Aula: Hipertensão I Site: gdenucci Email: denucci@gdenucci

1. Aula: Hipertensão I.ppt Site: www.gdenucci.com Email: denucci@gdenucci.com

2. ACETAZOLAMIDE N N C CH3CONH SO3NH2 C S

3. Proximal tubule lumen Interstitium/ blood Sodium bicarbonate reabsorption in the proximal tubule and mode of action of the carbonic anhydrase inhibitor acetazolamide 2K+ ATP 3Na+ ADP Na+ Na+ 2K+ H+ H+ HCO3- H+ Na+ HCO3- H2CO3 H2CO3- acetazolamide CO2+H2O CO2+H2O

4. FUROSEMIDE Cl NH CH2 O H2NO2S COOH

5. + 3 2 1 Thick ascending loop of Henle lumen Interstitium/ blood Loop diuretcs Transport mechanism in the thick ascending loop of Henle ATP 3Na+ ADP Na+ Na+ 2Cl- 2Cl- 2K+ K+ K+ 2K+ K+ K+ K+ K+ Cl- Cl- Cl- - Ca+ Ca+ Mg2+ Mg2+ Na+ Na+

6. CHLOROTHIAZIDE Cl N CH NH H2NO2S S O2

7. INDAPAMIDE Cl CH3 CONH N H2NO2S

8. 3 2 1 lumen Early distal tubule Interstitium/ blood Thiazide diuretcs Transport mechanism in the early distal tubule ATP 3Na+ ADP Na+ Na+ Cl- Cl- 2K+ K+ K+ Cl- Ca2+ Ca2+ Ca2+ 3Na+

9. TRIAMTERENE H2N N N NH2 N N NH2

10. SPIRONOLACTONE O O CH3 CH3 O SOOCH2

11. Adverse effects of diuretic drugs Carbonic anhydrase inhibitors Loop diuretics Thiazide and thiazide like diuretics Potassium-sparing diuretics Effects directly attributable to diuretic property Metabolic acidosis Hypokalemia Abnormal taste, lethargy, decreased libido (reduced by administration of NaHCO3) Hypokalemia (corrected by K+ supplements or combination with potassium sparing diuretics) Metabolic alkalosis Hypovolemia and hypotesion Hypocalcemia Hypomagnesemia Hypokalemia (corrected asfor loop diuretics) Metabolic alkalosis Hyponatremia Hypovolemia and hypotension Hypomagnesemia Hypercalcemia Hyperkalemia Metabolic acidosis

12. Adverse effects of diuretic drugs Carbonic anhydrase inhibitors Loop diuretics Thiazide and thiazide like diuretics Potassium-sparing diuretics Effects not directly related to diuretic property Occasionally hepatitis and blood dyscrasias as a result of immunological hypersensitivity reactions Hyperuricemia which may precipitate gout (enhanced uric acid absorption in proximal tubule as a result of volume depletion or decreased secretion due to competition at organic acid secretory mechanism) Hyperuricemia (mechanism as loop diuretics) Hyperglycemia which may reveal latent diabetes mellitus (due to reduced insulin secretion and alterations in glucose metabolism) An increase in plasma levels of low density lipoproteins (LDL) and cholesterol Impotence Nausea and vomiting (amiloride and triamterene) Diarrhea and peptic ulcer (spironolactona) Spironolactone binds to other steroid receptors which can result in: Gynecomastia Mestrual disorders Impotence Hirsutism Loss of libido

13. Notable intereractions between diuretcs and other drugs Diuretic drug(s) Drug(s) interacting Consequence Comment Acetazolamide Phenytoin Phenobarbital Primidone Osteomalacia and rickets Uncertain mechanism Acetazolamide Aspirin or salicylates Lethargy, confusion and coma Acetazolamide-induced acidosis results in more salicylate entering the central nervous system, which can lead to salicylate intoxication Thiazide, thiazide-like and loop diuretics Cardiac glycosides Ined cardiac glycoside-induced arrhythmias Hypokalemia potentiates action of cardiac glycosides Thiazide, thiazide-like and loop diuretics Hyperglycemia Thiazides and to a lesser extent loop diuretics decrease insulin secretion Sulfonylureas (oral hypoglycemic drugs) and insulin

14. Notable intereractions between diuretcs and other drugs Diuretic drug(s) Drug(s) interacting Consequence Comment Thiazide, thiazide-like and loop diuretics Lithium Increased plasma levels of lithium with risk of toxic effects Increased tubular reabsorption of lithium Thiazide, thiazide-like and loop diuretics Uricosuric agents Reduced effects of uricosuric agents Decreased tubular secretion of uricosuric agents Thiazide, thiazide-like and loop diuretics Nonsteroidal anti-inflammatory drugs Reduced diuretics response Interaction a result of inhibition of prostaglandin synthesis Loop diuretics Increased risk of ototoxicity Synergism of ototoxicity Aminoglycosides Cisplatin Potassium-sparing diuretics Increased risk of hyperkalemia Additive hyperlalemic effects ACE inhibitors and K supplements

15. Pharmacokinetic parameters for some diuretc drug Acetazolamide Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o., i.v., i.m. 100 8 (6-9) 0.2 Unchanged in urine Decrease dose in elderly and other patients with diminished renal function Alkalinization of urine may decrease urinary excretion of weak bases (e.g. quinidine) and increase their pharmacological effect

16. Pharmacokinetic parameters for some diuretc drug Furosemide Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o., i.v., i.m. 52 (27-80) 1.5 (0.5-2.0 0.2 – 0.3 About 75% of dose is excreted unchanged in urine Food intake reduces absorption

17. Pharmacokinetic parameters for some diuretc drug Chiorothiazide Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o., i.v. 7 - 33 15 - 27 0.3 Unchanged in urine Oral absorption decreases with dose

18. Pharmacokinetic parameters for some diuretc drug Indapamide Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o. High 17 (10-22) 60 L Extensive metabolism -

19. Pharmacokinetic parameters for some diuretc drug Triamterene Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o. 30-83 1.5 – 2.5 2.2 – 3.7 Rapid metabolism ---

20. Pharmacokinetic parameters for some diuretc drug Spironolactone Routes of administration Oral absorption (%) Half-life (h) Volume of distribution (L/kg) Elimination Comments p.o. 60 - 70 1.3 ± 0.3 (SD) Not known Extensive metabolism Absorption is variable because of poor solubility in water but is improved after food Canrenone is an active metabolite

21. The mechanism for controlling water permeability of the collecting duct lumen Collecting duct Interstitium/ blood 2K+ Principal cell ATP cAMP vasopressin Protein kinase A desmopressin H2O AQP-4 H2O H2O AQP-2 AQP-3

22. Mechanism of action of diuretic drug • Loop diuretcs block the Na+/K+/2Cl- constrasporter in the thick ascending loop of Henle, resulting in the excretion of 15-25% of filtered Na+ • Thiazide diuretics block the Na+/Cl- contransportee in the distal convoluted tubule, resulting in the excretion of 5% of filtered Na+ • Potassium-sparing diuretcs increase the Na+ excretion by 2-3% and decrease K+ excretion by acting on the late distal tubule and collecting duct

23. Mechanism of action of diuretic drug • Potassium-sparing diuresis is produced by blockade oh luminal Na+ channels (e.g. with amiloride or trianterene) or by blockade of cytoplasmic mineralocorticosteroid receptors (e.g. with spironolactone) • Osmotic diuretcs reduce water reabsorption resulting in a subsequent decrease of Na+ reabsorption in the proximal tubule and descending limb of the loop of Henle • Carbonic anhydrase inhibitors indirectly block Na+/H+ exchange in the proximal tubule, which results in the excretion of up to 5% of Na+ filtered at the glomerulus