Diuretics drugs that increase sodium and water excretion from the body by an action on the kidney.

1. Diuretics drugs that increase sodium and water excretion from the body by an action on the kidney. (2006)

2. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

3. Proximal convoluted tubule • - isosmotic reabsorbtion of aminoacids, glucose and cations • - secretion and reabsorption of weak acids – org. anions • sodium and water reabsorption – 50 % of sodium reabsorption • free water permeation • - bicarbonate reabsorption – HCO3-is not reabsorbet itself carbonic anhydrase According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

4. Thick portion of the ascending limb of the loop of Henle • - pumps Na+, K+ and Cl- into interstitium - 30-40 % of Na+ • major site of Ca2+ and Mg+ reabsorption – driven by K+ According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

5. Distal convoluted tubule pumps Na+ and K+ out of lumen – 10 % of Na+ Ca2+ reabsorption – parathyroid hormone – Na+/Ca2+ exchanger According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

6. Cortical collecting tubule Na+ reabsorption/ K+ secretion – aldosteron  a)  expression of Na+ channels at apical membrane, b) increase expression and activity of Na+/K+ATP-ase exchange – 2-4 % Na+ reabsorbed H+/K+ATPase - primary site of urine acidification – movement of K+ is accompanied by an equivalent movement of H+ According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

7. Carbonic anhydrase inhibitors • Loop diuretics • Thiazide diuretics • Potasium-sparing diuretics • Osmotic diuretics

8. 1. CARBONIC ANHYDRASE INHIBITORS Acetazolamide, dorzolamide inhibition of CA in brush border and intracelular CA in PCT – depletion of bicarbonate – metabolic acidosis HCO3- Na+ inside the tubuli  exchange for K+ in DCT – mild hypokalemia after 2-3 days HCO3- excretion slows (HCO3- depletion) – diuretic action is self limiting CA in ciliary epitelium – secretion of HCO3- into aqueous humor –  intraocular pressure - glaucoma CA in choroid plexus – secretion of HCO3- into cerebrospinal fluid – acidification – hyperventilation – protect against mountain (high-altitude) sickness

9. 1. CARBONIC ANHYDRASE INHIBITORS Clinical uses glaucoma mountain (high-altitude) sickness significant metabolic alkalosis Toxicitydrowsiness and paresthesias alergic reactions (sulfonamides) renal stones – precipitation of Ca2+ salts in alkaline urine potassium wasting

10. 2. LOOP DIURETICS Furosemide - act from luminal site - inhibits the cotransport Na+ K+ 2Cl-Na+ excretion from 1 % to 35 % - massive sodium chloride diuresis -  reabsorption of Ca2+ and Mg2+ - pulmonary vasodilating effect + venodilatation - - i.v. or orally - short acting – 3-6 h Clinical use heart failure refractory oedema renal failure with fluid overload hypertension hypercalcaemia

11. 2. LOOP DIURETICS Pharmacokinetics F  + rapid, protein binding > 95 %, elimination mainly via kidney (filtration and secretion), t1/2 = 2 h  prolonged in renal failure  10 hAdverse effects acute renal failure – prerenal failure - 2,5 l/h hypokalaemia (! digoxin !) metabolic alkalosis hypomagnesaemia – correct K+ (! digoxin !) hyperuricaemia ototoxicity alergic – rare blood dyscrasias  Li+

12. 3. THIAZIDE DIURETICS • Hydrochlorothiazide • act from luminal site- inhibit Na+ Cl- cotransportin early segment of DCT -  Na+/Ca2+-ATPase -  Ca2+ reabsorption- mild inhibition of CA- orally in the morning – onset 2 h - duration 6-12-20 h (dependent on drug)Clinical use hypertension cardiac failure resistant oedema prevention of stones – idiopatic hypercalciuria + maintain high urine output diabetes insipidus

13. 3. THIAZIDE DIURETICS Pharmacokinetics orally – F = 60-80 %, protein binding 65%, Vd = 0,5-1,1 l/kg, elimination – kidney 95% unchanged - CLtot of hydrochlorothiazide = CLCR  main mech. is GF but also secretion is involved (interaction at OAT), t1/2 = 6-8 h.Adverse effects impotence hypokalaemia and hypomagnesaemia (! digoxin !) hyponatremia hyperuricaemia impaired glucose tolerance allergy  Li+

14. 4. POTASIUM-SPARING DIURETICS inhibit Na+/K+ exchange in CCL – K+ retention + mild natriuresis combination with thiazides and loop diuretics Spironolactone act from basolateral site in CCL– competitive antagonist on intracelular aldosteron receptor  expression of Na+ channels and Na+/K+ ATPase Clinical useprimary hyperaldosteronismsecondary hyperaldosteronism – cirhosis, heart failure Adverse effectsmen - gynaecomastia, breast tenderness, women – menstrual irregularity – oestrogen action tumours in rodent

15. 4. POTASIUM-SPARING DIURETICS • Amiloride, triamteren • - act from luminal site (apical, canalicular) in CCL – block Na+ channels   Na+ clearance and  K+ and H+ clearance • long acting 12-24 h (8 h by Ritter 2000)Clinical use potassium wasting – diuretics – combination • Adverse effects !!! hyperkalemia !!! – monitoring – risk factors diabetes mellitus, ACEI, NSAID metabolic acidosis • Pk triamteren – t1/2 = 2 h, diuresis 8 h, metabolized prior to excretion

16. 5. OSMOTIC DIURETICS • Manitol, ureal, glycerine • filtered at the glomerulus but poorly reabsorbed - „holds“ water in the lumen by virtue of its osmotic effect - proximal tubulus - descending limb of the loop of Henle - collecting tubule  volume of urine +  Na+ lost • -  volume of plasma (water from the tissues to the circulation) – unsuitable for treatment of oedema (!!! cardiac failure !!!)

17. Clinical use to maintain high urine flow - solute overload from severe hemolysis or rhabdomyolysis reducing intraocular pressure in acute glaucoma reducing intracranial pressure Adverse effect pulmonary edema headache, nausea, and vomiting