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

A diuretic - is any drug that elevates the rate of bodily urine excretion (diuresis). All diuretics increase the excretion of water from the body.

Classification /due to location of action/ 1. Diuretics which increase glomerular filtration rate /Xanthines/ Caffeine, Theophyllinum Euphyllinum

2. Proximal convoluted tubule diuretics 2.1. Osmotic diuretic Mannitol 2.2. Carbonic anhydrase (CA) inhibitors Diacarbum (acetazolamide)

3. Loop (of Henle) diuretics Furosemidum Bumetanidum Ethacrynic acid 4. Distal convoluted tubule diuretics /Thiazides and thiazide-like drugs/ Hydrochlorothiazidum

5. Collecting duct diuretics 5.1. Antagonist of aldosterone Spironolactonum 5.2. Agents inhibit the Na+ channel in the apical membrane Amiloridum Triamterenum

Indications: Hypertension CHF, Nephrotic syndrome Poisonings

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

Mannitol Mechanism of Action Mannitol is a non-metabolizable osmotic diuretic and is filtered into the tubular space where it markedly increases tubular fluid osmolality. This results in impared reabsorption of fluid with a resultant increased excretion of water (some Na+ accompanies)

Pharmacokinetics of Mannitol: Given only i.v. and acts within 10 min; if given p.o. it causes an osmotic diarrhea (not well absorbed from gut). In pts with normal renal function t1/2 is approx. 1.2 hr.

Indications: Contraindications: prophylaxis against renal dysfunction, e.g. major surgical procedure Contraindications: CHF, chronic renal failure

Carbonic anhydrase (CA) inhibitors

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.

CA Inhibitors: Adverse Side Effects hypokalemia metabolic acidosis

Loop Diuretics

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.

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+.

Clinical uses of loop diuretics acute pulmonary oedema chronic heart failure cirrhosis of the liver complicated by ascites nephrotic syndrome renal failure.

Loop diuretics Adverse Side Effects hypokalemia metabolic alkalosis hypomagnesemia hyperuricemia dehydration (hypovolemia), leading to hypotension dose-related hearing loss (ototoxicity)

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.

Thiazides

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).

Clinical uses of thiazide diuretics Hypertension. Mild heart failure (loop diuretics are usually preferred). Severe resistant oedema (together with loop diuretics).

Thiazides have a week antihypertensive effect because reduce arterial wall sensitivity to NA (noradrenaline) and AT (Angiotensin). They potentiate significantly the effect of other antihypertensive drugs.

Thiazide Adverse Side Effects hypokalemia metabolic alkalosis dehydration (hypovolemia), leading to hypotension hyponatremia hyperglycemia in diabetics hyperuricemia (at low doses) Erectile dysfunction

Symptoms of hypokalemia muscle weakness paralysis arrhythmia

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)

Spironolactone Mechanism 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.

Potassium sparing diuretics

Spironolactone Pharmacokinetics: Given orally, spironolactone takes up to 2 days to be effective with a t1/2 approx. 20 hr.

Amiloride and triamterene Mechanism 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.

Clinical uses of potassium-sparing diuretics (e. g 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.

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

Arctostaphylos uva-ursi L. (Bearberry)

Stipites Cerasorum (Cherry)

Equisetum arvense (Common horsetail) Contains silicates with diuretic and urolitholytic effects.