Lecture 1 adithan diuretics july 22, 2016 mgmcri

1. Diuretics (1/2)
Dr. C.Adithan
Professor of Pharmacology

2. Overview of 1st
lecture
• Definition
• Physiology of Urine formation and drugs modifying it
• Classification
• Pharmacology of Thiazide diuretics and Loop diuretics
• Mechanism of action
• Indications
• Dose
• Side effects
• Drug interactions

3. Kidney functions
Balance of electrolytes, Plasma volume, Acid Base
Activation of Vitamin D
Synthesis of Erythropoietin, Urokinase
Excretion of Urea, Uric acid, Creatinine etc.
 Primary Function is to maintain homeostasis.
 Excretion is a by product of that homeostasis.
 Homeostasis is maintained by
Regulation of water volume, blood volume, and interstitial fluid volume.
 First warning signs about kidneys dysfunction ????

4. Causes of Generalized Oedema
• Cardiac Cause: Congestive cardiac failure
• Renal Cause: Nephrotic syndrome
• Hepatic Cause: Cirrhosis of liver
• Nutritional cause: Malnutrition
• Allergic reaction
• Drug Induced

5. Diuretics
Drugs which cause a net loss of Na+ and
water in urine.
(Except Osmotic diuretics which do not cause Natriuresis
but produce diuresis)
• Causes increase in urine volume due to increased osmotic pressure
in lumen of renal tubule.
• Causes concomitant decrease in extra-cellular volume (blood
volume)

6. In order to understand the Diuretics,
we need to know the physiology of Urine formation

7. PHYSIOLOGY OF URINE FORMATION
Three major steps are involved.
1) Glomerular filtration.
2) Tubular Reabsorption &
3) Active tubular secretion.
Nephron can be divided
into four sites.
- Proximal tubule
- Henle’s loop
- DCT
- Collecting duct.
Normal GFR is 125ml/min or
180 litres/day, of which 99% gets
reabsorbed and only 1.5 litres is
excreted as urine.

8. IntroductionIntroduction

9. Proximal tubule
Freely permeable to water,
Active absorption of NaCl, NaHCO3, Glucose, Amino Acids, Organic Solutes
This is followed by passive absorption of water
Osmotic diuretics act at PCT and also on LH (descending limb) byOsmotic diuretics act at PCT and also on LH (descending limb) by
interposing a countervailing osmotic forceinterposing a countervailing osmotic force
Substance % of filtrate reabsorbed in PCT
•65-80% of the filtrate is reabsorbed
•Most reabsorption is coupled to sodium ion movement
Sodium and Water ~66%
Organic solutes e.g. glucose
and amino acids
~100%
Potassium ~65%
Urea ~50%
Phosphate ~80%

10. Loop of Henle (LH)
• Descending limb-
Permeable to water
• Thick ascending limb –
Impermeable to water but
Permeable to sodium by Na+
K+
2Cl-
Co transport
About 25% of filtered sodium is absorbed here
Loop diuretics act here and blocks the co-transporter.

11. Macula Densa and Juxtaglomerular (JG) Apparatus
• Contact between Ascending limb with afferent arterioles
– by specialized columnar epithelial cells Macula Densa
• Macula Densa sense NaCl conc. in filtrate
• Gives signal to JG apparatus present in afferent
arterioles
• JG of afferent arterioles secrete Renin
• In low B.P. or low Na , renin secretion is increased
leading to Angiotensin secretion resulting in
vasoconstriction, sodium and water retention.

12. Distal Convoluted Tubule
• In the Early distal tubule 10% of NaCl is reabsorbed by Na-Cl
symport transporter mechanism.
• On reaching the DCT almost 90% of sodium is already
reabsorbed.
• Calcium excretion is regulated (Parathomone and Calcitriol,
increase absorption of calcium)
• Thiazides block Na-Cl symport transporter system.
• Thiazides are called moderate efficacy diuretics as they
reabsorb only 10% of sodium

13. Collecting Tubule and Collecting Duct
• Aldosterone- On membrane receptor and
cause sodium absorption by Na+
/H+
/ K+
Exchange
• ADH- Collecting tubular epithelium
permeable to water (Water enters through
aquaporin-2)

14. Nephron parts and their functions
SEGMENT FUNCTION
Glomerulus  Formation of glomerular filtrate
Proximal convoluted tubule (PCT)  Reabsorption: 100 % of glucose and amino acids65% of Na+
/K+
/ Ca2+
, Mg2+,
;
85% of NaHCO3, (activity of Carbonic anhydrase enzyme)
 Iso-osmotic reabsorption of water.,
 Secretion and reabsorption of organic acids and bases, including uric acid and drugs
penicillin, probenecid and most diuretics
Thin descending limb of LH  Passive reabsorption of water
Thick ascending limb of LH  Active reabsorption: 25% of filtered Na+
/K+
/2Cl−;
 Secondary re-absorption of Ca2+
and Mg2+
Distal convoluted tubule (DCT)
Active reabsorption of 4–8% of filtered Na+
Cl−;
Ca2+
reabsorption under
parathyroid hormone control
Cortical collecting tubule (CCT) Na+
reabsorption (2–5%) coupled to K+ and H+ secretion (under Aldosterone)
Medullary collecting duct Water reabsorption under Vasopressin control

15. The relative magnitudes of
Na+
reabsorption at sites
• PT - 65%
• Asc LH - 25%
• DT - 9%
• CD - 1%.

16. Classifications of Diuretics
• Thiazide Diuretics:
a) Thiazides: Hydrochlorothiazide, Benzthiazide
b) Thiazide like: Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide
• Loop Diuretics : Frusemide, Bumetanide, Torasemide, Ethacrynic acid
• Potassium Sparing Diuretics :
– Aldosterone Antagonist: Spironolactone, Canrenone, Eplerenone
– Directly Acting (Inhibition of Na+
channel): Triamterene, Amiloride
• Carbonic anhydrase inhibitors : Acetazolamide, Brinzolamide,
Dorzolamide
• Osmotic Diuretics : Mannitol, Glycerine, Urea, Isosorbide

17. 1. Osmotic diuretics
2. Carbonic anhydrase inhibitors
3. Loop Diuretics (High ceiling)
4. Thiazide diuretics
5. Potassium sparing diuretics
1. Osmotic diuretics
2. Carbonic anhydrase
inhibitors
3. Loop diuretics
4. Thiazide diuretics
5. Potassium diuretics

18. Thiazide diuretics
»Mechanism of action
»Individual drugs
»Pharmacokinetics
»Indications
»Dose
»Side effects and Precautions

19. THIAZIDES AND THIAZIDE LIKE DIURETICSTHIAZIDES AND THIAZIDE LIKE DIURETICS
Renal
tubule
Peritubular
capillary

20. 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

21. 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 ?)
• Hyperlipidemia (Cholesterol and TG)

22. Thiazide drugs
 Chlorthalidone: Used only for hypertension, long acting (t1/2 – 50 hr)
 Metolazone: Active even in low GFR. Additive with furosemide.
Used mainly for edema, occasionally for hypertension.
 Xipamide: More strong diuretic. Used for edema and hypertension
More incidence of hypokalaemia and
ventricular arrhythmia.
 Indapamide: Extensively metabolized.
Very less amount reach kidney.
Used only as antihypertensive.

23. Pharmacokinetics
 Well absorbed orally
 Rapid acting- within 60 minutes.
 Thiazides are organic acids they are secreted into the
proximal tubules.
 Partly excreted by the hepatobiliary system.

24. Thiazides - Uses
1) Hypertension (Hydrochlorothiazide, Indapamide)
2) Edema : Cardiac, Hepatic, Renal
• Less efficacious than loop diuretic
• Useful for maintenance therapy
1) Hypercalciuria and renal Ca stones
2) 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 15 ml/min

25. Thiazides Preparations
Drug Name Dose in mg (oral) Duration (hr) Cost (Rs)
per tablet
Chlorothiazide (1957) 500-2000 6-12
Hydrochlorothiazide 12.5-100 8-12 Rs.1.20 (25 mg)
Benzthiazide 25-100 12-18
Hydroflumethiazide 25-100 12
Chlorthalidone 50-100 48 Rs.2.40 (100 mg)
Metolazone 5-20 18 Rs.6 – 10 (2.5 mg)
Xipamide, Clopamide 10-40 12-24 Rs.3.20 (20mg)
Indapamide (No CAI) 2.5-5 24-36

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

27. Thiazide diuretics - Summary
 Medium efficacy diuretics – Inhibit Na Cl symport
 Cause more hyperuricemia and hypokalaemia than
loop diuretics
 Not effective in patients with renal dysfunction
 Decrease Ca excretion. Increase Mg excretion
 Duration of action varies between 6 – 48 hours

28. Loop diuretics
Mechanism of action
Individual drugs
Pharmacokinetics
Indications
Dose
Side effects and Precautions
Drug interactions

29. Comparison of loop and thiazide diuretics

30. Loop diuretics
 Generally cause greater diuresis than thiazides; used
when they are insufficient
 Can enhance Ca2+
and Mg2+
excretion
 Enter tubular lumen via proximal tubular secretion
(unusual secretion segment) because body treats
them as a toxic drug
 Drugs that block this secretion (e.g. probenecid)
reduces efficacy

31. High ceiling diuretics (Loop diuretics)

32. High ceiling diuretics (Loop diuretics)
 Furosemide – Also called frusemide. Rapid and short acting.
 Can be given IM, IV and oral
 Can produce up to 10 litres of urine per day.
 Effective even in patients with severe renal failure
 Cause peripheral venous dilation and relieves LVF
 Cause Ca and Mg excretion through urine
 Hyperuricemia and hypokalemia
 May cause ototoxicity
 Dose: 20 – 80 mg OD in morning

33. High ceiling diuretics (Loop diuretics)
 Bumetanide – similar to furosemide. 40 times more potent
 Can respond in patients resistant to furosemide
 Can be used in patients allergic to furosemide
 Can cause myopathy (rarely)
 Less ototoxicity compared to furosemide
 Used in CHF and pulmonary edema
 Dose: 1 – 5 mg OD in morning

34. High ceiling diuretics (Loop diuretics)
Torasemide – also called torsemide
Similar to furosemide – 3 times more potent
Slightly longer acting
Used in edema and hypertension

35. Uses - Loop diuretics
 Peripheral edema
 Acute pulmonary edema
 Cerebral edema – (osmotic diuretics more preferred)
 Hypertension – (not first choice. Only in presence of CHF, renal
insufficiency etc)
 With blood transfusion to prevent volume overload
 In hypercalcemia of pregnancy – IV infusion of large volume
saline, followed by furosemide to excrete calcium and
prevent volume overload

36. Loop & Thiazide drugs
Interactions
Potentiate antihypertensive drugs
Hypokalaemia by diuretics – cause digitalis toxicity,
arrhythmias
Furosemide with aminoglycosides – ototoxicity and
nephrotoxic
Cotrimoxazole with diuretics – thrombocytopenia
NSAIDS with furosemide – blunt action of furosemide

37. Loop & Thiazide drugs: Complications
 Hypokalaemia
 Acute saline depletion
 Dilutional hyponatremia
 Hearing loss
 Hyperuricemia
 Hyperglycaemia
 Hypocalcaemia with loop and hypercalcemia with
thiazides
 Magnesium loss

38. To be continued in the next class

39. Thank you
To be continued in the next class