Diuretics: Types and Mechanisms

• Diuretics are recommended as a first-line drug treatment option for hypertension.
• They cause direct arteriolar dilation, lead to a decrease in peripheral vascular resistance, and reduce extracellular fluid volume, plasma volume, and cardiac output which contributes to decreased blood pressure.
• In the nephron, water follows sodium. Water will not be absorbed and will be excreted as urine if sodium is not absorbed.
• Most potent to least potent diuretics: loop diuretics, mannitol (osmotic diuretic), metolazone (thiazide-like diuretic), thiazides, and potassium-sparing diuretics.
• Diuretics are classified according to their site of action, chemical structure, and potency.

Types of Diuretic Drugs

• Carbonic anhydrase inhibitors
• Loop diuretics
• Osmotic diuretics
• Potassium-sparing diuretics
• Thiazide and thiazide-like diuretics

Carbonic Anhydrase Inhibitors

• Acetazolamide (Acetazolam®) is the most commonly used carbonic anhydrase inhibitor. It is available in oral and parenteral forms.
• Benefits of use may outweigh potential fetal risks in pregnant women.
• Carbonic anhydrase inhibitors block carbonic anhydrase, preventing the exchange of H+ ions with sodium and water.
• Reduced H+ ion concentration in renal tubules, increases excretion of bicarbonate, sodium, water, and potassium; resorption of water is decreased, and urine volume is increased due to the inhibition of carbonic anhydrase.
• Used as adjunct drugs for long-term management of open-angle glaucoma and secondary glaucoma, edema secondary to heart failure, high-altitude sickness, and epilepsy.
• Contraindications: Known drug allergy, hyponatremia, hypokalemia, severe kidney or liver dysfunction, adrenal gland insufficiency, and cirrhosis.
• Adverse effects: Acidosis, hypokalemia, drowsiness, anorexia, paresthesias, hematuria, urticaria, photosensitivity, and melena.
• Interactions: Increased digoxin toxicity when combined with digoxin, hypokalemia with corticosteroids, and increased effects of amphetamines, carbamazepine, cyclosporine, phenytoin, and quinidine sulphate.

Loop Diuretics

• Examples: bumetanide, ethacrynic acid, and furosemide (Lasix®)
• Act on the ascending limb of the loop of Henle to block chloride and sodium resorption.
• Increase kidney prostaglandins, resulting in the dilation of blood vessels and reduced kidney, pulmonary, and systemic vascular resistance.
• Rapid onset and last at least 2 hours.
• Potent diuresis and subsequent loss of fluid which causes a reduction in blood pressure, pulmonary vascular resistance, systemic vascular resistance, central venous pressure, and left ventricular end-diastolic pressure.
• Can lead to potassium and sodium depletion and small calcium loss.
• Used for edema associated with heart failure and liver or kidney disease, hypertension control, increasing kidney excretion of calcium in patients with hypercalcemia and heart failure resulting from diastolic dysfunction.
• Adverse effects: dizziness, headache, tinnitus, blurred vision, nausea, vomiting, diarrhea, agranulocytosis, neutropenia, thrombocytopenia, hypokalemia, hyperglycemia, and hyperuricemia.
• Interactions: neurotoxic effects, nephrotoxic effects, increase serum levels of uric acid, glucose, alanine aminotransferase, and aspartate aminotransferase; thiazides (metolazone) cause sequential nephron blockade; NSAIDs may decrease the reduction of vascular resistance.
• Furosemide (Lasix): Most commonly used loop diuretic for pulmonary edema, edema associated with heart failure, liver disease, nephrotic syndrome, ascites, and hypertension.

Osmotic Diuretics

• Examples: mannitol (Osmitrol®), urea, organic acids, and glucose.
• Work along the entire nephron, mostly in the proximal tubule and descending loop of Henle.
• Nonabsorbable substances which produce an osmotic effect.
• Pull water into the renal tubules from the surrounding tissues.
• Inhibit tubular resorption of water and solutes, thus producing rapid diuresis.
• Increase glomerular filtration rate and renal plasma flow; help to prevent kidney damage during acute kidney injury, reduce intracranial pressure or cerebral edema associated with head trauma and excessive intraocular pressure.
• Used for treatment of patients in the early, oliguric phase of acute kidney injury, to promote excretion of toxic substances, to reduce intracranial pressure and cerebral edema and as a genitourinary irrigant in the preparation of patients for transurethral surgical procedures.
• Adverse effects: convulsions, thrombophlebitis, pulmonary congestion, headaches, chest pains, tachycardia, blurred vision, chills, and fever.
• Mannitol (Osmitrol): administered as intravenous (IV) infusion only. It may crystallize when exposed to low temperatures and requires the use of a filter.

Potassium-Sparing Diuretics

• Also known as aldosterone-inhibiting diuretics.
• Examples: amiloride (Midamor®), spironolactone (Aldactone®), and triamterene (often combined with hydrochlorothiazide).
• Work in the collecting ducts and distal convoluted tubules
• Interfere with sodium–potassium exchange and competitively bind to aldosterone receptors, block resorption of sodium and water usually induced by aldosterone secretion.
• Relatively weak compared with the thiazide and loop diuretics.
• Promote the excretion of sodium and water.
• Spironolactone and triamterene: Used for hyperaldosteronism, hypertension, reversing potassium loss caused by potassium-wasting diuretics, and certain cases of heart failure.
• Amiloride: Similar to spironolactone and triamterene but less effective in the long term.
• Adverse effects: dizziness, headache, cramps, nausea, vomiting, diarrhea, urinary frequency, weakness, and hyperkalemia.
• Spironolactone (Aldactone): Gynecomastia, amenorrhea, irregular menses, and postmenopausal bleeding.
• Interactions: Lithium, angiotensin-converting enzyme inhibitors, potassium supplements, and NSAIDs.

Thiazide and Thiazide-Like Diuretics

• Thiazide diuretics: hydrochlorothiazide (Urozide®)
• Thiazide-like diuretics: metolazone (Zaroxolyn®), chlorthalidone, and indapamide.
• Inhibit tubular resorption of sodium, chloride, and potassium ions in the distal convoluted tubule, resulting in osmotic water loss.
• Dilate the arterioles by direct relaxation.
• Decrease preload and afterload.
• Thiazides should not be used if creatinine clearance is less than 30 to 50 mL/min (normal is 125 mL/min), but metolazone remains effective to a creatinine clearance of 10 mL/min.
• Used for hypertension (most commonly prescribed), edematous states, idiopathic hypercalciuria, diabetes insipidus, and heart failure caused by diastolic dysfunction.
• Adverse effects: dizziness, headache, blurred vision, anorexia, nausea, vomiting, diarrhea, erectile dysfunction, jaundice, leukopenia, agranulocytosis, urticaria, photosensitivity, hypokalemia, glycosuria, hyperglycemia, hyperuricemia, and hypochloremic alkalosis.