1. 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

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 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

4. 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

5. 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?

7. 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

8. 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

9. Diuretics - Sites of Action

10. 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

11. Loop Diuretics-Preparations, dosage
Drug
Dose (mg)
Frusemide
20- 80
Torsemide
Bumetanide
0.5 – 2
Ethacrynic Acid
50-200
Which is the most potent loop diuretic?
Bumetanide

12. 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)

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

14. 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

15. 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

16. Carbonic Anhydrase Inhibitors

17. Acetazolamide - Site of Action

18. Carbonic Anhydrase (CA) Enzyme
Cytoplasm of Proximal tubule
C.A.
H2O + CO H2CO H+ + HCO3-
C.A.
Renal brush border (Luminal)
CA is also present in
Ciliary body of eye (Aquous humor formation)
Choroid plexus (CSF formation)

19. C.A. Inhibitor – Acetazolamide
CO2 + H2O H2CO3
H+ + HCO-3
Cytoplasmic (PT)
NaHCO3
Na+
CO2 + H2O H2CO HCO3 + H+
Na+ CA
Luminal
Net effect of Acetazolamide
Loss of HCO3, Na, K, Cl
Retention of H+  Met. Acidosis

20. 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

21. 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

22. Exercises on 1st Lecture

23. 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

24. 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

25. 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

26. To be continued in the next class

28. Title
Text

29. Title
Text

30. 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)