Pharmacology Diuretics

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Diuretics 1) the role of different portions of the nephron in ion exchange; 2) the sites of action and pharmacology of diuretics; 3) the therapeutic applications of diuretics

Transcript of Pharmacology Diuretics

Page 1: Pharmacology   Diuretics

Diuretics1) the role of different portions

of the nephron in ion exchange;

2) the sites of action and pharmacology of diuretics;

3) the therapeutic applications of diuretics

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A diuretic -

is any drug that elevates the rate of bodily urine excretion (diuresis).

All diuretics increase the excretion of water from the body.

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Classification /due to location of action/

1. Diuretics which increase glomerular filtration rate

/Xanthines/Caffeine, TheophyllinumEuphyllinum

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2. Proximal convoluted tubule diuretics

2.1. Osmotic diuretic Mannitol

2.2. Carbonic anhydrase (CA) inhibitors

Diacarbum (acetazolamide)

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3. Loop (of Henle) diureticsFurosemidum BumetanidumEthacrynic acid

4. Distal convoluted tubule diuretics/Thiazides and thiazide-like drugs/ Hydrochlorothiazidum

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5. Collecting duct diuretics5.1. Antagonist of aldosterone

Spironolactonum

5.2. Agents inhibit the Na+ channel in the apical membrane

AmiloridumTriamterenum

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Indications:

Hypertension CHF, Nephrotic syndrome Poisonings

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Proximal convoluted tubule diuretics

The proximal tubule (PT) determines the rate of Na+ and H2O delivery to the more distal portions of the nephron

A wide variety of transporters couple Na+ movement into the cell to the movement of amino acids, glucose, phosphate, and other solutes

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MannitolMechanism of Action

o Mannitol is a non-metabolizable osmotic diuretic and is filtered into the tubular space where it markedly increases tubular fluid osmolality.

o This results in impared reabsorption of fluid with a resultant increased excretion of water (some Na+ accompanies)

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Pharmacokinetics of Mannitol:

o Given only i.v. and acts within 10 min; o if given p.o. it causes an osmotic diarrhea

(not well absorbed from gut). o In pts with normal renal function t1/2 is

approx. 1.2 hr.

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Indications:

prophylaxis against renal dysfunction, e.g. major surgical procedure

Contraindications: CHF, chronic renal failure

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Carbonic anhydrase (CA) inhibitors

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Carbonic anhydrase (CA) inhibitors Mechanism of Action:

If CA activity is inhibited, HCO3- reabsorption is reduced and exits the proximal tubule in much larger amounts.

In the distal nephron, Na+ is largely reabsorbed (unlike HCO3-) and is exchanged for K+. Therefore acetazolamide primarily causes an increase in urinary HCO3-, K+, and water excretion.

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CA Inhibitors: Adverse Side Effects hypokalemia metabolic acidosis

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Loop Diuretics

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Loop Diuretics: Mechanism of Action block the Na+/K+/Cl- co-transporter in

the apical membrane of the thick ascending limb of Henle's loop. Therefore, loop diuretics increase urinary water, ions excretion.

cause dilation of the venous system and renal vasodilation - effects that may be mediated by prostaglandins.

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Loop diuretics: Pharmacokinetics - act within 20 min and t1/2 is approx. 1-

1.5 hr. - are rapidly absorbed from the gut and

can be given i.v. - are the most potent available and can

cause excretion of up to 20% of the filtered Na+.

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Clinical uses of loop diuretics acute pulmonary oedema chronic heart failure cirrhosis of the liver complicated by

ascites nephrotic syndrome renal failure.

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Loop diuretics Adverse Side Effects hypokalemia metabolic alkalosis hypomagnesemia hyperuricemia dehydration (hypovolemia), leading to

hypotension dose-related hearing loss (ototoxicity)

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Thiazides: Mechanism of Action They inhibit Na+ and Cl- transport in the

cortical thick ascending limb and early distal tubule.

They have a milder diuretic action than do the loop diuretics because this nephron site reabsorbs less Na+ than the thick ascending limb.

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Thiazides

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Thiazides: Pharmacokinetics

All are well absorbed from the gut. Onset of action is within approx. 1 hr;

effects can be long lasting but vary with the drug used (6-48 hr).

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Clinical uses of thiazide diuretics Hypertension. Mild heart failure (loop diuretics are

usually preferred). Severe resistant oedema (together

with loop diuretics).

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Thiazides have a week antihypertensive

effect because reduce arterial wall sensitivityto NA (noradrenaline) and AT (Angiotensin).

They potentiate significantly the effectof other antihypertensive drugs.

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Thiazide Adverse Side Effects hypokalemia metabolic alkalosis dehydration (hypovolemia), leading to

hypotension hyponatremia hyperglycemia in diabetics hyperuricemia (at low doses) Erectile dysfunction

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Symptoms  of hypokalemia

muscle weaknessparalysisarrhythmia

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Potassium sparing diuretics

These agents are often given to avoid the hypokalemia

They should never be given in the setting of hyperkalemia (diabetes mellitus, multiple myeloma, renal insufficiency)

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SpironolactoneMechanism of Action

It is a competitive antagonist of aldosterone. Therefore it blocks aldosterone-stimulated Na+ reabsorption and K+ and H+ excretion in the late distal tubule and collecting duct.

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Potassium sparing diuretics

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SpironolactonePharmacokinetics: Given orally, spironolactone takes

up to 2 days to be effective with a t1/2 approx. 20 hr.

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Amiloride and triamtereneMechanism of Action inhibit the Na+ channel in the apical

membrane of the late distal tubule and collecting duct.

Because K+ and H+ secretion in this nephron segment are driven by the electrochemical gradient generated by Na+ reabsorption, K+ and H+ transport into the urine is reduced.

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Clinical uses of potassium-sparing diuretics (e.g. amiloride, spironolactone) in heart failure, where either of these

improves survival in primary hyperaldosteronism (Conn's

syndrome) in resistant essential hypertension

(especially low-renin hypertension) in secondary hyperaldosteronism caused

by hepatic cirrhosis complicated by ascites.

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K+-sparing diuretics Adverse Side Effects hyperkalemia metabolic acidosis gynecomastia (aldosterone antagonists) gastric problems including peptic ulcer

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Arctostaphylos uva-ursi L. (Bearberry)

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Stipites Cerasorum(Cherry)

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Equisetum arvense(Common horsetail)

Containssilicates with diureticand urolitholytic effects.