This document discusses how drugs are eliminated by the kidneys and the mechanisms of renal injury caused by various drugs. It notes that many drugs can injure the kidneys through a few common mechanisms, such as altering renal blood flow or causing direct tubular toxicity. It provides examples of specific drugs that can cause these types of renal injuries. The document also discusses factors that influence drug dosing in patients with renal impairment and principles for safely prescribing drugs in such patients.

2. DRUGS AND THE KIDNEY
BY
Dr: Mahmoud A. Kora
Ass.prof of Int. Medicine & Nephrology
Menoufia University
2012

3. Who should be
interested in this topic
?

4. Every body should
be
?why

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

6. The second one is more
important
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.
 Activetubular 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

12.  Drug nephrotoxicity
Drugs 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 ????

13. 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.

14.  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

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

17. 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.

18. 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.

19. 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

20. 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 ???

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

22. Insulin in renal patients
Insulin resistance
Insulin catabolism

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

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

25. 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.

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

28. 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)

29.  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)

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

31. 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

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

33. 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.

34. 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.

35. 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)

36. 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.

37. ?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

39. 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.

40.  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

41. 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 :
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.

42. 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.

43. 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.

44. Dosing of antimicrobial drugs in renal
patients
Antimicrobial and antiprotozoal drugs
Drug Half-life Dosage for severe renal failure
Normal/ESRD
(h)
Amoxycillin 0.09-2.3/5-20 Maximum 500 mgq 8h
Amoxycillin Amoxycillin Maximum 375 mg q12 h
Clavulanic acid PO 0.9-2.3/5-20
Clavulanic
acid1/3-4
ampicillin 0.8-1.5/7-20 250-500 mg q6h
Cefotaxime IV 1/15 1g loading dose then 50% standard
dose

45. Drug Half-life Dosage for severe renal failure
Normal/ESRD
(h)
Ceftazidime IV 1.2/13-25 0.5-1 g q24h
Ceftriaxone IV 7-9/12-24 1-2 g q24h
Cefuroxime IV 1.2/17 750 mg q12h
Cefuroxime PO 1.2/17 Standard dose
Cephalexin 0.7/16 250-500 mg q12h
Chloroquiine 7-14 days/5- 50 days Treatment:50% standard
dose
Ciprofloxacin IV/PO 3-6/6-9 50% standard dose q12h
Calrithromycin 2.3-6.0/- 250 mg q12h
Cotrimoxazole Sulphamethoxazole PCP treatment:Standard dose
IV/PO 10/20-50 q48h
Sulphamethoxazole/ Trimethoprime PCP prophylaxis
Trimethoprime 9-13/20-49 25% Standard dose q48-72h
Erythromycin IV/PO 1.4/5-6 50-75% Standard dose
Max 1.5g in 24h

46. Drug Half-life Dosage for severe renal failure
Normal/ESRD
(h)
Flucloxacillin 0.8-1/3 Max PO 500 mg q6hIV 1g q 6 h
Gentamicin IV 1.8/20-60 Titrate to levels
Impenem/ cilastin IV Impenem ¼ 250 mg or 3.5 mg/kg q12 h
Cilastin1/15-24
Meropenem IV 1.1/6-8 50% standard dose q24h
Penoxymethyl-pencillin 0.6/4.1 Standard dose
Piperacillin IV 0.8-1.8/3.3-5.1 4 g q12 h
Piperacillin/dihydrochloride IV Piperacillin 0.18-0.3/3.3-5.1 4.5 g q12 h
Dihydrochloride 1/7
Quinine difydrochloride IV 9 healthy,18 malaria/ Treat,emt 5-10 mg/kg q24h
unchanged
Trimethoprim 9-13/20-49 50% standard dose
Vancomycin IV 6-8/200-250 Titrate to levels

47. 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

48.  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

49.  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

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

52. nk y ou
T ha