Comprehensive Overview of Diuretics and Antidiuretics

Comprehensive Overview of Diuretics and Antidiuretics

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  Mr. SATENDRA PRADHAN AssistantProfessor Department of Pharmacology COP, SVITS, Bilaspur Mr. SATENDRA PRADHAN Assistant Professor Department of Pharmacology COP, SVITS, Bilaspur
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  INTRODUCTION DIURETICS Diuretics are drugsthat increase the excretion of sodium (Na⁺), chloride (Cl⁻), and water by the kidneys, thereby increasing urine output (diuresis). They are mainly used to treat hypertension, edema, heart failure, kidney disorders, and some electrolyte-related conditions. 01 Also called Natriuretics Primary action is ↑ Na⁺ excretion (natriuresis); water follows passively along the osmotic gradient. 02 General Mechanism Each class blocks a specific Na⁺ transporter/channel at a distinct tubular site → ↓ Na⁺ reabsorption → water retained in the lumen → ↑ urine volume. 03 Site Determines Behaviour The nephron segment targeted (PCT, loop of Henle, DCT, or collecting duct) determines a drug's potency and its typical electrolyte side-effects. 04 Broad Clinical Utility Used for edema (cardiac, hepatic, renal), hypertension, hypercalcemia, raised ICP/IOP, and forced diuresis in poisoning.
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  INTRODUCTION Renal Physiology The nephronfilters ~180 L of plasma daily; over 99% of filtrate is reabsorbed. Diuretics act at specific tubular segments to block Na⁺ (and water) reabsorption. Proximal Convoluted Tubule ~65% Na⁺ reabsorbed Loop of Henle (Thick Asc. Limb) ~25% Na⁺ reabsorbed Distal Convoluted Tubule ~5% Na⁺ reabsorbed Collecting Duct ~2-3% Na⁺; ADH acts here Drug classes act at matching segments ↓ CA Inhibitors Loop Diuretics Thiazides · K⁺-Sparing VasopressinAnalogues KEY IDEA ✦More Na⁺ reabsorption blocked upstream → generally greater diuretic potency (loop > thiazide > K⁺-sparing/CAI).
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  DIURETICS Classification of Diuretics
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  DIURETICS Classification of Diuretics CarbonicAnhydrase Inhibitors Acetazolamide Loop Diuretics Furosemide, Bumetanide, Torsemide Thiazide Diuretics Hydrochlorothiazide, Chlorthalidone, Indapamide K⁺-Sparing — Aldosterone Antagonists Spironolactone, Eplerenone K⁺-Sparing — ENaC Blockers Amiloride, Triamterene Osmotic Diuretics Mannitol
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  DIURETICS Site of ActionAlong the Nephron PCT CA Inhibitors Acetazolamide Thick Ascending Limb Loop Diuretics Furosemide Early DCT Thiazides Hydrochlorothiazide Late DCT / Collecting Duct K⁺-Sparing Spironolactone, Amiloride Mannitol (osmotic) acts throughout the tubule wherever it is freely filtered but not reabsorbed — PCT, descending limb & collecting duct CLINICAL RULE OF THUMB ✦Proximal blockade (loop diuretics) = most Na⁺ escapes downstream reabsorption → most potent diuresis. ✦Distal blockade (thiazides, K⁺-sparing) = downstream segments have limited reabsorptive reserve → milder, ceiling effect. ✦Site of action also predicts electrolyte side-effects: loop & thiazide → hypokalemia; K⁺-sparing → hyperkalemia.
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  CLASS 1 Carbonic AnhydraseInhibitors Carbonic anhydrase inhibitors are diuretics that inhibit the enzyme carbonic anhydrase in the proximal convoluted tubule (PCT), reducing the reabsorption of sodium and bicarbonate and increasing the excretion of bicarbonate, sodium, potassium, and water. Weakest diuretic class — self-limiting due to metabolic acidosis PROTOTYPE DRUG ✦Acetazolamide (oral / IV) ✦Dorzolamide, Brinzolamide — topical, used only in glaucoma ✦Site of action: Proximal Convoluted Tubule (PCT) ✦Sulfonamide derivative — caution in sulfa allergy FEATURES ✦Only ~2-3% of filtered Na⁺ escapes reabsorption — mild diuresis ✦Produces alkaline, bicarbonate-rich urine ✦Effect wanes after a few days as metabolic acidosis develops ✦Non-diuretic uses exploit carbonic anhydrase inhibition elsewhere (eye, CNS, altitude)
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  CLASS 1 ·MECHANISM Carbonic Anhydrase Inhibitors — MOA Acetazolamide inhibits carbonic anhydrase in PCT cells & luminal brush border ↓ Conversion of CO₂ + H₂O ⇌ H₂CO₃ → H⁺ + HCO₃⁻ ↓ H⁺ available for the luminal Na⁺/H⁺ antiporter (NHE3) ↓ Na⁺ reabsorption and ↓ HCO₃⁻ reabsorption into blood Na⁺, HCO₃⁻, K⁺ and water remain in the tubular lumen Mild Diuresis with alkaline, bicarbonate-rich urine QUICK NOTES ✦Net effect: natriuresis + bicarbonaturia, NOT chloriuresis ✦Chronic use → self-limiting hyperchloremic metabolic acidosis ✦Same enzyme inhibition in the eye ↓ aqueous humor formation ✦Same mechanism in choroid plexus ↓ CSF formation (altitude sickness)
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  CLASS 1 ·CLINICAL Carbonic Anhydrase Inhibitors Drugs: Acetazolamide, Dorzolamide, Brinzolamide CLINICAL USES ✦Open-angle & acute angle-closure glaucoma (↓ aqueous humor) ✦Prophylaxis & treatment of acute mountain sickness ✦Correction of metabolic alkalosis ✦Urinary alkalinization — cystine & uric acid stones ✦Adjunct in epilepsy (absence seizures) ✦Idiopathic intracranial hypertension SIDE EFFECTS ✦Hyperchloremic metabolic acidosis ✦Hypokalemia ✦Drowsiness, paresthesia, fatigue ✦Renal calcium-phosphate stone formation ✦Sulfonamide hypersensitivity reactions ✦Contraindicated in hepatic cirrhosis (↑ ammonia → encephalopathy)
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  CLASS 2 Loop Diuretics Loopdiuretics are high-potency diuretics that act on the thick ascending limb of the loop of Henle by inhibiting the Na⁺–K⁺–2Cl⁻ (NKCC2) cotransporter, causing marked excretion of sodium, chloride, potassium, calcium, magnesium, and water. The most potent class — “High-Ceiling” Diuretics PROTOTYPE DRUGS ✦Furosemide, Bumetanide, Torsemide (sulfonamide-derived) ✦Ethacrynic acid — non-sulfonamide, used if sulfa-allergic ✦Site of action: Thick Ascending Limb of Loop of Henle ✦Given orally or IV; rapid onset FEATURES ✦Block ~25% of filtered Na⁺ reabsorption — no ceiling to dose-response until max effect ✦Abolish the medullary concentration gradient ✦Increase Ca²⁺ and Mg²⁺ excretion (opposite of thiazides) ✦Short half-life — usually dosed multiple times daily
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  CLASS 2 ·MECHANISM Loop Diuretics — MOA Furosemide secreted into PCT lumen via organic anion transporters, carried to thick ascending limb Binds & inhibits the Na⁺-K⁺-2Cl⁻ (NKCC2) cotransporter on the luminal membrane ↓ Reabsorption of Na⁺, K⁺ and 2Cl⁻ Loss of lumen-positive potential → ↓ paracellular Ca²⁺ & Mg²⁺ reabsorption ↓ Medullary interstitial hypertonicity → impaired urinary concentration Marked excretion of Na⁺, K⁺, Cl⁻, Ca²⁺, Mg²⁺ & water — Powerful Diuresis QUICK NOTES ✦“High-ceiling” = diuresis increases with dose, unlike thiazides ✦Also causes venodilation (↓ preload) — fast relief in pulmonary edema, even before diuresis begins ✦Ototoxic — risk rises with high IV doses or concurrent aminoglycosides ✦Effective even in reduced GFR (unlike thiazides)
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  CLASS 2 ·CLINICAL Loop Diuretics Drugs: Furosemide, Bumetanide, Torsemide, Ethacrynic acid CLINICAL USES ✦Acute pulmonary edema (rapid preload reduction) ✦Congestive heart failure ✦Chronic edema — hepatic, renal, cardiac origin ✦Hypertension with renal impairment ✦Hypercalcemia (with saline infusion) ✦Hyperkalemia & acute renal failure — to maintain urine flow SIDE EFFECTS ✦Hypokalemia & hypomagnesemia ✦Hypocalcemia ✦Metabolic (hypochloremic) alkalosis ✦Ototoxicity (dose-related, reversible) ✦Hyperuricemia — may precipitate gout ✦Dehydration, hypotension; sulfonamide hypersensitivity
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  CLASS 3 Thiazide &Thiazide-like Diuretics Thiazide diuretics are moderately potent diuretics that act on the distal convoluted tubule by blocking the sodium– chloride (Na⁺–Cl⁻) cotransporter, increasing sodium and water excretion while enhancing calcium reabsorption. Moderate potency — first-line agents for hypertension PROTOTYPE DRUGS ✦Hydrochlorothiazide (HCTZ), Chlorothiazide ✦Thiazide-like: Chlorthalidone, Indapamide, Metolazone ✦Site of action: Early Distal Convoluted Tubule (DCT) ✦Oral only; long duration of action KEY FEATURES ✦Block only ~5% of filtered Na⁺ — moderate, “flat” dose- response (ceiling effect) ✦Increase Ca²⁺ reabsorption (opposite of loop diuretics) ✦Lose efficacy when GFR falls below ~30 mL/min (except metolazone) ✦Widely combined with other antihypertensives
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  CLASS 3 ·MECHANISM Thiazide Diuretics — MOA Thiazide reaches the early Distal Convoluted Tubule (DCT) via organic anion secretion in PCT Binds & inhibits the Na⁺-Cl⁻ symporter (NCC) on the luminal membrane ↓ Na⁺ and Cl⁻ reabsorption at the DCT Mild volume contraction → compensatory ↑ proximal Na⁺ & Ca²⁺ reabsorption via Na⁺/Ca²⁺ exchanger Increased Na⁺, Cl⁻ and water excretion; Ca²⁺ excretion decreases — Moderate Diuresis QUICK NOTES ✦Mnemonic: “thiazide = calcium sparing”, “loop = calcium losing” ✦Also directly vasodilates — contributes to antihypertensive effect beyond diuresis ✦Metolazone remains effective even with poor renal function — often combined with loop diuretics for synergy ✦Slow onset, long duration — suited to chronic BP control
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  CLASS 3 ·CLINICAL Thiazide Diuretics Drugs: Hydrochlorothiazide, Chlorthalidone, Indapamide, Metolazone CLINICAL USES ✦Mild-to-moderate essential hypertension (first-line) ✦Chronic heart failure (mild, adjunct) ✦Nephrolithiasis — idiopathic hypercalciuria ✦Nephrogenic diabetes insipidus (paradoxical antidiuretic effect) ✦Adjunct in osteoporosis (↓ urinary Ca²⁺ loss) SIDE EFFECTS ✦Hypokalemia & hyponatremia ✦Hyperglycemia (impairs insulin release) ✦Hyperuricemia — may precipitate gout ✦Hyperlipidemia (mild, dose-related) ✦Hypercalcemia ✦Photosensitivity; erectile dysfunction
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  CLASS 4 Potassium-Sparing Diuretics Potassium-sparingdiuretics are diuretics that act on the late distal tubule and collecting duct to increase sodium and water excretion while conserving potassium by either blocking aldosterone receptors or inhibiting epithelial sodium (ENaC) channels. Weakest natriuretic effect — valued for conserving K⁺ Two distinct sub-mechanisms converge on the same principal cell target 4a. Aldosterone Antagonists Spironolactone, Eplerenone Competitively block the mineralocorticoid receptor — indirect action 4b. ENaC Blockers Amiloride, Triamterene Directly plug the epithelial Na⁺ channel — aldosterone- independent SHARED SITE & EFFECT ✦Both act on principal cells of the late DCT / collecting duct — the site aldosterone normally acts ✦Both ↓ Na⁺ reabsorption while ↓ K⁺ and H⁺ secretion → mild diuresis with potassium conservation ✦Main risk with both: hyperkalemia, especially combined with ACE inhibitors, ARBs or renal impairment
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  CLASS 4A ·MECHANISM Aldosterone Antagonists — MOA Spironolactone / Eplerenone diffuse into principal cells of the collecting duct Competitively block the cytoplasmic mineralocorticoid receptor Prevent aldosterone from inducing its target gene products ↓ Synthesis of ENaC channels & Na⁺/K⁺-ATPase pumps ↓ Na⁺ reabsorption; ↓ K⁺ and H⁺ secretion into lumen Mild Natriuresis with potassium & acid retention QUICK NOTES ✦Onset is slow (2-3 days) — needs new protein synthesis to be blocked ✦Spironolactone also blocks androgen & progesterone receptors → endocrine side effects ✦Eplerenone is more receptor-selective — fewer hormonal effects ✦Proven mortality benefit in heart failure (independent of diuresis)
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  CLASS 4A ·CLINICAL Aldosterone Antagonists Drugs: Spironolactone, Eplerenone CLINICAL USES ✦Primary hyperaldosteronism (Conn syndrome) ✦Resistant hypertension (add-on therapy) ✦Heart failure with reduced ejection fraction (mortality benefit) ✦Hepatic cirrhosis with ascites ✦Female hirsutism (spironolactone — antiandrogenic) SIDE EFFECTS ✦Hyperkalemia (danger with ACEI/ARB or renal impairment) ✦Gynecomastia & menstrual irregularities (spironolactone) ✦GI upset, peptic ulceration ✦Eplerenone: fewer endocrine effects but similar K⁺ risk
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  CLASS 4B ·MECHANISM ENaC Blockers — MOA Amiloride / Triamterene enter principal cells of the late DCT & collecting duct Directly block epithelial Na⁺ channels (ENaC) on the luminal membrane ↓ Na⁺ entry into the cell — independent of aldosterone Lumen becomes less electronegative → ↓ driving force for K⁺ & H⁺ secretion Na⁺ excreted in urine while K⁺ is conserved — Mild Diuresis QUICK NOTES ✦Action is direct & rapid — unlike aldosterone antagonists, no gene transcription required ✦Effective even when aldosterone is absent or receptor-blocked ✦Amiloride blocks the same channel lithium uses to enter principal cells — useful in lithium-induced nephrogenic DI ✦Often combined with thiazide/loop diuretics to offset K⁺ loss
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  CLASS 4B ·CLINICAL ENaC Blockers Drugs: Amiloride, Triamterene CLINICAL USES ✦Combined with K⁺-wasting diuretics (thiazide/loop) to prevent hypokalemia ✦Liddle syndrome (amiloride — blocks constitutively active ENaC) ✦Lithium-induced nephrogenic diabetes insipidus (amiloride) ✦Ascites of hepatic cirrhosis (adjunct) SIDE EFFECTS ✦Hyperkalemia (especially with renal impairment, ACEI/ARB) ✦Nausea, vomiting, leg cramps ✦Triamterene: renal stone formation, crystalluria, acute kidney injury (esp. with NSAIDs)
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  CLASS 5 ·MECHANISM Osmotic Diuretics Osmotic diuretics are agents that increase the osmotic pressure of the glomerular filtrate, preventing water reabsorption in the renal tubules and thereby increasing urine output. Prototype: Mannitol (IV infusion) Site of action: throughout the tubule (PCT, descending limb, collecting duct) Mannitol infused IV — freely filtered at the glomerulus Poorly reabsorbed by the tubular epithelium — remains in the lumen Raises the osmolarity of tubular fluid along the nephron Osmotically retains water in the lumen, limiting passive water & Na⁺ reabsorption ↑ Urine volume; pulls water from tissues into plasma — ↓ Intracranial & Intraocular Pressure QUICK NOTES ✦Does not act on a specific transporter — purely a physical osmotic effect ✦Expands plasma volume transiently before diuresis begins ✦Contraindicated in anuria and congestive heart failure (volume overload risk) ✦Also used to promote excretion of toxins in overdose (“forced diuresis”)
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  CLASS 5 ·CLINICAL Osmotic Diuretics Drugs: Mannitol CLINICAL USES ✦↓ Raised intracranial pressure (cerebral edema) ✦↓ Raised intraocular pressure (acute angle-closure glaucoma, pre-op) ✦Maintain urine flow — prevent oliguric acute renal failure ✦Promote excretion of toxins in poisoning / overdose SIDE EFFECTS ✦Transient plasma volume expansion → pulmonary edema risk in CHF ✦Dilutional hyponatremia, followed by dehydration ✦Headache, nausea, vomiting ✦Contraindicated in anuria and congestive heart failure
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  DIURETICS Comparison at aGlance Class Site Mechanism Potency Effect on K⁺ Example Carbonic Anhydrase Inhibitor PCT ↓ Carbonic anhydrase Mild ↓ (loss) Acetazolamide Loop Thick asc. limb Blocks NKCC2 Very High ↓ (loss) Furosemide Thiazide Early DCT Blocks NCC Moderate ↓ (loss) Hydrochlorothiazide Aldosterone Antag. Late DCT / CD MR blockade Mild ↑ (spare) Spironolactone ENaC Blocker Late DCT / CD Blocks ENaC Mild ↑ (spare) Amiloride Osmotic PCT → CD (all) Osmotic effect Variable Minimal Mannitol
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  INTRODUCTION ANTIDIURETICS 01 Goal: ConserveBody Water Used mainly to treat polyuric states (diabetes insipidus) where excessive dilute urine is lost. 02 Not All Act on ADH Directly Some are true ADH analogues; others (thiazides, NSAIDs, amiloride) work by indirect, paradoxical mechanisms. 03 Site of Action: Collecting Duct Nearly all classes converge on the principal cells of the collecting duct — the site where water permeability is regulated. 04 Choice Depends on DI Type Central DI responds to ADH analogues; nephrogenic DI needs indirect agents since the kidney is ADH-resistant. Antidiuretics are agents that reduce the rate of urine formation, chiefly by enhancing water reabsorption in the renal collecting duct — either by mimicking ADH, potentiating its action, or indirectly limiting fluid delivery to the diluting segments.
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  INTRODUCTION ADH (Vasopressin) —Normal Physiology ADH is synthesized in the hypothalamus, stored in the posterior pituitary, and released in response to ↑ plasma osmolarity or ↓ blood volume/pressure. ↑ Plasma osmolarity or ↓ blood volume stimulates hypothalamic osmoreceptors & baroreceptors ADH (vasopressin) released from the posterior pituitary into circulation ADH binds V2 receptors on the basolateral membrane of collecting duct principal cells Gs protein activates adenylate cyclase → ↑ cAMP → PKA activation Aquaporin-2 (AQP2) channels inserted into the luminal membrane ↑ Water reabsorption → Concentrated urine, Restored Plasma Osmolarity KEY POINT ✦This V2 → cAMP → AQP2 pathway is the exact target that Desmopressin mimics pharmacologically ✦ADH also acts on V1 receptors on vascular smooth muscle → vasoconstriction (a separate, non-renal effect) ✦Failure anywhere in this pathway (secretion or receptor response) causes diabetes insipidus
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  ANTIDIURETICS Classification of Antidiuretics VasopressinAnalogues(V2-selective) Desmopressin (DDAVP) Vasopressin / Terlipressin (V1- mediated) Vasopressin, Terlipressin Thiazide Diuretics Hydrochlorothiazide, Chlorthalidone Potassium-Sparing Diuretic Amiloride Prostaglandin Synthesis Inhibitors (NSAIDs) Indomethacin ADH-Sensitizing Agents (historical) Chlorpropamide, Carbamazepine
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  CLASS 1 Vasopressin Analogues(V2-Selective) First-line therapy for central diabetes insipidus PROTOTYPE DRUG ✦Desmopressin (DDAVP) — synthetic analogue of ADH ✦Available as intranasal spray, oral tablet, sublingual & IV/SC injection ✦Site of action: V2 receptors, collecting duct principal cells ✦Structural modification gives it high V2 selectivity & a longer half-life than natural ADH KEY FEATURES ✦Minimal V1 (vasoconstrictor) activity — far fewer pressor effects than natural vasopressin ✦Duration of action 8-20 hours depending on route — allows once/twice-daily dosing ✦Also used for its non-renal V2 effect: releasing stored vWF & factor VIII from endothelium ✦Dose must be individualized — overtreatment risks water intoxication
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  CLASS 1 ·MECHANISM Vasopressin Analogues — MOA Desmopressin binds V2 receptors on the basolateral membrane of collecting duct principal cells Activates Gs protein → stimulates adenylate cyclase ↑ Intracellular cAMP → activates Protein Kinase A (PKA) Aquaporin-2 (AQP2) vesicles translocate & fuse with the luminal membrane ↑ Water permeability → water reabsorbed along the osmotic gradient Concentrated urine & ↓ urine volume — Antidiuretic Effect QUICK NOTES ✦Desmopressin is V2-selective — essentially no V1 vasoconstrictor effect at therapeutic doses ✦Same V2/cAMP pathway on vascular endothelium also triggers release of von Willebrand factor & factor VIII ✦Requires functioning V2 receptors & AQP2 — will NOT work in nephrogenic DI ✦Fluid intake must be restricted with dosing to avoid dilutional hyponatremia
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  CLASS 1 ·CLINICAL Vasopressin Analogues Drugs: Desmopressin (DDAVP) CLINICAL USES ✦Central (neurogenic) diabetes insipidus — drug of choice ✦Nocturnal enuresis in children ✦Von Willebrand disease & mild Hemophilia A (releases stored vWF/factor VIII) ✦Correction of prolonged bleeding time in uremia / pre- operative bleeding disorders ✦Diagnostic water-deprivation / desmopressin stimulation test SIDE EFFECTS ✦Hyponatremia & water intoxication (can cause seizures if severe) ✦Headache, facial flushing ✦Abdominal cramps, nausea ✦Nasal congestion / local irritation (intranasal form) ✦Rare: allergic reactions at injection site
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  CLASS 2 ·MECHANISM Vasopressin / Terlipressin — MOA Prototype: Vasopressin (Pitressin), Terlipressin Non-selective — significant V1 activity alongside V2 Vasopressin/Terlipressin bind V1 receptors on vascular smooth muscle (splanchnic & systemic) Activates Gq protein → phospholipase C → ↑ IP₃ & DAG ↑ Intracellular Ca²⁺ → smooth muscle contraction Vasoconstriction — ↓ splanchnic/portal blood flow; ↑ systemic vascular resistance Weaker concurrent V2 activation on collecting duct gives a mild Antidiuretic Effect QUICK NOTES ✦Used mainly for its V1 vasoconstrictor effect — not primarily as a urine-concentrating agent ✦Terlipressin is a long-acting prodrug of vasopressin with more selective splanchnic action & fewer systemic pressor effects ✦Vasopressin itself can still be used for central DI when desmopressin is unavailable, but its V1 effects limit use
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  CLASS 2 ·CLINICAL Vasopressin / Terlipressin Drugs: Vasopressin (Pitressin), Terlipressin CLINICAL USES ✦Septic shock — vasopressor, catecholamine-sparing agent ✦Esophageal variceal bleeding & other GI hemorrhage (terlipressin preferred) ✦Hepatorenal syndrome (terlipressin) ✦Central diabetes insipidus (vasopressin, second-line to desmopressin) ✦Historical use: pulseless cardiac arrest (ACLS, no longer routinely recommended) SIDE EFFECTS ✦Vasoconstriction-related: angina, myocardial infarction ✦Mesenteric & peripheral ischemia — risk of digital/skin necrosis ✦Arrhythmias, hypertension ✦Hyponatremia & water intoxication (V2-mediated) ✦Local tissue injury on extravasation
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  CLASS 3 Thiazide Diuretics Aparadox: a diuretic used to treat polyuria PROTOTYPE DRUGS ✦Hydrochlorothiazide (HCTZ), Chlorthalidone ✦Normally classified as diuretics — site of action: early DCT (NCC transporter) ✦Mainstay treatment for nephrogenic diabetes insipidus ✦Often combined with amiloride for synergy & to offset K⁺ loss KEY FEATURES ✦Effect is independent of ADH — works even when the kidney cannot respond to ADH ✦Best combined with mild dietary Na⁺ restriction to potentiate the antidiuretic response ✦Reduces urine volume by roughly 30-50% in nephrogenic DI — partial, not complete, correction ✦Also useful as adjunct therapy in central DI alongside desmopressin
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  CLASS 3 ·MECHANISM Thiazide Diuretics — Paradoxical MOA Thiazide inhibits the Na⁺-Cl⁻ symporter (NCC) in the early DCT — its usual diuretic action Mild negative Na⁺ balance → slight extracellular volume contraction ↓ GFR & compensatory ↑ proximal tubule Na⁺ and water reabsorption Less tubular fluid is delivered to the distal diluting segments & collecting duct Reduced capacity to form dilute urine, regardless of ADH activity Net result: ↓ urine volume — A Paradoxical Antidiuretic Effect QUICK NOTES ✦The effect does NOT depend on ADH receptors or AQP2 — this is exactly why it works in nephrogenic DI ✦Mechanism hinges on proximal compensation, not on the distal NCC blockade itself ✦Low-salt diet enhances the effect by further contracting volume and boosting proximal reabsorption ✦Same mechanism explains why thiazides can worsen hyponatremia in other contexts
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  CLASS 3 ·CLINICAL Thiazide Diuretics Drugs: Hydrochlorothiazide, Chlorthalidone CLINICAL USES ✦Nephrogenic diabetes insipidus — mainstay therapy ✦Lithium-induced nephrogenic DI (combined with amiloride) ✦Adjunct in central DI to reduce free-water clearance ✦Idiopathic hypercalciuria with polyuria SIDE EFFECTS ✦Hypokalemia & hyponatremia ✦Hyperglycemia (impairs insulin release) ✦Hyperuricemia — may precipitate gout ✦Hypercalcemia ✦Photosensitivity; dizziness from volume contraction
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  CLASS 4 Potassium-Sparing Diuretic— Amiloride The specific antidote for lithium-induced nephrogenic DI PROTOTYPE DRUG ✦Amiloride — epithelial Na⁺ channel (ENaC) blocker ✦Normally classified as a potassium-sparing diuretic ✦Site of action: principal cells of the late DCT / collecting duct ✦Used specifically when lithium is the cause of nephrogenic DI KEY FEATURES ✦Lithium enters principal cells through ENaC and accumulates, impairing AQP2 responsiveness to ADH ✦Amiloride physically blocks the same channel lithium uses to enter the cell ✦Effect is preventive/protective rather than a direct pro-ADH action ✦Frequently combined with a thiazide for additive antidiuretic benefit
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  CLASS 4 ·MECHANISM Amiloride — MOA in Lithium-Induced NDI Chronic lithium therapy — lithium enters collecting duct principal cells through ENaC channels Intracellular lithium inhibits GSK-3β signalling & downregulates Aquaporin-2 expression Principal cells become progressively resistant to ADH → nephrogenic diabetes insipidus develops Amiloride blocks the luminal ENaC channel — the same route lithium uses to enter the cell Reduced intracellular lithium accumulation preserves AQP2 expression & ADH responsiveness Partial restoration of urine-concentrating ability — Reduced Urine Volume QUICK NOTES ✦Unlike thiazides, amiloride's benefit here is specific to lithium-induced NDI, not NDI in general ✦Also spares K⁺ — useful when combined with a K⁺-wasting thiazide ✦Does not reverse existing structural tubular damage from long-standing lithium use ✦Lithium levels & renal function should still be monitored regularly
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  CLASS 4 ·CLINICAL Potassium-Sparing Diuretic (Amiloride) Drugs: Amiloride CLINICAL USES ✦Lithium-induced nephrogenic diabetes insipidus — agent of choice ✦Combined with thiazides in other forms of nephrogenic DI ✦Offsets hypokalemia caused by concurrent thiazide/loop diuretic therapy ✦Adjunct in Liddle syndrome (unrelated indication, same drug) SIDE EFFECTS ✦Hyperkalemia — especially with renal impairment or ACEI/ARB co-therapy ✦Nausea, vomiting, leg cramps ✦Should be avoided in significant renal insufficiency ✦Requires periodic monitoring of serum K⁺ and lithium levels
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  CLASS 5 Prostaglandin SynthesisInhibitors (NSAIDs) An adjunct that works by removing a natural brake on ADH PROTOTYPE DRUG ✦Indomethacin — potent, non-selective COX inhibitor ✦Other NSAIDs (ibuprofen, aspirin) share the mechanism but are less potent antidiuretics ✦Site of action: renal cyclooxygenase (COX-1/COX-2) in the medulla & collecting duct ✦Always used as adjunct therapy, never alone KEY FEATURES ✦Most useful in nephrogenic DI, especially combined with a thiazide ± amiloride ✦Also reduces urine volume in partial central DI by potentiating residual ADH ✦Onset within hours; effect is dose-dependent and reversible on stopping the drug ✦Renal & GI toxicity limit long-term use — requires careful risk-benefit assessment
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  CLASS 5 ·MECHANISM NSAIDs (Indomethacin) — MOA Indomethacin inhibits cyclooxygenase (COX) enzyme in the renal medulla & collecting duct ↓ Synthesis of renal prostaglandins, chiefly PGE₂ PGE₂ normally antagonizes ADH by inhibiting adenylate cyclase in principal cells With PGE₂ synthesis reduced, this inhibitory brake on ADH signalling is removed Residual ADH action is potentiated → ↑ cAMP → ↑ AQP2 insertion ↑ Water reabsorption → Reduced Urine Volume QUICK NOTES ✦Effect requires SOME residual ADH activity or a partially responsive kidney — it potentiates, it doesn't replace ✦Works well as an add-on in nephrogenic DI even though the kidney is ADH-resistant, because prostaglandins act independently of receptor status ✦Also reduces renal blood flow & GFR — the same prostaglandin-dependent pathway explains its nephrotoxic potential
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  CLASS 5 ·CLINICAL Prostaglandin Synthesis Inhibitors Drugs: Indomethacin (prototype), Ibuprofen, Aspirin CLINICAL USES ✦Adjunct in nephrogenic diabetes insipidus (with thiazide ± amiloride) ✦Partial central diabetes insipidus — potentiates residual endogenous ADH ✦Reduces polyuria refractory to thiazide therapy alone ✦Used short-term given its toxicity profile SIDE EFFECTS ✦GI ulceration & bleeding ✦Nephrotoxicity — interstitial nephritis, papillary necrosis, acute kidney injury ✦Fluid retention & worsening hypertension ✦Increased cardiovascular risk with long-term use ✦Caution: can itself precipitate renal impairment, worsening the underlying problem
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  CLASS 6 ADH-Sensitizing Agents(Historical) Largely of historical interest — superseded by desmopressin PROTOTYPE DRUGS ✦Chlorpropamide — a first-generation sulfonylurea (also an oral hypoglycemic) ✦Carbamazepine — an anticonvulsant with an incidental antidiuretic effect ✦Clofibrate — a lipid-lowering agent, occasionally used similarly ✦None are true ADH analogues — they only work if some endogenous ADH remains KEY FEATURES ✦Only effective in partial (not complete) central DI ✦Chlorpropamide's antidiuretic effect was discovered incidentally in diabetic patients ✦Risk of significant hypoglycemia (chlorpropamide) limits practical use ✦Almost entirely replaced by desmopressin, which is safer and more predictable
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  CLASS 6 ·MECHANISM ADH-Sensitizing Agents — MOA Chlorpropamide/Carbamazepine act on collecting duct principal cells that still receive some endogenous ADH They sensitize the V2 receptor-adenylate cyclase coupling to circulating ADH A greater rise in cAMP is generated per unit of ADH present Enhanced PKA activation → increased Aquaporin-2 insertion into the luminal membrane Increased water permeability of the collecting duct for the same ADH level ↑ Urine Volume — but only if some residual ADH secretion exists QUICK NOTES ✦Useless in complete central DI (no ADH to potentiate) and in nephrogenic DI (receptor/AQP2 defect) ✦The exact molecular basis of chlorpropamide's receptor-sensitizing effect is incompletely understood ✦Chlorpropamide can itself cause SIADH-like water retention & dilutional hyponatremia as a side effect ✦Now largely of historical / academic interest only
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  CLASS 6 ·CLINICAL ADH-Sensitizing Agents Drugs: Chlorpropamide, Carbamazepine, Clofibrate CLINICAL USES ✦Partial central diabetes insipidus (historical alternative to desmopressin) ✦Occasionally used when desmopressin is unavailable or not tolerated ✦Chlorpropamide also treats type 2 diabetes mellitus (dual- purpose historically) SIDE EFFECTS ✦Hypoglycemia (chlorpropamide — sulfonylurea action) ✦Hyponatremia / SIADH-like water retention ✦Hepatotoxicity, blood dyscrasias (chlorpropamide) ✦Carbamazepine: sedation, ataxia, hepatic enzyme induction, blood dyscrasias ✦Largely replaced due to this unfavourable side-effect profile
• 44.
  SYNTHESIS All Antidiuretic Classesat a Glance Class Mechanism Best For Example VasopressinAnalogues Direct V2 agonism → cAMP → AQP2 Central DI (first-line) Desmopressin Vasopressin / Terlipressin V1 vasoconstriction (± weak V2) Shock, variceal bleed; central DI 2nd- line Terlipressin Thiazide Diuretics ↓ GFR → ↑ proximal reabsorption (paradox) Nephrogenic DI (mainstay) Hydrochlorothiazide K⁺-Sparing (Amiloride) Blocks ENaC — prevents lithium entry Lithium-induced nephrogenic DI Amiloride NSAIDs ↓ PGE₂ → potentiates residual ADH Adjunct in nephrogenic / partial central DI Indomethacin ADH-Sensitizing Agents Sensitizes V2–adenylate cyclase coupling Partial central DI (historical) Chlorpropamide
• 45.
  SYNTHESIS Diuretics vs Antidiuretics DIURETICSANTIDIURETICS ✦Goal: ↑ urine volume, ↓ body fluid & Na⁺ ✦Block Na⁺ / water reabsorption at various nephron sites ✦Used in edema, hypertension, heart failure, raised ICP/IOP ✦Risk: dehydration, electrolyte imbalance (hypo/hyperkalemia) ✦Goal: ↓ urine volume, conserve body water ✦Enhance water reabsorption via ADH (V2) / AQP2 pathway ✦Used in diabetes insipidus, enuresis, bleeding disorders (vWD) ✦Risk: water intoxication, hyponatremia