DIURETICS 15-09-23.pptx diuretics classification, mechanism of action, uses and adverse effects

diuretics classification, mechanism of action, uses and adverse effects

1. DIURETICS DR.R.KRISHNA PRIYA

2. Site 0f Actions of Diuretics

3. DIURETICS Drugs that cause net loss of sodium and water in urine

4. CLASSIFICATION High efficacy diuretics Medium efficacy diuretics Weak diuretics

5. CLASSIFICATION HIGH EFFICACY DIURETICS (a) Sulphamoyl derivatives : Furosemide , Torsemide , Bumetanide , piretanide , Azosemide,Tripamide (b) Phenoxyacetic acid derivative : Ethacrynic acid

6. CLASSIFICATION… MEDIUM EFFICACY DIURETICS (a) Benzothiadiazines ( thiazides ): Hydrochlorothiazide, Benzthiazide , Hydroflumethiazide , polythiazide , Clopamide (b) Thiazide like : Chlorthalidone , Metolazone , Xipamide , Indapamide .

7. CLASSIFICATION… WEAK OR ADJUNCTIVE DIURETICS (a ) Carbonic anhydrase inhibitors : Acetazolamide,methazolamide , dichlorophenamide (b ) Potassium sparing diuretics ( i ) Aldosterone antagonist : Spironolactone , Canrenone , Eplerenone , Pot. canreonate (ii ) Directly acting (Inhibitors of renal epithelial Na ⁺ channel) : Triamterene , Amiloride . (c ) Osmotic diuretics : Mannitol , Isosorbide , Glycerol

8. USES : GLAUCOMA ALKALINIZE URINE IN ACIDIC DRUG POISONING ACUTE MOUNTAIN SICKNESS ADVERSE EFFECTS : HYPOKALEMIA RENAL STONES ACIDOSIS CONTRA INDICATIONS : LIVER DISEASE : HEPATIC COMA precipitated in patients with cirrhosis due to excretion of NH3 in alkaline urine COPD :Worsening of acidosis is seen in patients with COPD

9. OSMOTIC DIURESIS MANNITOL Intravenously Metabolised in the body Freely filtered at glomerulus MOA:Draws water from tissues by osmotic action.Results in increased excretion of water and electrolytes Site of action : loop of henle and proximal tubule

10. Loop diuretics Chemistry Sulfonamide derivatives: Egs Furosemide,Torsemide , Bumetanide Phenoxy acetic acid derivative: Eg Ethacrynic acid Site of action Thick ascending limb of loop of Henle MOA Inhibition of Na + -K + -2Cl - symporter

11. Uses Intracranial pressure following head injury or tumour Acute congestive glaucoma Mannitol used to maintain osmolality of ECF after dialysis Adverse effects : Too rapid quantity pulmonary oedema Headache nausea vomiting

12. Loop diuretics

13. MOA : SITE OF ACTION : Thick ascending loop of henle USES: Initial stages of renal and cardiac odema loop diuretics preferred Iv frusemide along with isotonic saline is used in hypercalcemia as it promotes excretion of calcium in urine Acute pulmonary edema ,cerebral odema HTN With CCF /RENAL FAILURE ,HTN EMERGENCY. Blood transfusion

14. Side effects :electrolyte disturbances Hypokalemia Hyponatremia Hypocalcemia Hypomagnesemia Metabolic disturbances like Hyper glycemia, hyper uricemia,Hyper lipidemia Ototoxicity hypersensitivity

15. Thiazides Medium efficacy diuretic s

16. PHARMACOKINETICS: Absorption orally Excrerted urine Uses: Hypertension odema Hypercalciuria Diabetes insipidus Side effects : hypokalemia hyponatremia

17. Loop diuretics High efficacy High ceiling diuretic Efficacy increases with dose Loop diuretics

18. LOOP DIURETICS- MOA

19. Furosemide - actions Renal Diuresis – high efficacy, high ceiling On electrolytes Hyponatraemia Hypokalaemia Hypomagnesemia Hypocalcemia Hypochloraemia Alkalosis Hyperuricemia ↑ PGE₂, PGI₂ syn → ↑RBF Extrarenal Dilatation of peripheral blood vessels – subdiuretic doses Change in electrolyte composition of endolymph ↑ TGL, LDL; ↓ HDL Hyperglycemia Relative potency Bumetanide (40) >>>>> Torsemide (3) >> Frusemide (1)

20. Pharmacokinetics Routes – oral, I/V, I/M Secreted into tubules  competes with uric acid All undergo metabolism  Torsemide –active metabolite Bioavailility Onset t ½ Frusemide 60% 20- 40 min (oral) 10-20 min (I/M) 2-4 min (I/V) 1.5 hours Bumetanide 80% 0.8 hours Torsemide 80% 3.5 hours

21. USES Edema CCF - diuresis → rapid mobilisation of edema fluid → relief of symptoms Acute LVF - vasodilatation → ↓ preload & improve ventricular efficiency Redistributes blood from pulmonary to systemic circulation Nephrotic syndrome- controls pl. volume dependent rise in BP Hypertensive emergencies

22. Furosemide -Uses… Cerebral edema ( combi with osmotic diuretics) Acute renal failure ( oliguric → non- oliguric ) Anemia (blood transfusion) Hyperkalemia Hypercalcemia Anion overdose

23. ADR Hypokalemia Dilutional hyponatremia Hypocalcemia Hypomagnesimia Dehydration Alkalosis

24. ADR Hearing loss (due to changes in electrolyte conc. In endolymph ) Allergic manifestations (Less with Ethacrynic acid) Hyperuricemia Hyperglycemia Hyperlipidimia

25. THIAZIDES Classification Thiazides -Sulfonamide derivatives Thiazide like Site of action Early Distal convoluted tubule (cortical diluting segment) MOA Inhibition of Na + -Cl - symporter

26. THIAZIDES

27. Thiazides - actions Renal Diuresis – moderate efficacy, low ceiling Decreases blood volume & GFR(except metolazone ) Increses Ca reabsorption  thiazide induced vol depletion ↑ Na⁺ & Ca²⁺ reabsorption Hypomagnesemia Hyperuricemia Extrarenal Antihypertensive action  ↓ TPR, vessel wall stiffness → ↓ BP ↑ TGL, LDL; ↓ HDL Hyperglycemia

28. THIAZIDES… PK Well absorbed orally → PPB → less metabolised → mainly excreted unchanged in urine 100% oral BA – polythiazide PREPARATION Only oral ( chlorthalidone – parenteral) DOSE Hydrochlorthiazide – 12.5-100 mg/ day Indapamide – 2.5- 5 mg/ day

29. Kinetics t ½ (hours) Potency Chlorothiazide 1.5 0.1 Hydrochlorothiazide 2.5 1 Polythiazide 25 25 Chlorthalidone 47 1 Indapamide 14 20 Metolazone - 10

30. THIAZIDES-USES Edema - mainly for maintenance therapy Hypertension ( indapamide , chlorthalidone ) diuresis → ↓ ECF volume → ↓ CO ↓ TPR ↓ intracellular Na → ↓ vessel wall stiffness ↑ compliance ↓ responsiveness to AT II, NA Hypercalciuria  Renal stones Diabetes insipidus  Enhanced Na & water reabsorption at PCT due to volume depletion

31. THIAZIDES - ADR… Electrolyte imbalance Metabolic - Hyperglycaemia , hyperuricaemia & hyperlipidaemia Allergic reaction Impotence

32. POTASSIUM SPARING DIURETICS Chemistry Synthetic steroid : spironolactone Pyrazinoylguanidine derivative: amiloride Pteridine : triamterene Site of action Late distal convoluted tubule & collecting duct MOA Inhibits Na channels Direct inhibition Eg triamterene , Amiloride Via mineralocorticoid receptor Eg . Spironolactone,Eplerenone

33. POTASSIUM SPARING DIURETICS

34. Amiloride & Triamterene Direct inhibitors of sodium channels Retention of K and H ions  Hyperkalaemia &acidosis

35. Inh of renal epithelial Na+ channel-USES Cirrhotic edema Combi with thiazides , loop DA to prevent hypokalemia Cystic fibrosis - ↑ fluidity of resp. secretion Li⁺ induced DI – blocks Li reabsorption

36. Inh of renal epithelial Na+ channel-ADR Hyperkalemia , acidosis Amiloride Skin rashes, diarrhoea Triamterene Glucose intolerence , photosensitivity, megaloblastic anemia, muscle cramps, renal stones

37. spironolactone MOA -Antagonist of mineralocorticoid activty Anti androgenic effect  gynaecomastia Eplerenone  No anti androgenic action  Less ADR PK Not secreted into tubular lumen Well absorbed orally → PPB → completely metabolised in liver→ CANRENONE ( active metabolite ) T1/2 spironolactone – 2 hrs; canrenone - 18 hrs DOSE – 25-50 mg BD

38. POTASSIUM SPARING DIURETICS- USES Edema – esp in cirrhosis Hypertension Primary & secondary hyperaldosteronism Cystic fibrosis Lithium induced DI adjuvant to thiazides to prevent hypokalemia , To decrease resistance Amiloride

39. POTASSIUM SPARING DIURETICS- ADR Hyperkalemia Acidosis Peptic ulcer Abdominal upset, drowsiness, confusion Hirsuitism , gynaecomastia , impotence, menstual irregularities ( Spironolactone )

40. Eplerenone Selective aldosterone receptor antagonist(SARA ) No action on androgen, progesterone receptor Interfere with fibrotic & inflammatory effects of aldosterone; ↓ progression of albuminuria in DM ↓ myocardial perfusion defects after MI ↓ mortality rate by 15% in pts with post-MI cardiac failure

41. D/I of Potassium sparing diuretics Potassium supplements → hyperkalemia ARB,ACE-I ,NSAIDS, beta blockers → hyperkalemia ↑ digoxin levels Aspirin inhibits TS of Canrenone → blocks action Strong CYP3A inhibitors ↑ pl eplerenone

42. OSMOTIC DIURETICS MANNITOL Non electrolyte of low MW Pharmacologically inert Filtered from glomerulus;mininal reabsorption SITE OF ACTION Proximal tubule &descending limb of loop of henle MOA 1.Retains water isoosmotically in PT → dilutes luminal fluid → ↓ NaCl absorption 2.Draws water from IC compartment → ↓ intracellular oedema

43. Mannitol PK Not absorbed orally IV 10-20% solution USES Raised ICT/IOT- 1-1.5g/kg over 1 hr To maintain GFR in impending renal failure To counteract low pl osmolality d/t rapid dialysis

44. Mannitol CI ATN, anuria , pulm . edema, CHF, cerebral haemorrhage ADR Head ache d/t hyponatremia , nausea, vomiting, hypersensitivity rn . ISOSORBIDE & GLYCEROL Orally active

45. CARBONIC ANHYDRASE INHIBITORS Chemistry Sulfonamide derivatives Site of action Proximal convoluted tubule MOA Non competitive inhibition of carbonic anhydrase enzyme

46. CARBONIC ANHYDRASE INHIBITORS-MOA

47. CARBONIC ANHYDRASE INHIBITORS- ACTIONS Renal Inhibits H⁺ secretion in DCT,CD Maximum kaliuresis Self limiting action Extrarenal ↓ secretion of HCO₃ ⁻ to aqueous humour ↓ gastric acid , pancreatic HCO₃ ⁻ secretion ↑ seizure threshold Alters CO₂ transport in lungs

48. CARBONIC ANHYDRASE INHIBITORS-USES Glaucoma acetazolamide (oral) dorzolamide,brinzolamide (topical) Alkalinisation of urine – UTI, poisoning, cystinuria , uric acid calculi Metabolic alkalosis Epilepsy Diuretic – less used Acute mountain sickness ↓ resp. work in pts weaned from respirator Hyperkalemic periodic paralysis Hyperphosphatemia

49. CARBONIC ANHYDRASE INHIBITORS… PK Well absorbed orally excreted unchanged in urine DOSE - 250 mg OD/BD ; oral preparation

50. CARBONIC ANHYDRASE INHIBITORS… ADR Hypokalemia , acidosis Hypesensitivity reactions, rashes Drowsiness, paresthesia, fatigue Crystalluria CI – liver disease; alkaline urine interferes with ammonia elimination

51. THANK YOU…