DIURETICS----PHARMACOLOGY

DIURETICS

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Kidneys:

• Represent 0.5% of total body weight,but receive ~25% of the total arterialblood pumped by the heart. Each contains from one to two million nephrons

NEPHRON:

Blood processing unit which serves to produce urine ,1 million per kidney. IT Consists of

¨  – The glomerulus , The proximal convoluted tubule, The loop of Henle ,The distal convoluted tubule

Functions of Urinary System

¨  Kidneys carry out four functions

¤  Filter nitrogenous wastes, toxins, ions, etc. from blood to be excreted as urine. (Excretion of Wastes)

¤  Regulate volume and chemical composition of blood (water, salts, acids, bases). (Fluid and electrolytes )

¤  Produce regulatory enzymes. (Enzyme Production)

n  Renin – regulates BP/ kidney function

n  Erthropoeitin – stimulates RBC production from marrow.

¤  Metabolism of Vitamin D to active form. (Metabolism)

Diuretics:

• Increase output of urine. Primary indications are hypertension and mobilization of edematous fluid (e.g. kidney problems, heart failure, cirrhosis,…)

Basic mechanism:

• Block reabsorption of sodium and chloride => water will also stay in the nephron

• Diuretics that work on the earlier nephron have greatest effect, since they are able to block more sodium and chloride reabsorption

CLASSIFICATION

1.Carbonic Anhydrase Inhibitors

ü  Azetazolamide

2.Thiazides:

ü  Hydrochlorothiazide; Chlorothaizide ; Benzthiazide ; Cyclothiazide

3.Loop Diuretics

ü   Furosemide ;Ethacrynic acid; Bumetanide ;Torasemide

4.Potassium-sparing Diuretics

ü  Spironolactone ;Amiloride; Trimterene

5.Osmotic diuretics:

ü  Mannitol

1.  Carbonic anhydrase inhibitors:

• Azetazolamide

– Can trigger metabolic acidosis , Not in use as diuretic anymore, Primary indications is glaucoma (prevents production of aqeuous humor)

-Prophylaxis of Mountain sickness(prevent cerebral and pulmonary edema)

ADR’S

¨  Metabolic acidosis ; Renal stone formation ; Potassium depletion  ;Drowsiness ; Contraindicated with hepatic  cirrhosis patient as it increases NH4+ conc.

2.  Loop diuretics ( high ceiling diuretics):

– Act by inhibiting the Na+/K+/2Cl- symporter in the ascending limb in the loop of Henle

¨   Furosemide ;Ethacrynic acid; Bumetanide ;Torasemide

– Strong, but brief diuresis (within 1 hr, lasts ~ 4hrs)

- Give orally and parenterally

– Used for moderate to severe fluid retention and hypertension

– Most potent diuretics available

useful in emergency situation, hypercalcemia and hyperkalemia

– Major side effects:

loss of K+ (and Ca++ and Mg++), Ototoxictity (in conjunction with antibiotics), Hyperuricemia (furosimide and ethacrynic acid compete with uric acid), Acute hypovolemia ,Hypomagnesemia

3.  Thiazide diuretics:

– Act by inhibiting the Na+/Cl- symporter in the distal convoluted tube

¨  Hydrochlorothiazide ; Chlorothaizide  ; chlortalidone ; Benzthiazide ,Cyclothiazide …

¨  No change in acid –base status of body ; Hyperosmolar urine(Na& Cl ions) ;

¨  Major side effects: loss of K+ (and Mg++, but not Ca++ B/C it is controlled by PTH)

THERAPEUTIC USES

¨  HYPERTENSION ; HEART FAILURE ;  Iodiopathic HYPERCALCIURIA (urine stone)

Adverse effects:

ü  Potassium depletion (predispose patient to ventricular arrhythmias who is taking digoxin)

ü  Hyperuricemia  ; Hypercalcemia  ; Hyperglycemia ; Hyperlipidemia  ; hypersensitivity

4.Potassium-sparing diuretics:

– Act on the distal portion of the distal tube (where Na+ is exchanged for K+)

 • Spironolactone  Is an Aldosterone receptor antagonist its Onset of action requires several day

¨  Side effect:

¨  gynecomastia in male, menstrual irregularities in female, Hyperkalemia,nausea , Lethargy etc

Amiloride; Trimterene

– Block sodium channels ; Quick onset

•       Side effect: Leg cramp b/c of increased nitrogen and K+

Therapeutic use:

1. 1^st choice in heptic cirrhosis ; effective in  secondary hyperaldosteronism  ; Heart failure

5.Osmotic diuretics:

¨  – Small, non-reabsorbable molecules that inhibit passive reabsorption of water

¨  – Predominantly increase water excretion without significantly increasing Na+ excretion => limited use

¨  – Used to prevent renal failure, reduction of intracranial pressure does not cross blood-brain barrier => water is pulled out of the brain into the blood)

• Mannitol

¨  – Only given IV – can crystallize (=> given with filter needle or in-line filter)

¨  Side effects

¨  Dehydration