DRUGS AND THE KIDNEY BY Dr: Mahmoud A. KoraAss.prof of Int. Medicine & Nephrology Menoufia University 2012
Who should beinterested in this topic ?
Every body should be ?why
Because of 2 reasons the first oneis that we are all prescribing drugs all the time
The second one is more importantWhich is that every body usually has 2 kidneys
Many drugs can injure the kidneys,but they cause renal injury via only. a few common mechanismsMany patients who develop renalinjury after drug exposure haveidentifiable risk factors that could be???. modified
Renal elimination of drugsDrugs may be eliminated via the kidneys by two main mechanisms: Glomerular filtration: a passive process such drugs will be water-soluble. Activetubular secretion: drugs act as substrates for secretory processes that are designed to eliminate endogenous molecules. ???
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.
Renal injury can present as acute renal failure, Nephrotic syndrome, renal tubular dysfunction, or chronic renal failure
Drug nephrotoxicityDrugs can lead to renal damage in a number of different ways :1. 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 ????
Occurring in patients who are critically dependant upon RAA system. Cyclosporine A2. Direct tubular toxicity Aminoglycosides :disturbance of renal function is seen in up to a third of patients receiving aminoglycosides.
Cisplatin : selectively toxic to proximal tubules by inhibiting nuclear DNA synthesis Amophotercin:3.glumerulonephritis Gold : Is believed to induce an immune complex GN Penicillamine : It is dose related
4. Other nephrotoxic effects of drugs: Interstitial nephritis Retropertoneal fibrosis Drug induced SLE Nephrogenic DI
Drugs which accumulate and cause toxicity in patients with sever renal failure include:1.Pencillins and cephalosporins high dose.2.digoxin3. ErythromycinNephrotoxic drugs may lead to an acute deterioration of renal function in patients with CRF and they can severely excerbates renal damage in ARF.
Absorption of some drugs may be altered in uremia as a consequence ofedema 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.
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
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 ???
Diabetic drugs and the kidneyGlucophageInsulinTZDsAcarbosesDPP-IV Inhibitorssulphonylureas
Insulin in renal patientsInsulin resistanceInsulin catabolism
Liver diseases and the kidneyWhich organ you should be more careful about?HRSElectrolyte disturbanceRenal impairment in HCV
Heart failure and the kidney■ Diuretics■ digitalis■ B-blocker in HD patients
Radio-contrast nephropathyMild 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.
Risk factors for radio- contrast nephropathy High contrast load Hypovolaemia Myeloma , Hyperuricaemia Age High iodine content of contrast Diabetes Hypercalcaemia Pre-existing CRF
KDIGO 2012 Consider alternative imaging methods in patients at increased risk for CI-AKI. (Not Graded) Use the lowest possible dose of contrast medium in patients at risk for CI-AKI. (Not Graded) We recommend using either iso-osmolar or low- osmolar iodinated contrast media, rather than high- osmolar iodinated contrast media in patients at increased risk of CI-AKI. (1B) We recommend i.v. volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions, rather than no i.v. volume expansion, in patients at increased risk for CI-AKI. (1A)
We recommend not using oral fluids alone in patients at increased risk of CI-AKI. (1C) We suggest using oral NAC, together with i.v. isotonic crystalloids, in patients at increased risk of CI-AKI. (2D) Wesuggest not using theophylline to prevent CI- AKI. (2C) Werecommend not using fenoldopam to prevent CI- AKI. (1B) We suggest not using prophylactic intermittent hemodialysis (IHD) or hemofiltration (HF) for contrast-media removal in patients at increased risk for CI-AKI. (2C)
The objective is toobtain a therapeuticdrug concentration-time profile that istherapeutic and nottoxic.
GENERAL PRINCIPLESBe vigilant. Adverse renal effects of drugs are largely silent in the early stages. Identify patients at risk.Take precautionsManage the renal failure
When in doubt about thecause of renal failure, holdall potentially offendingdrugs
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.
Physical assessment should includeAn 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.
II. Measurement of renal functionthe 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)(x0.85if female) 72x Scr(mg/dl)
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.
?Do we have another optionCystatin –C is a good indicator of renal function specially in children and elderly patientsEstimated GFR is the best way to assess progression of kidney disease in chronic renal patients
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.
What are special concerns regarding the use of antimicrobial agents in patients with renal failure? The majority of antimicrobial agents are excreted at least partially by the kidney so that dose reductions often are apporpiate in patients with glumerular filtration rates less than 50% of normal. Gastrointestinal absorption of tetracycline and ciprofloxacin may me decreased if
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 penicillins and vancomycin. The adjustments can be made by :1. maintaining the usual dose and varying the dosing interval,2. maintaining the dosing interval and varying the dose,3. or a combination of the two.
they are taken with phosphate-binding antacids. Decreased protein binding may contribute to increased neurotoxicity of betalactam antibiotics in patients with renal failure.Nephrotoxicity of antimicrobial agents is a major concern in patients with impaired renal function and limited renal reserve. The majority offenders are the aminoglycosides and Amophotercin.
The catabolic effects of tetracycline may results in a rise in blood urea nitrogen and therefore its use should be avoided in patients with advanced renal insufficiency.Many of the penicillins are prepared with sodium or pottasium. High doses of such agents may be problematiac in renal patients with volume overload of hyperkalemia.
Dosing of antimicrobial drugs in renal patients Antimicrobial and antiprotozoal drugsDrug Half-life Dosage for severe renal failure Normal/ESRD (h)Amoxycillin 0.09-2.3/5-20 Maximum 500 mgq 8hAmoxycillin Amoxycillin Maximum 375 mg q12 hClavulanic acid PO 0.9-2.3/5-20 Clavulanic acid1/3-4ampicillin 0.8-1.5/7-20 250-500 mg q6hCefotaxime IV 1/15 1g loading dose then 50% standard dose
Drug Half-life Dosage for severe renal failure Normal/ESRD (h)Ceftazidime IV 1.2/13-25 0.5-1 g q24hCeftriaxone IV 7-9/12-24 1-2 g q24hCefuroxime IV 1.2/17 750 mg q12hCefuroxime PO 1.2/17 Standard doseCephalexin 0.7/16 250-500 mg q12hChloroquiine 7-14 days/5- 50 days Treatment:50% standard doseCiprofloxacin IV/PO 3-6/6-9 50% standard dose q12hCalrithromycin 2.3-6.0/- 250 mg q12hCotrimoxazole Sulphamethoxazole PCP treatment:Standard doseIV/PO 10/20-50 q48hSulphamethoxazole/ Trimethoprime PCP prophylaxisTrimethoprime 9-13/20-49 25% Standard dose q48-72hErythromycin IV/PO 1.4/5-6 50-75% Standard dose Max 1.5g in 24h
Drug Half-life Dosage for severe renal failure Normal/ESRD (h)Flucloxacillin 0.8-1/3 Max PO 500 mg q6hIV 1g q 6 hGentamicin IV 1.8/20-60 Titrate to levelsImpenem/ cilastin IV Impenem ¼ 250 mg or 3.5 mg/kg q12 h Cilastin1/15-24Meropenem IV 1.1/6-8 50% standard dose q24hPenoxymethyl-pencillin 0.6/4.1 Standard dosePiperacillin IV 0.8-1.8/3.3-5.1 4 g q12 hPiperacillin/dihydrochloride IV Piperacillin 0.18-0.3/3.3-5.1 4.5 g q12 h Dihydrochloride 1/7Quinine difydrochloride IV 9 healthy,18 malaria/ Treat,emt 5-10 mg/kg q24h unchangedTrimethoprim 9-13/20-49 50% standard doseVancomycin IV 6-8/200-250 Titrate to levels
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
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
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
You are what you repeatedly do; then excellence is not an art but just a habit Aristo