DIURETICS (2 of 2)

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DIURETICS (2 of 2)

• Dr R. P. Nerurkar
• Dept. of Pharmacology
• T. N. Medical College
• BYL Nair Ch. Hospital, Mumbai

DECEMBER 7, 2005
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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

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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

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Thiazides - Sites of Action
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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 lt 30ml/min, may
  reduce GFR further
• Metolazone ? additional action on PT, effective
  at low GFR, can be tried in refractory edema

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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)

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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
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Thiazides - Uses

• Hypertension (Hydrochlorothiazide, Indapamide)
• Edema Cardiac, Hepatic Renal
• Less efficacious than loop diuretic
• Useful for maintainence therapy
• Hypercalciuria and renal Ca stones
• 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
• Metolazone useful even when GFR is as low as
  15ml/min

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Thiazides -Adverse Effects

1. Hypokalemia
2. May ppt renal failure
3. Hyperuricemia
4. Hyperglycemia
5. Hyperlipidemia
6. Hypomagnesemia

1. Hypchloremic alkalosis
2. Hypersensitivity
3. ppt. Hypercalcemia
4. Not safe in pregnancy (all diuretics)

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Osmotic Diuretics

• Ideal properties
• Orally effective
• Well abosorbed
• Not metabolized
• Freely filtered at glomeruli
• Not reabsorbed
• Inert
• Cheap

• Drugs used
• Mannitol
• Glycerol
• Isosorbide

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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

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Osmotic diuretic - Preparations
Drug Daily dose
Mannitol I.V. 10 or 20 soln. 1-2 gm/kg 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
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Mannitol - USES

• ARF treatment prevention
• To maintain GFR during major surgeries, trauma
  cases, severe jaundice, hemolytic reactions etc
• To lower intracranial tension
• Before brain surgery Cerebral edema
• To lower intraocular tension
• Acute glaucoma Before intraocular surgeries
• Forced diuresis in drug poisoning
• (FAD in barbiturate poisoning
• To counteract low plasma osmolality after
  dialysis

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Mannitol -Adverse Effects

• 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
• Thrombophlebitis
• Headache (due to hyponatremia), Nausea
• If overdose ? dehydration ? hypernatremia

Monitoring of urine output, S. electrolytes, CVP
is very imp. Step 6 of rational pharmacotherapy
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Potassium Sparing Diuretics - Site of Action
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Potassium sparing diuretics MOA at cortical DT
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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 Fixed dose combinations with thiazides and frusemide available but not advisable Fixed dose combinations with thiazides and frusemide available but not advisable
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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

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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)

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Spironolactone - uses

• Edema more useful in cirrhotic and nephrotic
  syndrome
• breaks resistance to thiazides or frusemide in
  refractory edema
• To counteract K loss due to thiazides, frusemide
• Hypertension combined with thiazide
• Eplerenone is a new drug approved for HT, No
  gynaecomastia
• CHF as a adjunctive therapy it retards disease
  progression and reduces mortality
• RALES (Randomized ALdosterone Evaluation Study)
• Primary Hyperaldosteronism (Conns syndrome)

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Spironolactone Adverse Effects

• Hyperkalemia risk
• In CRF patients
• Patients taking ACEI (Enalapril) or ATRA
  (Losartan)
• KCl supplement
• Related to steroid structure
• Gynaecomastia, Impotence in males
• Hirsutism, menstrual irregualarities in females
• Misc drowsiness, abdominal upset
• Drug Interactions
• may increase digoxin levels in CHF
• NSAIDs (Aspirin) decreases its effect

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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

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Refractory Edema Diuretic Resistance

• Causes
• Decreased access
• Binding to proteins
• 2ndary hyperaldosteronism
• Delayed absorption
• Nephron hypertrophy

• Management
• Salt restriction Bed rest
• Omit NSAIDs
• Multiple doses
• Metolazone
• Spironolactone
• Combination of diuretics
• Thiazide Frusemide

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Exercises on 2nd Lecture
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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
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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
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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
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MCQ Effects of thiazides

• When used chronically to treat hypertension,
  thiazide diuretics have all of the following
  properties or effects EXCEPT

1. reduce blood volume or vascular resistance or
   both
2. have maximal effects on blood pressure at doses
   below maximum diuretic dose
3. may cause elevation of plasma triglyceride levels
4. decrease the urinary excretion of calcium
5. cause ototoxicity

Answer E
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MCQ Matching type

• One of the following diuretic is NOT
  properly matched with its indication for use

1. Hydrochlorothiazide Diabetes insipidus
2. Eplerenone Hypertension
3. Mannitol Acute pulmonary edema
4. Spironolactone Edema in cirrhosis of liver

Answer C
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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
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• End of diuretic lectures. Any Questions?

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