Download diuretics

DIURETICS (2 of 2)
Dr R. P. Nerurkar
Dept. of Pharmacology
T. N. Medical College &
BYL Nair Ch. Hospital, Mumbai
DECEMBER 7, 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 1st lecture
• Definition
• Physiology of Urine formation and drugs modifying it
• Classification and Mechanism of action
• Pharmacology of Loop diuretics and CA inhibitors
•
Group discussion and Exercises on
– Prescription writing,
– Patient oriented problem solving
– Identification of drugs acting
– ADR and drug interactions
Thiazides - Sites of Action
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)
5)
•
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
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
5)
Hyperlipidemia
10) Not safe in pregnancy
(all diuretics)
6)
Hypomagnesemia
Osmotic Diuretics
Ideal properties
1.
Orally effective
2.
Well abosorbed
3.
Not metabolized
4.
Freely filtered at glomeruli
5.
Not reabsorbed
6.
Inert
7.
Cheap
Drugs used
• Mannitol
• Glycerol
• Isosorbide
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

2)
To maintain GFR during major surgeries, trauma cases, severe
jaundice, hemolytic reactions etc
To lower intracranial tension
Before brain surgery
3)
To lower intraocular tension

4)
Acute glaucoma
Before intraocular surgeries
Forced diuresis in drug poisoning

5)
Cerebral edema
(FAD in barbiturate poisoning
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
Potassium Sparing Diuretics
- Site of Action
Potassium sparing diuretics
– MOA at cortical DT
Potassium sparing diuretics:
Preparations
Aldosterone Antagonist
Dose (mg)
Route
Spironolactone
25-100
oral
I.V.
K canrenoate
Eplerenone
25-100
oral
Amiloride
5
Oral, Aerosol
Triamterene
50
oral
Directly Acting
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

4)
Eplerenone is a new drug approved for HT, No gynaecomastia
CHF: as a adjunctive therapy it retards disease progression and
reduces mortality
–
5)
RALES (Randomized ALdosterone Evaluation Study)
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
Refractory Edema & Diuretic Resistance
Causes
Management
• Decreased access
 Salt restriction Bed rest
• Binding to proteins
 Omit NSAIDs
• 2ndary hyperaldosteronism
 Multiple doses
• Delayed absorption
 Metolazone
• Nephron hypertrophy
 Spironolactone
 Combination of diuretics
Thiazide + Frusemide
Exercises on 2nd Lecture
Question Fastest Finger First
Q . Arrange the following diuretics according to their
site of action starting from proximal to distal parts
of the nephron.
A. Triamterene
B. Hydrochlorothiazide
C. Acetazolamide
D. Bumetanide
Answer: C D B A
Prescription - Criticize and Correct
Prescription given to patient suffering from chronic
congestive heart failure with hypertension with
edema feet and basal crepts in the chest
Rx
Tab. Enalapril 20 mg twice daily
Tab. Digoxin 0.25 mg once a day
Inj. Hydrochlorothiazide 5 mg IV once a day
Tab. Spironolactone 50 mg twice daily
MCQ – Case Study type
A patient with long standing diabetic renal disease
and hyperkalemia and recent onset congestive
heart failure requires a diuretic. Which of the
following would be LEAST harmful in a patient with
severe hyperkalemia
A. Amiloride
B. Hydrochlorothiazide
C. Spironolactone
D. Losartan
Answer B
MCQ – Effects of thiazides
When used chronically to treat hypertension,
thiazide diuretics have all of the following
properties or effects EXCEPT
A. reduce blood volume or vascular resistance or both
B. have maximal effects on blood pressure at doses
below maximum diuretic dose
C. may cause elevation of plasma triglyceride levels
D. decrease the urinary excretion of calcium
E. cause ototoxicity
Answer E
MCQ – Matching type
One of the following diuretic is NOT
properly matched with its indication for use
A. Hydrochlorothiazide – Diabetes insipidus
B. Eplerenone – Hypertension
C. Mannitol – Acute pulmonary edema
D. Spironolactone – Edema in cirrhosis of liver
Answer C
True or False
1.
Amiloride is a drug of choice for lithium induced
nephrogenic diabetes insipidus
2.
Mannitol is contraindicated in barbiturate poisoning
3.
Spironolactone can be given intravenously
4.
Diuretics should be avoided in pregnancy induced
hypertension
5.
Metolazone is useful even when GFR is very low
Answer T F F T T
End of diuretic lectures. Any Questions?