DIURETICS

DIURETICS

• Diuretics are drugs which increase the excretion of salt & water in the

urine
 classification
1) High efficacy diuretics (loop diuretics)

Furosemide, Bumetanide, piretanide, Torsemide

2) Medium efficacy diuretics

a)Thiazides: Chlorothiazide, Hydrochlorothiazide, Polythiazide

b)Thiazides like: Chlorthalidone, metolazone, Clopamide, Indapamide, Xipamide

3) Weak (Adjunctive diuretics)

a)Carbonic anhydrase inhibitors: Acetazolamide

b)Potassium sparing diuretics Aldosterone antagonist: Spironolactone, Eplerenone

Na+ channel inhibitors: Amiloride, Triamterene

c)Osmotic diuretics: Mannitol, Glycerol, Isosorbide

 High efficacy diuretics (loop diuretics)

• Inhibitors of Na+-K+-2Cl- cotransport

• Primarily act on the ascending limb of Henle’s loop (site II).

• therefore these are called ‘loop diuretics’.

• The diuretic response increases as we go on increasing the dose, hence called as

‘high ceiling diuretics’.

• The efficacy of these drugs has been rated as highest amongst all diuretic agents,
hence also called as ‘high efficacy diuretics’.

• These drugs are capable of producing upto 10 L of urine in a day.

•
 MOA

• When given by oral/IM/IV route, these drugs on reaching the circulation, get
bound to plasma proteins & cannot pass through glomerulus.

• These drugs reach their site of action by the process of proximal tubular
secretion.

• These drugs inhibits Na+-K+-2Cl- cotransport at site II & inhibit the reabsorption
of NaCl. Thus the increased Na+ & Cl- reach the distal tubule & promote the loss
of H + & K+ along with increased loss of water causing profuse diuresis.

• The excretion of calcium & magnesium also increases.

• IV furosemide transiently decreases preload by increasing systemic venous

capacitance or peripheral pooling. This action is prostaglandin mediated & is

responsible for the quick relief in left ventricular failure & pulmonary edema.
 FUROSEMIDE

• Prototype drug

• Highly efficacious of all diuretics

• Well absorbed orally with bioavailability 60%

• Highly plasma protein bound

• Eliminated partly through glomerular filtration & partly through tubular

secretion. Some part is directly excreted in intestine through bile also.

• Has very rapid onset of action.

ie; within 2-5 min (after IV administration)

10-20 min (after IM administration)

20-40 min (after oral administration)

• t1/2 is 1-2 hr with maximum duration of action 3-6 hrs.

• Given in a dose of 20-80 mg by oral route once daily in the morning.

• In pulmonary edema, it is given in a dose of 40-80 mg IV.

 BUMETANIDE

• Similar to furosemide, but it is 40 times more potent.

• Well absorbed orally with bioavailability 80-100%.

• t1/2 is 60 min & may prolong in patients with kidney or liver impairment.

• It is preferred in furosemide non-response patients or furosemide allergic

patients.

• Dose: 1-5 mg oral route once daily in the morning & 1-4 mg by IM/IV route
TORASEMIDE (TORSEMIDE)

• 3 times more potent & longer acting than furosemide

• Rapidly & completely absorbed by oral route with t1/2 of 3.5 hrs.

• Duration of action: 4-8 hrs

• Dose : 2.5-5 mg OD for hypertension & 5-20 mg/day in edema.

 Indications

• Edematous conditions (associated with hepatic, renal or cardiac origin).

• Acute pulmonary edema : IV furosemide or its congeners produce prompt relief

• Hypertension

• In massive blood transfusion (to prevent renal overload)

• Acute renal failure: these drugs can convert oliguric phase of renal failure to
non-oliguric phase.

• Cerebral edema (intracranial pressure can be lowered)

• Acute hypercalcemia: the calcium excretion & urine flow is increased.

 ADR

• Electrolyte disturbances such as hypokalaemia, hyponatremia, hypocalcemia,

hypomagnesemia. So electrolyte monitoring should be done regularly.

• Metabolic disturbances such as hyperglycemia, hyperuricemia,

hyperlipidemia

• General disturbances such as nausea, vomiting, diarrhea, headache,

giddiness, myalgia etc.

• Reversible ototoxicity

• Hypersensitivity reactions
MEDIUM EFFICACY DIURETICS (THIAZIDES &
RELATED DIURETICS)

• Primary site of action in the cortical diluting segment (early DT, site III)

• They inhibit Na+- Cl- symport.

• Less powerful but long duration of action as compared to loop diuretics

 MOA

• When given by oral route, these drugs on reaching the circulation, get bound to
plasma proteins & cannot pass through glomerulus.

• These drugs reach their site of action by the process of proximal tubular secretion.

• These drugs inhibit Na+- Cl- symporter at site III & inhibit the reabsorption of NaCl.
This increases the loss of NaCl with water in the form of urine.

• Some of the thiazides & related drugs have additionally weak carbonic anhydrase
inhibitory action in proximal convoluted tubule.

• They inhibit urinary excretion of calcium & uric acid.

 HYDROCHLOROTHIAZIDE

• t1/2: 3-6 hrs

• In hypertension, it is given in a dose of 12.5-50 mg/day.

• In edema patients, it is given in a dose of 25-100 mg/day.

CHLORTHALIDONE

• t1/2: 40-50 hrs

• In hypertension, it is given orally in a dose of 12.5-50 mg once daily,

preferably in the morning
METOLAZONE

• Has a special property that it works even in severe renal failure patients with
GFR ≤ 15 ml/ min

• Synergistic effect when given with furosemide.

• In edema patients, it is given orally in a dose of 5-10 mg/day.

• In hypertension, it is given orally in a dose of 2.5-5 mg/day.

INDICATIONS

• Hypertension

• Edema

• Diabetes insipidus

• Hypercalciurea: thiazides act by reducing Ca2+ excretion

 ADR
• Electrolyte disturbances such as hypokalaemia, hyponatremia,
hypocalcemia, hypomagnesemia. So electrolyte monitoring should be
done regularly.

• Metabolic disturbances such as hyperglycemia, hyperuricemia,

hyperlipidemia

• General disturbances such as nausea, vomiting, diarrhea, headache,

giddiness, myalgia etc.
• Hypersensitivity reactions such as rashes & photosensitivity reactions occur in

sulphonamide sensitive patients.

• sometimes aggravated renal insufficiency, probably by reducing GFR

• Hearing loss with high ceiling diuretics

 Weak / Adjunctive diuretics

Carbonic anhydrase inhibitors- Acetazolamide

• It is a sulfonamide derivative which noncompetitively but reversibly inhibits
carbonic anhydrase in PT cells resulting in slowing of hydration of CO 2, decreased
availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter.

• The net effect is inhibition of HCO3- & accompanying Na+ reabsorption in PT.

• The resulting alkaline diuresis is only mild (maximal fractional Na + loss 5%).
Because part of the Na+ (but not HCO3-)rejected in the PT is reabsorbed at the
high capacity AscLH.
• Secretion of H+ in DT & CD is also interfered. Though H+ is secreted at this site by a H+-
ATPase.

• When Carbonic anhydrase inhibitors are given, the distal Na + exchange takes place only
with K+ which is lost in excess.

Pharmacokinetics

• Well absorbed orally

• Excreted unchanged in urine

• Action of a single dose lasts 8-12 hrs.

Dose

• 250 mg OD-BD
ADR

• Acidosis- more likely to occur in patients of COPD

• Hypokalemia

• Drowsiness, fatigue, abdominal discomfort

• Hypersensitivity reactions- fever, rashes

• Bone marrow depression is rare but serious

Uses

• Glaucoma

• To alkalinise urine

• Epilepsy

• acute mountain sickness

• Periodic paralysis

Contraindication: in liver disease ( may precipitate hepatic coma by interfering

with urinary elimination of NH3 due to alkaline urine)

 POTASSIUM SPARING DIURETICS
ALDOSTERINE ANTAGONIST- SPIRONOLACTONE

• Spironolactone competitively antagonizes the aldosterone. Hence prevent the

sodium & water reabsorption & cause diuresis.

• as sodium reabsorption is inhibited, the concomitant potassium secretion into

the tubules does not take place. Hence, the potassium sparing effect is

obtained.
Pharmacokinetics

• It is partially absorbed with only 65% bioavailability

• Metabolized in liver & converted to active metabolite ‘canrenone’.

• It also undergoes enterohepatic circulation.

• t1/2 is 1-2 hrs, while that of canrenone is ~ 18 hrs

• t1/2 may increase in case of cirrhosis.

Dose: 25-50 mg BD-QID

ADR

• Common side effects are hyperkalemia, epigastric distress, loose motion & mental confusion.

• It may also cause gynecomastia & erectile dysfunction in males, while menstrual irregularities in
Indications

• It is used in combination with high efficacy diuretics to compensate the K+ loss in

urine.

• Oedema due to cirrhosis of liver & nephrotic syndrome (aldosterone levels are
high in these conditions).

• Congestive heart failure & hypertension: as an adjuvant to other diuretics to

prevent hypokalemia.

• Conn’s syndrome

• Ectopic aldosterone production (secondary aldosteronism)

Interaction

• Given together with K+ supplements- dangerous hyperkalemia can occur

• Aspirin blocks spironolactone action by inhibiting tubular secretion of its active

metabolite canrenone.

• ACE inhibitors ( hyperkalemia can occur)

• Spiranolactone increases plasma digoxin concentration.

Na+ CHANNEL INHIBITORS- AMILORIDE,TRIAMTERENE

• These drugs act by inhibiting the renal epithelial Na+ channel & increase Na+

excretion with retention of K+ ions.

• They also reduce the excretion of Ca+ & Mg+ ions without changing renal

hemodynamics.
 TRIAMTERENE

• Its oral absorption is partial

• Metabolized in liver

• Excretion through urine

• t1/2 4 hrs

• Oral dose: 50-100 mg OD

• Common side effects: nausea, muscle cramps & dizziness

 AMILORIDE

• It is 10 times more potent than triamterene

• Oral absorption is very poor

• Metabolized in liver

• Excretion through urine

• Plasma t1/2 is 20 hrs

• Oral dose: 5-10 mg OD/BD

• Common side effects are hyperuricemia, headache, nausea & diarrhea

Indications

• In combination with thiazide these drugs are used to treat refractory oedema.

• In hypertension, to prevent hypokalemia induced by loop diuretics

• Lithium induce diabetes insipidus ( it blocks entry of lithium by sodium

channels in the collecting duct)

• Some case of cystic fibrosis

OSMOTIC DIURETICS- Mannitol, Isosorbide, Glycerol

• These drugs mainly act in the PCT & the descending limb of loop of Henle

• The effect of anti-diuretic hormone in the collecting duct is also decreased by

these agents

• These agents also inhibit the normal water reabsorption by their osmotic
effects & lead to increased urine excretion.

• The Na+ & water reabsorption is inhibited because these drug decrease the
contact time between tubular epithelium, causing natriuresis & excessive water
loss.
 MANNITOL

• It is pharmacologically inert

• It can be given in large quantities sufficient to raise osmolarity of plasma &

tubular fluid.

• It is minimally metabolized in the body, freely filtered at the glomerulus &

undergoes limited reabsorption; therefore excellently suited to be used as
osmotic diuretic.

• Mannitol appears to limit tubular water & electrolyte reabsorption in a variety

of ways.
Indications

• For decreasing intracranial tension (ICT) & intraocular tension (IOT).

• Dose: 1-2 gm/kg; it takes 60-90 minutes to reduce ICT/IOT. It decreases the
cerebral & ocular edema.

ADR

• The most common side effect is headache; while other side effects are nausea,
vomiting, dehydration, hyperkalemia, hyponatremia & pulmonary edema.

• It is contraindicated in pulmonary edema, established renal failure, acute left

ventricular failure, cerebral hemorrhage & congestive heart failure
ANTIDIURETICS
 ANTIDIURETICS

• Drugs that reduce urine volume, particularly in diabetes insipidus (DI) which is

their primary indication.

• Also known as ‘anti-aquaretics’, because they inhibit water excretion without

affecting salt excretion.

Antidiuretic drugs are divided in 3 groups

• Antidiuretic hormone (ADH, Arginine Vasopressin (AVP)), Lypressin,

Desmopressin, Terlipressin

• Thiazide diuretics & Amiloride

• Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine

 ANTIDIURETIC HORMONE (ARGININE VASOPRESSIN (AVP)

• It is a nonpeptide secreted by posterior pituitary along with oxytocin.

• The two main physiological stimuli for ADH release are rise in plasma
osmolarity & concentration of e.c.f.

• Osmoreceptors regulate their release.

• Osmoreceptors present in hypothalamus & volume receptors present in left

atrium, ventricles & pulmonary veins primarily regulate the rate of ADH release
governed by body hydration.
• Osmoreceptors are also present in the hepatic portal system which sense ingested

salt & release ADH even before plasma osmolarity is increased by the ingested salt.

• The human ADH is 8-arginine-vasopressin (AVP)

• It can raise blood pressure by constricting the blood vessels, hence also called

vasopressin.

• 8-lysine-vasopressin (Lypressin) is found in swine & has been synthetically

prepared.
• ADH exerts its effects by acting through V1 &V2 receptors

• V1 receptors: are located in vascular smooth muscle, uterine & other visceral
smooth muscles, intestinal cells in renal medulla, cortical collecting duct cells,
adipose tissue, brain, platelets, liver, anterior pituitary, certain areas in brain & in
pancreas etc

• Their clinical importance lies in the constriction of blood vessels mainly.

• V2 receptors: are located in the collecting duct cells, ascending limb of loop of
Henle cells & the endothelium of blood vessels.

• Their clinical importance lies in the antidiuretic effect by increasing the water
Other actions of AVP are,

• Increased GI peristalsis (large intestine)

• Uterine contractions are increased like oxytocin

• Regulation of temperature, systemic circulation & adrenocorticotropic

hormone release
 pharmacokinetics

• AVP is inactive orally because it is destroyed by trypsin.

• It can be administered by any parenteral route or by intranasal application.

• The peptide chain of AVP is rapidly cleaved enzymatically in many organs,

especially in liver & kidney.

• Plasma t1/2 is short & is ~ 25 minutes.

 LYPRESSIN

• It is 8- lysine vasopressin.

• Less potent than AVP

• It act on both V1 & V2 receptors

• Longer duration of action (4-6 hrs)

• It is being used in place of AVP- mostly for V1 receptor mediated actions.

• It is given IM/SC in a dose of 10IU

• The IV infusion of 20 IU diluted in 200 ml of dextrose is given over 10-20 min.

 TERLIPRESSIN

• It is a synthetic prodrug of vasopressin

• Specifically used for bleeding esophageal varices

• Dose: 2 mg IV, repeat 1-2 mg every 4-6 hrs as needed.

 DESMOPRESSIN

• This synthetic peptide is 10-12 times more potent than vasopressin.

• It is a selective V2 agonist.
• It is longer acting because enzymatic degradation is slow, duration of action 8-12
hrs.
• t1/2 1-2 hrs
• Desmopressin is the preparation of choice for all V2 receptor related indications
• The intranasal route is preferred, though bioavailability is only 10-20%.
• Orally: 0.1-0.2 mg thrice daily
• Parenterally: 2-4 μg/day by SC/IV route in 2-3 divided doses.
• Intranasally: adults: 10-40 μg/day in 2-3 divided doses
 Indications of ADH & vasopressin analogues

Diabetes insipidus: highly effective in central/ neurogenic DI, whereas

ineffective in renal/ nephrogenic DI.

Nocturnal enuresis: intranasal/ oral desmopressin at bedtime controls primary

nocturia by reducing urine volume.

Haemophilia & von Willebrand’s disease: AVP releases von Willebrand’s factor
& factor VIII, which are helpful in controlling bleeding.

• Actions based on V2 receptor activation & desmopressin is the drug of choice.

Bleeding esophageal varices: vasopressin analogues stop bleeding by

constricting mesenteric blood vessels & reducing blood flow through the liver

to the varices, allowing clot formation.

• This action is based upon V2 receptor activation & terlipressin is the drug of

choice.
 ADR

• Local side effects: nasal congestion, rhinitis & epistaxis

• Systemic side effects: headache, flushing, nausea, urticaria, abdominal

cramps, backache in females ( due to uterine contraction) & hyponatremia.

 THIAZIDE DIURETICS, AMILORIDE

Diuretic thiazides paradoxically exert an antidiuretic effect in patients of diabetes

insipidus.

Hydrochlorothiazide 25-50 mg TDS or equivalent dose of a longer acting agent is

commonly used.

Mainly effective in nephrogenic DI.

MOA: Thiazides induce a state of sustained electrolyte depletion so that the

glomerular filtrate is more completely reabsorbed iso-osmotically in the PT. finally
a smaller volume of less dilute urine is presented to the collecting ducts & the
same is passed out.
• Secondly, thiazides reduce glomerular filtration rate (GFR) & thus the fluid load

on tubules.

• High ceiling diuretics are also effective but are less desirable because of their

short & brisk action.

• In lithium induced nephrogenic DI, Amiloride is the most preferred drug

 MISCELLANEOUS DRUGS

 INDOMETHACIN

• Reduce polyurea in renal DI to some extent by reducing renal PG synthesis.

• It can be used in combination with thiazide/ amiloride in nephrogenic DI, other

NSAIDs are less active.

CHLORPROPAMIDE

• Sensitizes the kidneys to ADH actions.( it is not active when ADH is totally absent)

• It acts by reducing urine formation at pituitary level.

CARBAMAZEPINE

• It is an antiepileptic

• Decreases the urine volume in DI of pituitary origin.

• High doses are needed, adverse effects are marked.

 Drug interactions

• Loop diuretics & spironolactone enhance the digitalis toxicity by causing

hypokalemia.

• The level of lithium is raised by loop diuretics. Hence the combinations should

be avoided.

• Thiazides or high ceiling diuretics are intentionally given in combination with

anti-hypertensive to obtain synergistic effects.

• The combination of high ceiling diuretics & aminoglycoside antibiotics should

be avoided as both are ototoxic & nephrotoxic in nature.

• NSAIDs decrease the effect of high ceiling diuretics by inhibiting prostaglandin

synthesis in the kidney. Hence the combination should be avoided.

• Spironolactone should not be given with angiotensin converting enzyme

inhibitors / angiotensin receptor blockers as fatal hyperkalemia may occur.

 Nursing implications of diuretics & anti diuretics

• Assess for contraindication or cautions of diuretic use.

• Continuously monitor urinary output, cardiac response & heart rhythm of

patients receiving IV diuretics to monitor for electrolyte disturbances leading to
cardiac arrhythmia.

• If the patient is not catheterized, administer oral/ injectable diuretics early in

the day so that increased urination will not interfere with sleep.

• Monitor for adverse effects of diuretic therapy & take timely action accordingly.
• Patient should be educated, that thiazide diuretics may cause photosensitivity.

• The pulse of the patient on diuretic therapy should be palpated carefully to

assess the ectopic beats & if noted should be brought into the notice of the

physician.

• Evaluate the effectiveness of the teaching plan ( patient can name the drug,

dosage, adverse effects to watch for & specific measures to avoid them).