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DIURETICS (2 of 2) Dr R. P. Nerurkar Dept. of Pharmacology T. N. Medical College & BYL Nair Ch. Hospital, Mumbai DECEMBER 7, 2005.

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Presentation on theme: "DIURETICS (2 of 2) Dr R. P. Nerurkar Dept. of Pharmacology T. N. Medical College & BYL Nair Ch. Hospital, Mumbai DECEMBER 7, 2005."— Presentation transcript:


2 DIURETICS (2 of 2) Dr R. P. Nerurkar Dept. of Pharmacology T. N. Medical College & BYL Nair Ch. Hospital, Mumbai DECEMBER 7, 2005

3 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

4 Overview of 1 st lecture Definition Physiology of Urine formation and drugs modifying it Classification and Mechanism of action Pharmacology of Loop diuretics and CA inhibitors Group discussion and Exercises on –Prescription writing, –Patient oriented problem solving –Identification of drugs acting –ADR and drug interactions


6 Thiazides - Sites of Action

7 Thiazide Diuretics - Actions Acts on early part of distal tubules Inhibit Na + -Cl - symporter and reabsorption Increase NaCl excretion (5-10% Medium efficacy) Na exchanges with K + in the DT  K + loss  Hypokalemia Not effective in very low GFR of < 30ml/min, may reduce GFR further –Metolazone  additional action on PT, effective at low GFR, can be tried in refractory edema

8 Thiazide Diuretics - Other actions Hypotensive action reduce Ca ++ excretion  may ppt hypercalcemia in patients of hyperparathyroidism, bone malignancy with metastasis Increase Mg++ excretion Hypochloremic alkalosis Hyperuricemia Hyperglycemia (inhibit insulin release ?) Hyperlipidimia (Cholesterol and TG)

9 Thiazides Preparations Drug NameDose (oral)Duration (hr) Chlorothiazide (1957) 500-20006-12 Hydrochlorothiazide25-1008-12 Benzthiazide25-10012-18 Hydroflumethiazide25-10012 Chlorthalidone50-10048 Metolazone5-2018 Xipamide, Clopamide20-4012-24 Indapamide (No CAI) 2.5-524-36

10 Thiazides - Uses 1)Hypertension (Hydrochlorothiazide, Indapamide) 2)Edema : Cardiac, Hepatic Renal Less efficacious than loop diuretic Useful for maintainence therapy 3)Hypercalciuria and renal Ca stones 4)Diabetes Insipidus (DI) (Nephrogenic responds better) Paradoxical use, MOA - ? Reduce GFR, ? More complete reabsorption in PT Convenient, Cheaper than Desmopressin in Neurogenic DI Amiloride is the DOC for Lithium induced nephrogenic DI 5)Metolazone useful even when GFR is as low as 15ml/min

11 Thiazides -Adverse Effects 1)Hypokalemia 2)May ppt renal failure 3)Hyperuricemia 4)Hyperglycemia 5)Hyperlipidemia 6)Hypomagnesemia 7)Hypchloremic alkalosis 8)Hypersensitivity 9)ppt. Hypercalcemia 10)Not safe in pregnancy (all diuretics)

12 Osmotic Diuretics Ideal properties 1.Orally effective 2.Well abosorbed 3.Not metabolized 4.Freely filtered at glomeruli 5.Not reabsorbed 6.Inert 7.Cheap Drugs used Mannitol Glycerol Isosorbide

13 Mannitol - Actions not mediated by any receptors or target site Expands ECF volume – increase RBF, GFR Osmotic gradient in the tubular lumen prevent reabsorption of mainly H 2 O  dilute urine diuresis prevent Na + reabsorption - upto 20% NaCl excretion (Acute effect) May inhibit transport process in Asc loop of Henle classified as weak diuretic in some textbooks never used for chronic edema or as a natriuretic

14 Osmotic diuretic - Preparations DrugDaily dose Mannitol I.V. 10% or 20% soln. 1-2 gm/kg 100 – 300 ml rapid infusion Over 30 to 90 min Glycerol oral 1-1.5 gm/kg metabolized to glucose Isosorbide oral 1.5 gm/kg

15 Mannitol - USES 1)ARF : treatment & prevention To maintain GFR during major surgeries, trauma cases, severe jaundice, hemolytic reactions etc 2)To lower intracranial tension Before brain surgeryCerebral edema 3)To lower intraocular tension Acute glaucomaBefore intraocular surgeries 4)Forced diuresis in drug poisoning (FAD in barbiturate poisoning 5)To counteract low plasma osmolality after dialysis

16 Mannitol -Adverse Effects 1)Acute Intravascular volume expansion Before diuresis starts it exerts osmotic effect in the blood Contraindicated in pulmonary edema, Cardiac edema (CHF) and intracranial hemorrage, established renal failure 2)Thrombophlebitis 3)Headache (due to hyponatremia), Nausea 4)If overdose  dehydration  hypernatremia Monitoring of urine output, S. electrolytes, CVP is very imp. Step 6 of rational pharmacotherapy

17 Potassium Sparing Diuretics - Site of Action

18 Potassium sparing diuretics – MOA at cortical DT

19 Potassium sparing diuretics: Preparations Aldosterone AntagonistDose (mg)Route Spironolactone 25-100oral K canrenoate I.V. Eplerenone 25-100oral Directly Acting Amiloride 5Oral, Aerosol Triamterene 50oral Fixed dose combinations with thiazides and frusemide available but not advisable

20 Spironolactone - Actions Acts on cortical segment of distal tubules Competitive antagonist of Aldosterone Inhibit AIP  inhibit Na reabsorption Causes K’ retention (K sparing effect)  Hyperkalemia Mild saluretic (natriuresis) 3% of NaCl Never used alone as diuretic Useful when combined with thiazide or frusemide

21 Spironolactone - Pharmacokinetics Given orally microfine powder tab. Bioavailability 75% Converted to active metabolite canrenone K canrenoate is water soluble can be given I.V. gets converted to canrenone Onset of action is very slow (steroid receptors)

22 Spironolactone - uses 1)Edema more useful in cirrhotic and nephrotic syndrome breaks resistance to thiazides or frusemide in refractory edema 2)To counteract K loss due to thiazides, frusemide 3)Hypertension: combined with thiazide Eplerenone is a new drug approved for HT, No gynaecomastia 4)CHF: as a adjunctive therapy it retards disease progression and reduces mortality –RALES ( R andomized AL dosterone E valuation S tudy) 5)Primary Hyperaldosteronism (Conn’s syndrome)

23 Spironolactone – Adverse Effects 1)Hyperkalemia risk In CRF patients Patients taking ACEI (Enalapril) or ATRA (Losartan) KCl supplement 2)Related to steroid structure Gynaecomastia, Impotence in males Hirsutism, menstrual irregualarities in females 3)Misc: drowsiness, abdominal upset 4)Drug Interactions may increase digoxin levels in CHF NSAIDs (Aspirin) decreases its effect

24 Amiloride & Triamterene - Actions Direct action on DT and CD Amiloride sensitive or renal epithelial Na channels are blocked Weak diuretic never used alone Indirectly inhibit K + secretion Also inhibit H + secretion Amiloride in aerosol form  cystic fibrosis ADRs, precautions similar to spironolactone but does not cause sexual dysfunction

25 Refractory Edema & Diuretic Resistance Causes Decreased access Binding to proteins 2 nd ary hyperaldosteronism Delayed absorption Nephron hypertrophy Management Salt restriction Bed rest Omit NSAIDs Multiple doses Metolazone Spironolactone Combination of diuretics Thiazide + Frusemide

26 Exercises on 2 nd Lecture

27 Question Fastest Finger First Q. Arrange the following diuretics according to their site of action starting from proximal to distal parts of the nephron. A. TriamtereneB. Hydrochlorothiazide C. AcetazolamideD. Bumetanide Answer: C D B A

28 Prescription - Criticize and Correct Prescription given to patient suffering from chronic congestive heart failure with hypertension with edema feet and basal crepts in the chest Rx Tab. Enalapril 20 mg twice daily Tab. Digoxin 0.25 mg once a day Inj. Hydrochlorothiazide 5 mg IV once a day Tab. Spironolactone 50 mg twice daily

29 MCQ – Case Study type A patient with long standing diabetic renal disease and hyperkalemia and recent onset congestive heart failure requires a diuretic. Which of the following would be LEAST harmful in a patient with severe hyperkalemia A. Amiloride B. Hydrochlorothiazide C. Spironolactone D. Losartan Answer B

30 MCQ – Effects of thiazides When used chronically to treat hypertension, thiazide diuretics have all of the following properties or effects EXCEPT A.reduce blood volume or vascular resistance or both B.have maximal effects on blood pressure at doses below maximum diuretic dose C.may cause elevation of plasma triglyceride levels D.decrease the urinary excretion of calcium E.cause ototoxicity Answer E

31 MCQ – Matching type One of the following diuretic is NOT properly matched with its indication for use A.Hydrochlorothiazide – Diabetes insipidus B.Eplerenone – Hypertension C.Mannitol – Acute pulmonary edema D.Spironolactone – Edema in cirrhosis of liver Answer C

32 True or False 1.Amiloride is a drug of choice for lithium induced nephrogenic diabetes insipidus 2.Mannitol is contraindicated in barbiturate poisoning 3.Spironolactone can be given intravenously 4.Diuretics should be avoided in pregnancy induced hypertension 5.Metolazone is useful even when GFR is very low Answer T F F T T

33 End of diuretic lectures. Any Questions?




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