Diuretics

Professor C. B. Choudhary
Department of Pharmacology
NMCTH, Biratnagar
Kidney:The major excretory organ
 Functional unit: Nephron, 1 million nephrons in each kidney
 Functions of Kidney:

1. Regulatory:
◦ Fluid electrolyte balance
◦ Acid base balance
2. Excretory
◦ Excretion of nitrogenous waste products
3. Hormonal
◦ Production of renin
◦ Production of erythropoietin
◦ Activation of Vitamin D
Mechanism of Urine Formation
 Glomerular Filtration
 Tubular reabsorption
 Active Tubular secretion

◦ Urine formation begins in the glomerulus. The

volume of the fluid filtered is about 180L/day.
◦ More than 99% get reabsorbed in the renal tubules,
so urinary output 1-1.5L/day.
◦ After filtration, the fluid traverses in the renal
tubules.
◦ The tubular fluid contains Na +, K+, Cl-, HCO3-,
amino acids, glucose etc.
Proximal Convoluted Tubules
 Most of the filtered Na+ actively reabsorbed,
chloride reabsorbed passively along with sodium,
 Carbonic anhydrase playing an important role in

Na+-H+ exchange (Na+-H+ antiporter) and helps

in the reabsorption of HCO3-.
 Potassium, glucose, amino acids also reabsorbed

in the Proximal convoluted tubule(PCT).

 Proportionately, water also get reabsorbed, so

the tubular fluid in the PCT remain isotonic.

 Organic Acid Secretory Systems:
◦ Located in middle third of PT
◦ Secretes variety of organic acids like uric acid,
diuretics like thiazide, loop diuretics and antibiotics
like penicillin
 Organic Base Secretory System:
◦ In early and middle segments of PCT
◦ Secretes bases like Creatinine, choline
Loop of Henle
 The descending limb impermeable to Na+ and
Urea.
 Highly permeable to water, hence fluid in the

loop of henle becomes hypertonic .

 Tubular fluid with 3-fold rise in salt

concentration
Thick ascending limb of loop of Henle
 Renal tubule becomes impermeable to water but
highly permeable to Na+ and Cl-.
 Active reabsorption of Na+ and Cl- occurs by Na+-
K+-2Cl- - cotransporter (selectively blocked by
loop diuretics)
 Ca2+ and Mg2+ also reabsorbed at this site.

Cortical Diluting Segment (Early distal tubule)

 Impermeable to water

 Na+ and Cl- are reabsorbed with the help of Na+-

Cl- symporter (Blocked by thiazides)

Distal Convoluted Tubule and
Collecting duct
 Sodium actively reabsorbed, Cl- and water diffuse
passively
 Exchange of Na+/K+, H+ ions occur
 The Na+ - K+ exchange under the influence of
aldosterone (Aldosterone promotes Na + absorption and
K+ excretion)
 Absorption of fluid in the collecting duct(CD) under the
influence of ADH
 In the absence of ADH, CD becomes impermeable to
water and so a large amount of dilute urine is excreted.
 Normally H+ present in the urine convert NH3 to NH4 +
which is excreted.
Classification according to Efficacy
1. Low-efficacy diuretics
◦ Osmotic diuretics: Mannitol and glycerol
◦ Carbonic anhydrase inhibitors: Acetazolamide
◦ Potassium-sparing diuretics: Spironolactone,
amiloride, triamterene
2. Medium-efficacy diuretics
◦ Thiazides: Hydrochlorthiazide, Benzthiazide
3. High-efficacy diuretics
◦ Loop diuretics: Furosemide, bumetanide,
ethcrynic acid, torsemide
CL. according to the site of action in the Nephron
1. Drugs acting at the PCT (site1):
◦ Carbonic anhydrase inhibitor: Acetazolamide
2. Drugs acting at thick ascending limb of loop of Henle
(site 2)
◦ Loop diuretics: Furosemide, bumetanide, ethacrynic acid
3. Drugs acting at cortical diluting segment (site 3)
◦ Thiazides: Chlorthiazide, hydrochlorthiazide, benzthiazide,
polythiazide
◦ Thiazide like diuretics: Chlorthalidone, indapamide
4. Drugs acting at distal convoluted tubule (DCT, site 4)
◦ Spironolactone (aldosterone antagonist), amiloride, and
triamterene (directly acting drugs)
5. Drugs acting on entire nephron (main site of action is
the loop of henle)
◦ Osmotic diuretics: Mannitol, glycerol
High Efficacy, High Ceiling/ Loop Diuretics

Furosemide
 Sulfonamide derivative
 Most popular and powerful diuretic
 Mechanism of Action:
 Acts by inhibiting Na+/Cl- reabsorption in the thick ascending limb of
Henle’s loop
 Binds to luminal side of Na+ - K+-2Cl- cotransporter and blocks its
function
 Increased excretion of Na+ and Cl- in urine
 Also has a weak carbonic anhydrase inhibiting activity, hence
increases excretion of HCO3- and PO43-.
 Tubular fluid then reaching the DCT will have larger amount of Na+,
hence more Na+ exchanges with K+, leading to K+ loss.
 Also increase the excretion of Ca2+ and Mg2+
Therapeutic Uses: Loop Diuretics
 Edematous condition associated with CCF, Cirrhosis of
liver and renal disease including nephrotic syndrome
◦ Dose: 40-80 mg slow iv
 Acute Pulmonary Edema ( LVF following HTN)
 Cerebral Edema
 Hypertension (Though thiazides preferred) especially
if complicated by renal impairment
◦ Dose: 20 mg once daily orally or 40 mg every other day
 Can increase the rate of renal flow and enhance K+
excretion in acute renal failure, may convert oliguric
renal failure to non oliguric renal failure, helping in
management of renal failure
Therapeutic Uses: Loop Diuretics contd..
 Ingestion of toxic anions like Br-, I- and F- because
these are reabsorbed from the thick ascending LH.
 Mild hyperkalaemia succesfully treated with loop

diuretics as they enhance urinary excretion of K +.

This response is enhanced by simultaneous
administration of NaCl and water. (Pregnancy)
 With BT to prevent volume overload in severely

anaemic pts.
 Non-diuretic use: Can be used to treat mild to

moderate hypercalcaemia because they increase Ca2+

excretion and urine flow. Excess salt that is lost must
be replaced.
 Bumetanide : 40 times more potent than
Furosemide with lesser side effects, use increasing
because it may act on some cases not responding
to furosemide
 Ethacrynic acid: Out of use because of ototoxicity
and hepatotoxicity
 Torsemide: 3 times more potent and longer acting
than furosemide Dose: 2.5-5 mg once daily orally
 Indacrinone(Uricosuric diuretic) Ethacrynic acid
analogue, inhibits proximal tubular uric acid
absorption besides inhibiting Na+ and Cl- from
the thick ascending LH, useful for the pts of gout
requiring diuretic therapy
Adverse Effects
 Can cause hyperuricaemia and may precipitate the
attack of acute gout
 Hypercalciuria and hypomagnesaemia: A predictable
consequence of chronic use of loop diuretics
 Hypokalaemia with hypokalaemic metabolic alkalosis:
can be reversed with K+ replacement
 Ototoxicity (more with ethacrynic acid) by high doses
of loop diuretics
 Hyperglycaemia: Carbohydrate intolerance can
manifest due to inhibition of insulin release
 Hypersensitivity reactions in patients allergic to
sulfonamides
Drug Interactions
 May enhance digitalis toxicity and can cause cardiac
irregularities due to hypokalaemia
 Serum lithium level may rise due to loop diuretic therapy as
they may increase reabsorption of Li from the proximal tubule
 Loop diuretics and aminoglycoside antibiotics exhibit additive
ototoxicity and should not be used together
 Indomethacin and most NSAIDs by inhibiting PGE2 and PGI2
synthesis diminish the action of high ceiling diuretics
 Probenecid competitively inhibits tubular secretion of
furosemide at Proximal tubule and therefore decrease its
action.
 Cotrimoxazole with loop diuretics increase the chance of
thrombocytopenia.
Thiazides and Thiazide like diuretics –
Acting on proximal part of distal tubule
 Most widely used of the diuretic drugs
 Sulfonamide derivatives but their chemical structure
also resembles carbonic anhydrase inhibitors like
Acetazolamide
 Hydrochlorthiazide and Bendroflumethiazide are
prototype drugs
 All thiazide affects the distal tubule and all have
equal maximal diuretic effect differing only in
duration of action and potency
 Polythiazide 25-30 times more potent than
hydrochlorthiazide, while chlorthiazide exhibits
1/10th the potency of hydrochlorthiazide.
 Chlorthalidone: action lasts for more than 48
hrs while chlorthiazide remains for 1.5-2 hrs.
 when given by oral route, they are readily

absorbed by GIT, mainly secreted through the

PT by the organic acid secretory mechanisms.
 They reach the site of action – early part of

distal tubule.
 The longer acting agents have a high lipid

solubility.
Mechanism of Action
 Moderately powerful diuretic action causing
excretion of 8-10% of Na+ in the filtrate.
 Binds to the Cl- site of Na+Cl- cotransport system

and block the system, thus enhances excretion of

Na+ and Cl- in the early distal tubule.
 Primary site of action: Early distal tubule
 Since, Na+Cl- cotransport takes place on the luminal

side of distal tubular cells, thiazide should reach the

luminal side to block this transport .
 Thiazides reach the tubular fluid after being secreted

by proximal tubular organic acid secretory system.

Mechanism of Action contd…
 When more Na+ reaches the collecting duct from the
DT, high flow rate of filtrate produced by these
diuretics will favour increased excretion of K+.
 In contrast to loop diuretics, it produces decrease in
Ca2+ concentration of urine by promoting its
reabsorption.
 During diuresis with thiazides, the urine is rich in Na+
and Cl- but almost free of HCO3-, thus increased
concentration of HCO3- per unit volume of ECF.
 Also inhibits carbonic anhydrase in PT but it does not
seem to contribute significantly to its diuretic action.
Therapeutic Uses
 Hypertension: Thiazides are first line drugs.
 Congestive heart failure: Useful in management of

edema due to mild to moderate CHF.

 Edema: May be tried in hepatic or renal edema.

Renal edema may be due to Nephrotic syndrome,

acute glomerulonephritis or chronic renal failure.
 Renal stones and hypercalciuria: can be treated

with diuretics as they reduce calcium excretion.

 Diabetes Insipidus: Thiazides benefit such

patients by reducing plasma volume and GFR –

paradoxical effect.
Adverse Effects: Thiazides
 Hypokalemia: the most important side effect.
 Hyperuricaemia as they compete with uric

acid secretion (may aggravate attack of gout)

 Erectile dysfunction in males
 Hyperglycaemia induced by thiazides may

precipitate diabetes mellitus by inhibition of

insulin secretion
Adverse Effects: Thiazides contd..
 Hypochloraemic alkalosis with urine rich in
chloride ions. Not a major problem for normal
person as it can be compensated by respiration.
 Hypercalcaemia: inhibit secretion of Ca2+ and

should be used with caution in cases of

hyperparathyroidism.
 Hyperlipidaemia: Cause reversible increase in

total cholesterol,LDL and triglycerides on chronic

use.
 Hypersensitivity reactions:Such as skin rashes,

blood dyscrasias, rarely pancreatitis

 Chlorthalidone: Potent as hydrochlorthiazide with long
duration of action (48hrs), often used to treat
hypotension and is administered once daily
◦ Dose: 25-100 mg/day orally
 Indapamide: Highly lipid soluble non-thiazide diuretic
which is more potent and longer acting than
hydrochlorthiazide. Produces lesser hypokalaemia,
hyperglycaemia and hyperuricaemia.
◦ Dose: 3.5-5mg/day orally
 Metolazone: Non thiazide diuretic more potent and
longer acting than hydrochlorthiazide. Clinically useful
response even in severe renal failure as it can produce
Na+ excretion in in advanced renal failure
◦ Dose: 2.5-5mg/day orally
 Xipamide: More potent and longer acting, non thiazide
diuretic
Potassium Sparing Diuretics
 They indirectly conserve K+ while inducing
mild natriuresis, and are called “Potassium
sparing diuretics.”
 May be aldosterone antagonists

(Spironolactone) or directly inhibit ion

channels in distal tubule and collecting ducts
(triamterene and amiloride).
1. Inhibitors of Na+ channels at
collecting ducts
 Amiloride and Triamterene secreted through
organic base secretory system at the PT and
part of DT and collecting ducts
 Act by inhibiting luminal Na+ at the distal part

of DT and the collecting tubules

 Blocking of these channels inhibits Na+

reabsorption and K+ excretion

MOA
 Directly acting diuretics which enhance Na+
excretion and reduce K+ loss by acting on ion
channels in the distal tubule and collecting duct
 Blocks Na+ transport through sodium channels in

the luminal membrane

 As K+ excretion is dependent on Na+ entry, also

reduces K+ excretion.
 Amiloride by reducing lumen negative potential,

decreases H+ ion secretion from the intercalated

cells in CD, hence predisposes to acidosis.
Therapeutic Uses
 Used along with thiazides/loop diuretics for the
treatment of hypertension.
◦ Combination therapy increases the diuretic and
hypertensive effect of thiazide or loop diuretics.
◦ Also correct hyperkalaemia due to Thiazide/loop diuretics
◦ Dose (amiloride): 5-10 mg/day (Triamterene) 50-100
mg/day oral
◦ Amiloride 10 times more potent than triamterene
 To treat edematous conditions including liver
cirrhosis, as hyperkalaemia produced by them is
advantageous in these situations
 Also used to treat refractory oedema with thiazides
Therapeutic Uses contd..
 Amiloride Blocks entry of Li+ through Na+ channels
in the CD cells and mitigates Diabetes insipidus
induced by Li
 Amiloride given as an aerosol gives symptomatic
improvement in cystic fibrosis by increasing fluidity
of respiratory secretions
Adverse Effects
1. Triamterene
◦ Infrequent Nausea, dizziness, muscle cramps and
rise in blood urea
◦ Impaired glucose tolerance
◦ Photosensitivity
◦ Plasma t1/2: 4hrs, effect of a single dose lasts 6-8
hrs
2. Amiloride
1. Nausea, Diarrhea, Headache
Spironolactone
 An aldosterone receptor antagonist with a
limited diuretic action because it acts on distal
part of DT and CT from where only 3-5% NaCl
absorbed.
 Secreted through peritubular circulation.
 Slow onset but duration of action longer (t1/26-
24hrs) because active metabolite canrenone has
similar effects
 Mainly excreted through urine but also through
bile and undergoes enterohepatic circulation
which also contributes to prolonged action
MOA of Spironolactone
 Spironolactone is a synthetic steroid and
structurally related to aldosterone.
 Aldosterone binds to the specific mineralocorticoid
receptor (MR) in the late distal tubule and CD cells
resulting in retention of Na+ and excretion of K+.
 Spironolactone competes for aldosterone receptors
and blocks the mineralocorticoid receptor (MR).
 Spironolactone thus promotes Na+ excretion and K+
retention. More effective when circulating
aldosterone levels are high.
 Also increases Ca2+ excretion.
MOA of Spironolactone
Spironolactone
(Aldosterone antagonist

Binds aldosterone receptor Canrenone(metabolite)

Inhibits action of aldosterone

Increases Na+ and water excretion,

Decreases K+ excretion
Pharmacokinetic
 Given as microfined powder to enhance
bioavailability (75%)
 Highly bound to plasma proteins and slow

onset of action
 Metabolized in the liver
 Metabolites formed are active, canrenone has

a long t1/2 of almost 18 hr while that of

spironolactone is 1-2 hrs.
 Dose: 25-50mg
Adverse Effects
 Endocrine effects:
◦ Gyanecomastia
◦ Impotence in men
◦ Hirusitism
◦ Menstrual irregularities
 Nausea, Vomoting, Diarrhea, Peptic Ulcer
 Drowsiness, Mental confusion
 Hyperkalemia

Drug Interactions:
 ACE inhibitors and Spironolactone : Dangerous

hyperkalaemia can occur

Eplerenone
 New and more selective aldosterone antagonist
 Much lower affinity for androgen and progesterone receptors
than spironolactone
 So much less likely to produce hormonal disturbance like
gynaecomastia, impotence and menstrual irregularities.
 Particularly suitable for long term use in the therapy of
hypertension and chronic heart failure
 Risk of hyperkalaemia and GI disturbances as usual with
spironolactone
 Well absorbed orally, inactivated in Liver and excreted in urine
and faeces
 T1/2: 4-6 hrs
 Indicated especially in moderate to severe CHF, post
infarction, Left ventricular failure and hypertension
 It affords prognostic benefits in these conditions and can also
be used as an alternative to spironolactone
Carbonic Anhydrase Inhibitors
 Carbonic anhydrase: An enzyme that
catalyzes the formation of carbonic acid
which spontaneously ionises to H+ and HCO3-

 HCO3- combines with Na+ and is reabsorbed.

H20 + CO2 H2CO3

H2CO3 H+ + HCO3-
 By inhibiting the enzyme, they block sodium
bicarbonate reabsorption and cause HCO3-
diuresis.
 Carbonic anhydrase is present in the

nephron,ciliary body of eyes, gastric mucosa,

pancreas and other sites.
Acetazolamide
 Sulfonamide derivative carbonic anhydrase
inhibitor
 Enhances the excretion of sodium, potassium,

bicarbonate and water

 Loss of bicarbonate leading to metabolic acidosis
 Also increases some chloride clearance
 Other actions include:

1. Eye: Results in decreased formation of aquaeous

humour as ciliary body of eye secretes bicarbonate into
aquaeous humour.
2. Brain: Reduces formation of CSF as HCO3- is secreted
into CSF
Pharmacokinetics
 Well absorbed orally
 Onset of action within 60-90 minutes
 Duration of action: 8-12 hrs
 Excreted unchanged by kidney
 Dose: 250 mg OD/BD
Therapeutic Uses
1. Glaucoma :
◦ Decreases IOP, given orally
◦ Newer ones – methazolamide and dorzolamide better
tolerated and available as eye drops
2. Alkalinization of Urine : In overdosage of acidic
drugs
3. Metabolic Alkalosis:
◦ Enhances HCO3- excretion
◦ Alkalosis due to excess diuretics in patients with heart
failure respond to acetazolamide
4. Epilepsy:
◦ Used as an adjuvant as it increases seizure threshold
5. Mountain Sickness:
◦ In mountain climbers who rapidly ascend great heights
has severe pulmonary edema and/or cerebral edema
◦ Acetazolamide may relief symptoms by reducing
formation as well as the pH of CSF
◦ Also used for prophylaxis
6. Hyperphosphatemia:
◦ When severe can be treated with acetazolamide to
increase urinary phosphate excretion
Adverse Effects
◦ Metabolic acidosis due to HCO3- loss
◦ Renal stones – Ca++ is lost with HCO3- resulting in
hypercalcuria which may precipitate formation of renal
stone
◦ Hypokalaemia, Drowsiness and allergic reactions
Osmotic Diuretics
 Act indirectly by modifying the contents of
urinary filtrate by increasing the osmolarity.
 Water loss is more than Na+ loss
 Clinically used:
◦ Mannitol (20-25% iv)
◦ Glycerol (1.5g/kg orally)
 Pharmacologically inert substances that are
filtered from glomerulus but not reabsorbed
at all or incompletely reabsorbed by the
nephron
Mannitol
 Pharmacologically inert – Can be given in
large quantities sufficient to raise osmolarity
of plasma and tubular fluid.
 Minimally metabolised in the body, freely
filtered at the glomerulus and undergoes
limited reabsorption.
 MOA:
◦ Causes water to be retained in the proximal tubule
and descending limb of henle’s loop by osmotic
effect resulting in water diuresis
◦ Also loss of some Na+
Therapeutic Uses
 Maintain urine volume and prevent oliguria in
conditions like:
◦ Massive haemolysis
◦ Shock
◦ Severe Trauma
In such situations, prevents renal failure
◦ Dose: 500-1000ml over 24 hrs after a test dose of
12.5g iv as not all responds to mannitol
 Reduce intracranial and intraocular pressure
following head injury and glaucoma
◦ Fluid from edematous cells in brain gets mobilized due
to high osmolarity
Contraindications
 Acute tubular necrosis
 Anuria
 Pulmonary edema
 Acute Left Ventricular Failure
 CHF
 Cerebral Haemorrhage

Adverse Effects:
 Most common: Headache

 Nausea, Vomiting

 Hypersensitivity rare

Glycerol: Effective orally- reduces Intraocular and Intracranial

Pressure, can also be given topically to relieve corneal edema
Newer Agents
Vasopressin Antagonists
 A new class of drugs called arginine vasopressin (AVP) receptor
antagonist has been found to induce diuresis.
 3 drugs have been introduced:

◦ Conivaptan
◦ Tolvaptan
◦ Lixivaptan
 They inhibits the effect of ADH in the collecting tubule and
cause free water diuresis.
 Conivaptan is an antagonist of V1a and V2 receptors while

lixivaptan and tolvaptan are V2 antagonist.

 Conivaptan given parenterally while tolvaptan and lixivaptan

effective orally.
 Uses:

◦ In pts with syndrome of inappropriate ADH secretion (SIADH), vaptans

enhance water excretion and correct hyponatremia
Potassium Supplements
 Chronic use of diuretics can produce hypokalaemia
 Best way to ward off this is to use Na +channel

inhibitors
 Potassium Chloride in liquid form (Tablets may

cause GI ulcers) can be given orally Minimum dose:

20 mEq/day
 Estimation of serum electrolytes essential

Diuretics resistance:
 When diuretics used repeatedly, the response to
diuretics may fall
Thank You