DIURETIC DRUGS

Introduction Are drugs that induce a state of increased urine flow. Are inhibitors of renal ion transporters that decrease the reabsorption of Na⁺ at different sites in the nephron such that Na⁺ and other ions enter the urine in greater than normal amounts along with water.

Uses of diuretics Disorders involving abnormal fluid retention (edema) Treatment of hypertension

Diuretic classes DRUGS SITE OF ACTION Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics Potassium sparing diuretics Osmotic diuretics SITE OF ACTION PCT Ascending LH DCT Collecting tubules All areas in the nephron

Diuretics: Sites of Action Carbonic Anhydrase Inhibitors Eg: Acetazolamide Thiazides Eg: Chlorothiazide Na+ Cl- HCO3- K+ - Sparing Eg: spinolactone Na+ Na+ Cl- K+ K+ Loop Diuretics Eg: Furosemide

CARBONIC ANHYDRASE INHIBITORS Acetazolamide Dorzolamide Methazolamide

CARBONIC ANHYDRASE INHIBITORS ACTION : INHIBITS CARBONIC ANHYDRASE ENZYME SITE : PCT EFFECTS : NO H+ FOR REABSORPTION OF Na + HCO3- EXCRETION INCREASES CAUSES MILD DIURESIS ↓Na⁺/H⁺ antiport ↑Cl⁻ in the blood---hyperchloremia

Causes significant bicarbonate loss causing alkalinization of urine Hyperchloremic metabolic acidosis reduction in aqueous humor production

THERAPEUTIC USES Chronic treatment of GLAUCOMA ( MC INDICATION ) REDUCES AQUEOUS HUMOR PRODUCTION DECREASES IOP. DRUGS USED : ACETAZOLAMIDE, DORZOLAMIDE.

Acute Mountain Sickness Given nightly for 5 days before the ascent to prevent weakness, breathlessness, dizziness, nausea, cerebral and pulmonary edema

OTHER USES -- Metabolic alkalosis Can decrease production of CSF, therefore used to treat pseudotumor cerebri

SIDE EFFECTS BICARBONATURIA HYPOKALEMIA HYPERCHLOREMIA PARESTHESIAS RENAL STONES (calcium oxalate, struvite stone) SULFONAMIDE HYPERSENSITIVITY CI: in hepatic cirrhosis(hepatic encephalopathy)

Loop Diuretic Drugs Furosemide Bumetanide Torsemide Ethacrynic acid --no longer in use because of toxicity.

Action Inhibit the Na/K/Cl transport system in the luminal membrane of the thick ascending limb of Henle. Reabsorption of Na/K/Cl reduced → their excretion. Increases Ca²⁺, mg²⁺ excretion The most efficacious of all the diuretics They increase the synthesis of prostaglandins, with their diuretic effect enhanced by prostaglandins

USES Major uses: --Edematous conditions Acute pulmonary edema Acute hypercalcemia Management of edema HTN by ↓ing peripheral vascular resistance & reduction in blood volume Hyperkalemia Renal failure

SE Ototoxicity: more with ethacrynic acid Hypokalemia Metabolic alkalosis Hyperuricemia Hypocalcemia hypomagnesemia Gout Dehydration Cardiac arrhythmias Sulfonamide hypersensitivity except ethacrynic acid

Drug interactions Aminoglycosides: ↑ ototoxicity ↑ Digoxin toxicity due to electrolyte disturbance (hypokalemia) Chronic administration ↓es lithium clearance

THIAZIDES Most commonly used diuretic. Inhibition of Na⁺/Cl⁻ transporter from the distal convoluted tubule. ↑ing Na⁺ and Cl⁻ excretion → to ↑ diuresis Enhance calcium reabsorption in the distal convoluted tubule – reduces Ca excretion. Loss of K

Drugs Chlorothiazide Chlorthalidone Hydrochlorothiazide Indapamide Metalazone Methyclothiazide Trichlomethiazide

USES Essential HTN by vasodilatation of peripheral vasculature (K⁺ channel opener) CHF Renal failure Nephrogenic Diabetes Insipidus Hypercalciuria

SE Hypokalemia Metabolic alkalosis Hyperuricemia Hypercalcemia Cardiac arrhythmias Hypotension Hyponatremia Hyperlipidemia Hypersensitivity to sulfonamides Hyperglycemia

Drug interactions Increases digoxin toxicity Contraindicated in diabetics

POTASSIUM SPARING DIURETICS These diuretics inhibit aldosterone receptor at the Collecting tubule and late distal tubule by stimulating Na⁺ excretion and K⁺ retention ALDOSTERONE: It increases the reabsorption of sodium and water. Excretion of potassium in the distal tubules of the kidneys. Thus increases blood pressure.

ENAC: EPITHELIAL SODIUM CHANNELS

Drugs Spironolactone Amiloride Triamterene

Drugs Spironolactone: inhibits aldosterone at its receptor sites. Increasing Na and H2O excretion while retaining K

USES OF SPIRONOLACTONE Diuretic: given in conjunction with a thiazide and loop diuretics to prevent K-excretion Diuretic of choice in patients with hepatic cirrhosis Secondary hyperaldosteronism Heart failure to prevent cardiac remodeling

SE Hyperkalemia Gynecomastia (spironolactone) Anti androgen effects (spironolactone) Menstrual irregularities GIT disturbance

Triamterene and Amiloride MOA: blocks Na transport channels resulting in a decrease in Na/K exchange not dependent on the presence of aldosterone Causes retention of K⁺

Side effect Leg cramps (Triamterene & Amiloride) Increased BUN (Triamterene & Amiloride)

Osmotic diuretics Have ability to carry water with them into the tubular fluid, therefore increasing water excretion. Acts on all parts of the nephron.

OSMOTIC DIURETICS MANNITOL/urea Parental (I.V.) increase water excretion. Increased tubular fluid osmolarity Increase urine volume. Less effect or no effect on Na excretion

USES To increase urine volume in anuric conditions such as toxic ingestion, trauma, drug toxicities. To decrease intracranial or intraocular pressure. Acute renal failure

SE Dehydration Hypovolemia Hyponatremia Headache Nausea & vomiting Pulmonary edema: very common with mannitol