DRUGS AND THE KIDNEY

2. DRUGS AND THE KIDNEY BY Hany Elbarbary

3. Who should be interested in this topic ?

4. Every body should bewhy?

5. Because of 2 reasonsthe first one is that we are all prescribing drugs all the time

6. The second one is moreimportant Which is that every body usually has 2 kidneys

7. Many drugs can injure the kidneys, but they cause renal injury via only a few common mechanisms. Many patients who develop renal injury after drug exposure have identifiable risk factors that could be modified. ???

8. Renal elimination of drugs Drugs may be eliminated via the kidneys by two main mechanisms: • Glomerular filtration: a passive process such drugs will be water-soluble. • Active tubular secretion: drugs act as substrates for secretory processes that are designed to eliminate endogenous molecules. ???

9. When renal disease leads to a reduction in nephron, the kidney’s ability to eliminate drugs declines in proportion to the decline in glomerular filtration rate. As renal failure progresses, drugs filtered or secreted by the kidney can accumulate , potentially resulting in toxicity.

10. Renal injury can present as acute renal failure, Nephrotic syndrome, renal tubular dysfunction, or chronic renal failure

11. Drug nephrotoxicity Drugs can lead to renal damage in a number of different ways : • Alteration of renal blood flow • NSAIDs:alteration in prostaglandin metabolism can lead to critical reduction in glumerular perfusion, interstitial nephritis can also result from NSAIDs • ACE inhibitors and ARBs: ARF or renal impairment ????

12. Occurring in patients who are critically dependant upon RAA system. • Cyclosporine A 2. Direct tubular toxicity • Aminoglycosides :disturbance of renal function is seen in up to a third of patients receiving aminoglycosides.

13. Cisplatin : selectively toxic to proximal tubules by inhibiting nuclear DNA synthesis • Amphotercine B 3.glumerulonephritis • Gold : Is believed to induce an immune complex GN • Penicillamine : It is dose related

14. 4. Other nephrotoxic effects of drugs: • Interstitial nephritis • Retropertoneal fibrosis • Drug induced SLE • Nephrogenic DI

16. Drugs which accumulate and cause toxicity in patients with sever renal failure include: 1.Pencillins and cephalosporins high dose. 2.digoxin 3. Erythromycin Nephrotoxic drugs may lead to an acute deterioration of renal function in patients with CRF and they can severely excerbates renal damage in ARF.

17. Absorption of some drugs may be altered in uremia as a consequence of edema of the gastrointestinal tract coupled with uremic nausea ,vomiting or gastroparesis. Alteration in the distribution of drugs vary depending on the agents . Acidic drugs will have a higher free fraction in the plasma of uremic patients as a consequence of decrease protein binding.

18. How nephrotoxic are the NSAIDs ? PG have relatively little effect on the normal kidney in the euvolemic person However in renal insufficiency or hypovolemic states PG are important in maintaining adequate glomerular flow and pressure by VD of renal arteries , ↑ Na loss and ↑ rennin release

19. nephrotoxic effects of NSAIDs ↑ Na retention and blood volume (CHF) Papillary necrosis ↑ K Acute allergic interstitial nephritis ass with fenoprofen ATN Interstitial nephritis with aspirin ,caffeine ???

20. Diabetic drugs and the kidney Glucophage Insulin TZDs Acarboses DPP-IV Inhibitors sulphonylureas

21. Insulin in renal patients Insulin resistance Insulin catabolism

22. Liver diseases and the kidney Which organ you should be more careful about? HRS Electrolyte disturbance Renal impairment in HCV

23. Heart failure and the kidney ■ Diuretics ■ digitalis ■ B-blocker in HD patients

24. Radio-contrast nephropathy Mild renal dysfunction may complicate up to 10% of angiographic procedures and IVUs. Radio-contrast nephropathy is manifest by non oliguric ARF, typically occurring 1-5 days after the procedure. Intra- renal vasoconstriction, mediated largely by endothelin, and tubular cell toxicity (with ATN) are important in the pathogenesis . The ARF is fully reversible.

25. Risk factors for radio- contrast nephropathy • High contrast load • Hypovolaemia • Myeloma , Hyperuricaemia • Age • High iodine content of contrast • Diabetes • Hypercalcaemia • Pre-existing CRF

26. Management of drug nephrotoxicity

27. A careful history and physical examination are always the first steps in clinical evaluation of patients with renal disease. Particularly important for this purpose is the history of previous drug allergy or toxicity and the use of concurrent medications.

28. Physical assessment should include An estimate of the extracellular fluid volume. Oh ?? Edema or ascites increases the distribution volume of many drugs, while dehydration contracts this volume. Evidence of impaired function of other excretory organs should be sought. Stigmata of liver disease are clue that the drug dose may need to be altered.

29. II. Measurement of renal function the rate of elimination of drugs excreted by the kidneys is proportional to the glomerular filtration rate. The serum creatinine , creatinine clearance is needed to determine renal function before prescribing many drugs . The Cockcroft and Gault equation is useful for this purpose, as shown in the following formula: CrCl (ml/min)= (140-age)x (BW in kg)(x0.85iffemale) 72x Scr(mg/dl)

30. The Scr reflects muscle mass as well as glomerular filtration rate. Scr measurement within the normal range are frequently used to establish normal renal function. This may cause serious over- dose and resultant toxic drugs accumulation in elderly or debilitated patients with decreased muscle mass.

31. Do we have another option? Cystatin –C is a good indicator of renal function specially in children and elderly patients Estimated GFR is the best way to assess progression of kidney disease in chronic renal patients

32. GENERAL PRINCIPLES Manage the renal failure Be vigilant. Adverse renal effects of drugs are largely silent in the early stages Identify patients at risk . Take precautions .

34. Pretreatment hydration can reduce the nephrotoxic potential of many drugs. • So ,it is very simple steps by which you can avoid getting yourself and your patient in a big problem.

35. When in doubt about the cause of renal failure, hold all potentially offending drugs

36. How should antibiotic doses be adjusted in patients with renal failure? Several antibiotics need dosage modification in the presence of renal failure, most cephalosporins, many penicillin's and vancomycin. The adjustments can be made by : • maintaining the usual dose and varying the dosing interval, • maintaining the dosing interval and varying the dose, • or a combination of the two.

37. The objective is to obtain a therapeutic drug concentration- time profile that is therapeutic and not toxic.

38. Dosing of antimicrobial drugs in renal patients Antimicrobial and antiprotozoal drugs

41. Dosing of common drugs in renal patients Allopurinol-GFR 30 ml/min use 100mg,60ml/min use 200mg,90ml/min use 300mg Corticosteroids-no need to change the dose NSAIDs :-most are metabolized in the liver , aspirin is a good choice in renal impairment, - In ESRD patients ,no need for dose adjustment

42. In patients with low urine output avoid sulindac owing to renal stone formation. Reduce dose of ketoprofen Penicillamine ,avoid if GFR less than 50ml/min Cyclosporine, no dose adjustment in renal insufficiency, however use of Cyclosporine can worsen renal insufficiency Gold , if GFR 50-75ml/min use 50% of usual dose ,if less than 50% avoid gold

43. Methotrexate ,take care from hematologic toxicity Tacrolimus (FK506,prograf)….Gout Sulfasalasine ,no change in dose. Mycophenylate mofetil (cellcept) ,mainly hepatic metabolism ,but if GFR less than 25 ml/min reduce dose by 25%. Tramadol , give dose every 12 h instead of every 6h Narcotics, avoid using Darvon and Mepiridine, for others if GFR less than 10ml/min cut 50% of the dose ,if GFR 10-50ml/min use 75% of the dose

44. You are what you repeatedly do; then excellence is not an art but just a habit Aristo

45. Thanks