Diuretics

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.

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 

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Edematous states  Congestive heart failure  Hepatic cirrhosis  Renal disease  Idiopathic edema Non-edematous states  HPN  Nephrolithiasis  Hypercalcemia  Diabetes insipidus

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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LOOP OR HIGH-CEILING DIURETICS 

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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

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. 

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. 

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.

THIAZIDE DIURETICS 

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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.

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Nephrogenic diabetes insipidus

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

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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

THIAZIDE DIURETICS 

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ADR  

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 

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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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POTENTIAL DRUG INTERACTIONS

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CARBONIC ANHYDRASE INHIBITORS

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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.

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

SUMMARY 

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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 