DRUGS AND THE KIDNEYDRUGS AND THE KIDNEY

BY

Dr: Mahmoud A. KoraAss.prof of Int. Medicine & Nephrology

Menoufia University

2012

Who should be Who should be interested in this topicinterested in this topic

??

Every body should Every body should bebe

whywhy??

Because of 2 reasonsBecause of 2 reasonsthe first onethe first one

is that we are all prescribing is that we are all prescribing drugs all the timedrugs all the time

The second one is moreThe second one is moreimportantimportant

Which is that every body usually has 2 kidneys

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 .???

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.Active tubular 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 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 ????

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.

Cisplatin : selectively toxic to proximal

tubules by inhibiting nuclear DNA synthesis Amophotercin:

3.glumerulonephritisGold :

Is believed to induce an immune complex GN

Penicillamine :

It is dose related

4. Other nephrotoxic effects of drugs:Interstitial nephritis Retropertoneal fibrosisDrug induced SLENephrogenic DI

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.

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.

How nephrotoxic are the How nephrotoxic are the NSAIDs ?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 NSAIDsnephrotoxic effects of NSAIDs

↑ Na retention and blood volume (CHF)Papillary necrosis↑ KAcute allergic interstitial nephritis ass with

fenoprofenATNInterstitial nephritis with aspirin ,caffeine ???

Diabetic drugs and the kidneyDiabetic drugs and the kidney

GlucophageInsulinTZDsAcarbosesDPP-IV Inhibitorssulphonylureas

Insulin in renal patientsInsulin in renal patients

Insulin resistance Insulin catabolism

Liver diseases and Liver diseases and the kidneythe kidney

Which organ you should be more careful about?

HRSElectrolyte disturbanceRenal impairment in HCV

Heart failure and the kidneyHeart 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 nephropathyHigh contrast loadHypovolaemia Myeloma , HyperuricaemiaAgeHigh iodine content of contrastDiabetesHypercalcaemiaPre-existing CRF

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)

KDIGO 2012

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)

We suggest not using theophylline to prevent CI-AKI. (2C)

We recommend 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 to obtain a therapeutic drug concentration- time profile that is therapeutic and not toxic.

GENERAL PRINCIPLESGENERAL 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

When in doubt about the When in doubt about the cause of renal failure, hold cause of renal failure, hold all potentially offending all potentially offending drugsdrugs

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 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.

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)

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 optionDo 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

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 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.

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 drugs DrugHalf-life

Normal/ESRD

(h)

Dosage for severe renal failure

Amoxycillin0.09-2.3/5-20Maximum 500 mgq 8h

Amoxycillin

Clavulanic acid PO

Amoxycillin

0.9-2.3/5-20

Clavulanic acid1/3-4

Maximum 375 mg q12 h

ampicillin0.8-1.5/7-20250-500 mg q6h

Cefotaxime IV1/15 1g loading dose then 50% standard dose

DrugHalf-life

Normal/ESRD

(h)

Dosage for severe renal failure

Ceftazidime IV1.2/13-250.5-1 g q24h

Ceftriaxone IV7-9/12-241-2 g q24h

Cefuroxime IV1.2/17750 mg q12h

Cefuroxime PO1.2/17Standard dose

Cephalexin0.7/16250-500 mg q12h

Chloroquiine7-14 days/5- 50 daysTreatment:50% standard dose

Ciprofloxacin IV/PO3-6/6-950% standard dose q12h

Calrithromycin2.3-6.0/-250 mg q12h

Cotrimoxazole

IV/PO

Sulphamethoxazole/

Trimethoprime

Sulphamethoxazole

10/20-50

Trimethoprime

9-13/20-49

PCP treatment:Standard dose q48h

PCP prophylaxis

25% Standard dose q48-72h

Erythromycin IV/PO1.4/5-650-75% Standard dose

Max 1.5g in 24h

DrugHalf-life

Normal/ESRD

(h)

Dosage for severe renal failure

Flucloxacillin0.8-1/3Max PO 500 mg q6hIV 1g q 6 h

Gentamicin IV1.8/20-60Titrate to levels

Impenem/ cilastin IVImpenem ¼

Cilastin1/15-24

250 mg or 3.5 mg/kg q12 h

Meropenem IV1.1/6-850% standard dose q24h

Penoxymethyl-pencillin0.6/4.1Standard dose

Piperacillin IV0.8-1.8/3.3-5.14 g q12 h

Piperacillin/dihydrochloride IVPiperacillin 0.18-0.3/3.3-5.1

Dihydrochloride 1/7

4.5 g q12 h

Quinine difydrochloride IV9 healthy,18 malaria/ unchanged

Treat,emt 5-10 mg/kg q24h

Trimethoprim9-13/20-4950% standard dose

Vancomycin IV6-8/200-250Titrate 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 doseNSAIDs :-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 ketoprofenPenicillamine ,avoid if GFR less than 50ml/minCyclosporine, 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)….GoutSulfasalasine ,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

Thank youThank youThank youThank you