Drugs and the Kidney: Renal Function, Dialysis, and Pharmacokinetics Exploration

2. Drugs in kidney diseases 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 kidney disease

4. Normal Kidney Function • 1 Extra Cellular Fluid Volume control • 2 Electrolyte balance • 3 Waste product excretion • 4 Drug and hormone elimination/metabolism • 5 Blood pressure regulation • 6 Regulation of haematocrit • 7 regulation of calcium/phosphate balance (vitamin D3 metabolism)

5. 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

6. 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

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

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

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

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

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

12. Drugs and normal kidney

16. Effects of renal disease on drugs

18. 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

19. 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.

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

21. 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

22. Effect of dialysis on drugs: Drug clearance during dialysis : -Adsorption -Convection -Diffusion drugs that have small volume of distribution more effectively removed by dialysis

23. Effect of dialysis on drugs • Molecular weight • Water solubility • Degree of protein binding • Membrane clearance Drugs with MW >500 daltons poorly cleared by conventional HD membranes. Protein or tissue binding or lipid soluble are not dialyzed properly.(<90% proteinbound) For drugs not removed by HD, it is unusual to be removed by peritoneal dialysis. High-flux membranes (porous) are more permeable to drugs.(treatment time,BFR,DFR)

24. Effect of dialysis on drugs • Hemofiltration modalities are using in ICU for management of acute renal failure significantly increase drug removal due to increase plasma protein loss.(treatment of theophylline and aspirin poisoning) • A drug significantly removed by this modality if is not protein bound and distributed in plasma. • Measurement of serum drug level may be helpful in guiding the need for supplemental dosing.

25. Drug dosing in PD : • PD is less efficient in removing drugs than HD • LMW drugs and small volume of distribution are more effectively removed • Depends on number and volume exchange done daily and dwell time. • Depends on residual kidney function. • Factors favoring absorption include inflamation of membrane and concentration gradient.

26. Drug dosing in CRRT: • Provide less of a challenge for drug dosing • Continuous nature of clearance is analogous with drug removal by kidney • Depends on MW,membrane characteristic, BFR,DFR .

27. Drug dosing recommendations: • loading dose is equal to usual dose in normal kidney function. • In HD many drugs are given only at the end of dialysis. • Maintenance dose of most drugs should be given after dialysis.

29. Drugs toxic to the kidney

30. Patient –related risk factors for drug-induced nephrotoxicity • Absolute or effective intravascular depletion • Age older than 60 years • Diabetes • Exposure to multiple nephrotoxins • Heart failure • Sepsis • Underlying renal insufficiency (glumerular filtration rate <60 ml per minute per 1.73m2)

32. Drug toxicity is responsible for 18-27% of Acute Renal injury • 6 major mechanisms are involved: • Hemodymanic mediated • Glomerulonephritis • Acute tubular necrosis • Interstitial nephritis • Papillary necrosis • Obstructive uropathy

33. glomerulus

34. 1- Hemodynamic mediated Effect • Gradient pressure between afferent and efferent arterioles are responsible for glomerular filtration. • Drug involved: • NSAID • ACE inhibitors • ARB • Calcineurin inhibitor

35. A- NSAID • They are nephrotoxic in patients with borderline renal function, spesis or haert failure • COX inhibition will block PG synthesis (vasodialtor) and consequently, V.C will dominate and blood flow and GFR will decrease . • PG also important for maintaining fluid and electrolyte hemostasis.

36. NSAIDs (Non-steroidal anti inflammatory drugs) • Commonly used • Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance • Naproxen have the least cardiovascular risk • Antithrombotic effect of ASA antagonized by NSAID • Chronic renal impairment • Habitual use • Exacerbated by other drugs ( anti-hypertensives, ACE inhibitors)

37. Nephrotoxic potential of Nsaid determine by potency, length of action,period of administration • A hypersensivity reaction of Nsaid may provoke AKI associated with preuteinuria and nephrotic syndrome and allergic interstitial nephritis

39. B & C- ACEIs and ARB • Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) are inhibiting Renin system and decrease the blood hemodynamic: • It produces VD and decrease perfusion pressure and decreases GFR • At the start of the treatment a decrease of urine volume and increase of creatinine by 30% indicates • Damage is reversible • Rehydration of patient is advisable • Initiate treatment with short acting (captopril) and titrate later with long acting

40. It is contraindicated to prescribe it for patients with renal artery stenosis…. Why???

41. D- Immunosuppressing agentsCalcineurin inhibitors • Cyclosporine and Tacrolimus forms immunophillin complex which inhibits protein calcineurin and mediates T- cell response • It produces VC of afferent arteriols by increasing endothelin and thromboxan A2, affecting renal perfusion • Nephrotoxicity is the dose limiting toxicity • It can cause also interstitial nephritis and produce nephritis in renal transplant • Therapeutic drug monitor is essential to reduce dose when needed

42. Drug toxicity is responsible for 18-27% of Acute Renal injury in USA • 6 major mechanisms are involved: • Hemodymanic mediated • Glomerulonephritis • Acute tubular necrosis • Interstitial nephritis • Papillary necrosis • Obstructive uropathy

43. 2- Glomerulonephritis • 4 Different immunological drug induced GN: • Minimal change syndrome: by: NSAID, ampicillin, rifampicin • Focal segmental glomeruloscerosis (FSGS): lithium, heroin • Membranous nephropathy (MN): NSAID, gold therapy, mercury, penicillamine • Membranoproliferative: hydralazine

44. Drug toxicity is responsible for 18-27% of Acute Renal injury in USA • 6 major mechanisms are involved: • Hemodymanic mediated • Glomerulonephritis • Acute tubular necrosis • Interstitial nephritis • Papillary necrosis • Obstructive uropathy

45. 3- Acute Tubular Necrosis • Due to ischemia from exposure to toxin. Death of the tube, sloughing of Renal tubules. • Caused by: • Aminoglycosides • Amphotericin B • Radiocontrast dye • Cisplatin

46. Aminoglycosides • Highly effective antimicrobials • Particularly useful in gram -ve sepsis • bactericidal • BUT • Nephrotoxic • Ototoxic • Narrow therapeutic range

47. Aminoglycisdes • Gentamycin and Kanamycin • Affecting PCT by binding of +ve charges of AG to phospholipids in plasma, mitochondria and lysosomal membranes. It will interfere in the functions of organelles. • Renal toxicity appears 5-10 days of treatment by monitoring serum creatinine. • AKI is reversible

48. Prescribing Aminoglycosides • Once daily regimen now recommended in patients with normal kidneys • High peak concentration enhances efficacy • long post dose effect • Single daily dose less nephrotoxic • Dose depends on size and renal function • Measure levels!

49. Amphotericin B • In 80% of patients after 3-4 grams • Affecting PCT and DCT to increase permeability and increase O2 requirements, VC of blood vessels. • Avoid co administration of other nephrotoxic agents especially: carbicillin and Ticarcillin

50. Intravenous contrast Used commonly • CT scanning, IV urography, Angiography • Unsafe in patients with pre-existing renal impairment • Risk increased in diabetic nephropathy, heart failure & dehydration • Can precipitate end-stage renal failure • Cumulative effect on repeated administration