2. By the end of this class, MBBS
Sem III students will be able
to:
Classify diuretics
Explain the mechanism of action of loop
diuretics and thiazide diuretics
Compare the adverse effects of loop diuretics
and thiazide diuretics
List their uses
Identify their common drug interactions
6. Relevant Physiology
Pharmacologically,
nephron is divided into:
Site I: Proximal
Convoluted Tubule
Site II: Thick Ascending
Limb of Loop of Henle
Site III: Cortical Diluting
segment of Loop of
Henle
Site IV: Distal
Convoluted Tubule and
7. Urinary constituent
movements: Site I
Sodium Potassium Water
Reabsorbed Reabsorbed
Along the
osmotic gradient
4 Processes:
• Direct entry
• Coupled to
absorption of
anions
• Exchanged with H+
• Passive diffusion
Utilizes:
• Paracellula
r pathways
Utilizes:
• Transcellular
aquaporin-1
channels
• Paracellular
pathways
8. Urinary constituent
movements: Site II
Movement of only salts occur
Impermeable to water
Luminal fluid
Cuboidal
cells of TAL
(medullary
portion)
Na+-K+-2Cl-
K+ Cl-
K+
Na+
Na+
Ca2+, Mg2+
Extracellular fluid
9. Urinary constituent
movements: Site III
Movement of only salts occur
Impermeable to water
Luminal fluid
Extracellular fluid
Cl-Na+
Na+-Cl- symporter No reabsorption or secretion of K+
10. Urinary constituent
movements: Site IV
Comprises of
Distal tubule
Collecting duct
Two types of cells
Principal cells
Intercalated cells
11. Urinary constituent
movements: Site IV
Principal cells
Intercalated
cells
Luminal fluid
Extracellular fluid
K+
Na+
Na+
Na+
Amiloride sensitive renal epithelial Na+
channels
• Sodium channel
• Present in renal epithelial cells
• Sensitive to amiloride
Modulated by aldosterone
H+
12. Diuretics
Causes net loss of Na+ and water in urine
Natriuretics
Reabsorption of Na+
PT: 65-70%
TAL: 20-25%
DT: 8-9%
CD: 2-3%
16. High ceiling diuretics
Furosemide, Bumetanide, Torasemide
Dose dependent diuresis occurs
Up to 10L/d of urine can be produced
Quick onset of action
Intravenous: 2-5 mins, Oral 20-40 mins
Short duration of action
4-6 hours
17. Furosemide: Mechanism of
action
Secreted by Organic anion transporter (OATP)
present in PT cells
Reaches Thick Ascending Limb of LoH
Inhibits Na+-K+-2Cl- cotransporter
• Decreased absorption of Na+
• High amount of Na+ and water excreted in
urine
19. Furosemide: Mechanism of
action
Minor actions:
Inhibits Carbonic anhydrase enzyme in PT
• Increase HCO3
- excretion
• Mild alkalosis in high dose (due to loss of
Cl-)
Increased local PG synthesis
• Altered intrarenal haemodynamic
20. Furosemide: Other actions
Prompt increase in systemic venous
capacitance
PG mediated
Decreases left ventricular filling pressure
Affords quick relief in Left ventricular failure
and Pulmonary oedema
21. Furosemide: Pharmacokinetics
Absorption after oral administration takes 2-3
hours
Bioavailability 60%
Reduced in severe congestive heart failure
Plasma t1/2 1-2 hour
Single oral dose acts for 4-6 hrs
Prolonged in pulmonary oedema, renal and
hepatic insufficiency
23. Medium efficacy diuretics
Thiazide and thiazide like drugs
Have flat dose-response curves
Acts in cortical diluting segment of
LoH or early DT
Acts by inhibiting Na+-Cl- symporter
Additional carbonic anhydrase
inhibitor action
Alkaline urine rich in Cl- produced
24. Thiazide: Mechanism of action
Secreted by OATP in PT
Reaches cortical diluting segment or early DT
along luminal fluid
Inhibits Na+-Cl- symporter
Decreased Na+ and Cl- absorption
Increased urine passed
25. Thiazide: Mechanism of action
Luminal fluid
Extracellular fluid
Cl-Na+
Na+-Cl- symporter No reabsorption or secretion of K+
26. Thiazides: Other actions
Additional carbonic anhydrase inhibitory action
Increase HCO3
- and PO4
3- excretion
Reduces GFR
By reducing blood volume and by inducing
intrarenal haemodynamic changes
• Not effective in patients with low GFR
Extrarenal actions
Slow developing fall in BP
Elevation of blood sugar
27. Thiazides: Pharmacokinetics
Well absorbed orally
Action starts within 1 hour, duration 6-48 hrs
Hydrochlorothiazide: 6hrs
Chlorthalidone: 48 hrs
Variable distribution (depends on lipid
solubility)
Eliminated mainly unchanged in urine
28. Thiazides: Uses
Hypertension
One of the First line drugs (Chlorthalidone)
Oedema
Diabetes Insipidus (DI)
Nephrogenic DI
Hypercalciuria with recurrent calcium stones in
the kidney
29. ADRs: Loop Diuretics vs
Thiazides
Loop Diuretics Thiazide
Hypokalaemia Less common
More
common
Acute Saline
Depletion
Seen
Not So
Common
Dilutional
Hyponatremia
After vigorous use
of Loop diuretics in
CHF
Rare
30. ADRs: Loop Diuretics vs
Thiazides
Loop Diuretics Thiazide
GIT and CNS
Disturbances
Nausea/Vomiting, diarrhoea,
headache, giddiness, weakness,
paraesthesia, impotence
Allergic
manifestation
• Rashes, photosensitivity
• Rarely blood dyscrasias
• Sulphonamide hypersensitivity
Hearing Loss
Only with Loop
diuretics
31. ADRs: Loop Diuretics vs
Thiazides
Loop Diuretics Thiazide
Mental
Confusion and
hepatic coma
Due to brisk
diuresis in
cirrhotic patients
Magnesium
depletion
Seen after prolonged use
Renal
insufficiency
Can be used in
renal
insufficiency
Aggravated
due to
decreased
GFR
32. ADRs: Loop Diuretics vs
Thiazides
Loop
Diuretics
Thiazide
Hyperuricemia Less common
High dose
thiazides
Hyperglycaemi
a,
hyperlipidaemi
a
Hypocalcaemia
Seen on
chronic Not seen
33. Drug Interactions: Loop
diuretics and Thiazides
Potentiates all other antihypertensives
As it induces Hypokalaemia:
Enhances digitalis toxicity
Increased risk of Cardiac arrhythmia
Reduces sulfonylurea action (oral
hypoglycaemics)
34. Drug Interactions: Loop
diuretics and Thiazides
Additive ototoxicity and nephrotoxicity of
aminoglycosides
Actions reduced when used with indomethacin
and other NSAIDs
Probenecid and diuretics reduces each other’s
actions
Serum Lithium level rises
35. Post Test
All of the following are the adverse effects of
thiazide diuretics EXCEPT:
?Hypomagnesemia
?Hypovolaemia
?Hypocalcaemia
?Hypokalaemia
36. Conclusion
Diuretics can be broadly grouped into three
categories
Loop diuretics acts by inhibiting Na+-K+-2Cl-
cotransporter, Thiazides act by inhibiting Na+-Cl-
symporter
Loop diuretics and thiazides share some side
effects and have some specific side effects
Are commonly employed in HTN, oedema
Drug interactions of loop diuretics can enhance
If a drug is active in PT, compensatory mechanisms will act and decrease the effect produced, hence weak diuretics
If a drug is active in TAL, significant step in urine formation is blocked: THE DRUGS WILL BE HIGHLY EFFICACIOUS (compensatory mechanism post TAL is only 10-12%)
If a drug is active in DT, significant steps in urine formation (85-95%) is already over, so they will be less efficacious
If a drug is active in late DT and CD, it will effect only 2-3% of urine formation, hence weak diuretics
Oedema:
Preferred in CHF
Nephrotic syndrome, chronic renal failure, resistant edema
Impending acute renal failure
Acute pulmonary oedema (acute Left Ventricular Failure, following Myocardial Infarction)
Hypertension
Co-existing renal insufficiency, CHF, resistant cases, hypertensive emergencies
Along with Blood Transfusion
Hypercalcemia of malignancy
Cerebral edema
Combined with osmotic diuretics to improve efficacy
Longer acting drugs cause more K+ loss
Symptoms- weakness, fatigue, muscle cramps, cardiac arrhythmias
Prevented/ treated by- high dietary intake, (KCl supplements, concurrent use of K+ sparing agents- ACE inhibitors/ AT1 antagonists: cirrhotics, cardiac pts-post MI, receiving digitalis, antiarrhythmics, TCA, elderly pts)
Acute saline infusion: treat with saline infusion
Dilutional Hyponatremia: water retained due to compensatory mechanism of kidney, Na not rertained due to diuretics, ecf gets diluted, pt thirsty, t/t: withhold diuretics, restrict water intake, give glucocorticoids, treat co-existing hypokalemia
Longer acting drugs cause more K+ loss
Symptoms- weakness, fatigue, muscle cramps, cardiac arrhythmias
Prevented/ treated by- high dietary intake, (KCl supplements, concurrent use of K+ sparing agents- ACE inhibitors/ AT1 antagonists: cirrhotics, cardiac pts-post MI, receiving digitalis, antiarrhythmics, TCA, elderly pts)
Acute saline infusion: treat with saline infusion
Dilutional Hyponatremia: water retained due to compensatory mechanism of kidney, Na not rertained due to diuretics, ecf gets diluted, pt thirsty, t/t: withhold diuretics, restrict water intake, give glucocorticoids, treat co-existing hypokalemia
Longer acting drugs cause more K+ loss
Symptoms- weakness, fatigue, muscle cramps, cardiac arrhythmias
Prevented/ treated by- high dietary intake, (KCl supplements, concurrent use of K+ sparing agents- ACE inhibitors/ AT1 antagonists: cirrhotics, cardiac pts-post MI, receiving digitalis, antiarrhythmics, TCA, elderly pts)
Acute saline infusion: treat with saline infusion
Dilutional Hyponatremia: water retained due to compensatory mechanism of kidney, Na not rertained due to diuretics, ecf gets diluted, pt thirsty, t/t: withhold diuretics, restrict water intake, give glucocorticoids, treat co-existing hypokalemia
Longer acting drugs cause more K+ loss
Symptoms- weakness, fatigue, muscle cramps, cardiac arrhythmias
Prevented/ treated by- high dietary intake, (KCl supplements, concurrent use of K+ sparing agents- ACE inhibitors/ AT1 antagonists: cirrhotics, cardiac pts-post MI, receiving digitalis, antiarrhythmics, TCA, elderly pts)
Acute saline infusion: treat with saline infusion
Dilutional Hyponatremia: water retained due to compensatory mechanism of kidney, Na not rertained due to diuretics, ecf gets diluted, pt thirsty, t/t: withhold diuretics, restrict water intake, give glucocorticoids, treat co-existing hypokalemia