DRUGS AND THE KIDNEY

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DRUGS AND THE KIDNEY

• BY
• Hany Elbarbary

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Who should be interested in this topic ?
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Every body should bewhy?
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Because of 2 reasonsthe first one is that we
are all prescribing drugs all the time
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The second one is moreimportant

• Which is that every body usually has 2 kidneys

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• 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. ???

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• 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. ???

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• When renal disease leads to a reduction in
  nephron, the kidneys 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.

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

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• Drug nephrotoxicity
• Drugs can lead to renal damage in a number of
  different ways
• Alteration of renal blood flow
• NSAIDsalteration 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
  ????

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• 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.

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• 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

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

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• 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.

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• 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.

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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

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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 ???

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Diabetic drugs and the kidney

• Glucophage
• Insulin
• TZDs
• Acarboses
• DPP-IV Inhibitors
• sulphonylureas

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Insulin in renal patients

• Insulin resistance
• Insulin catabolism

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Liver diseases and the kidney

• Which organ you should be more careful about?
• HRS
• Electrolyte disturbance
• Renal impairment in HCV

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Heart failure and the kidney

• Diuretics
• digitalis
• B-blocker in HD patients

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• 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.

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

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Management of drug nephrotoxicity
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• 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.

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• 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.

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• 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)(x0.85if
  female)
• 72x Scr(mg/dl)

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• 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.

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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

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GENERAL PRINCIPLES

• Be vigilant. Adverse renal effects of drugs are
• largely silent in the early stages
• Identify patients at risk .
• Take precautions .

Manage the renal failure
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• 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.

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

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

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• Dosing of antimicrobial drugs in renal patients
• Antimicrobial and antiprotozoal drugs

Dosage for severe renal failure Half-life Normal/ESRD (h) drug
Maximum 500 mgq 8h 0.09-2.3/5-20 Amoxycillin
Maximum 375 mg q12 h Amoxycillin 0.9-2.3/5-20 Clavulanic acid1/3-4 Amoxycillin Clavulanic acid PO
250-500 mg q6h 0.8-1.5/7-20 ampicillin
1g loading dose then 50 standard dose 1/15 Cefotaxime IV
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Dosage for severe renal failure Half-life Normal/ESRD (h) Drug
0.5-1 g q24h 1.2/13-25 Ceftazidime IV
1-2 g q24h 7-9/12-24 Ceftriaxone IV
750 mg q12h 1.2/17 Cefuroxime IV
Standard dose 1.2/17 Cefuroxime PO
250-500 mg q12h 0.7/16 Cephalexin
Treatment50 standard dose 7-14 days/5- 50 days Chloroquiine
50 standard dose q12h 3-6/6-9 Ciprofloxacin IV/PO
250 mg q12h 2.3-6.0/- Calrithromycin
PCP treatmentStandard dose q48h PCP prophylaxis 25 Standard dose q48-72h Sulphamethoxazole 10/20-50 Trimethoprime 9-13/20-49 Cotrimoxazole IV/PO Sulphamethoxazole/ Trimethoprime
50-75 Standard dose Max 1.5g in 24h 1.4/5-6 Erythromycin IV/PO
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Dosage for severe renal failure Half-life Normal/ESRD (h) Drug
Max PO 500 mg q6hIV 1g q 6 h 0.8-1/3 Flucloxacillin
Titrate to levels 1.8/20-60 Gentamicin IV
250 mg or 3.5 mg/kg q12 h Impenem ¼ Cilastin1/15-24 Impenem/ cilastin IV
50 standard dose q24h 1.1/6-8 Meropenem IV
Standard dose 0.6/4.1 Penoxymethyl-pencillin
4 g q12 h 0.8-1.8/3.3-5.1 Piperacillin IV
4.5 g q12 h Piperacillin 0.18-0.3/3.3-5.1 Dihydrochloride 1/7 Piperacillin/dihydrochloride IV
Treat,emt 5-10 mg/kg q24h 9 healthy,18 malaria/ unchanged Quinine difydrochloride IV
50 standard dose 9-13/20-49 Trimethoprim
Titrate to levels 6-8/200-250 Vancomycin IV
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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

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• 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

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• 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

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

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Thanks