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?