DIURETICS 1 of 2 Dr R P Nerurkar

DIURETICS (1 of 2) Dr R. P. Nerurkar Dept. of Pharmacology T. N. Medical College & BYL Nair Ch. Hospital, Mumbai DECEMBER 5, 2005

Learning Objectives At the end of my 2 lectures you should be able to 1) List 5 major types of diuretics and their mechanism and site of action 2) List the major applications and toxicities of them 3) Describe the measures that reduce K+ loss during natriuresis 4) List the Rx of hypercalcimia and hypercalciuria 5) manage refractory edema cases 6) List Rx of nephrogenic diabetes insipidus

Overview of Diuretic lectures • Definition • Physiology of Urine formation and drugs modifying it • Classification and Mechanism of action • Pharmacology of Individual class of diuretics • Group discussion and Exercises on – Prescription writing, – Patient oriented problem solving – Identification of drugs acting according – ADR and drug interactions

Physiology of Urine Formation • Nephron • Glomerular filtration, Reabsorption, Secretion • GFR 120 ml/min • 99 % reabsorbed • Urine formation 1 ml/min 60 ml/hr 1. 5 L/day • Most diuretics prevent reabsorption of Na & H 2 O

Diuretic - Definition • Diuretic = drug which increase urine formation – Increase urine volume (Diuresis) – Increase excretion of Na and H 2 O (Natriuresis) • Mechanisms of diuresis – Extrarenal • By increasing Cardiac output : Digoxin, Dopamine in CHF • By Inhibiting ADH : H 2 O, alcohol – On the kidney (Nephron) – Most diuretics • Inhibit Na and H 2 O reabsorption Q. What will be the uses of diuretics in therapuetics?

Diuretics- Classification 1) High efficacy (upto 25% Na. Cl excretion) Loop diuretics 1. Frusemide, Torsemide, Bumetanide (SO 2 NH 2 group) 2. Ethacrynic acid (No SO 2 NH 2 group) 3. Organic mercurials: Mersalyl (Now obsolete) 2) Medium efficacy (5 – 10 % Na. Cl excretion) 1. Thiazides : Hydrochlorothiazide, Chloro. Th, Benz. Th, Hydroflume. Th, Clopamide, Poly. Th 2. Thiazide like : Chlorthalidone, Metolazone, Xipamide, Indapamide

Diuretics- Classification 3. Carbonic Anhydrase Inhibitors (5%Na. Cl excretion ) 1. 4. 5. Potassium Sparing Diuretics (3% Na. Cl excretion) 1. Aldosterone Antagonists Spironolactone, eplerenone 2. Directly acting: Amiloride, Triamterene Osmotic Diuretics (upto 20% Na. Cl excretion) 1. 6. Acetazolamide, Methazolamide, Dichlorphenamide Mannitol, Glycerol, Isosorbide Misc: Theophylline

Diuretics - Sites of Action

Loop Diuretics- Frusemide MOA • Acts on thick ascending part of Loop of Henle • Inhibit Na+-K+-2 Cl-cotransport and reabsorption • Increase Na. Cl excretion (upto 25% High efficacy) • Na exchanges with K+ in the DT K+ loss • Effective in very low GFR of < 30 ml/min • Other actions – Increase Ca++, Mg ++ excretion – Induce renal PG synthesis (blocked by NSAIDs) – Direct vasodilatation (IV route) imp. In pulm edema, LVF

Loop Diuretics-Preparations, dosage Drug Dose (mg) Frusemide 20 - 80 Torsemide 2. 5 - 20 Bumetanide 0. 5 – 2 Ethacrynic Acid 50 -200 Which is the most potent loop diuretic? Bumetanide

Loop Diuretics- USES 1) Edema : Cardiac (CHF), Hepatic (cirrhotic Ascites), Renal (Nephrotic syndrome) 2) Acute pulmonary edema 3) Cerebral edema (Mannitol preferred) 4) Acute hypercalcemia 5) Acute Renal failure 6) Forced diuresis in drug poisoning (Barbiturate)

Loop Diuretics- USES contd 7) Hypertension (Thiazides preferred) 8) Hyperkalemia mild 9) Along with massive blood transfusion 10) Anion overdose (Iodide, Bromide, Flouride)

Loop Diuretics-Adverse Effects 1) Hypokalemia ü Clinical Features : may Increase digoxin toxicity, arrhythmia Muscle weakness, fatigue, cramps ü To prevent Hypokalemia • Use low dose • Give KCl supplement (oral solution or IV infusion) • Combine with K sparing diuretic • Advice: More intake of K containing food: coconut water, fruit juice 2) Hypochloremic Alkalosis 3) Dehydration 4) Hyponatremia 5) Ototoxicity: more likely with IV use, in RF, other ototoxic drugs

Loop Diuretics-Adverse Effects 6) Hyperuricemia 7) Hyperglycemia 8) Hyperlipidemia 9) Allergic reaction (SO 2 NH 2 group) 10) Hypomagnesemia 11) Overzealous use may precipitate volume depletion • Hepatic encephalopathy in hepatic coma • Renal failure • Cardiac failure

Carbonic Anhydrase Inhibitors

Acetazolamide - Site of Action

Carbonic Anhydrase (CA) Enzyme Cytoplasm of Proximal tubule C. A. H 2 O + CO 2 H 2 CO 3 C. A. H+ + HCO 3 - Renal brush border (Luminal) CA is also present in • Ciliary body of eye (Aquous humor formation) • Choroid plexus (CSF formation)

C. A. Inhibitor – Acetazolamide CO 2 + H 2 O CA Cytoplasmic (PT) H 2 CO 3 H+ + HCO-3 Na+ CO 2 + H 2 O CA H 2 CO 3 Luminal HCO 3 + Na. HCO 3 H+ Na+ Net effect of Acetazolamide • Loss of HCO 3, Na, K, Cl • Retention of H+ Met. Acidosis

Effects of Acetazolamide 1) Inhibits CA in the proximal tubule 2) Loss of HCO 3, Na, Cl in urine 3) Hypokalemia 4) Urine becomes alkaline and acidosis develops 5) Acidosis limits the diuretic action within 2 weeks Rarely used as diuretics

Acetazolamide ADVERSE EFFECTS USES 1. Hypokalemia, Fatigue • Glaucoma Oral Acetazolamide 2. Acidosis 3. Sedation 4. Paresthesias • To alkalinize the urine 5. Abdominal discomfort • Periodic paralysis 6. Allergic reactions • Epilepsy 7. C/I in liver disease • Rarely as a diuretic or topical dorzolamide • Acute mountain sickness

Exercises on 1 st Lecture

Question Fastest Finger First Q. Starting with lower to higher efficacy arrange the following diuretics according their efficacy (ability to cause maximum % excretion of the filtered Na+) 1. A. Amiloride B. Furosemide 2. C. Hydrochlorothaizide D. Mannitol Answer: A C D B

MCQ – Case Study type A 70 year old man is admitted with a history of heart failure and acute left ventricular myocardial infarction. He has severe pulmonary edema. Which of the following drugs is LEAST likely to prove useful in the treatment of acute pulmonary edema. 1. A. Bumetanide B. Ethacrynic acid 2. C. Furosemide D. Hydrochlorothiazide Answer D

True or False 1. NSAIDs may reduce the efficacy of loop diuretics 2. Acetazolamide does not lower intraocular tension 3. Frusemide overdose may cause alkalosis 4. Bumetanide is more potent than frusemide 5. Frusemide is useful in the Rx of hypercalciuria Answer T F T T F

To be continued in the next class

Title 6) Text

Title 6) Text

Table 1: (Comparsion of Loop diuretic with Thiazides) Parameters Site of action Loop diuretic Efficacy Ca excretion Rx of hypertension Site of action All values are Mean + S. E (n=6) Thiazide