Drugs and the Kidney

• What are the three main mechanisms of renal drug excretion?

  1. Glomerular filtration
  2. Tubular secretion
  3. Tubular reabsorption
• Where does glomerular filtration occur, and what does it filter?

  • Occurs in the glomerulus of the nephron.
  • Filters small, unbound drug molecules from the plasma into the renal tubule.
  • Protein-bound drugs are NOT filtered due to their large size.
• What factors affect glomerular filtration of drugs?

  1. Molecular size – Only drugs <20 kDa are freely filtered.
  2. Protein binding – Bound drugs are not filtered.
  3. Glomerular filtration rate (GFR) – Higher GFR increases drug excretion.
• What is tubular secretion, and where does it occur?

  • Active transport of drugs from blood into the renal tubule.
  • Occurs mainly in the proximal tubule.
  • Involves anion and cation transporters to remove drugs efficiently.
• What are the key transporters involved in tubular secretion?

  1. Organic anion transporters (OATs) – Transport acidic drugs (e.g., penicillin, NSAIDs).
  2. Organic cation transporters (OCTs) – Transport basic drugs (e.g., morphine, metformin).
  3. P-glycoprotein (P-gp) – Pumps drugs like digoxin into urine.
• How does tubular secretion affect drug clearance?

  • Enhances drug excretion, especially for protein-bound drugs that escape filtration.
  • Can be saturated if transporter capacity is exceeded.
• What is tubular reabsorption, and where does it occur?

  • Passive or active movement of drugs back into the blood.
  • Occurs mainly in the proximal and distal tubules.
  • Lipophilic, non-ionised drugs are reabsorbed easily.
• How does urine pH influence drug reabsorption?

  • Acidic urine favours excretion of basic drugs (e.g., amphetamines).
  • Alkaline urine favours excretion of acidic drugs (e.g., aspirin).
  • Ionised drugs remain in urine and are not reabsorbed.
• What is the clinical relevance of urine pH manipulation in drug excretion?

  • Used in overdose management:
  • Alkalinisation of urine (e.g., with sodium bicarbonate) enhances excretion of acidic drugs like aspirin.
  • Acidification of urine (e.g., with ammonium chloride) enhances excretion of basic drugs.
• How does renal impairment affect drug excretion?

  • Decreased GFR → Reduced filtration of drugs.
  • Reduced transporter activity → Impaired secretion.
  • Prolonged drug half-life → Increased risk of toxicity.
• What are diuretics?

  • Drugs that increase urine output by promoting water and electrolyte excretion.
  • Work by inhibiting sodium (Na⁺) reabsorption at different sites in the nephron.
• What are the five main classes of diuretics?

  1. Loop diuretics (e.g., furosemide)
  2. Thiazide diuretics (e.g., hydrochlorothiazide)
  3. Potassium-sparing diuretics (e.g., spironolactone, amiloride)
  4. Carbonic anhydrase inhibitors (e.g., acetazolamide)
  5. Osmotic diuretics (e.g., mannitol)
• Where do loop diuretics act in the nephron?

  • Thick ascending limb of the loop of Henle
  • Inhibit the Na⁺/K⁺/2Cl⁻ symporter, preventing sodium reabsorption.
  • Results in loss of Na⁺, K⁺, Cl⁻, and water in urine.
  • Leads to strong diuresis (high ceiling diuretics).
  • Example: Frusemide
• What are the clinical uses of loop diuretics?

  • Acute pulmonary edema
  • Chronic heart failure
  • Hypertension (when thiazides are ineffective)
  • Hypercalcemia (increases Ca²⁺ excretion)
  • Renal failure (to maintain urine output)
• What are common side effects of loop diuretics?

  • Hypokalemia (low K⁺)
  • Metabolic alkalosis
  • Hypovolemia (excess fluid loss)
  • Ototoxicity (hearing loss, especially with aminoglycosides)
  • Hyperuricemia (can trigger gout)
• Where do thiazide diuretics act in the nephron?

  • Distal convoluted tubule (DCT)
  • Inhibit the Na⁺/Cl⁻ symporter, reducing sodium and chloride reabsorption.
  • Moderate diuresis (less potent than loop diuretics).
• What are the clinical uses of thiazide diuretics?

  • First-line treatment for hypertension
  • Chronic heart failure (mild cases)
  • Nephrogenic diabetes insipidus
  • Prevents recurrent kidney stones (reduces urinary Ca²⁺ excretion)
• What are common side effects of thiazide diuretics?

  • Hypokalemia (low K⁺)
  • Hyperglycemia (may impair insulin secretion)
  • Hypercalcemia (increased Ca²⁺ reabsorption)
  • Hyperuricemia (can worsen gout)
  • Hyponatremia (low Na⁺)
• Where do potassium-sparing diuretics act in the nephron?

  • Late distal tubule & collecting duct
  • Spironolactone & eplerenone: Aldosterone receptor antagonists → decrease Na⁺ reabsorption & K⁺ secretion.
  • Amiloride & triamterene: Block epithelial sodium channels (ENaC), preventing Na⁺ reabsorption.
• What are the clinical uses of potassium-sparing diuretics?

  • Spironolactone: Used for heart failure, liver cirrhosis (ascites), hyperaldosteronism.
  • Amiloride & triamterene: Used with thiazides to prevent hypokalaemia.
• What are the side effects of potassium-sparing diuretics?

  • Hyperkalemia (can cause arrhythmias)
  • Gynecomastia (spironolactone has anti-androgen effects)
  • Menstrual irregularities (spironolactone)
• Where do carbonic anhydrase inhibitors act in the nephron?

  • Proximal convoluted tubule
  • Inhibit carbonic anhydrase enzyme → reduce HCO₃⁻ (bicarbonate) reabsorption.
  • Results in mild diuresis and metabolic acidosis.
  • Example: Acetazolamide
• What are the clinical uses of carbonic anhydrase inhibitors?

  • Glaucoma (reduces aqueous humor production)
  • Altitude sickness (prevents respiratory alkalosis)
  • Epilepsy (reduces CNS excitability)
  • Urinary alkalinisation (to excrete acidic drugs like aspirin)
• What are the side effects of carbonic anhydrase inhibitors?

  • Metabolic acidosis (due to HCO₃⁻ loss)
  • Hypokalemia
  • Paresthesia (tingling sensation)
  • Renal stones (due to alkaline urine)
• Where do osmotic diuretics act in the nephron?

  • Entire nephron, especially proximal tubule & loop of Henle
  • Freely filtered but not reabsorbed → increase osmotic pressure in the filtrate → prevent water reabsorption.
  • Example: Mannitol
• What are the clinical uses of osmotic diuretics?

  • Raised intracranial pressure (ICP)
  • Acute glaucoma (reduces intraocular pressure)
  • Acute kidney injury (prevents tubular obstruction)
• What are the side effects of osmotic diuretics?

  • Dehydration
  • Electrolyte imbalances
  • Pulmonary edema (fluid shifts into vascular space)
• What are the main clinical uses of diuretics?

  • Hypertension (lowering blood pressure)
  • Oedema (associated with heart failure, liver cirrhosis, and kidney disease)
  • Hypercalcemia (specific diuretics promote calcium excretion)
  • Acute kidney injury (certain diuretics can maintain urine flow)
  • Glaucoma (reducing intraocular pressure)
• Why are loop and thiazide diuretics often combined with potassium-sparing diuretics?

  To prevent hypokalemia, which is a common side effect of loop and thiazide diuretics.
• Which diuretics are contraindicated in kidney failure?

  • Thiazides (ineffective in severe kidney failure)
  • Potassium-sparing diuretics (risk of severe hyperkalemia)
• Why must diuretics be used cautiously in elderly patients?

  Older adults are more prone to hypotension, dehydration, and electrolyte imbalances, increasing the risk of falls and acute kidney injury.