DIURETICS (1 of 2)

Dr R. P. Nerurkar

Dept. of Pharmacology

T. N. Medical College &

BYL Nair Ch. Hospital, Mumbai

DECEMBER 5, 2005

Learning ObjectivesAt the end of my 2 lectures you should be able to

1) List 5 major types of diuretics and their mechanism

and site of action

2) List the major applications and toxicities of them

3) Describe the measures that reduce K+ loss during

natriuresis

4) List the Rx of hypercalcimia and hypercalciuria

5) manage refractory edema cases

6) List Rx of nephrogenic diabetes insipidus

Overview of Diuretic lectures

• Definition

• Physiology of Urine formation and drugs modifying it

• Classification and Mechanism of action

• Pharmacology of Individual class of diuretics

• Group discussion and Exercises on – Prescription writing,

– Patient oriented problem solving

– Identification of drugs acting according

– ADR and drug interactions

Physiology of Urine Formation

• Nephron

• Glomerular filtration, Reabsorption, Secretion

• GFR 120 ml/min

• 99 % reabsorbed

• Urine formation 1ml/min 60ml/hr 1.5L/day

• Most diuretics prevent reabsorption of Na & H2O

Diuretic - Definition

• Diuretic = drug which increase urine formation– Increase urine volume (Diuresis)

– Increase excretion of Na and H2O (Natriuresis)

• Mechanisms of diuresis– Extrarenal

• By increasing Cardiac output : Digoxin, Dopamine in CHF

• By Inhibiting ADH : H2O, alcohol

– On the kidney (Nephron) – Most diuretics

• Inhibit Na and H2O reabsorption

Q. What will be the uses of diuretics in therapuetics?

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

Diuretics - Sites of Action

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

Acetazolamide - Site of Action

H2O + CO2 H2CO3 H+ + HCO3-

Cytoplasm of Proximal tubule

C.A.

C.A.

Renal brush border (Luminal)

Carbonic Anhydrase (CA) Enzyme

CA is also present in

• Ciliary body of eye (Aquous humor formation)

• Choroid plexus (CSF formation)

C.A. Inhibitor – Acetazolamide

CO2 + H2O H2CO3

H+ + HCO-3

H+ Na+

Na+ NaHCO3

CO2 + H2O H2CO3 HCO3 +

CA

CA

Luminal

Cytoplasmic (PT)

Net effect of Acetazolamide

• Loss of HCO3, Na, K, Cl

• Retention of H+ Met. Acidosis

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

• Hypokalemia, Fatigue

• Acidosis

• Sedation

• Paresthesias

• Abdominal discomfort

• Allergic reactions

• C/I in liver disease

USES

• Glaucoma Oral Acetazolamide or topical dorzolamide

• Acute mountain sickness

• To alkalinize the urine

• Periodic paralysis

• Epilepsy

• Rarely as a diuretic

Exercises on 1st Lecture

Question Fastest Finger First

Q . Starting with lower to higher efficacy arrange the

following diuretics according their efficacy (ability to

cause maximum % excretion of the filtered Na+)

A. Amiloride B. Furosemide

C. Hydrochlorothaizide D. Mannitol

Answer: A C D B

MCQ – Case Study type

A 70 year old man is admitted with a history of

heart failure and acute left ventricular myocardial

infarction. He has severe pulmonary edema. Which

of the following drugs is LEAST likely to prove

useful in the treatment of acute pulmonary edema.

A. Bumetanide B. Ethacrynic acid

C. Furosemide D. Hydrochlorothiazide

Answer D

True or False

1. NSAIDs may reduce the efficacy of loop diuretics

2. Acetazolamide does not lower intraocular tension

3. Frusemide overdose may cause alkalosis

4. Bumetanide is more potent than frusemide

5. Frusemide is useful in the Rx of hypercalciuria

Answer T F T T F

To be continued in the next class

Title

6) Text

Title

6) Text

Table1:(Comparsion of Loop diuretic with Thiazides)

Parameters Loop diuretic Thiazide

Site of action

Efficacy

Ca excretion

Rx of hypertension

Site of action

Site of action

All values are Mean + S.E (n=6)