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 ????
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.
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%.
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
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
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
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