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BYL Nair Ch. Hospital, Mumbai

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

2 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

3 Overview of 1st 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


5 Thiazides - Sites of Action

6 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

7 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)

8 Thiazides Preparations
Drug Name Dose (oral) Duration (hr) Chlorothiazide (1957) 6-12 Hydrochlorothiazide 25-100 8-12 Benzthiazide 12-18 Hydroflumethiazide 12 Chlorthalidone 50-100 48 Metolazone 5-20 18 Xipamide, Clopamide 20-40 12-24 Indapamide (No CAI) 2.5-5 24-36

9 Thiazides - Uses Hypertension (Hydrochlorothiazide, Indapamide)
Edema : Cardiac, Hepatic Renal Less efficacious than loop diuretic Useful for maintainence therapy Hypercalciuria and renal Ca stones 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 Metolazone useful even when GFR is as low as 15ml/min

10 Thiazides -Adverse Effects
Hypokalemia May ppt renal failure Hyperuricemia Hyperglycemia Hyperlipidemia Hypomagnesemia Hypchloremic alkalosis Hypersensitivity ppt. Hypercalcemia Not safe in pregnancy (all diuretics)

11 Osmotic Diuretics Ideal properties Drugs used Mannitol Glycerol
Orally effective Well abosorbed Not metabolized Freely filtered at glomeruli Not reabsorbed Inert Cheap Drugs used Mannitol Glycerol Isosorbide

12 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 H2O  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

13 Osmotic diuretic - Preparations
Drug Daily 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

14 Mannitol - USES ARF : treatment & prevention
To maintain GFR during major surgeries, trauma cases, severe jaundice, hemolytic reactions etc To lower intracranial tension Before brain surgery Cerebral edema To lower intraocular tension Acute glaucoma Before intraocular surgeries Forced diuresis in drug poisoning (FAD in barbiturate poisoning To counteract low plasma osmolality after dialysis

15 Mannitol -Adverse Effects
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 Thrombophlebitis Headache (due to hyponatremia), Nausea If overdose  dehydration  hypernatremia Monitoring of urine output, S. electrolytes, CVP is very imp. Step 6 of rational pharmacotherapy

16 Potassium Sparing Diuretics - Site of Action

17 Potassium sparing diuretics – MOA at cortical DT

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

19 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

20 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)

21 Spironolactone - uses Edema more useful in cirrhotic and nephrotic syndrome breaks resistance to thiazides or frusemide in refractory edema To counteract K loss due to thiazides, frusemide Hypertension: combined with thiazide Eplerenone is a new drug approved for HT, No gynaecomastia CHF: as a adjunctive therapy it retards disease progression and reduces mortality RALES (Randomized ALdosterone Evaluation Study) Primary Hyperaldosteronism (Conn’s syndrome)

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

23 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

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

25 Exercises on 2nd Lecture

26 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. Triamterene B. Hydrochlorothiazide C. Acetazolamide D. Bumetanide Answer: C D B A

27 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

28 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

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

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

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

32 End of diuretic lectures. Any Questions?




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