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

Learning Objectives At the end of my 2 lectures you should be able to List 5 major types of diuretics and their mechanism and site of action List the major applications and toxicities of them Describe the measures that reduce K+ loss during natriuresis List the Rx of hypercalcimia and hypercalciuria manage refractory edema cases 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 1ml/min  60ml/hr 1.5L/day Most diuretics prevent reabsorption of Na & H2O

Diuretic - Definition Diuretic = drug which increase urine formation Increase urine volume (Diuresis) Increase excretion of Na and H2O (Natriuresis) Mechanisms of diuresis Extrarenal By increasing Cardiac output : Digoxin, Dopamine in CHF By Inhibiting ADH : H2O, alcohol On the kidney (Nephron) – Most diuretics Inhibit Na and H2O reabsorption Q. What will be the uses of diuretics in therapuetics?

Diuretics- Classification High efficacy (upto 25% NaCl excretion) Loop diuretics Frusemide, Torsemide, Bumetanide (SO2NH2 group) Ethacrynic acid (No SO2NH2 group) Organic mercurials: Mersalyl (Now obsolete) Medium efficacy (5 –10 % NaCl excretion) Thiazides : Hydrochlorothiazide, ChloroTh, BenzTh, HydroflumeTh, Clopamide, PolyTh Thiazide like : Chlorthalidone, Metolazone, Xipamide, Indapamide

Diuretics- Classification Carbonic Anhydrase Inhibitors (5%NaCl excretion ) Acetazolamide, Methazolamide, Dichlorphenamide Potassium Sparing Diuretics (3% NaCl excretion) Aldosterone Antagonists Spironolactone, eplerenone Directly acting: Amiloride, Triamterene Osmotic Diuretics (upto 20% NaCl excretion) 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+-2Cl-cotransport and reabsorption Increase NaCl excretion (upto 25% High efficacy) Na exchanges with K+ in the DT  K+ loss Effective in very low GFR of < 30ml/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 Edema : Cardiac (CHF), Hepatic (cirrhotic Ascites), Renal (Nephrotic syndrome) Acute pulmonary edema Cerebral edema (Mannitol preferred) Acute hypercalcemia Acute Renal failure Forced diuresis in drug poisoning (Barbiturate)

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

Loop Diuretics-Adverse Effects Hypokalemia Clinical Features : may Increase digoxin toxicity, arrhythmia Muscle weakness, fatigue, cramps 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 Hypochloremic Alkalosis Dehydration Hyponatremia Ototoxicity: more likely with IV use, in RF, other ototoxic drugs

Loop Diuretics-Adverse Effects Hyperuricemia Hyperglycemia Hyperlipidemia Allergic reaction (SO2NH2 group) Hypomagnesemia 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. H2O + CO2 H2CO3 H+ + HCO3- C.A. Renal brush border (Luminal) CA is also present in Ciliary body of eye (Aquous humor formation) Choroid plexus (CSF formation)

C.A. Inhibitor – Acetazolamide CO2 + H2O H2CO3 H+ + HCO-3 Cytoplasmic (PT) NaHCO3 Na+ CO2 + H2O H2CO3 HCO3 + H+ Na+ CA Luminal Net effect of Acetazolamide Loss of HCO3, Na, K, Cl Retention of H+  Met. Acidosis

Effects of Acetazolamide Inhibits CA in the proximal tubule Loss of HCO3, Na, Cl in urine Hypokalemia Urine becomes alkaline and acidosis develops Acidosis limits the diuretic action within 2 weeks Rarely used as diuretics

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

Exercises on 1st 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+) A. Amiloride B. Furosemide 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. A. Bumetanide B. Ethacrynic acid C. Furosemide D. Hydrochlorothiazide Answer D

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

To be continued in the next class

Title Text

Title Text

Table1:(Comparsion of Loop diuretic with Thiazides) Parameters Loop diuretic Thiazide Site of action Efficacy Ca excretion Rx of hypertension This Table 1 shows the various Pk parameters of valproate in single dose study design. There was no significant change in any of the parameter studied when mentat was co-administered with mentat. All values are Mean + S.E (n=6)