Diuretics Overview and Mechanisms

Diuretics

• Diuretics increase the excretion of sodium and water.
• They typically work by decreasing the reabsorption of electrolytes in the renal tubules.
• Aldosterone stimulates sodium reabsorption in the distal tubule and increases potassium and hydrogen secretion.
• Vasopressin (ADH) increases the number of water channels in the collecting ducts, causing water reabsorption.
• They are widely used, and often come with specific classifications based on their efficacy.

Introduction

• Aldosterone stimulates sodium reabsorption and potassium and hydrogen secretion in the distal tubule, also stimulates the synthesis of Na+/K+-ATPase and Na+ channel production in the basolateral and luminal membranes.
• Cell surface aldosterone receptors may mediate a faster increase in sodium channel permeability.
• Diuretics increase the sodium load in the distal tubules and, except in K+-sparing agents, increase potassium secretion and excretion.
• Vasopressin (ADH) increases the number of water channels in the collecting ducts, promoting water reabsorption.
• Cranial diabetes insipidus, the lack of ADH, results in large volumes of hypotonic urine, treated with vasopressin (or desmopressin).
• These drugs aim to decrease sodium and water reabsorption, consequently increasing excretion, maintaining osmotic balance.
• They are among the most commonly prescribed drugs globally.

Classification

High Efficacy Diuretics

• Inhibitors of Na+-K+-2Cl- cotransport.
• Sulphamoyl derivatives include Furosemide and Bumetanide.
• Phenoxyacetic acid derivative: Ethacrynic acid.
• Organomercurials: Mersalyl.

Medium Efficacy Diuretics

• Inhibitors of Na+-Cl- symport.
• Benzothiadiazines (Thiazides): Chlorothiazide, Hydrochlorothiazide, Bendroflumethiazide, Hydroflumethiazide, Clopamide.
• Thiazide-like compounds: Indapamide, Xipamide, Metolazone.

Weak or Adjunctive Diuretics

• Carbonic anhydrase inhibitors: Acetazolamide, Ethoxzolamide.
• Potassium-sparing diuretics:
• Aldosterone antagonists: Spironolactone.
• Directly acting inhibitors of renal epithelial Na+ channels: Triamterene, Amiloride.
• Xanthines: Theophylline.
• Osmotic diuretics: Mannitol, Isosorbide, Glycerol.
• Acidifying or alkalinizing salts: Ammonium chloride, Potassium citrate, Potassium acetate.

High Ceiling (Loop) Diuretics

• Natriuretic effects are greater than other classes.
• Diuretic response is dose dependent, up to 10 Liters per day.
• Effective in patients with severe renal failure.
• Major site of action is the thick ascending loop of Henle.
• Inhibits Na+-K+-2Cl- cotransport.
• Abolishes the cortico-medullary osmotic gradient and blocks water clearance. Increases potassium excretion.
• Transient increase in renal blood flow and redistribution from outer to mid-cortical zone. Absorbed rapidly orally, about 60% bioavailability. Low lipid solubility, highly bound to plasma proteins, and excreted unchanged in glomerular filtration and tubular secretion. Plasma half-life is about 1–2 hours but prolonged in hepatic or renal disease.

Uses of Loop Diuretics

• Edema (including pulmonary edema caused by acute left ventricular failure).
• Cerebral edema.
• Forced diuresis.
• High blood pressure.
• Blood transfusions.

Adverse Effects of Loop Diuretics

• Hyponatremia.
• Hypotension.
• Hypovolemia.
• Hypokalemia (potentially unimportant unless there are additional risk factors).
• Severe electrolyte imbalance and dehydration.
• Increased calcium and magnesium excretion.
• Hypomagnesemia may occur.
• Overuse, especially in high doses or intravenously, may cause irreversible deafness.

Thiazide and Related Diuretics

• Primary site of action is the cortical diluting segment or early distal tubule.
• Inhibits Na+-Cl- symporter at the luminal membrane.
• The diuretic action does not primarily affect the cortico-medullary osmotic gradient.
• Decreases positive free water clearance (in the absence of ADH), but does not affect negative free water balance (in the presence of ADH).
• Primarily target the distal segments of the tubules, inhibit sodium chloride reabsorption, thus increasing Na+, chloride, and water excretion.
• Increased sodium in the distal tubule stimulates the exchange of sodium with potassium and hydrogen, thus increasing their excretion leading to hypokalemia and metabolic acidosis.
• By reducing blood volume and intra-renal hemodynamic changes, effectiveness is reduced in low renal function (GFR).
• Well absorbed orally, can be administered via oral route, and exhibits onset of action within 1 hour. Their lipid solubility and lower rate of hepatic clearance lead to prolonged effects.

Uses

• Edema.
• Hypertension.
• Diabetes insipidus.
• Hypercalciuria.

Adverse Effects of Thiazide Diuretics

• Hypokalemia (can precipitate cardiac arrhythmias, especially in patients on digitalis).
• Hyperuricemia (serum uric acid often increases due to competition for secretion).
• Glucose intolerance.
• Lipids: Thiazides potentially increase serum cholesterol, at least for the first 6 months of medication administration.

Drug Interactions

• Thiazides potentiate the effect of other antihypertensives.
• Hypokalemia induced by diuretics enhances digitalis toxicity.
• High-ceiling diuretics enhance the nephrotoxicity of aminoglycosides and first-generation cephalosporins, and diminish the action of high-ceiling diuretics.

Potassium-Sparing Diuretics (KSDs)

• Weak when used alone; Given to retain potassium.

• Often used in combination with thiazides and loop diuretics to prevent hypokalemia.

• Act on aldosterone-responsive segments of the distal nephron.

• Aldosterone stimulates sodium reabsorption, producing a negative electrical charge, which drives potassium and hydrogen into the lumen for excretion.

• The KSDs decrease sodium reabsorption by blocking either aldosterone or sodium channels.

• This causes a reduction in the electrical charge across the tubular epithelium, reducing the driving force for potassium secretion.

• These drugs may cause severe hyperkalaemia, particularly if renal impairment is present. Hyperkalaemia may also occur in the presence of ACE inhibitors (e.g., captopril), because these drugs decrease aldosterone secretion.

• Competitively blocks aldosterone binding to its receptor leading to increase Na+ (Cl- and water) excretion.

• Used mainly in liver disease with ascites, Conn's syndrome (primary hyperaldosteronism), and severe heart failure. Sodium channel blockers (e.g., amiloride and triamterene) decrease luminal membrane sodium permeability in the distal nephron. This increases sodium (and water) excretion while decreasing potassium excretion.

Carbonic Anhydrase Inhibitors

• Carbonic anhydrase is an enzyme involved in the reversible reaction between water, carbon dioxide, and bicarbonate.
• Involved in CO2 and bicarbonate transport and hydrogen secretion.
• Found in renal tubular cells, gastric mucosa, exocrine pancreas, ciliary body of the eyes, and red blood cells.
• Acetazolamide, a sulfonamide derivative, non-competitively inhibits carbonic anhydrase.
• Net effect of the inhibition is decreased bicarbonate reabsorption in the proximal tubules.
• This inhibits hydration of CO2, thus slowing down hydrogen ion transport, leading to a milder diuresis.

Uses of Carbonic Anhydrase Inhibitors

• Acetazolamide is: No longer used as a diuretic (self-limiting action). Used to treat glaucoma, urinary alkalization, epilepsy, periodic paralysis, and acute mountain sickness.

Adverse Effects of Carbonic Anhydrase Inhibitors

• Acidosis.
• Hypokalemia.
• Drowsiness.
• Paraesthesia.
• Fatigue.
• Abdominal discomfort.
• Hypersensitivity reactions.

Contraindications of Carbonic Anhydrase Inhibitors

• Liver disease.

Osmotic Diuretics (Mannitol)

• Mannitol is a non-electrolyte of low molecular weight, pharmacologically inert.
• Can be given in large quantities.
• Not metabolised in the body.
• Limits tubular water and electrolyte reabsorption in various ways:
• Expanding extracellular fluid volume increases glomerular filtration rate (GFR) and inhibits renin release.
• Increasing renal blood flow reduces medullary hypertonicity, consequently decreasing passive salt reabsorption.
• Retains water iso-osmotically in proximal tubules.
• Inhibits transport process in the thick ascending loop of Henle.

Uses

• Maintaining GFR and urine flow in imminent renal failure.
• Forced diuresis.
• Intracranial pressure reduction.
• Intraocular tension reduction.
• Counteracting low plasma osmolality due to rapid haemodialysis or peritoneal dialysis.

Contraindications

• Acute tubular necrosis.
• Anuria.
• Pulmonary oedema.
• Acute LVF.

Side Effects (S/E)

• Headache.
• Nausea.
• Vomiting.

This quiz provides a comprehensive overview of diuretics, including their role in sodium and water excretion. It explores the mechanisms by which aldosterone and vasopressin affect renal function and the classification of different types of diuretics based on efficacy. Test your knowledge on the physiological impacts and clinical uses of these important medications.