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
• Few MCQs
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: To maintain homeostasis (Excretion is a by product).
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
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. 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 (moderate efficacy) : block only 10% of Na reabsorption
12. 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)
13. Nephron parts and their functions
SEGMENT FUNCTION
Glomerulus Formation of glomerular filtrate
Proximal convoluted tubule (PCT) Reabsorption: 100 % of glucose and amino acids
65% 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
14. The relative magnitudes of
Na+
reabsorption at sites
• PT - 65%
• Asc LH - 25%
• DT - 9%
• CD - 1%.
18. THIAZIDES AND THIAZIDE LIKE DIURETICSTHIAZIDES AND THIAZIDE LIKE DIURETICS
Renal
tubule
Peritubular
capillary
19. 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
20. 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)
21. 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.
22. 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.
23. 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
26. 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
27. Loop diuretics
Frusemide, Bumetanide, Torasemide, Ethacrynic acid
Mechanism of action
Individual drugs
Pharmacokinetics
Indications
Dose
Side effects and Precautions
Drug interactions
29. Loop diuretics
Sulfonamide derivative
Most popular powerful loop diuretic.
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 reduces efficacy
(e.g. probenecid)
30. Mechanism of action
Frusemide blocks the Na+
, K+
, 2Cl-
symporter in the ascending
limb of the LH. Inhibit NaCl reabsorption
Enhance the excretion of K+
, Ca++
and Mg++
(but Ca++
is reabsorbed
in the distal tubule).
Prolonged use can cause hypomagnesemia.
Increase reabsorption of uric acid
Vasodilation in renal vasculature and increase renal blood flow.
Intravenous frusemide causes vasodilatation and
reduces left ventricular filling pressure
32. High ceiling diuretics (Loop diuretics)
Furosemide –Rapid and short acting, Can be given IM, IV and oral
Given Intravenously (10 mg) acts in 2-5 minutes;
Orally (40 mg) it takes 20-40 minutes, Can produce upto 10 L of urine/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
Better tolerated because the adverse effects like hypokalemia,
ototoxicity, hyperglycaemia and hyperuricaemia are milder but may
cause myopathy
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
Oedema
Acute renal failure, In chronic renal failure large doses are needed.
Acute pulmonary oedema
Cerebral oedema
Forced diuresis: In poisoning due to fluoride, iodide and bromide
respond to furosemide with saline infusion.
Hypertension: With renal impairment
Thiazides are preferred diuretics in primary hypertension.
Acute hypercalcemia and hyperkalemia:
36. Loop diuretics: Adverse effects
Hypokalaemia and metabolic alkalosis
Hypokalaemia should be particularly prevented in post MI patients
and in patients who are receiving digitalis.
Hyponatraemia, hypovolaemia, hypotension and dehydration,
Hypocalcaemia
Hypomagnesaemia
Hyperuricaemia, Hyperglycaemia
Ototoxicity
Allergic reactions like skin rashes can occur.
Remember 6 Hypo, 2 Hyper & 1 O
37. 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
38. MCQ 1s
A 50-year old man has a history of frequent episodes of renal
colic with high calcium with renal stone. The most useful diuretic
in the treatment of recurrent calcium stone is
a) Furosemide
b) Spironolactone
c) Hydrochlorothiazide
d) Acetazolamide
39. MCQ 2s
An elderly patient with h/o of heart disease and having difficulty
in breathing. She was diagnosed to have pulmonary oedema.
Which of the following drug is indicated?
a) Spironolactone.
b) Furosemide
c) Acetazolamide.
d) Chlorthalidone
e) Hydrochlorothiazide.
40. MCQ 3s
A 60 years old male patient with kidney stone has been placed
on a diuretic to decrease calcium excretion. After few weeks, he
develops an attack of gout. Which diuretic was he taking?
a) Furosemide
b) Hydrochlorothiazide.
c) Spironolactone.
d) Triamterene.
41. MCQ 4s
A 65 years old hypertensive patient was treated with a thiazide.
Her B.P was well controlled and reads at 120/76 mm Hg, After few
months of medication, she complains of being tired and weak. An
analysis of the blood may show low values for
a) Calcium
b) Uric acid
c) Potassium.
d) Sodium.
42. MCQ 5
Indomethacin can antagonize the
diuretic action of furosemide by
a) Blocking the ascending limb of loop of Henle
b) Enhancing salt and water reabsorption in distal tubules
c) Increasing aldosterone secretion
d) Preventing prostaglandin mediated intrarenal
hemodynamic action
43. Useful suggestions
Obtain baseline values
Monitor periodically
lab values, weight, current level of urine output
Electrolytes, especially potassium, sodium, and chloride
BUN, serum creatinine, uric acid, and blood-glucose levels
for side effects orthostatic hypotension, hypokalemia, hyponatremia,
polyuria
Assess for circulatory collapse, dysrhythmias, hearing loss, renal failure, and anemia
Advice to take diuretics in the morning, change position slowly, monitor weight
If necessary advice to take potassium supplements, and consume potassium–rich foods
(e.g, tender coconut)
