Their most important antihypertensive role beyond primary aldosteronism is in resistant hypertension — the PATHWAY-2 trial established spironolactone as the most effective fourth-line agent for resistant hypertension, superior to bisoprolol and doxazosin.

Spironolactone is non-selective, also binding progesterone and androgen receptors, causing gynecomastia, breast tenderness, and menstrual irregularities. Eplerenone is selective for the mineralocorticoid receptor and avoids these sex hormone adverse effects, making it preferred in men who develop spironolactone-related sexual or hormonal side effects. Both require potassium monitoring, especially in chronic kidney disease or when combined with renin-angiotensin-aldosterone system inhibitors. Amiloride and triamterene directly block epithelial sodium channels in the collecting duct, independent of aldosterone.