Diuretics Pharmacology PDF

Pharmacology of DiureticsOrPillsWater Rekha Yesudas, MPhil, Ph.D. PCOM Pharmacology, 2024 Copyright © 2024, This presentation is intended for students use only. No part of this presentation may be distrib...

Pharmacology of DiureticsOrPillsWater Rekha Yesudas, MPhil, Ph.D. PCOM Pharmacology, 2024 Copyright © 2024, This presentation is intended for students use only. No part of this presentation may be distributed, reproduced or uploaded/posted on any Internet websites without the expressed written consent from the author. 1  Learning Objectives 1.List the major diuretics and their clinical indications. 2.Explain the mechanism of action of major diuretics. 3.Discuss the pharmacokinetics and major drug interactions of diuretics. 4.Describe the common and severe adverse effects of commonly used diuretics. Patient:the 5.Summarize in major contraindications hypertension medicationof diuretics. presents with edema. 2  Goal of diuretic drugs Remove extra fluid and minerals through urine – To reduce edema. – Treat hypertension. – Management of vascular congestion in all forms of heart failure. Increase urination. – Take this drug at morning: to avoid nocturia (minimize urination during night. Sequential nephron blockade is a potent combination for Refractory congestion: 3 effective but increases risk of renal dysfunction &  Indications Heart failure, Renal disease , Cirrhosis Edema, Hypertension, Ascites diuresis, Fluid overload. a b 4  CA I Osm Loop Thiaz K+ ENaC K+ 5 Aldo  Classes of Diuretics CA I: Acetazolamide Osmotic: Mannitol Loop: Furosemide, Ethacrynic acid K+ wasting Thiazide: Chlorthalidone, HCTZ K+ sparing: Spironolactone, Triamterene Diuretics sites of action ⇢ Acetazolamide is a carbonic anhydrase inhibitor, and 6 is not indicated for heart failure. I. Carbonic Anhydrase inhibitors 7  Diamox® Acetazolamide Weaker diuretic with site of action, @ eye, brain & kidneys. I: Glaucoma. High altitude pulmonary edema, Metabolic alkalosis. Acute mountain sickness or Altitude sickness (Prophylaxis for people with a prior history of acute mountain sickness). By using acetazolamide, high elevation ventilatory acclimatization takes only 1 day (that normally takes 3-5 days). MOA: inhibits secretion of H+ ions by blocking carbonic anhydrase. Increase Removalelimination of of bicarbonates decrease bicarbonates. aquous humor & cerebrospinal fluid. Decrease pH in CSF improve ventilation = more O2 intake & CO2 exhalation. 8  Acetazolamide Drug induces bicarbonate diuresis and metabolic acidosis, which stimulates ventilation and increases alveolar and arterial oxygenation. PK: 98% is protein bound. Must be secreted through PCT. 9 Acetazolamide & Metabolic Acidosis HCO3- depletion: Too much acid in the body when too many bicarbonates are excreted. Carbonic anhydrase inhibitors increase NaHCO3 diuresis ⇢ urine alkaline ⇢ blood acidic ⇢ (hyperchloremic) metabolic acidosis. Act on central chemoreceptors ⇢ increase ventilation. [high altitude] ⇣ CSF production, ⇣ aqueous humor secretion. AE: Metabolic acidosis K wasting, drowsiness with large dose. 10 II. Osmotic diuretics Patient: cerebral edema after a head injury Patient: Glaucoma O Mann 11  Osmitrol® Mannitol Pharmacologically and metabolically inert substances filtered in the glomerulus, but not reabsorbed. Massive diuresis. I: Best drug to reduce intracranial pressure (cerebral edema) & intraocular pressure (glaucoma). Promote toxic substance excretion. 12  Mannitol: MOA Create a powerful osmotic gradient Create a massive diuresis by working @ PCT & descending limb of loop of Henle. It cannot cross BBB but increases tonicity of plasma. Therefore, mannitol draws water out of brain parenchyma into the intravascular space. Mannitol travels to the kidney & excreted. Draws water from vitreous humor. 13  Mannitol PK: IV- When given intravenously, it is excreted rapidly by the kidneys. [Mannitol is poorly absorbed orally. Oral administration result in osmotic diarrhea]. Nontoxic simple sugar, not metabolized & not reabsorbed. Mannitol is cleared by kidney, water follows. Freely filtered through glomeruli. Osmotic diuretics extract water from intracellular compartments, increasing extracellular fluid volume. Intracranial pressure reduction begins 15- 30’ after administration (effect lasts from 1.5 to 6 hrs). Diuresis occurs 30’ to 3hrs post-administration. 14  Greatest III. Loop diuretics natriuretic effect 👉 One of the cornerstones of treatment for ♥️ failure. Patient: chronic kidney disease Patient with heart failure 15  Case answer: Patients with chronic kidney disease, & volume overload generally respond to the combination of dietary restriction and diuretic therapy with loop diuretic given daily. Thiazide diuretic and aldosterone Rr antagonists are not used for patients with renal function impairment because they can cause changes of plasma potassium level. 16  How effective are they? Most frequently used diuretics due to their rapid onset & efficacy. – Act on Ascending limb of loop of Henle. – Promote excretion of Na, K, Cl: inhibits N/K/Cl symporter. Achieved by inhibiting Na-K-2Cl carrier: Blocks up to 25% of sodium reabsorption Loop diuretics reduce sodium & chloride reabsorption in the thick ascending limb of loop of Henle. Also ⇣K absorption. Loop diuretics have a ceiling dose: dose that shows maximum fractional sodium excretion. Induce renal prostaglandin "the phenomenon in synthesis. which a drug reaches – ⇡renaleffect, a maximum blood so flow. that increasing the 17 drug dosage does  Types of loop diuretics Type 1: are sulfa drugs- Furosemide, Torsemide, Bumetanide. Type 2: are non-sulfa drugs- Ethacrynic acid. I: fluid diuresis in heart failure, edema, cirrhosis, Common AEs: Sulfa allergies Hypokalemia ⇢Metabolic alkalosis. ⇣Na+, ⇣K+, ⇣Cl-, ⇣H+, ⇣Ca2+, ⇣ Mg2+ DI: Increases Li clearance. Aminoglycoside- enhanced ototoxicity. Digoxin- ⇡ toxicity due to electrolyte imbalance. NSAID- reduced efficacy. 18  Lasix® Furosemide Very effective, powerful diuretic. By far most common loop diuretic. I: Diuretic, Hyperkalemia, hypercalcemia. Furosemide is 1st line therapy for heart failure. MOA: Blocks Na-K-2Cl cotransporter at thick ascending limb of loop of Henle. Inhibiting NaCl, increases water excretion. K+ unable to be reabsorbed. Loss of Ca & Mg. 19  Furosemide PK: twice/thrice daily. Bioavailability is extremely variable (10-90%). [improve by taking before meals/food disrupts absorption]. 50% excreted unchanged in urine. Rest metabolized into glucuronide in the kidneys. Renal dysfunction shows decreased repone. Patients with severe edema? Inadequate GI absorption. Not responding? Switch to IV furosemide or oral torsemide. ½ life ~ 1.5 hrs AE: Hypokalemia, CI: Sulfonamide allergy: potential risk of cross reactivity due to the sulfonamide moiety in structure. 20  Demadex® Torsemide Much more potent. Advantage: mitigation of cardiac fibrosis compared to furosemide. PK: once daily. Predictable bioavailability. Torsemide has a higher bioavailability than Furosemide (40mg F= 20mg T =1 mg Bumetanide). Extremely well absorbed (80-90%), regardless of edema, since undergoes substantial hepatic elimination. ½ life ~ 4 hrs. Bumex® Bumetanide: High oral availability. 21  Edecrin® Ethacrynic acid Safe during sulfa allergy, since no sulfa moiety in the structure. I: For patients who has known hypersensitivity reactions to sulfonamides. Less commonly used drugs AE: Ototoxicity Damage hair cells in inner ear. During sunbath Etha killed my Ear 22 Why loop diuretics cause & Hypokalemia? thiazide s 23  Hypokalemia & Metabolic Alkalosis An increase in quantity of bicarbonates relative to the volume of water in the extracellular fluid. Metabolic alkalosis is maintained only if the kidneys are unable to excrete the excess bicarbonate. 2 most common causes- vomiting & diuretic use. Diuretics that cause hypokalemia are associated with loss of H+. This leads to metabolic alkalosis. – Plasma bicarbonate concentration greater than 30mmol/L, and an arterial pH above 7.45. 2 classes of diuretics cause both hypokalemia & alkalosis – Loop diuretics & thiazide diuretics. Blocks N+ reabsorption ⇢ increase Na+ load at collecting ducts ⇢ loss of K+ ⇢ hypokalemia. 24  Moderate IV. Thiazide diuretics natriuretic effect 👉 Reliable class of antihypertensive diuretics Patient: essential hypertension Patient: renal stone 25  Case answer: Patients with renal stones caused by hypercalciuria could benefit from thiazide therapy. Increased Ca reabsorption at PCT and DCT, can lower 90% incidence of new stones. Reducing ~ 50% Ca excretion by promoting Ca reabsorption. Eg: drugs to use Hydrochlorothiazide, Chlorthalidone. thiazi loop Hydrochlorothiazide de and furosemide being first-line drugs in the treatment of hypertension, are among others the most frequently prescribed drugs in the world. 26  Drugs end in thiazide chlor Works by directly inhibiting Na/Cl co- transporters at DCT. I: essential hypertension. Enhanced Ca reabsorption: ⇣ Ca secretion: so blood Ca rises. but increased Mg secretion. Increase Li+ levels: CI with patients who has bipolar disorders taking Li+containing medications. Risk for Hyperglycemia and Gout: increases uric acid. Increases urea reabsorption at PCT. This increases plasma uric acid level., Photosensitivity Monitor electrolyte imbalance. – Lower Na: results hyponatremia – Lower K+: More K+ eliminated Prescribe K+ supplement. 27  Microzide® Hydrochlorothiazide Well tolerated drug makes you urinate more & reduce blood volume. I: Primary agent or an adjunct for essential hypertension, adjunctive therapy for peripheral edema. MOA: Antagonizes sodium-chloride symporter. Inhibits Na & Cl reabsorption at DCT. Also ⇡ Vasodilation. PK: less potent, shorter half-life, inferior drug (as far as cardiovascular outcome evidence), but still most used (marketing?). Only 40-60% protein bound compared to Chlorthalidone, 1/2 life is ~5.5 to 14 hrs. AE: Electrolyte derangement, Hyperglycemia 28 (decreased K+ level may reduce insulin level in  Thalitone® Chlorthalidone Potent drug. Thiazide-like diuretic with sulfonamide gp. I: Hypertension, Fluid retention, prevent Ca+ kidney stones. MOA: Inhibits Na/Cl reabsorption at DCT. Antagonize sodium-chloride symporter. This elevates Na content in lumen ⇢ elevates intratubular volume ⇢ promotes diuretic effect. Reduce Ca excretion into urine= protects from renal stones. 29  How chlorthalidone prevents Lower calciumkidney phosphate stones? supersaturation via both reduction of urine calcium excretion & urine pH. Chlorthalidone, and presumably other thiazide type drugs make urine more acidic. Thiazide type drugs ideal for preventing calcium phosphate type stones and calcium oxalate stones. Lowering calcium phosphate supersaturation (hampering formation of the calcium phosphate film needed for overgrowth of calcium oxalate on plaque), & by reducing calcium oxalate supersaturation itself. 30  Microzide® Chlorthalidone PK: Oral. High protein binding to albumin (affinity for erythrocyte carbonic anhydrase). ~75% protein bound (~60%) on albumin). Elimination ½ life~ 45 to 60 hrs (2 to 3 days). Undergoes partial hepatic metabolism. Major portion will be excreted unchanged via kidneys. Very small pills (hard to break if needed). AE: Electrolyte derangement results from increased diuresis and altering of nephron physiology. Hypokalemia (most significant), but may cause hyponatremia or hypochloremia. Indapamide: Thiazide-like diuretic with sulfonamide gp. ⇢ promote diuretic effect. 31  Case A patient taking thiazide diuretic had too much food and drinks in a party. Next day he felt pain in right elbow. Diagnosed with gout. MOA? Rationale: Increased purine intake & decreased uric acid secretion. Increased urate reabsorption and decreased urate secretion in PCT results in chronic use of diuretics (risk ~80%). Purines are metabolized into uric acid, hence high purine diet (animal protein) increase the uric acid level. Alcohol & saturated fat decrease body’s ability to eliminate uric acid. 32  🔵 V. K+ sparing diuretics 2 steroid drugs: Spironolactone, Eplerenone 2 ENaCs: Amiloride, Triamterene (epithelial Na channel blockers) Eplerenone Spi Tried A-Milo-ride Epileptic Spy Tried AMiloRide 33  Types Triamterene & Amiloride: K+ sparing effect is by blocking collecting tubule Na+ channels. More reliable than spironolactone. Do not antagonize aldosterone. Effective regardless of aldosterone status. – Blocks Na+ channels of luminal membrane. – Decrease K+ secretion in collecting ducts. Spironolactone & Epierenone: Aldosterone blockers. For hypokalemia & hypertension. Trina & Amila 34  ENaC blockers Epithelial sodium channel blockers reduce Na reabsorption. 35  Dyrenium® Triamterene K+ sparing diuretic: Prevent losing too much potassium. I: Treatment of edematous states (fluid retention), Hypertension. [No good data= no decrease in the risk of stroke risk, heart attack risk]. MOA: Binds on Na channels of nephron collecting duct (late DCT & CD on the luminal side of principal cells. [blocks transmembrane channels which do Na+ uptake & K+ secretion]. Preventing K+ elimination from kidneys. PK: oral drug for monotherapy or combination ½ life~2 hrs AE: Dehydration, Hyperkalemia. Muscle craps due to lowering K+ 36  Midamor® Amiloride To lower bd pressure. I: Adjunctive treatment with thiazide diuretics during uncomplicated hypertension or heart failure. To prevent risk of hypokalemia. Also for nephrogenic diabetes insipidus. MOA: ENaC blockers. Works independently of aldosterone. Also can reduce response to ADH. PK: AE: well tolerated drug. risk of Hyperkalemia. Black box warning: hyperkalemia. 37  Aldosterone blockers First-line: high doses of drugs to treat 👉 Cannot act directly on sodium transporters Patient: with ascites Patient with cirrhosis 38  Aldactone Spironolactone ® Weaker type of diuretic to prevent K+ loss. Mostly used in combination therapy. I: congestive heart failure, refractory hypertension [not a 1st line for essential hypertension]. Add on therapy for resistant Htn., cirrhosis. Hyper-aldosteronism/Cohn disease. MOA: Aldosterone Rr antagonist operating at the late DCT & CD on the apical aspect of these sites. Works on the intercalated cells where these transporters are located. – Benefits through neurohormonal modulation. – effects on ventricular remodeling. AE: Gynecomastia, Hyperkalemia. 39  Eplerenone its increased selectivity for the mineralocorticoid receptor relative to glucocorticoid, progesterone, and androgen receptors. I: LV systolic dysfunction, congestive heart failure after an acute MI. Hypertension MOA: Aldosterone Rr blocker. Aldosterone is implicated in the progression of myocardial fibrosis, especially following myocardial infarction. Eplerenone binds to mineralocorticoid receptors competitively, antagonizing aldosterone. 40 PK: 3-6 hrs ½ life, so twice daily. VI. SGLT inhibitors 41  SGLT-2 inhibitors: as diuretics In patients with Type-2 diabetes & cardiovascular diseases. Prevents adverse cardiorenal events. (~30% reduction) Keep you from reabsorbing glucose ⇢ eliminate water & sodium. How? Sodium-Glucose Transporter-2: for the absorption of sodium + glucose from PCT. ~90% of glucose reabsorption at PCT by SGLT-2 transporters. Canagliflozin, Dapagliflozin, Empagliflozin etc. inhibits SGLT-2. MOA: No glucose reabsorption: ⇣ sodium absorption ⇣Plasma volume, ⇡glycosuria ⇡urine output. 42  Diuresis and Pregnancy https://pmc.ncbi.nlm.nih.gov/articles/PMC2628835/ Diuretics can be used during pregnancy in certain cases, such as to treat severe maternal illness, life-threatening conditions, or to replace a drug with known adverse fetal effects. Some commonly prescribed diuretics include: amiloride, chlorothiazide, furosemide, spironolactone, hydrochlorothiazide, and triamterene 43 Summary Done ! 44