Diuretics

1. Diuretics

2. Outline 1. Sites of drug action 2. Osmotic diuretics 3. Carbonic anhydrase inhibitors 4. Thiazide diuretics 5. Loop diuretics 6. Potassium-sparing diuretics

3. Definitions • Diuretics: substance that promotes the excretion of urine • caffeine, yerba mate, nettles, cranberry juice, alcohol • Natriuretic: substance that promotes the renal excretion of Na+

4. Renal Physiology • renal epithelial transport • tubular reabsorption • proximal tubule • loop of Henle • thick ascending limb • distal convoluted tubule • collecting tubule • tubular secretion • collecting tubules

5. Summary: Sites of Action

6. Osmotic Diuretics • Do not interact with receptors or directly block renal transport • activity dependent on development of osmotic pressure • Mannitol (prototype) • Urea • Glycerol • Isosorbide

7. Mechanism of Action • osmotic diuretics are not reabsorbed • increases osmotic pressure specifically in the proximal tubule and loop of Henle • prevents passive reabsorption of H2O • osmotic force solute in lumen > osmotic force of reabsorbed Na+ • increased H2O and Na+ excretion

8. Therapeutic Uses • Mannitol • drug of choice: non-toxic, freely filtered, non-reabsorbable and non-metabolized • administered prophylatically for acute renal failure secondary to trauma, CVS disease, surgery or nephrotoxic drugs • short-term treatment of acute glaucoma • infused to lower intracranial pressure • Urea, glycerol and isosorbide are less efficient • can penetrate cell membranes

9. Side Effects • increased extracellular fluid volume • cardiac failure • pulmonary edema • hypernatremia • hyperkalemia secondary to diabetes or impaired renal function • headache, nausea, vomiting

10. Carbonic Anhydrase Inhibitors • limited uses as diuretics • Acetazolamide • prototype carbonic anhydrase inhibitor • developed from sulfanilamide (caused metabolic acidosis and alkaline urine)

11. Mechanism of Action • inhibits carbonic anhydrase in renal proximal tubule cells • carbonic anhydrase catalyzes formation of HCO3- and H+ from H2O and CO2 • inhibition of carbonic anhydrase decreases [H+] in tubule lumen • less H+ for for Na+/H+ exchange • increased lumen Na+, increased H2O retention

12. Therapeutic Uses • used to treat chronic open-angle glaucoma • aqueous humor has high [HCO3-] • acute mountain sickness • prevention and treatment • metabolic alkalosis • sometimes epilepsy • mostly used in combination with other diuretics in resistant patients

13. Side Effects • rapid tolerance • increased HCO3- excretion causes metabolic acidosis • drowsiness • fatigue • CNS depression • paresthesia (pins and needles under skin) • nephrolithiasis (renal stones) • K+ wasting

14. Thiazide Diuretics • active in distal convoluted tubule • Chlorothiazide (prototype) • Hydrochlorothiazide • Chlorthalidone • Metolazone

15. inhibit Na+ and Cl- transporter in distal convoluted tubules • increased Na+ and Cl- excretion • weak inhibitors of carbonic anhydrase, increased HCO3- excretion Mechanism of Action • increased K+/Mg2+ excretion • decrease Ca2+ excretion

16. Therapeutic Uses • hypertension • congestive heart failure • hypercalciuria: prevent excess Ca2+ excretion to form stones in ducts • osteoperosis • nephrogenic diabetes insipidus • treatment of Li+ toxicity

17. Pharmacokinetics • orally administered • poor absorption • onset of action in ~ 1 hour • wide range of T 1/2 amongst different thiazides, longer then loop diuretics • free drug enters tubules by filtration and by organic acid secretion

18. hypokalemia • increased Na+ exchange in CCD • volume-contraction induced aldosterone release • hyponatremia • hyperglycemia • diminished insulin secretion • elevated plasma lipids • hyperuricemia • hypercalcemia Side Effects

19. Loop Diuretics • active in “loop” of Henle • Furosemide (prototype) • Bumetanide • Torsemide • Ethacrynic acid

20. Mechanism of Action • enter proximal tubule via organic acid transporter • inhibits apical Na-K-2Cl transporter in thick ascending loop of henle • competes with Cl- binding site • enhances passive Mg2+ and Ca2+ excretion • increased K+ and H+ excretion in CCD • inhibits reabsorption of ~25% of glomerular filtrate

21. Therapeutic Uses • edema: cardiac, pulmonary or renal • chronic renal failure or nephrosis • hypertension • hypercalcemia • acute and chronic hyperkalemia

22. Pharmacokinetics • orally administered, rapid absorption • rapid onset of action • bound to plasma proteins: displaced by warfarin, and clofibrate • increase toxicity of cephalosporin antibiotics and lithium • additive toxicity with other ototoxic drugs • inhibitors of organic acid ion transport decrease potency (i.e. probenecid, NSAID’s)

23. Side Effects • hypokalemia • hyperuricemia • metabolic alkalosis • hyponatremia • ototoxicity • Mg2+ depletion

24. K+ sparing diuretics • three groups • steroid aldosterone antagonists • spironolactone, eplerenone • Pteridines • triamterene • Pyrazinoylguanidines • amiloride

25. K+ sparing diuretics function in CCD • decrease Na+ transport in collecting tubule Mechanism of Action • Spironolactone • competitive antagonist for mineralocorticoid receptor • prevents aldosterone stimulated increases in Na+ transporter expression • Triamterene/Amiloride • organic bases • secreted into lumen by proximal tubule cells • inhibit apical Na+ channel

26. primary hyperaldosteronism (adrenal adenoma, bilateral adrenal hyperplasia) • congestive heart failure • cirrhosis • nephrotic syndrome • in conjunction with K+ wasting diuretics Therapeutic Uses

27. Pharmacokinetics • Spironolactone • orally administered • aldactazide: spironolactone/thiazide combo • Amiloride • oral administration, 50% effective • not metabolized • not bound to plasma proteins • Triamterine • oral administration, 50% effective • 60% bound to plasma proteins • liver metabolism, active metabolites

28. Side Effects • hyperkalemia: monitor plasma [K+] • spironolactone: gynecomastia • triamterene: megaloblastic anemia in cirrhosis patients • amiloride: increase in blood urea nitrogen, glucose intolerance in diabetes mellitus

29. Antibiotics

30. Antibiotics • Sulfonamides • Penicillins • Cephalosporins • Tetracyclines • Aminoglycosides • Quinolones • Macrolides

31. What are Antibiotics? • Antibiotics = “against life” • Antibiotics are molecules that stop microbes, both bacteria and fungi, from growing or kill them outright. • Antibiotics can be either natural products or synthetic chemicals.

32. Antibiotics • Medications used to treat bacterial infections • Ideally, before beginning antibiotic therapy, the suspected areas of infection should be cultured to identify the causative organism and potential antibiotic susceptibilities.

33. Antibiotics • Empiric therapy: treatment of an infection before specific culture information has been reported or obtained • Prophylactic therapy: treatment with antibiotics to prevent an infection, as in intra-abdominal surgery

34. Antibiotics • Bactericidal: kill bacteria • Bacteriostatic: inhibit growth of susceptible bacteria.

37. Antibiotics can be categorized based on their target specificity: • narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria. • broad-spectrum antibiotics affect a wide range of bacteria.

38. Primary Modes of Action

39. Bacteriocidal • A bacteriocide is a substance that kills the bacteria of choice and, preferably, nothing else. • Microbe death is usually achieved by disruption of the bacterial cell membrane leading to lysis.

40. BacterialAntibiotics • Antibiotics were created at a time when previously untreatable infections such as tuberculosis, gonorrhea, and syphilis could be almost incredibly treated. • Bacteria have been successful because they are capable of adapting to changes in their environment. • Penicillin is the best-known antibiotic, which is used to treat bacterial infections, such as syphilis, gonorrhea, meningitis, and anthrax.

41. Antibiotics: Penicillins • First introduced in the 1940s • Bactericidal: inhibit cell wall synthesis • Kill a wide variety of bacteria • Also called “beta-lactams”

42. Penicillins: Side Effects • Common side effects: • nausea, vomiting, diarrhea, abdominal pain • Other side effects are less common

43. Antibiotics: Cephalosporins • Semisynthetic derivatives from a fungus • Structurally and pharmacologically related to penicillins • Bactericidal action • Broad spectrum • Divided into groups according to their antimicrobial activity

44. Cephalosporins: Side Effects • similar to penicillins

45. Antibiotics: Tetracyclines • Natural and semi-synthetic • Obtained from cultures of Streptomyces • Bacteriostatic—inhibit bacterial growth • Inhibit protein synthesis • Stop many essential functions of the bacteria

46. Tetracyclines: Therapeutic Uses • Wide spectrum: • gram-negative, gram-positive, protozoa, Mycoplasma, Rickettsia, Chlamydia, syphilis, Lyme disease • Demeclocycline is also used to treat SIADH, and pleural and pericardial effusions

47. Tetracyclines: Side Effects May also cause: • Vaginal moniliasis • Gastric upset • Enterocolitis • Maculopapular rash

48. Antibiotics: Aminoglycosides • gentamicin (Garamycin) • kanamycin • neomycin • streptomycin • tobramycin • amikacin (Amikin) • netilmicin

49. Aminoglycosides • Natural and semi-synthetic • Produced from Streptomyces • Poor oral absorption; no PO forms • Very potent antibiotics with serious toxicities • Bactericidal • Kill mostly gram-negative; some gram-positive also

50. Aminoglycosides: Side Effects Ototoxicity and nephrotoxicity are the most significant • Headache • Paresthesia • Neuromuscular blockade • Dizziness • Vertigo • Skin rash • Fever • Superinfections