Transcript diuretics

DIURETICS (1 of 2)
Dr R. P. Nerurkar
Dept. of Pharmacology
T. N. Medical College &
BYL Nair Ch. Hospital, Mumbai
DECEMBER 5, 2005
Learning Objectives
At 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 )

4.
5.
Potassium Sparing Diuretics (3% NaCl excretion)

Aldosterone Antagonists Spironolactone, eplerenone

Directly acting: Amiloride, Triamterene
Osmotic Diuretics (upto 20% NaCl excretion)

6.
Acetazolamide, Methazolamide, Dichlorphenamide
Mannitol, Glycerol, Isosorbide
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
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)
C.A. Inhibitor – Acetazolamide
CA
CO2 + H2O
H2CO3
Cytoplasmic (PT)
H+ + HCO-3
Na+
CO2 + H2O
H2CO3
CA
Luminal
HCO3 +
NaHCO3
H+ Na+
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
USES
•
• Glaucoma Oral Acetazolamide
Hypokalemia, Fatigue
or topical dorzolamide
•
Acidosis
•
Sedation
•
Paresthesias
• To alkalinize the urine
•
Abdominal discomfort
• Periodic paralysis
•
Allergic reactions
• Epilepsy
•
C/I in liver disease
• Rarely as a diuretic
• Acute mountain sickness
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
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Title
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Table1:(Comparsion of Loop diuretic with Thiazides)
Parameters
Site of action
Loop diuretic
Efficacy
Ca excretion
Rx of hypertension
Site of action
Site of action
All values are Mean + S.E (n=6)
Thiazide