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

Edematous states Congestive heart failure Hepatic cirrhosis Renal disease Idiopathic edema

Non-edematous states HPN Nephrolithiasis Hypercalcemia Diabetes insipidus

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. 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.

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

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

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

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.

THIAZIDE DIURETICS

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 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 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.

SOA: Collecting tubule ADR:

Hyperkalemia, hyperchloremic metabolic acidosis

Gynecomastia, menstrual disorders, testicular atrophy

Peptic ulcer, acute renal failure, kidney stones, increased uric acid

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.

CARBONIC ANHYDRASE INHIBITORS

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.

POTENTIAL DRUG INTERACTIONS

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

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. 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 cross-

allergenic 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-protein-coupled

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