Pharmacology Notes

Eplerenone blocks sodium reabsorption, by antagonism of aldosterone.

Eplerenone is an aldosterone antagonist and has been shown to reduces mortality when added to standard therapy and initiated within 14 days of acute myocardial infarction if the patient has heart failure and a left ventricular ejection fraction of less than 40%.

Hyperkalaemia may occur if eplerenone is used in combination with potassium supplements, ACE inhibitors, potassium-sparing diuretics or angiotensin II receptor blockers—particularly in patients with renal impairment. Before initiating therapy with eplerenone, monitor baseline potassium, and then review at 1 week, 1 month, and thereafter every 3 months, or if adjusting the dose or there are changes in renal function.

Spironolactone blocks sodium reabsorption, by antagonism of aldosterone. Low-dose spironolactone (25 mg daily) in combination with a loop diuretic and an angiotensin converting enzyme (ACE) inhibitor has been shown to improve prognosis in patients with severe heart failure.

Spironolactone is also a relatively weak antiandrogen and is used to treat visible manifestations of androgenisation in women (eg acne, androgenetic alopecia and hirsutism). It acts by competitive binding and blockade of the androgen receptor. It may be used for treatment of hirsute women in whom blood testosterone levels are low.

Hyperkalaemia may occur if spironolactone is used in combination with potassium supplements, ACE inhibitors, potassium-sparing diuretics or angiotensin II receptor blockers—particularly in patients with renal impairment. Before initiating therapy with spironolactone, monitor baseline potassium, and then review at 1 week, 1 month, and thereafter every 3 months, or if adjusting the dose or there are changes in renal function.

The active metabolite of spironolactone is an antagonist of aldosterone and of androgens. The latter property leads to gynaecomastia in men and intermenstrual or postmenopausal bleeding in women. Spironolactone is often used with a combined oral contraceptive in women to improve its antiandrogenic effectiveness and to avoid the relatively common adverse effect of irregular menstruation. Other adverse effects associated with spironolactone include tender and enlarged breasts, polyuria (with initial therapy), postural hypotension and loss of sodium.

Antiandrogens are teratogenic and have the potential to feminise male fetuses. They should be avoided in pregnancy; contraception is imperative in women of child-bearing potential who are using antiandrogens.

Amiloride and triamterene block sodium reabsorption at the distal renal tubule, and are sometimes used in combination with loop or thiazide diuretics to reduce the potassium loss that accompanies sodium reabsorption in that part of the nephron.

Hyperkalaemia may occur if potassium-sparing diuretics are used in combination with potassium supplements, ACE inhibitors, aldosterone antagonists or angiotensin II receptor blockers—particularly in patients with renal impairment.

The main action of thiazides (hydrochlorothiazide) and related diuretics (chlorthalidone, indapamide) is to inhibit the reabsorption of sodium and chloride in the proximal (diluting) segment of the distal tubule. These drugs do not have significant natriuretic activity when used in low doses for the treatment of hypertension. They lower blood pressure by a vasodilator effect, which appears to result from activation of calcium-dependent potassium channels in blood vessels and probably in the heart. In renal impairment they are less effective as diuretics but may still lower blood pressure. Duration of action and equivalent dose varies widely, but as single agents they are equivalent in most aspects. Although they are effective diuretics in mild heart failure, their main clinical application is in hypertension.

Adverse effects include hypokalaemia, hyponatraemia, and elevated plasma glucose, urate and calcium. However, with the low doses currently recommended, metabolic adverse effects are minimised. Higher doses are associated with increased risk of metabolic disturbances without additional antihypertensive effect. Hypersensitivity and photosensitivity may occur. Thiazide diuretics are chemically related to sulfonamides, and should not be used in patients who have had a serious allergic reaction to sulfonamides. Although indapamide has a sulfur molecule in its structure it is not a sulfonamide. It has, however, also been associated with skin rashes.

Loop diuretics (frusemide, bumetanide and ethacrynic acid) inhibit chloride-coupled sodium/potassium absorption in the ascending limb of the loop of Henle. This process accounts for retention of up to 20% of filtered sodium. Loop diuretics retain activity in renal impairment when given in higher than usual dose. All presently available loop diuretics have a short duration of action. They promote excretion of potassium and calcium as well as sodium.

Hypovolaemia and prerenal uraemia result from excessive doses of loop diuretics. Hypokalaemia is frequent, and hyponatraemia is a serious potential complication. Other adverse effects include metabolic alkalosis, hyperuricaemia, hyperglycaemia, rashes, cytopenias, other presumed hypersensitivity reactions, and tinnitus, vertigo and deafness (particularly with rapid intravenous administration). Ethacrynic acid can be used in patients allergic to frusemide and bumetanide, but it has a greater risk of ototoxicity and other adverse effects.