DIURETICS

 Diuretics are drugs that increase the volume of urine excreted.

 Most diuretic agents are inhibitors of renal ion transporters that decrease
the reabsorption of Na+ at different sites in the nephron.
 As a result, Na+ and other ions, such as Cl−, enter the urine in greater
than normal amounts along with water, which is carried passively to
maintain osmotic equilibrium.
 Diuretics, thus, increase the volume of urine and often change its pH, as
well as the ionic composition of the urine and blood.
 In addition to the ion transport inhibitors, other types of diuretics include
osmotic diuretics, aldosterone antagonists, and carbonic anhydrase
inhibitors.

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  Diuretics are most commonly used for management of abnormal fluid
retention (edema) or treatment of hypertension.
CLASSIFICATION OF DIURETICS:
1. Thiazide diuretics:
- Chlorthiazide
- Hydrochlorthiazide
- Hydrofluthiazide
- Benzthiazide
- Bendroflumethiazide

Thiazide like diuretics:

- Indapamide
- Metolazone
- Xipamide
- Chlorthalidone
2. Loop diuretics:
- Furosemide
- Bumetanide
- Ethacrynic acid
- Torsemide
3. Carbonic anhydrase inhibitors:
- Acetazolamide
- Brinzolamide
- Dorzolamide
4. Potassium sparing diuretics:
 Aldosterone antagonists:
- Spironolactone
- Eplerenone
 Direct renal sodium channel blockers:
- Amiloride
- Triamterene
5. Osmotic diuretics:
- Mannitol
- Isosorbide mononitrate
- Urea
- Glycerol

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THIAZIDE DIURETICS:
 Known as medium efficacy diuretics.
 Act on early DCT.
 Long acting drugs.
MOA:
 Na+Cl- symport in early distal tubule & increase Na+Cl- excretion.
 Net loss of Na+, K+, Cl-, HCO3- in urine. Unlike loop diuretics, thiazide
decreases Ca+2 excretion.
 Also have weak Carbonic anhydrase inhibition action.
CU:
 Hypertension
 Used in Calcium nephrolithiasis as they reduce urinary excretion of Ca+2
(hypercalcaemia)
 Oedema (not in hepatic oedema)
 Combined with loop diuretic in severe CHF.
 Diabetes insipidus
PK:
 Oral administration
 Have long duration of action & excreted in urine.
AE:
 Hypokalaemia
 Hypercalcaemia due to urinary excretion of calcium and
hypomagnesemia.
 Metabolic disorders:
- Hyperglycemia
- Hyperlipidaemia
- Hyperuricaemia
- Hypersensitive reactions
- Photosensitivity
- Rashes
 Not preferred as anti-hypertensive agents in young males because of
Gynaecomastia.
 It should be avoided during pregnancy because they reduce placental
perfusion by decreasing blood volume which causes foetal death

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THIAZIDE LIKE DIURETICS:
 Chlorthalidone – used in HTN because of its long duration.
 Metolazone, Xipamide – useful for oedema.
 Using of thiazide like diuretics is superior to thiazide diuretics in
decreasing BP because less incidence of hypokalaemia.
LOOP DIURETICS: (High ceiling diuretics)
 Also called as high efficacy diuretics.
 Site of action – thick ascending limb of loop of Henle.
MOA:
 Loop diuretics bind to luminal side of Na+ K+ 2Cl- cotransporter and
block its function. Therefore, reabsorption of these ions is decreased.
 Increased excretion of Na+, K+, HCO3-, Mg+2, Ca+2 etc.
 Have weak CA inhibition activity.
 Furosemide having rapid onset action
CU:
 Acute pulmonary oedema
 Used in initial stages of renal, cardiac & hepatic oedema
 HTN (loop diuretics can be used in HTN associated with CCF/renal
failure and in hypertensive patients).
 Cerebral oedema
 To prevent overload during blood transfusions.
PK:
 Loop diuretics are administered orally or parenterally.
 Their duration of action is relatively brief (2 to 4 hours), allowing patients
to predict the window of diuresis.
 They are secreted into urine.
AE:
 Electrolyte disturbances:
- Hyponatremia
- Hypocalcaemia – can cause gout
- Hypomagnesemia – can cause arrhythmias
 Ototoxicity – characterized by vertigo, tinnitus & deafness
 Hypersensitive reactions – eosinophilia, photosensitivity, skin rashes
 Nephrotoxicity
 Metabolic disturbances: hyperglycemia, Hyperuricaemia, hyperlipidemia
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CARBONIC ANHYDRASE INHIBITORS:

 Site of action – acts mainly on PCT of nephron & also acts on CD of

nephron.
MOA:
 Inhibition of CA enzyme in PCT leads to – prevents the formation of H+
ions.
 Thus, Na+-H+ exchange is prevented. Na+ & HCO3- is excreted in urine.
 In DCT, increased Na+-K+ exchange leads to loss of K+.
 The net effect is loss of Na+, K+, HCO3- in urine resulting to alkaline
urine.
CU:
 Acute congestive glaucoma - acetazolamide (oral route)
 Chronic, simple glaucoma - Dorzolamide, Brinzolamide (topical route)
 Acute mountain sickness
 Alkalinisation of urine during acid-drug poisoning.
 Miscellaneous – supportive agent in epilepsy, familial periodic paralysis
PK:
 Administered through oral route & intravenous route.
 It is approximately 90% protein bound and eliminated renally by both
active tubular secretion and passive reabsorption.
AE:
 Metabolic acidosis (mild)
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  potassium depletion
 renal stone formation
 Drowsiness
 Paresthesia
 The drug should be avoided in patients with hepatic cirrhosis, because it
could lead to a decreased excretion of NH4+.
POTASSIUM SPARING DIURETICS:
ALDOSTERONE ANTAGONISTS:
 Potassium-sparing diuretics act in the collecting tubule to inhibit Na+
reabsorption & K+ secretion.
 These drugs should be avoided in patients with renal dysfunction because
of the increased risk of hyperkalemia.
MOA:
 Spironolactone is a synthetic steroid that antagonizes aldosterone at
intracellular cytoplasmic receptor sites rendering the spironolactone–
receptor complex inactive.
 It prevents translocation of the receptor complex into the nucleus of the
target cell, ultimately resulting in a failure to produce mediator proteins
that normally stimulate the Na+/K+ exchange sites of the collecting
tubule.
 Thus, a lack of mediator proteins prevents Na+ reabsorption and,
therefore, K+ and H+ secretion.
 Eplerenone is another aldosterone receptor antagonist, which has actions
comparable to those of spironolactone, although it may have less
endocrine effects than spironolactone.
 In most edematous states, blood levels of aldosterone are high, causing
retention of Na+.
 Spironolactone antagonizes the activity of aldosterone, resulting in
retention of K+ and excretion of Na+.
CU:
 Secondary Hyperaldosteronism
 CHF
 Resistant HTN due to primary Secondary Hyperaldosteronism (Conn’s
syndrome).
 Ascites
 Polycystic ovary syndrome

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PK:
 Administered through oral route, gets partly absorbed & are significantly
bound to plasma proteins.
 Metabolized in liver and the active metabolite is Canrenone. The
metabolites, along with the parent drug, are thought to be responsible for
the therapeutic effects.
AE:
 Hyperkalaemia
 Nausea, Vomiting
 Diarrhoea, Peptic ulcer
 Drowsiness, Mental confusion
 Menstrual disturbances, Gynaecomastia, decreased libido.
DIRECT RENAL SODIUM CHANNEL BOCKERS:
 Triamterene and Amiloride block Na+ transport channels, resulting in a
decrease in Na+/K+ exchange.
 Although they have a potassium sparing diuretic action similar to that of
the aldosterone antagonists, their ability to block the Na+/K+ site in the
collecting tubule does not depend on the presence of aldosterone.
 Like the aldosterone antagonists, these agents are not very efficacious
diuretics. Both triamterene and Amiloride are commonly used in
combination with other diuretics, usually for their potassium sparing
properties.
 Much like the aldosterone antagonists, they prevent the loss of K+ that
occurs with thiazide and loop diuretics.
 The side effects of triamterene include increased uric acid, renal stones
and K+ retention.
OSMOTIC DIURETICS:
MOA:
 Draw water from tissue by osmotic action by acting on loop of henle and
PCT.
 This leads to increased excretion of water and electrolytes.
 A number of simple, hydrophilic chemical substances that are filtered
through the glomerulus, such as mannitol and urea, result in some degree
of diuresis.
 Filtered substances that undergo little or no reabsorption will cause an
increase in urinary output.

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  The presence of these substances results in a higher osmolarity of the
tubular fluid and prevents further water reabsorption, resulting in osmotic
diuresis.
 Only a small amount of additional salt may also be excreted.
 Because osmotic diuretics are used to increase water excretion rather than
Na+ excretion, they are not useful for treating conditions in which Na+
retention occurs.
 Net result: increased urine volume due to urinary excretion of H2O, Na+,
K+, Ca+2, Mg+2, Cl-, HCO3- etc.
CU:
 Decrease intracranial tension after head injury or trauma.
 Reduces elevated IOP in acute congestive glaucoma.
 Used to prevent acute renal shutdown in shock, cardiovascular surgery.
 Maintain osmolarity of ECF after dialysis.
PK:
 Administered intravenously.
 Mannitol - Pharmacologically inert, freely filtered at glomerulus.
AE:
 Glycerol – cause hyperglycemia
 Too much quantity of IV Mannitol cause marked expansion of ECF
volume leading to pulmonary oedema.
 Headache
 Nausea
 Vomiting