Diuréticos

The relative magnitudes of Na+

reabsorption at sites
•PT - 65%
•Asc LH - 25%
•DT - 9%
•CD - 1%.
 Diuretics
• Carbonic Anhydrase Inhibitors (Site I)
–Brinzolamide, Acetazolamide, Dorzolamide
• Osmotic Diuretic (Site II)
–Glycerine, Urea, Mannitol, Isosorbide
• Loop Diuretics (Site III)- TALH
– Frusemide/ Furosemide, Bumetanide, Torasemide, Ethacrynic acid
• Thiazide Diuretics (Site IV)
– Hydrochlorothiazide, Clopamide, Benzthiazide, Chlorthalidone,
Metolazone, Xipamide, Indapamide
• Potassium Sparing Diuretics (Site V)
– Aldosterone Antagonist
• Spironolactone, Canrenone, Eplerone
– Direct Acting (Inhibition of renal epithelial Nq+ channel
• Triamterene, Amiloride (more potent)
Diuretics- Classification
1) High efficacy (upto 25% NaCl excretion)
Loop diuretics
 Frusemide, Torsemide, Bumetanide (SO2NH2 group)
 Ethacrynic acid (No SO2NH2 group)
 Organic mercurials: Mersalyl (Now obsolete)

2) Medium efficacy (5 –10 % NaCl excretion)

 Thiazides : Hydrochlorothiazide, ChloroTh, BenzTh,
HydroflumeTh, Clopamide, PolyTh
 Thiazide like : Chlorthalidone, Metolazone, Xipamide,
Indapamide
Diuretics- Classification
3. Carbonic Anhydrase Inhibitors (5%NaCl excretion )
 Acetazolamide, Methazolamide, Dichlorphenamide

4. Potassium Sparing Diuretics (3% NaCl excretion)

 Aldosterone Antagonists Spironolactone, eplerenone
 Directly acting: Amiloride, Triamterene

5. Osmotic Diuretics (upto 20% NaCl excretion)

 Mannitol, Glycerol, Isosorbide

6. Misc: Theophylline
Carbonic An-hydrase Inhibitors Thiazide diuretics

Osmotic Diuretics

Potassium Sparing Diuretics

Loop Diuretics (High Ceiling)
Loop Diuretics
Loop Diuretics- Frusemide MOA
• Acts on thick ascending part of Loop of Henle
• Inhibit Na+-K+-2Cl-cotransport and reabsorption
• Increase NaCl excretion (upto 25% High efficacy)
• Na exchanges with K+ in the DT  K+ loss
• Effective in very low GFR of < 30ml/min
• Other actions
• Increase Ca++, Mg ++ excretion
• Induce renal PG synthesis (blocked by NSAIDs)
• Direct vasodilatation (IV route) imp. In pulm edema, LVF
Loop Diuretics-Preparations, dosage

Drug Dose (mg)

Frusemide 20- 80

Torsemide 2.5 - 20

Bumetanide 0.5 – 2

Ethacrynic Acid 50-200

Which is the most potent loop diuretic? Bumetanide

Loop Diuretics- USES

1) Edema : Cardiac (CHF), Hepatic (cirrhotic Ascites),

Renal (Nephrotic syndrome)
2) Acute pulmonary edema
3) Cerebral edema (Mannitol preferred)
4) Acute hypercalcemia
5) Acute Renal failure
6) Forced diuresis in drug poisoning (Barbiturate)
Loop Diuretics- USES contd
7) Hypertension (Thiazides preferred)
8) Hyperkalemia mild
9) Along with massive blood transfusion
10) Anion overdose (Iodide, Bromide, Flouride)
Loop Diuretics-Adverse Effects
1) Hypokalemia
 Clinical Features : may Increase digoxin toxicity, arrhythmia
Muscle weakness, fatigue, cramps
 To prevent Hypokalemia
• Use low dose
• Give KCl supplement (oral solution or IV infusion)
• Combine with K sparing diuretic
• Advice: More intake of K containing food: coconut water, fruit juice

2) Hypochloremic Alkalosis
3) Dehydration
4) Hyponatremia
5) Ototoxicity: more likely with IV use, in RF, other ototoxic drugs
Loop Diuretics-Adverse Effects

6) Hyperuricemia
7) Hyperglycemia
8) Hyperlipidemia
9) Allergic reaction (SO2NH2 group)
10) Hypomagnesemia
11) Overzealous use may precipitate volume depletion
• Hepatic encephalopathy in hepatic coma
• Renal failure
• Cardiac failure
Carbonic Anhydrase Inhibitors

Carbonic Anhydrase Inhibitors

 Carbonic Anhydrase (CA) Enzyme

Cytoplasm of Proximal tubule

C.A.

H2O + CO2 H2CO3 H+ + HCO3-

C.A.

Renal brush border (Luminal)

CA is also present in
• Ciliary body of eye (Aquous humor formation)
• Choroid plexus (CSF formation)
Effects of Acetazolamide

1) Inhibits CA in the proximal tubule

2) Loss of HCO3, Na, Cl in urine
3) Hypokalemia
4) Urine becomes alkaline and acidosis develops
5) Acidosis limits the diuretic action within 2 weeks

Rarely used as diuretics

Acetazolamide

ADVERSE EFFECTS USES

• Glaucoma Oral Acetazolamide
• Hypokalemia, Fatigue or topical dorzolamide
• Acidosis • Acute mountain sickness
• To alkalinize the urine
• Sedation
• Periodic paralysis
• Paresthesias • Epilepsy

• Abdominal discomfort • Rarely as a diuretic

• Allergic reactions
• C/I in liver disease
Thiazides
Thiazide Diuretics - Actions
• Acts on early part of distal tubules
• Inhibit Na+-Cl- symporter and reabsorption
• Increase NaCl excretion (5-10% Medium efficacy)
• Na exchanges with K+ in the DT  K+ loss 
Hypokalemia
• Not effective in very low GFR of < 30ml/min, may
reduce GFR further
• Metolazone  additional action on PT, effective at low
GFR, can be tried in refractory edema
Thiazide Diuretics - Other actions
• Hypotensive action
• reduce Ca++ excretion may ppt
hypercalcemia in patients of hyperparathyroidism,
bone malignancy with metastasis

• Increase Mg++ excretion

• Hypochloremic alkalosis
• Hyperuricemia
• Hyperglycemia (inhibit insulin release ?)
• Hyperlipidimia (Cholesterol and TG)
Thiazides Preparations

Drug Name Dose (oral) Duration (hr)

Chlorothiazide (1957) 500-2000 6-12

Hydrochlorothiazide 25-100 8-12

Benzthiazide 25-100 12-18
Hydroflumethiazide 25-100 12
Chlorthalidone 50-100 48
Metolazone 5-20 18
Xipamide, Clopamide 20-40 12-24
Indapamide (No CAI) 2.5-5 24-36
Thiazides - Uses
1) Hypertension (Hydrochlorothiazide, Indapamide)
2) Edema : Cardiac, Hepatic Renal
• Less efficacious than loop diuretic
• Useful for maintainence therapy

3) Hypercalciuria and renal Ca stones

4) Diabetes Insipidus (DI) (Nephrogenic responds better)
• Paradoxical use,
• MOA - ? Reduce GFR, ? More complete reabsorption in PT
• Convenient, Cheaper than Desmopressin in Neurogenic DI
• Amiloride is the DOC for Lithium induced nephrogenic DI
5) Metolazone useful even when GFR is as low as 15ml/min
Thiazides -Adverse Effects
1) Hypokalemia 7) Hypchloremic alkalosis
2) May ppt renal failure 8) Hypersensitivity
3) Hyperuricemia 9) ppt. Hypercalcemia
4) Hyperglycemia 10) Not safe in pregnancy
(all diuretics)
5) Hyperlipidemia
6) Hypomagnesemia
Osmotic Diuretics

Ideal properties Drugs used

1. Orally effective
• Mannitol
2. Well abosorbed
3. Not metabolized • Glycerol
4. Freely filtered at glomeruli • Isosorbide
5. Not reabsorbed
6. Inert
7. Cheap
Mannitol - Actions
• not mediated by any receptors or target site
• Expands ECF volume – increase RBF, GFR
• Osmotic gradient in the tubular lumen prevent reabsorption
of mainly H2O  dilute urine diuresis
• prevent Na+ reabsorption - upto 20% NaCl excretion (Acute
effect)
• May inhibit transport process in Asc loop of Henle
• classified as weak diuretic in some textbooks
• never used for chronic edema or as a natriuretic
Osmotic diuretic - Preparations

Drug Daily dose

Mannitol I.V. 1-2 gm/kg

10% or 20% soln. 100 – 300 ml rapid infusion
Over 30 to 90 min
Glycerol oral 1-1.5 gm/kg
metabolized to glucose
Isosorbide oral 1.5 gm/kg
Mannitol - USES
1) ARF : treatment & prevention
 To maintain GFR during major surgeries, trauma cases, severe
jaundice, hemolytic reactions etc

2) To lower intracranial tension

Before brain surgery Cerebral edema

3) To lower intraocular tension

 Acute glaucoma Before intraocular surgeries

4) Forced diuresis in drug poisoning

 (FAD in barbiturate poisoning

5) To counteract low plasma osmolality after dialysis

Mannitol -Adverse Effects
1) Acute Intravascular volume expansion
• Before diuresis starts it exerts osmotic effect in the blood
• Contraindicated in pulmonary edema, Cardiac edema
(CHF) and intracranial hemorrage, established renal failure

2) Thrombophlebitis
3) Headache (due to hyponatremia), Nausea
4) If overdose  dehydration  hypernatremia

Monitoring of urine output, S. electrolytes, CVP is very imp.

Step 6 of rational pharmacotherapy
 Spironolactone

Amiloride
Potassium sparing diuretics: Preparations

Aldosterone Antagonist Dose (mg) Route

Spironolactone 25-100 oral

K canrenoate I.V.

Eplerenone 25-100 oral

Directly Acting
Amiloride 5 Oral, Aerosol

Triamterene 50 oral

Fixed dose combinations with thiazides and frusemide

available but not advisable
Spironolactone - Actions
• Acts on cortical segment of distal tubules
• Competitive antagonist of Aldosterone
• Inhibit AIP  inhibit Na reabsorption
• Causes K’ retention (K sparing effect) 
Hyperkalemia
• Mild saluretic (natriuresis) 3% of NaCl
• 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
• Onset of action is very slow (steroid receptors)
Spironolactone - uses
1) Edema more 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
 Eplerenone is a new drug approved for HT, No gynaecomastia

4) CHF: as a adjunctive therapy it retards disease progression and

reduces mortality
• RALES (Randomized ALdosterone Evaluation Study)

5) Primary Hyperaldosteronism (Conn’s syndrome)

Spironolactone – Adverse Effects
1) 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

4) Drug Interactions
• may increase digoxin levels in CHF
• NSAIDs (Aspirin) decreases its effect
Amiloride & Triamterene - Actions
• Direct action on DT and CD
• 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, precautions similar to spironolactone
but does not cause sexual dysfunction
A - Acetazolamide
Carbonic Anhydrase Inhibitors (Site I)

GM- Glycerine, Mannitol Osmotic Diuretics (Site I, II and…)

Brings FruTE- Bumetanide, Furosemide,

Loop Diuretics (Site III)
Torasemide, Ethacrynic acid

Cuts MIXs with Big Hands-

Clopamide, Chlorthalidone, Metolazone, Indapamide, Xipamide,
Benzthiazide, Hydrochlorthiazide, Thiazide Diuretics (Site IV)

And Starts Taking- Amiloride,

Spironolactone, Triamterene Potassium Sparing Diuretics (Site V)
Diuretic Site of Action Adverse Effects Special points
Carbonic PTC Metabolic Acidosis Weak, Used in Glaucoma, Petit mal epilepsy,
anhydrase (inhibition of CAE) Acute mountain sickness, to alkaline the urine
inhibitors

Osmotic PTC, LOH, DCT Shifting of fluid from Potent

Diuretics (Osmotic retention of water, intracellular to Used in Glaucoma, Poisoning, Increased ICT,
Dilates Afferent arterioles, extracellular, impending ARF
Increased hydrostatic Hyponatremia,
pressure in glomerulus Pulmonary edema

Loop Thick Ascending Limb of Hyponatremia Most potent, Most Potent is Bumetanide,
Diuretics Henle Hypomagnesaemia Effective even in low GFR, All except Ethacrynic
(NaK2Cl inhibition) Hypocalcaemia acid are sulphonamide related,
Weak CAI action Hyperuricemia Venodilatation, Decrease Left Ventricle Pressure,
Hyperglycemia Used in Acute LVF, Pulmonary Edema, Nephrotic
Hyperlipidemia syndrome, ARF, NSAIDS blunt effect, Cerebral
Hyperuricemia edema, short term tt of Hypertension, to reduce
Ototoxic (ECA) volume overload during transfusion,

Thiazide DCT Hypokalemic Moderate, Chlorthalidone is Longest acting,

Diuretics (NaCl) metabolic alkalosis Paradoxical effect in Diabetes Insipidus
(Gitelman’s First line in Hypertension,
Syndrome)
Hypercalcemia
Potassium CD HyperKalemia Weak, As supplement to other to counter the
Sparing Antiandrogenic effect hypokalemia, Canrenone is active metabolite, used in
Conn’s syndrome (Primary Hyperaldosteronism) cirrhotic
Diuretics
edema, polycystic ovary
MCQs on Diuretics
• Reabsorption of which of the following is affected maximum by action
of vasopressin?
• Water
• Chloride
• Potassium
• Hydrogen

A
• Bumetanide belongs to which of the following class of diuretics?
• Carbonic anhydrase inhibitor
• Aldosterone antagonist
• Thiazide diuretics
• Loop diuretics

D
• All of the following compounds produce diuretic action by
acting on thick ascending part of loop of henle EXCEPT
• Ethacrynic acid
• Torasemide
• Furosemide
• Clopamide

D
• Which of the following is thiazide like diuretics?
• Spironolactone
• Triameterene
• Metolazone
• Acetazolamide

C
• Which of the following is carbonic anhydrase inhibitor?
• Acetazolamide
• Spironolactone
• Benzthiazide
• Clopamide

A
• Which of the following is NOT an aldosterone antagonist?
• Spironolactone
• Canrenone
• Eplerenone
• Triameterene

D
• Among all of the following which is most potent?
• Frusemide
• Bumetanide
• Torasemide
• Ethracrynic acid

B
• Spirnolactone may be beneficial in all of the following
clinical conditions EXCEPT
• Nephrotic edema
• Hypertension
• Congestive heart failure
• Hyperkalaemia

D
• Which of the following is not an adverse effect of
Furosemide?
• Hyperuricaemia
• Hyperglycaemia
• Hyperlipidemia
• Hypermagnesaemia

D
• Which of the following drugs can precipitate
hypercalcaemia?
• Spironolactone
• Hydrochlorthiazide
• Furosemide
• Mannitol

B
• Thiazides induced hyperuricaemia may be prevented by
administration of which of the following?
• Allopurinol
• Probenecid
• Mannitol
• Furosemide

A
• Which of the following is most appropriate mechanism of
action of Triametrene
• Inhibition of Miniralocorticoid receptors
• Inhibition of Na+K+2Cl- channels
• Inhibition of Na+Cl– channels of DCT
• Inhibition of renal epithelial Na+ channels

D
• Which of the following drug is used in acute mountain
sickness
• Acetazolamide
• Spironolactone
• Domperidone
• Ethacrynic acid

A
• Site of action of spironolactone is
• Proximal Convoluted Tubule
• Descending limb of Loop of Henle
• Collecting Duct
• Ascedning limb of loop of henle

C
• Which of the following is converted by Angiotensin
Converting Enzyme
• Angiotensinogen to Angiotensin I
• Angiotensin I to Angiotensin II
• Angiotensin II to Angiotensin III
• Inactivation of Angiotensin III

B
• Renin is secreted from
• Macula Densa cells
• Juxta Glomerular Cells
• Specialized cells of Ascending limb of henle
• Specialized cells of efferent arterioles

B
• Which of the follwing is NOT an indication of Acetazolamide
• Petit mal epilepsy
• Periodic Paralysis
• To acidfy urine
• To alkalinise urine

C
• In loop of henle what percentage of sodium is reabsorbed
• 65%
• 25%
• 9%
• 1%

B
• Which of the following diuretics is not a sulphonamide
derivative
• Ethacrynic acid
• Furosemide
• Bumetanide
• Torasemide

A
• Which of the follwing diuretic is active even when GFR is
less than 20ml/min
• Chlorthiazide
• Chlorthalidone
• Metolazone
• Clopamide

C
• Which of the following is NOT indicated in Diabetes Insipidus?
• Desmopressin
• Hydrochlorthiazide
• Chlorpropamide
• Mannitol