DIURETICS

PCT
Thick ascending limb of Loop of Henle
DCT
CD
Diuretics:-
These are the drugs which cause a net loss of Na+ and water in urine.
• Diuretics are among the most widely prescribed drugs.
• very effective in the treatment of:
 Oedema: CHF, pregnancy, & nutritional
 nephrotic syndrome
 diabetes insipidus
 hypertension
 cirrhosis of liver
 and also lower the intracellular and CSF pressure.
I. Classification (based on potency)

1. High efficacious/Highly potent/High ceiling diuretics (inhibitors of Na+-

K+-2Cl- cotransport) (20-25% natriuresis)
Ex: Loop diuretics: Furosemide, Bumetanide, Torasemide

2. Medium efficacious/ potent diuretics ( inhibitors of Na+- Cl- symport

5-8%natriuresis)
Ex: Thiazide diuretics : Hydrochlorthiazide, Benzthiazide, Chlorthalidone,
Metalazone, Indapemide
Osmotic diuretics: Mannitol, Glycerol, Isosorbide
3. Mildly potent/ weak efficacious (induces 2-3% of natriuresis)

Ex: carbonic anhydrase inhibitors: Acetazolamide

Xanthene derivatives: theophylline, aminophylline

Potassium sparing diuretics: spironolactone, amiloride

II. Based on site of action:-

1. Diuretics acting at PCT:-

CAIs: acetazolamide, metazolamide, dorzolamide

Xanthene derivatives: aminophylline, thiophylline

2. Diuretics acting at LH:-
Osmotic diuretics: glycerol, mannitol, isosorbide
Loop diuretics: furosemide, bumetanide, torasmide

3. Diuretics acting at DCT:-

Thiazide diuretics: hydrochlorthiazide, chlorothalidone, indapemide

4. Diuretics acting at CT:-

Aldosterone antagonists: spironolactone
Direct acting: amiloride, triamterene
Carbonic Anhydrase Inhibitor:
ex: Acetazolamide (prototype drug)
– Carbonic anhydrase catalyses : CO2+H2O H2CO3

– H+ ion produced by the breakdown of H2CO3, exchanged for Na+ & is

also combined with HCO3- in the lumen of the PCT

Reduces Na+-H+-exchange
–
Inhibition of Bicarbonate (HCO3-) reabsorption
–
Urinary excretion of K+ HCO3- major excretory anion) Na+
–
NaHCO3 is excreted along with H2O
–
• Pharmacological actions:-
On diuresis:- increased urinary excretion of HCO3-

Allows excretion of NaCl, approx. 70% 0f K+

Other actions:- lowering i.o.t. due to reduced aqu. Humour (rich in HCO3-)

 raises CO2 Level in brain and lowers its pH & causes sedation, elevates
seizure threshold

• P.K. :-
it is well absorbed orally, excreted unchanged in urine
 action of single dose lasts 8-12 hrs
 ADEs:-
• Metabolic acidosis
• Renal stones (Phosphate and Calcium stone)
• Renal potassium wasting; (NaHCO ) enhances K+ secretion
3
-

(hypokalemia)
• Drowsiness, paresthesia, disorientation, renal stone (in case of urine alkalinization)
• Bone marrow depression rare but serious

Contraindication:-
• Liver cirrhosis (CAI inhibits conversion of NH to NH )
3 4

• NH increased encephalopathy
3
 Clinical uses:-
• Glaucoma
• Prevent mountain sickness (high altitude sickness) inhibit secretion of
bicarbonate by the choroid plexus; Acidosis of the CSF results in
hyperventilation
• Urinary alkalinization: preventing uric acid and cysteine stones (promote
excretion of certain acidic drugs)
• Used for their diuretic effect only if edema is accompanied by significant
Metabolic alkalosis
• As adjuvant in absence seizures (increases seizure threshold)
 Xanthene derivatives:- it is a very weak diuretic agent

• Has v limited clinical uses due to development of rapid tolerance

• MOA: induces vasodilation of glomerular afferent arterioles

• which in turn increases perfusion rate of kidney and g.f.r.

• Also it inhibits adenosine, actions of A1 receptor

Drugs acting at LH:-

 Osmotic diuretics:

Exerts medium efficacious diuretic effect

Indirectly by modifying/ altering contents of tubular lumen

These agents are pharmacologically inert

Enhances osmolality of both plasma and tubular fluid

Also they are not metabolized or completely not absorbed

PCT, Descending thick limb of LH & CT allow free permeation of water

(main site of action for osmotic diuretics)
Being poorly reabsorbed they remain in tubular lumen, reduces reabsorption
of water
This facilitates enhanced excretion of water (more marked than natriuresis)
Mannitol (prototype drug)
 Low molecular wt. sugar
 Administered large doses by i.v.
MOA:
• Volume of ECF increased by drawing excess of water from intracellular space
of cells
• Since viscosity of blood is reduced all these contributes for increased blood
flow to kidney
 Now tubular fluid rendered hypotonic because it comprises solutes &
mannitol
 So reabsorption of water from lumen is inhibited
 Makes the tubular fluid more dilute

P.K.:- oral absorption is poor(osmotic diarrhoea) , given i.v.

• Doesn’t undergo metabolism instead only glomerular filtration

ADEs:-
• Hyponatraemia
• Nausea, head ache, dry mouth, emesis, excessive thirst, chest pain
• Thrombophlebitis (may diffuse out of vasculature)
• Worsens cardiac failure/ pulmonary edema
Contraindications:-
• Anuria (absence of urine production)
• In patients hypersensitive to mannitol

Clinical uses:-
In acute renal failure(ARF) : condition characterized by raid reduction in GFR.
• Due to shock, haemolytic reaction, cardiovascular surgery
• Mannitol is infused in a dose of 200mg/kg, b.w. in a time period of 10-15 mins
• Results in excessive bulging of tubular components due to accumulation of fluid in
them
In the treatment of cerebral edema
Treatment of elevated i.o.p. : mannitol has extractive property, so used in
glaucoma, surgery (pre & post)
In the treatment of poisoning
Treatment of Dialysis Disequilibrium Syndrome(DDS): caused during
haemodialysis, characterised by rapid extrusion of electrolytes from ECF into ICF
• This reduces osmolality of ECF because of this water from extracellular
compartment is directed towards intracellular compartment
• Causes hypotension, nausea, headache
• Osmotic diuretics act by counteracting the lowered osmolality & extract water
from IC compartment.
o Ideal properties for a substance to act as an ideal osmotic diuretics:

 It should exert osmotic effect

 It should be pharmacologically inert

 It should be freely filtered at the glomerulus

 It should not be reabsorbed

Loop diuretics/ high ceiling diuretics (steep dose response curve):-
• In normal doses, loop diuretics are capable of inducing up to 20-30% of natriuresis
• On increasing dose up to 30-40% natriuresis
• Such an excretion is not exhibited by any other diuretics
• The loop diuretics act promptly, even among patients who have poor renal function or
who have not responded to thiazides or other diuretics
• They secrete in the PCT by organic acid transport mechanism then reaches LH
• Where it inhibits Na+-K+-2Cl- symporter
• Ex: furosemide(prototype drug), torsemide, bumetanide(40 times more potent)
(sulphonamide derivatives)
• ethacrynic acid is a phenoxyacetic acid derivative, indacrinone (EA analogue)
 MOA:-
– Loop diuretics should be excreted into the lumen
– Inhibits Na+, K+, 2Cl- symporter significantly increases the excretion of
Na+, K+, Cl-
– Osmotic gradient for water reabsorption is also decreased increasing
water excretion
– Ca2+ and Mg2+ are excreted as well.
Pharmacological actions:-
On diuresis
• increases the excretion of Na+, K+, Cl-, Ca2+ and Mg2+ also water
• Reduces excretion of uric acid by inhibiting the secretion of uric acid in PCT
(Hyperuricaemia)
Kidney: induces generation of vasodilatory PGs in kidney
• Therefore, it is concomitantly administered with NSAIDs (inhibits PG
synthesis)
Peripheral vasodilation, reduces venous capacitance
Increases uric acid and blood glucose level
P.K.: rapid absorption after oral administration (BA 60%)
• Rapid onset of action but shorter duration
• Secreted fraction undergoes urinary excretion
• Unsecreted fraction undergoes glucuronide conjugation in liver

ADEs: being highly potent diuretic

• Hypokalaemia, hypomagnesaemia, alkalosis, hyponatremia,
hyperglycaemia, hyperurecaemia
• Sulfonamide reactions
• Nausea, diarrhoea, emesis
• Vasodilation
• Ototoxicity , more when given with aminogycosides
Uses:
• Congestive heart failure (1st line drug)
• Acute pulmonary edema

• Edema due to renal failure, nephrotic syndrome

• Hypercalcemia (that induced by malignancy) and renal calcium stones
• Severe hypertension

• Forced diuresis during drug/chemical intoxication (drug that excreted

through the kidney in active form)
Thiazide diuretics:-

• Thiazide diuretics consist of 2 distinct groups:

• Those containing a benzothiadiazine ring: hydrochlorothiazide,

chlorothiazide (thiazide diuretics)

• Those that lack this heterocyclic structure but contain an unsubstituted

sulfonamide group (thiazide like diuretics) metolazone, xipamide and
indapamide. (longer duration of action)
Mechanism of Action
– Thiazides are secreted by proximal tubules but works in DCT
– Inhibit Na+ - Cl- symporter from the lumen to tubular cells & increases
Na+, Cl- excretion (and water)
Pharmacological actions:-
 On diuresis:-
• Increases Na+ and Cl- excretion
• Hypokalaemia: appreciable amount of Na+ and Cl- reaches CT where K+
exchanged for Na+
• Inhibits uric acid secretion hyperuricaemia and gout
• Decreases Ca2+ excretion
tends to increase plasma Ca++
Retards osteoporotic process
• Increases Mg2+ excretion
P.K.:-
• Thiazide diuretics administered orally (except chlorthalidone, less
lipophilic)
• Actively secreted into PCT by organic acid pump
• May also enter liver by hepatic organic acid transporter (specially in renal
disease)
• Duration of action depends on degree of protein binding
ADEs:- head ache, nausea, paraesthesia, hypokalaemia, hyperuricaemia,
hyperglycaemia and hypercholesterolemia (not favourable for DM and
dyslipidaemia)

• Sulphonamide reactions

• Hypercalcaemia (long-term) good for elderly

 Interactions:-
• Potentiates anti-hypertensive drugs action
• Increases the risk of arrhythmia when combined with digitalis, quinidine and
other antiarrhythmias (due to hypokalaemia)
• Reduces efficacy of anticoagulant and uricosuric
• Reduces the efficacy oral antidiabetics
• NSAID reduce the efficacy of thiazide
 CIs:-
• In pregnancy
• Renal insufficiency
• Hypersensitivity
 Clinical uses:-
• Hypertension (single drug or in combination 1st line drug)
• To mobilize edema fluid in Chronic, mild- heart failure
• Edema (loop diuretic is preferable)
• Nephrogenic Diabetes insipidus: when body is unresponsive to
vasopressin
• Prevention of Ca++ excretion in osteoporosis and calcium nephrolithiasis
(enhance tubular reabsorption)
Potassium sparing diuretics:-
• Weak diuretics act by inhibiting reabsorption of Na+ and excretion of K+
• Chronic use of diuretics require oral administration of potassium supplements or
potassium sparing diuretics
• Specially for patients with CHF and Cirrhosis
Inhibitors of Na+ channels at CT:- ex: amiloride, triamterene
 These drugs are secreted through organic base secretory system at PCT
 Later act at CT by blocking ENaC
 Therefore, inhibits Na+ reabsorption and excretion K+
• By blocking Na+ reabsorption, reduces driving force for K+
• Mode of action is independent of Aldosterone (given in Addison’s disease)
Uses:
• Edema
• Hypertension in comb. With loop n thiazide diuretics
• Hypokalaemia
• Cystic fibrosis (by increasing fluidity of respiratory secretion)
ADEs:-
• Hyperkalaemia (should not be given along with potassium supplement)
• Triamterene causes rise in blood urea, nausea, dizziness and muscle cramps
• Amiloride causes diarrohea
Aldosterone receptor antagonist:- Spiranolactone
• Onset of action is slow but longer duration of action (16-24 hrs)
• Its active metabolite is Canrenone
• MOA: spironolactone competes for Aldosterone receptor in cells of DCT & CT
• Drug-receptor complex is unable to attach to DNA
• Therefore inhibits transcription, translation & production of aldosterone
mediators proteins
• Latter is responsible for opening of Na+ channel
• In turn inhibits Na+ reabsorption & K+ excretion
Uses:
• Edema due to primary hyperaldosteronism (Conn’s syndrome)
• In hypertension

ADEs:-
• Hyperkalaemia
• GI disturbances, skin rashes, impotence in male, menstrual
irregularities
Summary:-
Antidiuretics (anti-aquaretics):-
• Inhibit water excretion without affecting salt excretion

• Reduces urine volume, given in DI (diabetes insipidus)

• 3 classes:-

1. Anti-diuretic hormone (ADH, vasopressin) :- desmopresin, lypressin,

terlipressin

2. Thiazide diuretics, amiloride

3. Miscellaneous: indomethacin, chlorpropamide, carbamazepine

• ADH: it is nonapeptide, secreted by posterior pituitary along with oxytocin

• ADH release rate is regulated by Osmoreceptor in hypothalamus and

volume receptors present in left atrium, ventricles and pulmonary veins

• ADH release is stimulated by Increase in plasma osmolarity & contraction

of ECF

• Receptors of vasopressin (GPCR): 2 types

• V1 receptors :