Drugs in acute kidney injury

2. Drugs in acute kidney injury DrNoushinHashemi.M.D. Nephrologist

3. Drugs and the Kidney 1- Renal Physiology and Pharmacokinetics 2- Drugs and the normal kidney 3- Effect of renal disease on drug metabolism 4- Drugs toxic to the kidney 5- Prescribing in acute kidney injury

4. Regulation of blood pressure Acid-base balance Excreting metabolic waste products such as creatinine, urea, and uric acid Removal of drug metabolites Solute and water transport Erythropoietin production Calcium & phosphate regulation Vitamin D activation Renal function

5. Hypertension Acidosis Water overload Hyperkalemia Anemia Hypocalcemia & hyperphosphatemia Vitamin D deficiency Consequences of renal dysfunction

6. Definition: • Inability of the kidneys to do their functions Renal failure

7. How to measure renal function?

8. Definition: • The volume of glomerular filtrate formed each minute in the nephrons of both kidneys. Glomerular Filtration Rate

10. glomerulus

11. The normal value for GFR depends on age, sex, and body size. Nl GFR: 120 cc/min (180 lit/day) Nlgfr

12. GFR cannot be measured directly, but could be estimated from the urinary clearance of an ideal filtration marker. An ideal filtration marker is defined as a solute that is freely filtered at the glomerulus, nontoxic, neither secreted nor reabsorbed by the kidney tubules, and not changed during its excretion by the kidney. The gold standard of exogenous filtration markers is inulin. GFR = (Ux X V)/Px Measurement of gfr

13. Tests of renal function cont. • 24h Urine sample-Creatinine clearance • gold standard Inulin clearance • urea understimate and cr overestimate GFR

14. The most common methods utilized to estimate the GFR are the serum creatinine concentration. Nl serum creatinin: 0.5-1.5 mg/dl creatinine

15. Serum Creatinine and GFR • Muscle metabolite - concentration proportional to muscle mass • High:muscular young men • Low: conditions with muscle wasting • Elderly • Muscular dystrophy • Anorexia • Malignancy • women • “Normal” range 70 to 140 μmol/litre

16. Creatinine Clearance Estimation of GFR Urine crt × Urine volume Crt clearance= Plasma crt (140-AGE) × WEIGHT Crt clearance= 72 × Crt. (Cockcroft-Gault equation)

17. GFR Estimation • Cockroft-Gault Formula CrCl=Fx(140-age)xweight/CreaP F♀=1.04 F♂=1.23 • MDRD Formula • EPI(race,age,gender,cr)

18. Estimation of GFR, Why? • Assess the degree of kidney impairment • Patients do not develop symptomatic uremia until renal insufficiency is severe (GFR < 15 mL/min). • To follow the course of the disease • the GFR will fall in roughly inverse proportion to the rise in P Cr • Drug dosing: • Failure to account for GFR reductions in drug dosing can lead to significant morbidity and mortality from drug toxicities (e.g., digoxin, aminoglycosides).

19. Clinical Estimation of renal function • Clinical examination pallor, volume status, blood pressure measurement, urinalysis • Blood tests • Routine Tests • haemoglobin level • electrolyte measurement (Na ,K , Ca, PO4) • urea

20. Pharmacokinetics • Absorption • Distribution • Metabolism • Elimination • filtration • secretion

21. Farmacodynamic • Complex interactions of other farmacologic factors including drug concentration,receptor-drug interaction and effect on body chemistry and clinical factors such as concurrent disease and degree of organ dysfunction

22. دوز منطقی دارو و زمان لازم برای عملکرد هدف اصلی روش های درمانی کسب اثر سودمند دارو با حداقل اثرات سوء ترکیب اصول فارماکوکینتیک و فارماکودینامیک فارماکودینامیک تعیین کننده رابطه غلظت دارو با اثر آن فارماکوکینتیک تعیین کننده رابطه دوز دارو با غلظت آن در بدن یا تعیین کننده سرعت و طول دوره ای است که دارو به اندام هدف می رسد.

25. Drugs and normal kidney

30. Effects of renal disease on drugs

31. Effect of uremia on drug disposition • 1-Bioavalability : uremia decreases GI absorption of drugs (dissolution ,alkalinization,first pass hepatic metabolism , impaire protein binding) 2-Distribution: -edema and ascites :increase volume of distribution -dehydration and muscle wasting :decrease volume of distribution -combination of decrease serum Alb concentration and reduction in Alb affinity reduce protein binding in uremia

32. 3-Metabolism: -uremia slows the rate of reduction and hydrolysis reactions . -uremia alter the deposition of drugs metabolize by liver through changes in plasma protein binding.

33. TABLE 57-2 -- Drugs That Have Active or Toxic Metabolites in Dialysis Patients Cardiac glycosidesClorazepateCephalosporins Chloral hydrateClofibrateDesipramineDiltiazemEncainideEsmololH2-blockersHydroxyzineImipramine

34. TABLE 57-2-- Drugs That Have Active or Toxic Metabolites in Dialysis Patients cont….. IsosorbideLevodopaLorcainide MeperidineMetronidazole MethyldopaMiglitolMinoxidil Morphine NitrofurantoinNitroprussideProcainamidePrimidone Propoxyphene Pyrimethamine QuinidineSerotonin reuptake inhibitorsSpironolactoneSulfonylureasSulindac ThiazolidinedionesTriamtereneTrimethadioneVerapamilVidarabine

36. Renal failure

37. ACUTE or CHRONIC? Once renal failure detected, the first step is:

38. What is the importance? • ARF Reversible • CRF Irreversible

39. Acute renal failure (ARF) is a syndrome characterized by rapid decline in GFR(hours to days). Chronic renal failure is a syndrome characterized by slow decline in GFR( months to years). Definition

40. Retention of nitrogenous waste products • Azothemia • Uremia • Oliguria (urine output <400 mL/d) • Electrolyte and acid-base abnormalities frequent clinical features

41. ARF: Signs and Symptoms • Hyperkalemia • Nausea/Vomiting • HTN • Pulmonary edema • Ascites • Asterixis • Encephalopathy

42. داروها در نارسایی حاد کلیه

43. Drug dosing in AKI : • Why is important? • What is the problem ? • Examples • Summery • advice

44. Medical optimization in AKI : • Kidneys are one of the major excretory pathway for removal of drugs • Drugs accumulate during an episode of AKI and result deteroriation of kidney function, bone marrow or CNS toxicity

45. Eliminate the potential cause/risk , contributory factor for AKI • Avoid inappropriate combination of medication in AKI • Ensure that dose of prescribe medication are appropriate for level of kidney function • Ensure that all medication prescribe are appropriate

46. Points to note : • Which medication should be suspend? • Which medication should not be suspend? • Which medication may be used with caution ? • Are there any alternative options ?

47. If a medication must be used : • Amend doses appropriate to the patients level of renal function • Monitor drug level of drug when ever possible • Keep course of treatment as short as possible • Discuss treatment with pharmacist/microbiologist

48. Medication optimization : • Is the patient receive medication which may impaire renal function ? - ACEI - ARB -NSAID-DIURETICS-CONTRAST MEDIA consider whidholding of this agents during episode of AKI

49. Medication : a-is the patient taking any other medication which could exacerbate AKI ? Consider withholding them b-is patient receive any medication which the dose need to be amend ? c-amend medication doses appropriate to the degree of renal function

50. Educate the ptient before discharge about which medication to start and when . Which medication to avoid • Ensure comprehensive information on which medication to restart