Diuretics Classification: 1. Carbonic Anhydrase Inhibitors 2. Osmotic Diuretics 3. Na+K+2Cl symport Inhibitors 4. Na+Cl symport Inhibitors 5.

Renal epithelial sodium channels Inhibitors 6. Mineralocorticoid receptors Antagonists Introduction Function Effects increase urine production by acting on the kidney most agents affect water balance indirectly by altering electrolyte absorption/secretion osmotic agents affect H2O balance directly natriuretic diuretics diuresis associated with inc Na excretion concomitant loss of H2O and dec ECM volume used for mgt of edema, HPN, CHF, & abnormalities in body fluid distribution can cause lectrolyte imablances such as: hypokalemia hyponatremia hypochloremia distrubances in acid-base balance

Therapeutic uses Side effects

Carbonic anhydrase Inhibitors MOA Prototype - Inhibit carbonic anhydrase in Acetazolamide all parts of the body Methozolamide - Kidney: effects are in proximal tubule **sulfonamide - Drugs reduce HC03derivatives reabsorption and concomitant Na+ uptake - Also inhibit excretion of H+ and coupled Na+ uptake - Absorbed in GI tract by the proximal tubule - Urine pH changes are observed in 30 minutes

Therapeutic Uses - Rarely used as diuretics - Most useful in treating glaucoma, serve to decrease the rate of HCO3- formation of the aqueous humor & reduce ocular pressure - Sometimes used as adjuvants in treating seizure disorder, tolerance is high. - May be used to produce a desired alkalinization of urine to enhance renal secretion of uric acid and cysteine - May be used prophylaxis & treatment of acute mountain sickness - ***with Tubuloglomerular feedback (TGF)

AE - Metabolic acidosis d/t reduction in bicarbonate stores. Urine alkalinity dec the solubility of calcium salts & inc the propensity for renal calculi formation Potassium wasting may be severe - Large doses: drowsiness & paresthesias - CI: in the presence of hepatic cirrhosis

Osmotic Diuretics - agents influencing water excretion Mannitol - Extraction of water from Urea intracellular compartments expansion of the extracellular **given IV fluid volume inc in Renal Blood flow (RBF) dec in

- Used in prohylaxis of acute renal failure resulting from physical trauma or surgery. - If filtration is reduced, sufficient mannitol usually enters the

- Bec of the osmotic forces that reduces the intracellular volume ultimately expand the ECV, serious AE may occur in Px with CHF - Hyponatremia headache,

medullary tonicity -

Glycerin **orally taken

tubule to promote urine output May also be useful for reducing cerebral edama and intraocular pressure Parenteral urea approved for the reduction of intracranial and intraocular pressure Used primarily for ophthalmic procedures Topical anhydrous glycerin for corneal edema

Vomiting and nausea - Hypernatremia and dehydration - Expansion of ECF vol pulmonary edema and CHF

Inhibitors of Na+K+2Cl Symport Loop Diuretics / High Ceiling Diuretics Furosemide - A: GIT - Used in the treatment of CHF Derivatives: - E: by filtration & tubular by reducing acute pulmonary Piretanide secretion; some occurs via edema and edema refractory to Bumetanide hepatic-biliary route other organs Ethacrynic - Aministered either - Synergistic with thiazide torsemide - Orally or parenterally diuretics and coadministered - Used to treat HPN, esp - Inhibit NaCl reabsorption in the thick ascending limb of the individuals with diminished loop of Henle by inhibiting renal function NKCC2, a specific Na/K/2Cl - Treat hypercalcemia and cotransporter. Because of high halide poisoning capacity for NaCl reabsorption in this segment, agents active at this site markedly increase water and electrolyte excretion and are referred to as high-

- Hypotension and volume depletion as well as hypokalemia because of enhanced secretion of K - May also produce alkalosis d/t enhanced H+ secretion - Can cause dose-related ototoxicity, esp patients with renal impairment. - Can cause hypersensitivity reactions

ceiling diuretics - Cause increased renal PG production,w/c accounts for some of their activity - Reduce reabsorption of Cl and Na; they increase L, Mg and Ca excretion Inhibitors of Na/Cl Symport Thiazides Hydrochlorthiazide A: GIT and produce diuresiss within 1-2 hours Chlorthiazide Inhibit active reabsorption available only for of NaCl in the distal convoluted parenteral use tubule by interfering with Na/Cl cotransporter (NCC), a specific Na/Cl transport protein net excretion of Na and an accompanying volume of water: a. agents increase excretion of Cl, Na, K, and at high doses HCO3-; b. redcue the excretion of Ca Can be derivatives of sulfonamides, which inhibit carbonic anhydrase diminished HCO3- reabsorption by the proximal tubule

Preferred class of diuretic for treatment of HPN when renal function is normal, often used in combination with other antihypertensive agents to enhance their blood pressurelowering effects Reduce the formation of new calcium stones in idiopathic hypercaliuria May be useful in atients with diabetes insipidus that is not responsive to ADH Often used in combination with potassium sparing diuretic to manage mild cardiac edema, cirrhotic or nephrotic edema, and edema produced by hormone imbalances. Tx of Meneiere disease

- Clinical Indications of Hydrochlorthiazide - Hypertension blood volume TPR (direct effects on vascular smooth muscle) used as monotherapy additive or synergistic effects when combined with other classes of antihypertensive drugs best initial therapy for uncomplicated hypertension inexpensive, effective and well tolerated - Edema 20 to: Cardiac - CHF Hepatic - Cirrhosis Renal Nephrotic syndrome,

Chronic renal failure, Acute Glomerulonephritis ineffective if GFR is less than 30-40 ml/min Adverse effects: Dermatologic skin rashes photosensitivity Gastrointestinal anorexia nausea, vomiting diarrhea CNS headache paresthesias, vertigo Hematologic blood dyscrasias Fluid and Electrolyte abnormalities ECF volume depletion hypotension Hypokalemia increased risk for Digitalis-induced arrhythmia if combined with Quinidine Torsades des pointes

(Polymorhic ventricular tachycardia); usually self-limiting but may deteriorate into fatal ventricular fibrillation Hyponatremia - can be fatal or nearly-fatal Hypochloremia, hypomagnesemia, hypercalcemia, hyperuricemia Metabolic alkalosis - Sexual dysfunction impotence / erectile dysfunction - Dyslipidemia Total cholesterol, Triglycerides LDL Cholesterol - Hyperglycemia impaired glucose tolerance decrease efficacy of hypoglycemic drugs unmask latent diabetes mellitus Thiazide- like Chlorthalidone* Indapamide

Same as above

Have properties similar to thiazide diuretics, however, may be effective

Same as above

Metolazone

in the presence od some renal imparment INdapamide has proven useful diabetic pateients with HPN, reduces the risk of cardiovascular diseases.

Potsssium Sparing Diuretics Renal Epithelium Sodium Channel Inhibitors Triamterene* - Bind to block ENaC and thereby Amiloride decrease absorption of Na and excretion of K in the cortical collecting tubule, independent of the presence of mineralocorticoids - Triamterene increases urinary excretion of Mg; amiloride does not - Amiloride metabolized in LIVER - Both drugs are secreted in the proximal tubule Mineralocortocoid Receptor Antagonists Spironolactone* - Inhibit the action of Eplerenone aldosterone by competitively binding to the

- Used to manage CHF, cirrhosis and edema caused by secondary hyperaldosteronism - Available in comination pdts containing thiazide or loop diuretics to treat HPN

- Prodeuces hyperkalemia- most common - Ventricular arrhythmias - GIT nausea, vomiting, diarrhea - CNS headache

- Used in combination with a thiazide or loop diuretic to treat HPN, CHF, and refractory

- Cause: - Hyperkalemia, hyperchloremic metabolic acidosis, arrhythmias,

mineralocorticoid receptor and preventing subsequent cellular events that regulate K and H secretion and Na reabsorption (impt action: reduction in the biosynthesis of ENaC, the Na channel n principal cells of clleting duct) - Active only when endogenous mineralocorticoid is present, effects are enhanced when hormone levels are elevated - A: GIT - M: Liver

edema. - Used to induce diuresis in clinical situations associated with hyperaldosteronism, such as in adrenal hyperplasia and in the presence of aldosteroneproducing adenomas when surgery is not feasible.

- Spironolactone associated with gynecomastia and menstrual abnormalities - CI: - Patients with renal insufficiency esp DM.