Diuretics for Undergraduate it will helpful for understanding topic

It will be Helpful for MBBS Students

1. Compare and contrast between loop diuretics
and thiazides or thiazides like diuretics.
 MOA, Uses and side effect of loop diuretics
MOA, Uses and side effect of loop diuretics
Short notes on Osmotic diuretics.
Shor notes on Potassium Sparing diuretics

2. DIURETIC- agent that increase urine
volume.
(increase sodium+water)
Natriuretic- increase in renal sodium
excretion.
Aquaretic-increase excretion of solute
free water. (osmotic diuretic+ADH)

4. THIAZIDES or thiazides like diuretic
LOOP DIURETICS
K
+
SPARING DIURETICS
CARBONIC ANHYDRASE INHIBITORS
OSMOTIC DIURETICS

6. Furosemide (prototype)
Bumetanide
Torsemide
Ethacrynic acid

7. Secreted in proximal tubule by acid mechanisms
Act on the ascending loop of Henle to inhibit
sodium and chloride transport
Mechanism of action
Blockade of Na+K+2Cl- transporter in the thick
ascending loop of Henle
Acts at luminal side of thick ascending
limb(NaK2Cl transporter)
Competition with Cl
-
ion for binding

9. Loss of diluting ability: Increased Na,
Cl and K excretion
Loss of electrostatic driving force:
increased excretion of Ca
2+
, Mg
2+
and
NH
4
+
Increased electrostatic driving force in
CCD: increased K
+
and H
+
excretion

10. Additional non-tubular effects
1. Renal vasodilatation and
Redistribution of blood flow
2. Increase in renin release
3. Increase in venous capacitance
These effects mediated by release of
prostaglandins from the kidney.

11. Rapid GI absorption. Also given i.m. and
i.v.
Extensively protein bound in plasma
Short half-lives in general
Elimination: unchanged in kidney or by
conjugation in the liver and secretion in
bile.

12. EDEMA due to CHF, nephrotic syndrome or
cirrhosis
Acute heart failure with PULMONARY EDEMA
HYPERCALCEMIA
not in widespread use for the treatment of
hypertension (except in a few special cases
e.g. hypertension in renal disease)
Cerebral edema –manitol is prefered
To counteract fluid overload during blood
transfusion (severe anaemia/)

13. Hyperkalemia
Acute Renal Failure-enhance K
secretion, used to flush intratubular
cast
Anion Overdose-bromide,fluride,
iodide
Forced diuresis

14. Hypokalemia
Metabolic alkalosis
Hypercholesterolemia
Hyperuricemia
 Hyperglycemia
 Hyponatremia

15. Dehydration and postural
hypotension
Hypocalcemia (in contrast to
thiazides)
Hypersensitivity
OTOTOXICITY (especially if given
by rapid IV bolus)

16. Effect of loop diuretic reduced by non-
steroidal anti-inflammatory drugs
Potentiate hypotensive effects of "ACE"
inhibitors
Potentiated ototoxicity or nephrotoxicity
of amphotericin B, aminoglycosides,
many others

17. Hydrochlorothiazide
Chlorothiazide- can be given parentral
Benzthiazide
Hydroflumethiazide
Chlorthalidone- slowly reabsorbed
longeracting
Indapamide

18. Collecting Duct
receives fluid from the DCT
◦when antidiuretic hormone (ADH) is
present, this duct will become porous
to water. Water from the collecting
duct fluid then moves by osmosis into
the “salty” (hyperosmotic) interstitium
of the medulla. 2-5% Na/Cl/H
◦The last segment to save water for the
body

19. Hydrochlorothiazide
Chlorthalidone
Indapamide
5–10%
Indapamide

SR
(does not have
metabolic effects)
•cardioprotector
•nephroprotector

20. Mechanism of Action
Thiazides freely filtered and secreted in proximal
tubule
Bind to the electroneutral NaCl cotransporter
Thiazides impair Na
+
and Cl
-
reabsorption in the
early distal tubule: “low ceiling”

21. Increased K
+
Excretion Due To:
Increased urine flow
Increased Na
+
-K
+
exchange
Increased aldosterone release

22. Increase distal Ca re-absorption (direct
effect)
ocauses an increase in plasma calcium.
oThis is unimportant NORMALLY but
makes thiazides VERY inappropriate
o choice for hypercalcemic patients

23. Thiazides promote
distal tubular Ca
2+

reabsorption by
Na/Ca Exchanger
(PTH)
Prevent “excess”
excretion which
could form stones
in the ducts of the
kidney

24. K ion does not
recycle across apical
No lumen positive
potential in this
segment
 Ca and Mg are not
driven out of tubular
lumen electric force
Ca ion is actively
reabsorbed by the DCT
epithelial cell via an
apical Ca + ion
channel and
basolateral Na+/Ca+
exchanger
====parathyroid
hormone

25. Oral administration –only
 absorption poor
Diuresis within one hour
T
1/2
for chlorothiazide is 1.5 hours,
chlorthalidone 44 hours
Distribution in extracellular space
Elimination unchanged in kidney
Variable elimination kinetics and
variable half-lives of elimination
ranging from hours to days.

26. HYPERTENSION –sub diuretic dose
Thiazides reduce blood pressure and
associated risk of CVA and MI in
hypertension
they should be considered first-line therapy
in hypertension (effective, safe and cheap)
Mechanism of action in hypertension is
uncertain – involves vasodilation that is not
a direct effect but a consequence of the
diuretic/natriuretic effect

27. 2) EDEMA (cardiac, liver renal)
3) IDIOPATHIC
HYPERCALCIURIA
Condition characterized by recurrent
stone formation in the kidneys due to
excess calcium excretion
Thiazide diuretics used to prevent
calcium loss and protect the kidneys
4) DIABETES INSIPIDUS

28. Initially, they were used at high doses
which caused a high
Incidence of adverse effects. Lower doses
now used cause
fewer adverse effects. Among them are:
DEHYDRATION (particularly in the
elderly) leading to POSTURAL
HYPOTENSION

29. Hypokalemia due to:
◦Increased availability of Na
+
for exchange at
collecting duct
◦Volume contraction induced aldosterone release
Hyperuricemia
◦Direct competition of thiazides for urate
transport
◦Enhanced proximal tubular reabsorption
efficiency
Hyperglycemia
◦Diminished insulin secretion
◦Related to the fall in serum K
+
Elevated plasma lipids

30. HYPERLIPIDEMIA; mechanism unknown but
cholesterol increases usually trivial (1%
increase)
IMPOTENCE
HYPONATREMIA due to thirst, sodium loss,
inappropriate ADH secretion (can cause
confusion in the elderly), usually after
prolonged use

31. Less common problems
HYPERSENSITIVITY - may manifest as
interstitial nephritis, pancreatitis, rashes,
blood dyscrasias (all very rare)
METABOLIC ALKALOSIS due to increased
sodium load at the distal convoluted tubule
which stimulates the sodium/hydrogen
exchanger to reabsorb sodium and excrete
hydrogen
HYPERCALCEMIA

32. 3%
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4. Potassium-
sparing diuretics
They have weak
diuretic action
and save K
+
.
Often they are used
in combination with
diuretics, causing
hypokalemia.

33. Potassium-sparing diuretics
Competitive
aldosterone
antagonists:
•Spironolactone
•Eplerenone
Blockers of the
amiloride-
sensitive
Na
+
channels:
•Amiloride
•Triamterene

34. Mechanism of action
Inhibition of Na/K exchange at aldosterone
dependent distal tubular site
Spironolactone – competes with aldosterone
for regulatory site
Triamterene - decreases activity of pump
directly

35. Spironolactone
Mechanism of action: aldosterone antagonist
Aldosterone receptor function
Spironolactone prevents conversion of the receptor
to active form, thereby preventing the action of
aldosterone

36. Pharmacokinetics
70% absorption in GI tract
Extensive first pass effect in liver and
enterohepatic circulation
Extensively bound to plasma proteins
100% metabolites in urine
Active metabolite: canrenone (active)
Canrenoate (converted to canrenone)

37. Therapeutic Uses
Prevent K loss caused by other diuretics in:
◦Hypertension
◦Refractory edema
◦Heart failure
Primary aldosteronism

38. Administration
Dose orally administered (100 mg/day)
Spironolactone/thiazide prep (aldactazide,
25 or 50 mg of each drug in equal ratio)

39. Toxicity
Hyperkalemia - avoid excessive K
supplementation when patient is on
spironolactone
Androgen like effects due to it steroid
structure
Gynecomastia
GI disturbances

40. Triamterene and Amiloride
Non-steroid in structure, not aldosterone
antagonists

41. Pharmacokinetics
Triamterine
◦50% absorption of oral dose
◦60% bound to plasma proteins
◦Extensive hepatic metabolism with active
metabolites
◦Secreted by proximal tubule via organic cation
transporters
Amiloride
◦50% absorption of oral dose
◦not bound to plasma proteins
◦not metabolized, excreted in urine unchanged
◦Secreted by proximal tubular cation
transporters

42. Therapeutic uses
Eliminate K wasting effects of other diuretics in:
◦Edema
◦Hypertension

43. Toxicity
Hyperkalemia. Avoid K+ supplementation
Drug interaction - do not use in
combination with spironolactone since the
potassium sparing effect is greater than
additive
Caution with ACE inhibitors
Reversible azotemia (triamterine)
Triamterene nephrolithiasis. 1 in 1500
patients

44. spironolactone
May produce adrenal and sex hormone effects
with LONG-TERM use
Both drugs may produce electrolyte imbalance

45. Acetazolamide
Dichlorphenamide

Methazolamide
Ethoxzolamide

47. 1.Carbonic anhydrase (CA) facilitates
excretion of H
+
and recovery of bicarbonate
by the proximal renal tubule and ciliary
epithelium of the eye. Sodium is recovered in
exchange for H
+
.

48. 1.Inhibitors block CA
2. Block sodium recovery. A very mild
diuresis is produced (this is really a side
effect of their use in glaucoma) because
relatively unimportant mechanism for Na
recovery and because proximal tubule site
means that other sodium recovery
mechansims continue to process their
normal fraction of the sodium load.

49. Glaucoma - ???
Urine alkalinise urine- UTI/promote Excretion
Of acidic Drugs
Acute moutain sickness- lowering PH/
decreasing CSF
Absence Sei zure- only adzuvant/ increase Cl-
S/E- Hyperchloraemic acidosis, Hypokalaemia

50. Mannitol -----given iv
 Urea
Glycerin

51. 1.Reduce tissue fluid (edema) by creating
osmotic draw from tissue to blood stream
2.Reflex cardiovascular effect by osmotic
retention of fluid within vascular space which
increases blood volume (contraindicated with
Congestive heart failure)

52. 1.Diuretic effect
oMakes H
2
O reabsorption far more difficult
for tubular segments insufficient Na & H
2
O
capacity in distal segments
oIncreased intramedullary blood flow
(washout)
oIncomplete sodium recapture (asc. loop).
this is indirect inhibition of Na
reabsorption (Na stays in tubule because
water stays)

53. oNet diuretic effect:
oTubular concentration of sodium decreases
oTotal amount of sodium lost increases
oGFR unchanged or slightly increased

54. 1.Fluid and electrolyte imbalance
oproduces over-expansion of extracellular fluid
and circulatory overload.
oCirculatory overload may be accompanied by
dilutional hyponatremia.
oHyperkalemia is possible /

55. 1.Extravasation
omay cause edema and skin necrosis. (Be
careful with mannitol).
Extravasation may also occur into central
nervous system Be careful with cranial
trauma cases (hemorrhage leads to
extravasation

56. Onset
= 1 - 3 hours (diuresis)
= 15 - 30 minutes (cerebral edema)
Duration
= 3 - 6 hours
Elimination is 80 - 90% renal

57. ICT/IOP- ?????
-Decrease formation of aqueous homour
-Also due to osmotic action it encourage
movement of water from brain parenchyma
CSF and Aqueous Humour
-To maintain GFR and Urinary Flow before onset
of renal failure

58. To counteract low osmolality of plasma /ECF
due to rapid haemoldylasis/ peritoneal dialysis

59. Acute tubular necrosis
Anuria
Pulmonary edema
Acute Left Ventricular failure
CHF

60. 1.Carbonic anhydrase inhibitors are never
used as diuretics but do reduce production
of aqueous humor (eye).
2.OSMOTIC diuretic

61. 1.Thiazide diuretics produce a mild but sustained
diuresis that tends to be limited by dehydration.
They are useful for chronic diuretic therapy in
congestive heart failure and primary hypertension.
2.Loop diuretics produce a potent but short-lived
diuresis that is not limited by dehydration. They
are most useful for emergency reduction of fluid
volumes in congestive heart failure. Because of
advertising and potency (over-rated) they are the
primary class of diuretics used in veterinary
medicine.