Lecture_22_&_23-_Diuretics.pdf

Diuretics Basic Pharmacology Block PHRM 211, 212, 213, 214 & 215 1 Objectives 1. Explain main actions of major classes of diuretics. 2. Describe the pharmacokinetic/Pharmacodynamic differences between diuretics. 3. List the clinical uses and adverse effects of diuretics. 2 Diuretics Drugs that aid i...

Diuretics Basic Pharmacology Block PHRM 211, 212, 213, 214 & 215 1 Objectives 1. Explain main actions of major classes of diuretics. 2. Describe the pharmacokinetic/Pharmacodynamic differences between diuretics. 3. List the clinical uses and adverse effects of diuretics. 2 Diuretics Drugs that aid in removing excess extracellular fluid and electrolytes and increased urine flow. These agents are ion transport inhibitors that decrease the reabsorption of Na+ at different sites in the nephron. As a result, Na+ and other ions such as Cl- enter the urine in greater amounts than normal along with water. 3 4 Summary of diuretic drugs Diuretic Drugs Thiazide Diuretics PotassiumSparing Osmotic Diuretics 1.Hydrochlorothiazide 1. Amiloride 1. Mannitol 2. Metolazone 2. Spironolactone 2. Urea 3. Ethacrynic acid 3. chlorthiazide 3. Triamterene 4. Eplerenone 4. Torsemide 4. Indapamide 5. Chlorthalidone Carbonic Anhydrase Inhibitor Loop Diuretics 1. Acetazolamide 1. Bumetanide 2. methazolamide 2. Furosemide 5 Thiazides (Hydrochlorothiazide, Metolazone) Thiazides (Frontline, 1st of equals): Hydrochlorothiazide, Metolazone The prototypical thiazide is hydrochlorothiazide Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs 6 Thiazides action Mechanism of action: 1. The thiazide derivatives act mainly in early distal tubule to inhibit Na-Cl cotransporter  inhibit water/Na+ reabsorption. 2. Increased excretion of Na+ and Cl BP by depletion body of Na+ → ↓ blood volume (BV)/plasma volume (PV) 3. Loss of K+ 4. Loss of Mg2+ 5. Decreased urinary calcium excretion 7 Therapeutic uses High clinical value as antihypertensive & combination therapy - Inexpensive, effective, retain effectiveness with elderly. - Convenient to administer, and well tolerated. Hypercalciuria – Patients with calcium oxalate stones in the urinary 8 Adverse effects Hypokalemia ↑ uric acid retention → hyperuricemia in 70% of patients Hyperglycemia Hypercalcemia: The thiazides inhibit the secretion of Ca2+, sometimes leading to elevated levels of Ca2+ in the blood. Erectile dysfunction (less common in the low doses used and its reversible). 9 Loop diuretics (Bumetanide, furosemide) Loop diuretics drugs have the highest efficacy in mobilizing Na+ and Cl– from the body (the most efficacious diuretic), capable of the excretion of 15-25% of filtered Na+. Inhibit the cotransport of Na+/K+/2Cl– in the luminal membrane in the ascending limb of the loop of Henle. 10 Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs 11 Adverse effects Ototoxicity (ethacrynic acid>furosemide>bumetanide) – Particularly when used in conjunction with aminoglycoside antibiotics. Hyperuricemia Hyperglycemia Acute hypovolemia the – Hypotension, shock, and cardiac arrhythmias. Hypokalemia Hypomagnesemia. Hypocalcemia Metabolic alkalosis (Due to increase HCO3) 12 Therapeutic uses Generally not used in hypertension pharmacotherapy Mainly used to decrease edema The loop diuretics are the drugs of choice for reducing the acute pulmonary edema of heart failure. 13 Potassium-sparing diuretics Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion. 1. Aldosterone antagonists: Spironolactone, Eplerenone 2. Epithelial sodium channel blockers Amiloride, Triamterene Used as adjunct therapy (usually with thiazide & loop), least potent Act at collecting tubule and duct, can cause hyperkalemia Used also in heart failure 14 Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs Adverse effects: Gynecomastia in males and menstrual irregularities in females, hyperkalemia, nausea and hyponatremia. 15 Carbonic anhydrase inhibitor (Acetazolamide) Inhibits the enzyme carbonic anhydrase in the proximal tubular epithelial cells. 16 Carbonic anhydrase inhibitor Carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their diuretic effect, because they are much less efficacious than the thiazides or loop diuretics – Treatment of glaucoma – Mountain sickness Adverse effects: Metabolic acidosis (mild), Hypokalemia, renal stone formation 17 Osmotic diuretics The primary effect involves an increased fluid loss caused by the osmotically active diuretics molecules, this result in reduced Na+ and water reabsorption from the proximal tubule. An additional contribution to the diuresis induced by that osmotic diuretic is the increase in renal blood flow that follows their administration. Mannitol: Therapeutic uses: Treatment of patients with increased intracranial pressure or acute renal failure. Adverse effects: Dehydration and hyponatremia. * Can only be given intravenously because it is not absorbed when given orally.18 19