DIURETICS  Drugs that increase the renal excretion of solutes and water.

 Drugs that increase the excretion of sodium and water from the body by an action on the kidneys.

DOA: 3-5 hours. t1/2: 90 minutes.  Plasma CHON binding:Strong. MOA: Inhibits the NA/K/Cl transport system in the luminal membrane of the thick ascending limb of the loop of Henle.

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CLASSIFICATION Drugs acting directly on the nephron  Loop diuretics  Thiazide diuretics  Potassium-sparing diuretics  Drugs acting indirectly by modifying the content of the filtrate  Osmotic diuretics  Carbonic anhydrase inhibitors THERAPEUTIC INDICATIONS   Edematous states  Congestive heart failure  Hepatic cirrhosis  Renal disease  Idiopathic edema Non-edematous states  HPN  Nephrolithiasis  Hypercalcemia  Diabetes insipidus

LOOP OR HIGH-CEILING DIURETICS  ADR  Hypokalemic metabolic alkalosis  Ototoxicity  Hyperuricemia  Hypomagnesemia, hypocalcemia  Allergic reactions, nausea, deafness  Hypovolemia, hypotension CLINICAL USES  Acute pulmonary edema and other edematous conditions  Acute hypercalcemia, hyperkalemia  Acute renal failure  Anion overdose: Bromide, fluoride, and iodide

THIAZIDE DIURETICS  Short-acting (up to 12 hours)  Chlorothiazide, hydrochlorothiazide

LOOP OR HIGH-CEILING DIURETICS Anthranilic derivatives with sulfonamide substituent (furosemide, bumetanide) or aryloxyacetic acid without a sulfonamide component (ethacrynic acid).  AGENTS: Ethacrynic acid, furosemide, bumetanide, muzolimine, piretanide, torsemide.  PHARMACOKINETICS  Administered by: Oral or parenteral route.  Peak effect: 30-60 minutes. 

Intermediate-acting (12-24 hours)  Bendroflumethazide, benzthiazide, cyclothiazide, hydroflumethiazide, metolazone, quinethazone, trichlormethiazide  Long-acting (> 24 hours)  Chlorthalidone, indapamide, methyclothiazide, polythiazide Chlorthalidone, Indapamide, and Metolazone: Thiazide-like diuretics à with sulfonamide residue and same MOA.  Structural Features

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Benzene ring with a sulfonamide group at position 7 and halogen at position 6. Saturation of 3,4 double bonds à increased potency (hydrochlorothiazide). Lipophilic substituents at position 3 or methyl groups at position 2 à enhanced potency and prolonged activity (cyclothiazide). Replacement of sulfonyl group in position 1 by carbonyl group à prolonged activity (quinethazone). Thiazides without the sulfonamide group (diazoxide) à anti-HPN activity without diuretic activity.

Nephrogenic diabetes insipidus

THIAZIDE DIURETICS  PHARMACOKINETICS  Administration: Oral.  Onset of action: Within 12 hours.  Peak effects: 4-6 hours.  Duration of action: 8-12 hours.  Excretion: Tubular secretion. MOA: Inhibits NaCl cotransporter in the luminal side of the distal convoluted tubule.

POTASSIUM-SPARING DIURETICS  AGENTS: Spironolactone (steroid analogue antagonist of aldosterone), eplerenone, triamterene, amiloride (pteridine orpyrazine derivative).  PHARMACOKINETICS  Spironolactone: Oral, t1/2 of 10 minutes, canrenone (active metabolite) à t1/2 of 16 hours.  Triamterene: Oral, DOA of 12-16 hours, metabolized in liver, excreted through the urine (unchanged).  Amiloride: Oral, DOA of 24 hours, excreted through the urine (unchanged). POTASSIUM-SPARING DIURETICS  MOA

SOA: ADR:   

Spironolactone: Competes with aldosterone for receptor sites à inhibition of sodium-retaining action of aldosterone (distal tubule). Triamterene/Amiloride: Blocks sodium transport channels à decreased sodium reabsorption and potassium excretion. Collecting tubule Hyperkalemia, hyperchloremic metabolic acidosis Gynecomastia, menstrual disorders, testicular atrophy Peptic ulcer, acute renal failure, kidney stones, increased uric acid


Hypokalemic metabolic alkalosis Hyperuricemia, impaired carbohydrate tolerance  Hypercholesterolemia, hyponatremia  Sulfonamide-type allergic reactions  Weakness, fatigue, paresthesia, headache, restlessness  Male impotence, encephalopathy  NAV, bloating, constipation CLINICAL USES  HPN  CHF  Nephrolithiasis due to idiopathic hypercalciuria

POTASSIUM-SPARING DIURETICS  CLINICAL USES  Primary hyperaldosteronism  Secondary hyperaldosteronism due to hepatic cirrhosis complicated by ascites

To prevent potassium loss in combination with potassium-losing diuretics  As adjunct with thiazides and loop diuretics to treat HPN CONTRAINDICATIONS  Oral potassium administration à fatal hyperkalemia  Liver disease  ACE inhibitor or b-blocker 

OSMOTIC DIURETICS AGENTS: Mannitol, urea, glycerin, sorbitol. ADMINISTRATION: Intravenous. Duration of Action: 1-2 hours.  MOA: Prevents the normal absorption of water by interposing a counteracting osmotic force.  SOA: Proximal tubule, descending limb of Henle’s loop, collecting tubule.  ADR: Extracellular volume expansion manifested by headache, NAV; dehydration, hyponatremia.  CLINICAL USES: Short-term treatment of glaucoma; cerebral edema associated with tumors and neurosurgical procedures (decreases ICP); to prevent development of renal failure associated with severe traumatic injury, CV and other complicated procedures; renal extraction of bromide, barbiturates, salicylates, etc. in overdosage.

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b-blocker + thiazide à Increased blood glucose, urates, and lipids Digitalis glycosides + thiazide/loop diuretic à Hypokalemia ACE inhibitor + K-sparing diuretic à Hyperkalemia, cardiac effects Aminoglycosides + loop diuretic à Ototoxicity, nephrotoxicity Adrenal steroids + thiazide/loop diuretic à Enhanced hyperkalemia Chlorpropamide + thiazide à Hyponatremia Loop diuretic/thiazides + NSAID à decreased effects of diuretic

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AGENTS: Acetazolamide, dichlorphenamide, dorzolamide, methazolamide. Given orally except for dorzolamide which is used topically for glaucoma. MOA: Inhibits the enzyme that catalyzes the dehydration of carbonic acid à reduced sodium bicarbonate absorption. SOA: Proximal tubule. Duration of action: 8-12 hours. ADR: Metabolic acidosis, potassium depletion, renal stones, drowsiness and paresthesia, sulfonamide allergy, GI upset, BM depression. CLINICAL USES: Glaucoma, urinary alkalinization, metabolic alkalosis, acute mountain sickness, epilepsy (adjuvant). CONTRAINDICATION: Hepatic cirrhosis à decreased ammonia excretion.

SUMMARY  LOOP DIURETICS  Used for conditions associated with moderated or severe HPN or fluid retention (HF, cirrhosis, nephrotic syndrome).  They are sulfonamides except ethacrynic acid. THIAZIDES  Used to treat mild to moderate HPN, mild heart failure, chronic calcium stone formation, and nephrogenic diabetes insipidus.  Most important toxicity is potassium wasting.  They are sulfonamides. POTASSIUM-SPARING DIURETICS  Used for prevention of potassium wasting by other diuretics.  Spironolactone and eplerenone are particularly effective in treating heart failure and other high-aldosterone conditions.  The major toxicity is hyperkalemia.

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Eplerenone has no anti-androgen effects. They are not sulfonamides.

CARBONIC ANHYDASE INHIBITORS  Used as therapy for galucoma and altitude sickness and to reduce metabolic alkalosis.  May cause hepatic encephalopathy.  They are sulfonamides and are crossallergenic with other sulfonamides. OSMOTIC DIURETICS  Used to treat acute glaucoma and to protect the kidney from solute overload caused by crush injury or chemotherapy.  Mannitol is the major osmotic diuretic.

VASOPRESSIN (ADH, anti-diuretic hormone) A peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling BP.  Possesses antidiuretic and vasopressor properties.  A deficiency of the hormone results in diabetes insipidus.  MOA: Activates 2 subtypes of G-proteincoupled receptors: 1. V1 receptors – on vascular smooth muscle cells; mediate vasoconstriction. 2. V2 receptors – on renal tubule cells; reduce diuresis through increased water permeability and water resorption in the collecting tubules.  Administered IV or IM.  t ½ of circulating vasopressin: 15 minutes.  ADR: Headache, nausea, abdominal cramps, agitation, and allergic reactions; hyponatremia, seizures, vasoconstriction.  ADH agonist: Desmopressin  ADH antagonists: Conivaptan, Tolvaptan 

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