DIURETICS AND ANTIDIURETICS

- Diuretic is an agent which increases urine and solute

excretion.
- A natriuretic is an agent which increases sodium
excretion from the kidney
- An aquaretic is a drug that enhances the excretion of
water.
CLASSIFICATION
1. HIGH EFFICACY DIURETICS
- Furosemide, bumetanide, piretanide, torsemide

2. MODERATE EFFICACY DIURETICS

- THIAZIDES-
Benzothiadiazides- chlorothiazide, hydrochlorothiazide,
polythiazide, benzthiazide
- THIAZIDE- RELATED AGENTS-
Chlorthalidone, clopamide, indapamide

3. LOW EFFICACY DIURETICS

- POTTASIUM SPARING DIURETICS- Triamterene, amiloride
- CARBONIC ANHYDRASE INHIBITORS- Acetazolamide,
methazolamide
- OSMOTIC DIURETICS- Mannitol, urea, glycerol
- METHYLXANTHINES- Theophylline

4. NEWER AGENTS
- VASOPRESSIN ANTAGONISTS- Conivaptan, tolvaptan, lixivaptan
- ADENOSINE A1 RECEPTOR ANTAGONISTS- Rolophylline
- SGLT2 INHIBITORS- Dapagliflozin, canagliflozin
HIGH EFFICACY / LOOP DIURETICS
FRUSEMIDE (FUROSEMIDE)
- Furosemide is a sulfonamide derivative and the most
popular and powerful loop diuretic.
Actions and Mechanism of action
- Frusemide acts by inhibiting NaCl reabsorption in the
thick ascending limb of the Henle’s Loop.
- It blocks the Na+ K+ 2Cl- SYMPORTER in the thick ascending
limb of the Henle’s loop because of which it is called a
loop diuretic.
- It greatly increases the excretion of Na+ and Cl- in the
urine.
- Loop diuretics are highly efficacious because a large
amount of NaCl- is absorbed in this segment.

Other actions
- Loop diuretics enhance the excretion of K+, Ca++ and Mg+
- They increase reabsorption of uric acid in the proximal
tubule.
- They cause Vasodilation in renal vasculature and
increase renal blood flow.
- Intravenous frusemide causes venodilation and reduces
left ventricular filling pressure
- It also induce the synthesis of PGE2 which inhibits
reabsorption of sodium into the loop of Henle thereby
contributing to their diuretic action.

Pharmacokinetics
- Frusemide and other loop diuretics are rapidly and
almost completely absorbed orally.
- Given intravenously, frusemide acts in 2-5 minutes, while
following oral use, it takes 20- 40 minutes.
- They are partly metabolized in the liver and the
metabolites are excreted by the kidneys by glomerular
filtration and tubular excretion
- Bumetanide is 40 times more potent. Bioavailability is 80
percent and onset of action is faster than frusemide.

Adverse effects of Loop Diuretics

1) HYPOKALEMIA AND METABOLIC ALKALOSIS
- Because loop diuretics inhibit reabsorption of sodium in
the loop of Henle, a high sodium fluid is delivered to the
collecting duct.
- In the collecting duct, K+ and H+ are secreted in large
amounts in exchange for sodium leading to HYPOKALEMIA
and METABOLIC ALKALOSIS.
- Symptoms of Hypokalemia are seen with serum K+ levels
less than 2.5 mEq/L.
- Manifestations include irritability, drowsiness, confusion,
dizziness, muscle weakness and cardiac arrhythmias.
- Hypokalaemia can be prevented by high dietary intake of
K+, oral K+ supplements
2) HYPONATRAEMIA, DEHYDRATION, HYPOVOLAEMIA AND HYPOTENSION
- All these are due to diuresis and natriuresis- should be
treated with saline infusion.
- When salt and water are lost due to rapid diuresis,
body tries to compensate by increasing retention of water
and salt.
- However, salt retention is not possible because of
diuretics and only water gets retained.
- This results in dilution of ECF and hyponatraemia leading
to electrolyte imbalance and oedema.

3) HYPERURICAEMIA
- Hypovolaemia leads to increased uric acid absorption in
the proximal tubule.
- Hence, loop diuretics can cause hyperuricaemia and may
lead to gout on long term use
- ALLOPURINOL may be needed

4) HYPOCALCEMIA
- Loop diuretics may cause hypocalcaemia- which may result
in Osteoporosis on long term use

5) HYPOMAGNESEMIA
- More pronounced in patients with dietary deficiency.
- Oral magnesium supplements may be needed

6) OTOTOXICITY
- Na+, K+, 2Cl- cotransport is important in the inner Ear.
- Loop diuretics cause hearing loss by a toxic effect on the
hair cells in the internal ear.
- Associated tinnitus and vertigo may also occur.
- More common with ETHACRYNIC ACID.
7) HYPERGLYCEMIA AND HYPERLIPIDEMIA
- Mild in therapeutic doses

8) GIT DISTURBANCES
- Nausea, vomiting and diarrhoea (common with Ethacrynic
acid)

9) ALLERGIC REACTIONS
- Skin rashes, eosinophilia

USES
1) Oedema
- Relief of oedema of all origins like Cardiac, hepatic, or
renal oedema.

2) Acute Renal failure

- Enhance urine output and K+ excretion.
- Useful in impending acute renal failure.
- In chronic renal failure, large doses are needed.

3) Cerebral Oedema
- Frusemide is used as an alternative or in combination
with osmotic diuretics.

4) Acute pulmonary oedema and acute LVF

- Quickly relieved by IV frusemide due to its immediate
vasodilator effect and then by diuretic action

5) Forced diuresis
- In poisoning due to drugs like barbiturates and
salicylates
- Anion overdosage- poisoning due to fluoride, iodide and
bromide
 6) Hypertension
- With renal impairment may be treated with loop
diuretics like Thiazides

7) Acute hypercalcaemia and hyperkalaemia

- Loop diuretics enhance excretion of Ca+ and K+

THIAZIDES AND THIAZIDE- LIKE DIURETICS

- CHLOROTHIAZIDE was the first thiazide to be synthesized.
Actions and Mechanism of Action
- Thiazides have a moderate efficacy as diuretics because
90 percent of filtered sodium is already reabsorbed
before reaching the distal tubule.
- This group of drugs bind to the Cl- site of Na+ Cl-
cotransport system and block the system.
- In contrast to the loop diuretics, thiazides inhibit
urinary excretion of Ca++ and uric acid resulting in
hypercalcaemia and hyperuricaemia
- Thiazides may cause hyperglycaemia and may precipitate
diabetes in borderline hyperglycaemic patients due to
inhibition of insulin release.
Pharmacokinetics
- They are well absorbed orally and are rapid acting-
within 60 minutes.

Adverse effects
- Hypokalaemia is the most important side effect of
thiazide use.
- Metabolic alkalosis, hyperuricaemia, hypotension.
- Hyperglycaemia induced by thiazides may precipitate
diabetes mellitus by inhibition of insulin secretion.
- Thiazides can cause impotence in men
- Weakness, fatigue, anorexia, gastrointestinal disturbances
and allergic reactions are seen.
Uses
1) Hypertension
- Thiazides are the first line drugs

2) Congestive Heart Failure

- They are useful in the management of oedema due to mild
to moderate CHF

3) Oedema
- Thiazides may be tried in renal or hepatic oedema
- Metolazone may be combined with loop diuretics

4) Renal stones and hypercalciuria

- It can be treated with thiazides that reduce calcium
excretion.

5) Diabetes insipidus
- Thiazides benefit such patients by reducing plasma
volume and GFR- a paradoxical effect.
 -
INDAPAMIDE
- It is particularly suitable in hypertension because it is
claimed to lower blood pressure in subdiuretic doses
- It is well absorbed orally and has a longer duration of
action.

POTASSIUM SPARING DIURETICS

- They may act by two ways. They may be aldosterone
antagonists (spironolactone) or directly inhibit ion
channels in distal tubule and collecting duct
(triamterene, amiloride)
SPIRONOLACTONE
- Aldosterone regulates the sodium absorption and
potassium secretion in the collecting tubule and ducts.
- It enhances the Na+ reabsorption through Na+ channels in
the collecting tubule and enhances K+ secretion.
- Spironolactone binds to the mineralocorticoid receptors
on the distal tubule and collecting duct and
competitively inhibits the action of aldosterone.
 Adverse effects
- Endocrine side effects include gynaecomastia, impotence
in men, hirsuitism and menstrual irregularities in women
are seen with large doses of spironolactone
- Mild to significant hyperkalaemia particularly in
patients with renal insufficiency

AMILORIDE AND TRIAMTERENE

- They are directly acting agents which enhance Na+
excretion and reduce K+ loss by acting on ion channels in
the luminal membrane.

CARBONIC ANHYDRASE INHIBITORS

- Carbonic anhydrase is an enzyme that catalyses the
formation of carbonic acid which spontaneously ionises to
H+ and HCO3-
- This HCO3- combines with Na+ and is reabsorbed.
- By inhibiting the enzyme, carbonic anhydrase inhibitors
block sodium bicarbonate reabsorption and cause HCO3-
diuresis.
ACETAZOLAMIDE
- It enhances the excretion of sodium, potassium,
bicarbonate and water.
- There is some increase in chloride clearance.
- Other actions include
1. Eye- There is decreased formation of aqueous humour
and thereby decreased intraocular pressure due to
action of carbonic anhydrase inhibitors
2. Brain- Reduces formation of CSF

Pharmacokinetics
- Acetazolamide is absorbed orally, onset of action is
within 60- 90 minutes and duration of action is 8- 12 hours.

Adverse effects
- Metabolic acidosis
- Renal stones
- Hypokalaemia, drowsiness and allergic reactions
Uses
1) Glaucoma
- Intraocular pressure is decreased by acetazolamide

2) Alkalinisation of urine
- It is required in over dosage of acidic drugs.

3) Metabolic alkalosis
- Acetazolamide enhances HCO3- excretion.
- Alkalosis due to excess diuretics in patients with heart
failure responds to acetazolamide.
 4) Mountain Sickness
- Acetazolamide may relieve symptoms of pulmonary oedema
in mountain climbers by reducing the formation of CSF

5) Epilepsy
- It is used as an adjuvant a it increases the seizure
threshold.

6) Hyperphosphatemia
- It can be treated with acetazolamide to increase the
urinary phosphate excretion.

OSMOTIC DIURETICS
- Mannitol is a pharmacologically inert substance not
absorbed orally and causes osmotic diarrhoea
- When given IV, mannitol gets filtered by the glomerulus
but is not reabsorbed.
- Mannitol opposes the action of ADH in the collecting tubule.
- Adverse effects are dehydration, ECF volume expansion,
hyponatraemia, headache, nausea, vomiting and allergic
reactions
 Uses
1. To maintain urine volume and prevent oliguria in
conditions like massive haemolysis, rhabdomyolysis, shock
and severe trauma. Mannitol prevents renal failure.
2. To reduce intracranial and intraocular pressure-
following head injury and glaucoma, respectively.

NEWER AGENTS
1. VASOPRESSIN ANTAGONISTS
- Three drugs have been introduced in this group.
Conivaptan, tolvaptan, lixivaptan.
- They inhibit the effects of ADH in the collecting tubule
and cause free water diuresis.
- Patients with syndrome of inappropriate ADH secretion
(SIADH) should be treated with restriction of water
intake.

2. ADENOSINE A1 RECEPTOR ANTAGONISTS

- They decrease NaCl reabsorption in the proximal tubule
and collecting duct.

3. SODIUM GLUCOSE COTRANSPORTER 2 (SGLT 2) INHIBITORS

- Most of the glucose is reabsorbed through SGLT 2 and
inhibition of this transporter can lower the reabsorption
and enhance renal excretion of glucose.

Contraindications for Diuretics

1. Toxaemia of pregnancy
- Diuresis induced in pregnancy results in reduced foetal
circulation which may result in foetal death.
 2. Hepatic cirrhosis
- Diuretics can cause mental disturbances and hepatic
coma in cirrhosis patients.

ANTIDIURETICS
- Antidiuretics are drugs that reduce urine volume. These
include
1. Antidiuretic hormone (vasopressin)
2. Vasopressin analogs- desmopressin, terlipressin
3. Thiazide diuretics
4. Miscellaneous- Chlorpropamide, carbamazepine

ANTIDIURETIC HORMONE
- It is secreted by the posterior pituitary along with
oxytocin.
- It is released in response to two stimuli- dehydration
and rise in plasma osmolarity.

Vasopressin Receptors
- V1 receptors- mediate vasoconstriction
- V2 receptors- mediate water retention in the collecting
duct.
- Both are G protein- coupled receptors.

- V1 receptors are of two subtypes-

V1a- present on vascular and other smooth muscles,
urinary bladder, platelets, liver and CNS.
V1b receptors are present on the anterior pituitary.

- V2 receptors are present in the renal collecting ducts

where they enhance reabsorption of water.
 Actions
- ADH enhances water reabsorption by acting on the
collecting duct.
- ADH activates the V2 receptors present on the cell
membrane of colleting duct and increases water
permeability of cells.
- ADH causes vasoconstriction and increases BP
- It also acts on other smooth muscles to increase
constriction and peristalsis in the gut (cramps).
- Vasopressin contracts the uterus. It is given parenterally
SC / IM / IV injection.

Adverse effects
- Intranasally ADH can cause nasal irrigation, allergy,
rhinitis, and atrophy of nasal mucosa.
- Other effects include nausea, abdominal cramps and
backache.

Uses
Mediated through V1 receptors
- Bleeding oesophageal varices- ADH constricts mesenteric
blood vessels
- Before abdominal radiography- ADH promotes expulsion of
gases from the bowel
- Cardiac arrest- IV vasopressin reverts asystolic
cardiac arrest.

Mediated through V2 receptors

- Diabetes insipidus of pituitary org.- treated- desmopressin
- Nocturnal enuresis- Desmopressin controls bed wetting.
- Bleeding disorders- ADH - factor 8 and prevent bleeding.
- Renal concentration test- a small dose of desmopressin (2
microgram) can enhance the urine conc. to a great extent,
if the kidneys are normal.