Diuretics (2/2)

Dr. C.Adithan

Professor of Pharmacology

Overview of 2nd lecture• Pharmacology of

– Potassium sparing diuretics: (a) Aldosterone antagonists (b) Na+ Channel Blockers

– Osmotic diuretics – Carbonic anhydrase inhibitors

• Mechanism of action• Indications• Dose • Side effects• Drug interactions

• Few MCQs

•

Classifications of Diuretics• Thiazide Diuretics: a) Thiazides: Hydrochlorothiazide, Benzthiazide b) Thiazide like: Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide

• Loop Diuretics : Frusemide, Bumetanide, Torasemide, Ethacrynic acid

• Potassium Sparing Diuretics : – Aldosterone Antagonist: Spironolactone, Canrenone, Eplerenone– Directly Acting (Inhibition of Na+ channel): Triamterene, Amiloride

• Carbonic anhydrase inhibitors : Acetazolamide, Brinzolamide, Dorzolamide• Osmotic Diuretics : Mannitol, Glycerine, Urea, Isosorbide

1. Osmotic diuretics2. Carbonic anhydrase inhibitors3. Loop Diuretics (High ceiling)4. Thiazide diuretics5. Potassium sparing diuretics

1. Osmotic diuretics2. Carbonic anhydrase

inhibitors3. Loop diuretics4. Thiazide diuretics5. Potassium sparing

diuretics

Potassium Sparing Diuretics– Aldosterone Antagonist: Spironolactone, Canrenone, Eplerenone– Directly Acting (Inhibition of Na+ channel): Triamterene, Amiloride

»Mechanism of action»Individual drugs»Pharmacokinetics»Indications»Dose»Side effects and Precautions

Potassium sparing diuretics

Spironolactone - Actions

• Acts on cortical segment of distal tubules• Competitive antagonist of Aldosterone• Inhibit ATP inhibit Na reabsorption• Mild saluretic (natriuresis) 3% of NaCl• Causes K + retention (K + sparing effect)

Hyperkalemia • Never used alone as diuretic• Useful when combined with thiazide or frusemide

Spironolactone - Pharmacokinetics

• Given orally microfine powder tab.• Bioavailability 75%• Converted to active metabolite canrenone • K canrenoate is water soluble can be given

I.V. gets converted to canrenone

Spironolactone - uses1) Oedema: Useful in cirrhotic and nephrotic syndrome

breaks resistance to thiazides or frusemide in refractory edema

2) To counteract K + loss due to thiazides, frusemide

3) Hypertension: combined with thiazide

4) CHF: as an adjunctive therapy, it retards disease progression and reduces mortality

5) Primary Hyperaldosteronism (Conn’s syndrome)

Spironolactone – Adverse Effects1) Hyperkalemia risk

• In CRF patients• Patients taking ACEI (Enalapril) or ATRA (Losartan)• KCl supplement

2) Related to steroid structure• Gynaecomastia, Impotence in males• Hirsutism, menstrual irregualarities in females

3) Misc: drowsiness, abdominal upset

Drug Interactions• may increase digoxin levels in CHF• NSAIDs (Aspirin) decreases its effect

Potassium sparing diureticsEplerenone

More selective aldosterone antagonistLess hormonal adverse effectsHyperkalaemia risk similar to spironolactone

UseModerate to severe CHFPost MI Left Ventricular dysfunction

Amiloride & Triamterene - Actions

• Directly inhibits pumps in distal tubules and collecting ducts therefore independent of aldosterone

Amiloride sensitive or renal epithelial Na channels are blocked Weak diuretic, never used alone Indirectly inhibit K+ secretion Also inhibit H+ secretion Amiloride in aerosol form cystic fibrosis ADRs: Relatively fewer than spironolactone, does not cause

sexual dysfunction

Triamterene & AmilorideOnset of action much faster than spironolactone

Reduce loss of potassium in urine

Predispose to acidosis (conserve K + and H +)

Hyperkalaemia with K + supplements, ARBs, ACEIs

Amiloride: 10 times more potent than triamterene

Used along with thiazides to prevent hypokalaemia

Potassium sparing diuretics: Preparations

Aldosterone Antagonist

Dose (mg) Route

Spironolactone 25-100 oral

K canrenoate I.V. Eplerenone 25-100 oralDirectly ActingAmiloride 5 Oral, AerosolTriamterene 50 oral

Fixed dose combinations with thiazides and frusemide available but not advisable

• Acetazolamide

• Methazolamide

Carbonic Anhydrase Inhibitors (CAIs)

CARBONIC ANHYDRASE INHIBITORS

Less potent than loop diuretics or thiazidesMechanism of action:• 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. • They induce metabolic acidosis which reduces their diuretic effect

within 2 to 4 days

CARBONIC ANHYDRASE INHIBITORSAcetazolamide :sulphonamide derivativeEnhances excretion of sodium , potassium, bicarbonate and water.

Other Actions 1. Eye- reduces intra ocular pressure. 2. Brain- reduces the formation of CSF

Pharmacokinetics: Well absorbed orally,

Onset of action within 60-90 min,

Duration of action 8-12 hr.

Excreted unchanged by the kidney

CAI: Adverse Effects

• Metabolic acidosis(due to HCO3 loss)• Anorexia• Hematuria• Photosensitivity• Melena

Hypokalemia Drowsiness Paresthesias Urticaria Renal stones : Ca++ is

lost with HCO3 resulting in hypercalciuria.

CARBONIC ANHYDRASE INHIBITORSPresent status:

• Adjunct drugs in the long-term management of open-angle glaucoma• Alkalinization of urine: Uric acid and cysteine excretion can be

enhanced by HCO3- (more soluble in alkaline urine).• Metabolic alkalosis: Alkalosis due to excess diuretics in patients with

heart failure responds to acetazolamide.• Hyperphosphatemia• Used with miotics to lower IOP before ocular surgery in certain cases• Also useful in the treatment of:

– Edema – Epilepsy– High-altitude sickness

OSMOTIC DIURETICS

OSMOTIC DIURETICSMannitol is a pharmacologically inert substance.• Mannitol gets filtered by the glomerulus but

is reabsorbed.• It causes water retention in the proximal

tubule and descending limb of Henle’s loop by osmotic effect resulting in water diuresis.

• There is also some loss of sodium. Adverse effects are dehydration, ECF volume

expansion, hyoponatraemia, headache, nausea, vomiting and allergic reactions.

Uses• To maintain urine volume and prevent oliguria in conditions like

massive haemolysis, rhabdomyolysis, shock and severe trauma. In such situations mannitol prevents renal failure.

• To reduce intracranial and intraocular pressure. • Contraindicated in patients who have already gone into renal

failure, mannitol can be dangerous since it can cause pulmonary edema and may precipitate heart failure due to volume expansion.

• Glycerol is effective orally – reduces Intraocular and intracranial pressure.

• Methylxanthines like theophylline have mild diuretic effect.

Diuretic Site of Action Adverse Effects Special pointsLoop Diuretics Thick

Ascending Limb of Henle(NaK2Cl inhibition)Weak CAI action

HyponatremiaHypomagnesaemiaHypocalcaemiaHyperuricemiaHyperglycemiaHyperlipidemiaHyperuricemiaOtotoxic (ECA)

Most potent, Most Potent is Bumetanide, Effective even in low GFR, All except Ethacrynic acid are sulphonamide related,Used in Acute LVF, Pulmonary Edema, Nephrotic syndrome, ARFNSAIDS blunt effect

Thiazide Diuretics DCT(NaCl)

Hypokalemic metabolic alkalosis (Gitelman’s Syndrome)Hypercalcemia

Moderate, Chlorthalidone is Longest acting, Paradoxical effect in Diabetes InsipidusFirst line in Hypertension,

Diuretic Site of Action Adverse Effects Special pointsCarbonic anhydrase inhibitors

PTC(inhibition of CAE)

Metabolic Acidosis Weak, Used in Glaucoma, Petit mal epilepsy, Acute mountain sickness, to alkaline the urine

Osmotic Diuretics

PTC, LOH, DCT Shifting of fluid from intracellular to extracellular, Hyponatremia, Pulmonary edema

Used in Glaucoma, Poisoning, Increased ICT, impending ARF

Potassium Sparing Diuretics

CD HyperkalemiaAntiandrogenic effect

Weak, As supplement to other to counter the hypokalemia, Canrenone is active metabolite, used in Conn’s syndrome (Primary Hyperaldosteronism), cirrhotic edema

Generalized Oedema

• Cardiac Cause: Congestive cardiac failure

• Renal Cause: Nephrotic syndrome

• Hepatic Cause: Cirrhosis of liver

• Nutritional cause: Malnutrition

• Allergic reaction

• Drug Induced

Points to Remember – Clinical Practice

• Don’t use diuretics overenthusiastically. (dehydration, hypotension)

• Brisk diuresis in cirrhosis may precipitate hepatic coma. (hypokalemia, alkalosis and increased NH3 levels)

• Diuretics not used in Toxaemia of Pregnancy. (Blood volume is low despite edema. Diuretics will compromise

placental circulation)

• Most of Loop and Thiazide diuretics are sulphonamide derivatives. (Think of allergic manifestations)

• Hypokalemia by diuretics precipitates digitalis, quinidine side effects

• Hypokalemia by diuretics decrease sulfonylurea action (reduced insulin release due to reduced action of ATP dependent potassium channel)

• High ceiling not given with Amino-glycosides• ACE inhibitors with Thiazides reduce the chances of

hypokalemia (FDC)• Probenecid inhibits tubular secretion of Frusemide and

Thiazides and reduce action• Potency of producing hypokalaemia

CAsI>Thiazides>Loop• NSAIDS reduce diuretic action due to PG inhibition and

affecting glomerular blood flow

• Acetazolamide action is self limiting• Spironolactone breaks the Thiazide resistance• Aspirin blocks Spironolactone action by inhibiting tubular

secretion of canrenone• Spironolactone can produce dangerous hyperkalaemia when

used along with ACEI and ARBs• Spironolactone has antiandrogenic side effects• Eplirenone is new potassium sparing diuretics with less

antiandrogenic effects• Osmotic diuretics indicated in impending ARF.

(Don’t use if ARF has set in)

MCQs

MCQ 1

1. The principal renal site of action ofa) Triamterene: Ascending limb of the loop of Henleb) Spironolactone: Descending limb of the loop of Henlec) Frusemide: Proximal tubuled) Osmotic diuretics: Distal tubulee) Thiazides: Cortical diluting segment

MCQ 2sA 50-year old man has a history of frequent episodes of renal colic with high calcium with renal stone. The most useful diuretic in the treatment of recurrent calcium stone is

a) Furosemideb) Spironolactonec) Hydrochlorothiazided) Acetazolamide

MCQ 3sAn elderly patient with h/o of heart disease and having difficulty in breathing. She was diagnosed to have pulmonary oedema. Which of the following drug is indicated?

a) Spironolactone.b) Furosemidec) Acetazolamide.d) Chlorthalidonee) Hydrochlorothiazide.

MCQ 4sA 60 years old male patient with kidney stone has been placed on a diuretic to decrease calcium excretion. After few weeks, he develops an attack of gout. Which diuretic was he taking?

a) Furosemideb) Hydrochlorothiazide.c) Spironolactone.d) Triamterene.

MCQ 5A 65 years old hypertensive patient was treated with a thiazide. Her B.P was well controlled and reads at 120/76 mm Hg, After few months of medication, she complains of being tired and weak. An analysis of the blood may show low values for

a)Calciumb)Uric acidc) Potassium.d)Sodium.

MCQ 6Indomethacin can antagonize the diuretic action of furosemide by 

a) Blocking the ascending limb of loop of Henleb) Enhancing salt and water reabsorption in distal

tubulesc) Increasing aldosterone secretiond) Preventing prostaglandin mediated intrarenal

hemodynamic action

MCQ 7One of the following statements about Spironolactone are NOT correct:

a)has low therapeutic efficacy when used alone

b)may cause gynaecomastiac) may cause hyperkalaemia in patients whose

renal function is impairedd)may be combined with triamterene

MCQ 8One of the following statements about Hyperkalemia is NOT correct:

a)Is a particular risk if Amiloride is used in a patient with impaired renal function

b)If severe may require dialysis for correctionc) Increases if sodium bicarbonate is givend)Can be corrected by infusion of glucose and

insuline)Causing ECG changes is an indication to

give calcium gluconate

Which of the following is carbonic anhydrase inhibitor?a) Acetazolamideb) Spironolactonec) Benzthiazided) Clopamide

MCQ 9

Which of the following is NOT an aldosterone antagonist?a) Spironolactoneb) Canrenonec) Eplerononed) Triamterene

MCQ 10

Spironolactone may be beneficial in all of the following clinical conditions EXCEPT

a) Nephrotic edemab) Hypertensionc) Congestive heart failured) Hyperkalemia

MCQ 11

Which of the following condition is a contraindication for mannitol administration?

a) Acute congestive glaucomab) Head injuryc) Impending acute renal failured) Acute Pulmonary oedema

MCQ 12

Which of the following is most appropriate mechanism of action of Triamterene

a) Inhibition of Mineralocorticoid receptorsb) Inhibition of Na+K+2Cl – channelsc) Inhibition of Na+Cl– channels of DCTd) Inhibition of renal epithelial Na+ channels

MCQ 13

Site of action of spironolactone isa) Proximal Convoluted Tubuleb) Descending limb of Loop of Henlec) Collecting Ductd) Ascending limb of loop of Henle

MCQ 14

Thank you