critical care medicine

1. DIURETICS
MODERATOR: DR GOUTHAM
PRESENTER: DR SPOORTI PUJARI

2. DEFINITION :
These are drugs which cause a net loss of Na+ and water in urine
There are several categories of diuretics. All diuretics
increases the excretion of water from body

4. CLASSIFICATION
Diuretics are Classified as:
1. High ceiling /Loop diuretics…
2. Thiazides.
3.Carbonic anhydrase inhibitors.
4.Potassium –sparing diuretics.
5.Osmotic diuretics.

5. DIURETICS CLASSIFICATION
1.HIGH EFFICACY DIURETICS:
(Inhibitors of Na+,K+,2Cl- cotransport)
(a) Sulphamoyl deravatives:
Furosemide.
Bumetanide.
Torasemide.
(b) Phenoxyacetic acid derivative:
Ethacrynic acid.

6. 2.Medium efficacy diuretics :
( Inhibitors of Na+,Cl- symport)
(a) Benzothiadiazines(THIAZIDES):
Hydrochlorothiazide
Benzthiazide
Hydroflumethiazide
(b) Thiazide-like diuretics:
Chlorthalidone
Metolazone
Indapamide

7. 3.Weak or adjunctive diuretics:
(a) Carbonic anhydrase inhibitors:
Acetazolamide
(b) Potassium –sparing diuretics:
(i)Aldosterone antagonist:
Spironolactone
Eplerenone
(ii)Inhibitors of renal epithial Na+ channel:
Triamterene
Amiloride

8. (c) Osmotic diuretics:
Mannitol
Isosorbide
Glycerol

10. High-ceiling Diuretics
Mechanism of action:
• Act by inhibiting Na-K-2Cl cotransporter in Thick Ascending LOH.

11. • Loop diuretics when administered at maximum dose will lead to the
excretion of 20-25 percent of filtered sodium.
• They act at medullary and cortical aspects of TLOH,including macula
densa.
• At each these sites sodium entry is primarily mediated by Na-K-2Cl
carrier. This channel is activated when all the 4 sites are occupied.
• Loop diuretics mainly bind to the Chloride site and inhibit the carrier,
which leads to reduced reabsorption of sodium and its excretion.
• Loop diuretics also effect the renal calcium handling. The
reabsorption of calcium is mainly due to electrochemical gradient
created by the Nacl transport . By inihibition of Nacl transporter leads
to the parallel reduction in the calcium reabsorption and increase in
calcium excretion.

12. PHARMACOKINETICS:
• Onset of action- 30minutes for oral dose
- 5minutes for intravenous dose
• Duration of action- diuresis peaks in about 2 hours and lasts about 6
to 8 hours
• Most diuretics have short duration of action and require twice daily
dosing.

13. Indications
• Loop diuretics are DOC in severe edema conditions like:
1. Congestive heart failure
2. cirrhosis of liver
3. nephrotic syndrome
4. Ascites, lymphedema, idiopathic edema.
5. Congenital heart disease
6. Pulmonary edema
• Hypercalcemia

14. Side effects
• Hypokalemia
• Ototoxicity
• Hyperuricemia
• Hypomagnesemia
• Allergic reactions
• Dehydration

15. Thiazide
diuretics
• Mechanism of action :

16. • The thiazide diuretics primarily inhibit sodium transport in the distal
convoluted tubule, although they may also have more modest effects
along the proximal tubule and cortical collecting tubule
• In the distal convoluted tubule, an apical Na-Cl cotransporter is
responsible for most sodium transport. Thiazides act by inhibiting this
transporter.
• Some thiazide-type drugs (such as chlorothiazide) also modestly
impair sodium transport in the proximal tubule, due to partial
inhibition of carbonic anhydrase

17. • In addition, thiazides may impair sodium reabsorption along the
collecting duct in the setting of hypovolemia by inhibiting a
sodium-dependent chloride bicarbonate exchanger.
• Thiazides increase the reabsorption of calcium at DT and PCT
as a consequence of reducing ECF volume, which enhances
proximal reabsorption.
• ANTIHYPERTENSIVE:
Vasodialator effect initiated by reduction in plasma Na levels, which
thereby reduces intracellular Ca levels in vascular smooth muscle via
Na/Ca exchanger

18. Indications
• Essential hypertension
• Refractory edema
• Recurrent kidney stones
• High urine calcium

19. Side effects
• Diuretic induced hyponatremia
• Hypokalemia
• Hypomagnesemia
• Impaired glucose tolerance
• Hyperlipidemia
• Hyperuricemia (gouty arthritis)
• Allergic reactions, weakness, fatigability.

20. Carbonic
anhydrase
inhibitors
• Mechanism of action:
Reversible inhibition of the enzyme
carbonic anhydrase resulting in
reduction of hydrogen ion secretion
at renal tubule and an increased
renal excretion of sodium,
potassium, bicarbonate, and water.
Decreases production of aqueous
humor and inhibits carbonic
anhydrase in CNS to retard
abnormal and excessive discharge
from CNS neurons.

21. Pharmacokinetics
• Onset of action: oral-1 to 1.5hrs
IV - 2 to 10mins
Duration of action : oral- 8 to 12hours
IV-4 to 5 hours
Dose: 1) GFR normal : no dose adjustment
2) GFR 30-50ml/min: 125 to 250 mg twice daily
3)GFR10-30ml/min,on HD: avoid use as the drug will accumulate and
result in CNS toxicity. Can use 125mg under absolute indication
4)GFR<10ml/min: avoid use

22. Indications:
• Treatment of chronic simple (open-angle) glaucoma (a major indication)
• Also used to treat secondary glaucoma, and pre-operatively in acute angle-
closure glaucoma where delay of surgery is desired in order to lower
intraocular pressure.
• Edema due to congestive heart failure
• Seizure disorder
• Acute mountain sickness

23. Adverse effects
• Aplastic anemia
• Growth retardation
• Hypersenstivity reactions
• Metabolic acidosis
• Paresthesia
• Electrolyte disturbances
• loss of appetite, taste alteration and gastrointestinal disturbances such as
nausea, vomiting and diarrhea
• polyuria
• occasional instances of drowsiness and confusion

24. Potassium sparing diuretics
• K-sparing diuretics act on the Cortical collecting duct.
• Normal process:
-Cells in this region of the nephron absorb Na via luminal membrane epithelial Na channels
(ENaC). Na influx across the luminal membrane leaves lumen-negative potential, which drives
the reabsorption of Cl and efflux of potassium. Cytoplasmic Na is transported across the
basolateral cell membrane by the Na/K ATPase.
-The gene expression and surface localization of ENaC is modulated by aldosterone, which
binds to an intracellular mineralocorticoid receptor, that increases expression of several genes
including those that encode ENaC and the Na/K ATPase.
• The collecting duct is the major site of action (in the kidney) of mineralocorticoid receptor
antagonists (spiranolactone & epilerinone), which decrease the expression of ENaC.
• Direct ENaC inhibitors (amiloride & triamterene) inhibit Na influx through epithelial Na channels
in the luminal membrane.

26. Indication
• Used to counteract the potassium-wasting effects of thiazides.
• Hyperaldosteronism
• Hypokalemia
• HFnEF and HFrEF treatment
• Drug Resistant hypertension

27. Side effects
• Antiandrogenic effects: Gyanaecomastia, impotence
• Electrolyte disturbances
• Dehydration

28. Osmotic diuretics- Mannitol
• A non-reabsorbable solute that is filtered by the glomerulus, but
cannot be reabsorbed, causing water to be retained in the region of
the proximal tubule & descending limb of Henle's loop.
• This prevents the normal absorption of water in these regions due to
the presence of a countervailing osmotic force. As a result, urine
volume increases.
• The increase in urine flow also decreases the contact time between
fluid & the tubular epithelium, which reduces Na reabsorption as well
as water reabsorption.
• Thus resulting loss of Na is of lesser magnitude than the loss of water,
resulting in excessive water loss and hypernatremia.

30. • Indications:
• To reduce intracranial pressure in neurologic conditions
• To reduce intraocular pressure before eye surgery
• Pharmacokinetics:
• poorly absorbed from the GI tract when administered orally - causing
an osmotic diarrhea
• must be given parenterally for systemic effects.
• excreted by glomerular filtration within 30-60 mins without any
important reabsorption, secretion or metabolism
• Dose: 0.5 to 1g/kg
• Iv bolus over 20mins
• Repeat dosing every 6 hours

31. • Side Effects:
• Extracellular volume expansion.This can complicate heart failure &
produce pulmonary edema.
• Headache, nausea & vomiting are commonly observed
• Dehydration, hyperkalemia & hypernatremia.
These side effects can result from use of mannitol without adequate
water replacement.

32. Diuretics in patients with heart failure
• Goal of therapy
To eliminate the fluid retention
• Therapy with diuretics
1. Type of agent- loop diuretics
- oral diuretic therapy with furosemide is started
-If patient cannot be effectively dialyzed with high dose furosemide
(>200mg) switch from furosemide to torsemide or bumetanide.
2. Route of administration
• Intravenous diuretics (either as a bolus or a continuous infusion) are
more potent than equivalent oral doses and are sometimes required
for unstable or severe disease.

33. 3. Dosing
• Oral – For patients with more chronic HF, the usual starting oral dose
is 20 to 40 mg of furosemide. If a patient does not respond to initial
dosing, the dose should be increased rather than giving the same
dose twice a day.
• If there is a good but short response, more frequent dosing may be
needed.
• Maximum single oral doses of furosemide are 40 to 80 mg for
patients with a normal glomerular filtration rate (GFR).
• In patients with renal insufficiency, a higher maximum dose of 160 to
200 mg of furosemide can be given(maximum daily dose of 600 mg).
• The usual initial oral dose of torsemide is 5 to 10 mg with maximum
individual dose of 100 mg (maximum daily dose of 200 mg).

34. • Intravenous – The usual initial intravenous bolus dose of furosemide
is 20 to 40 mg or up to 2.5 times the previously ineffective oral dose;
if no response is obtained, the dose may be repeated every two hours
with doubling of the dose as needed up to maximum doses.
• In patients with a normal GFR (typically estimated from the serum
creatinine concentration), the maximum intravenous doses are
usually 40 to 80 mg of furosemide, 20 to 40 mg of torsemide, or 1 to
2 mg of bumetanide. However, at times, higher doses are needed.
4. Monitoring – In stable patients on a stable diuretic regimen, the fluid
and electrolyte complications of diuretic therapy (eg, volume depletion,
hypokalemia with loop diuretics, and hyperkalemia with
spironolactone) are complete at two to three weeks.

35. 4. Refractory congestion causes –
I. advanced HF
II. advanced kidney disease
III. hypoalbuminemia
IV. high fluid or sodium intake
V. possible hypovolemia
VI. lack of adherence to the diuretic regimen
VII. Inability to absorb oral diuretics

36. In patients with refractory edema despite therapy with a high-dose
loop diuretic,options for the management of volume overload include :
• Switch to a more reliably absorbed oral loop diuretic (ie, torsemide or
bumetanide in place of furosemide).
• Use intravenous diuretics.
• In patients who meet monitoring criteria, add a thiazide or other
nonloop diuretic to augment diuresis.
• Perform hemodialysis if other measures are unsuccessful.

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