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SAFE USE OF MEDICINES IN PATIENTS WITH RENAL DISEASES

J Kabahizi, RMH/KFH QUOTE "Will, determination, and power of

memory are attributed to the kidney. The ability to keep a secret is attributed to the kidney's power of retention and safeguarding against leakage. The Neijing defined that "the kidney stores jing, and jing houses will power." In turn, if kidney jing becomes exhausted, a weak will and poor memory will result” ByTaosm

SCOPE 1.  INTRODUCTION 2.  EFFECTS OF CKD ON DRUGS PHARMAKINETICS 3. DIALISABILITY OF THE DRUGS 3.  ESTIMATION OF RENAL FUNCTION 4. STAGE OF CKD 5. PATHOGENESIS OF DRUGS NEPHROTOXICITY 6. COMMON MEDICATION ASSOSIATED WITH RENAL INJURY 7.  MANAGEMENT OF DRUGS TOXICITY 8. KEY POINTS 9. CONCLUSION

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1. INTRODUCTION

Ø The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function

Ø Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function

Ø  In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease

INTRODUCTION CNTD

Ø A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function.

Ø  The distinct steps involve calculating: I.  The patient's glomerular filtration rate, choosing and

administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations.

II.  If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity.

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INTRODUCTION CNTD

Ø Medication use accounts for 2% of hospital admissions for acute renal failure and up to 15% of admissions into intensive care

Ø Up to 16% of patients with baseline normal renal function who experience renal failure within the hospital setting have medication-induced renal failure.

 

Rate of adverse drug events in ambulatory patients with CKD

N=267 Rate (per 100 patients)* PATIENT  REPORTED  Hypoglycemia 57.6 Falling/ severe dizziness 23.1 Nausea, vomiting ± diarrhea 21.1 Hyperkalemia 18.1 Confusion 16.9

DETECTED AT STUDY VISIT Hypoglycemia 8.3 Hyperkalemia 8.3 Bradycardia 6.4 *Adjusted for sociodemographics, comorbid conditions, GFR, and number of medications

Adapted  from  Ginsberg  JS,  et  al.  J  Am  Soc  Nephrol  2014.  

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SAFE USE OF MEDICINES IN PATIENTS WITH RENAL DISEASE  Ø World Kidney Day Top Events

and Things to Do Ø Attend a World Kidney Day Event -

see here for a United States Event Map.

Ø Drink plenty of water - 6 to 8 cups daily.

Ø Stop smoking. Smoking reduces the flow of blood to the kidneys, which in turn causes them to operate inefficiently.

WORLD KIDNEY DAY CTND

Ø Smoking  also  increases  the  risk  of  developing  kidney  cancer  by  50%.  

Ø Limit  your  consumpFon  of  over-­‐the-­‐counter  pills  such  as  Ibuprofen  which  can  cause  damage  to  your  kidneys.  

Ø Get  your  kidney  funcFon  checked  if  you  are  in  a  'high  risk'  category  

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2. EFFECTS OF CKD ON DRUGS PHARMACOKINETICS

Ø ABSORPTION    Ø DISTRIBUTION    Ø METABOLISM    Ø ELIMINATION  

DIALYSABILITY  Ø The clearance of a drug by

haemodialysis gives a measure of the rate of removal of drug from the blood .

Ø  This information is given by the dialysability of the drug

Ø  Knowledge of the dialysability is crucial for adequate dosage recommendations of drugs given to patients on dialysis

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3. ESTIMATION OF RENAL FUNCTION3

Ø  CrCl is the single most common clinical test for the assessment of renal fx. Cr is a product of creatinine metabolism on muscle mass.

Normal Cr = 0.5 – 1.5 mg/dL Ø  Cockcroft and Gault Formula:

(140-age)(body weight in kg) (72)(serum creatinine)

Women x 0.85  

 

ESTIMATION OF RENAL FUNCTIONCtnd  

Calculating the CrCl •  79 YO, Female •  Serum creatinine =1.2 mg/dL

•  65 Kg Important to note there is a

normal loss of nephrons due to the aging process.

140-79)(65)x 0.85 (1.2)(72)

Est. CrCl = 39 mL/min `

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CKD PROGRESSION: BIOLOGY VERSUS “IATROGENESIS”?

time

NSAID for Gout

Gentamicin forUTI

Contrast forcoronary cath

CHF with diuresisleading to AKIand low BP

GFR

Baseline rate of decline in GFR

ESRD

Fink, et al, AJKD, 2009

CKD PROGRESSION: BIOLOGY VERSUS “IATROGENESIS”?

time

NSAID for Gout

Gentamicin forUTI

Contrast forcoronary cath

CHF with diuresisleading to AKIand low BP

GFR

Baseline rate of decline in GFR

ESRD

Fink, et al, AJKD, 2009

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ESTIMATION OF RENAL FUNCTIONCTND  MODIFICATION OF DIET IN RENAL DISEASE (MDRD) STUDY FORMULA

GFR (mL/min/1.73m2) = 186x(Scr) -1.154 x (age) -0.203 x (0.742, if female) x (1.212, if black)

•  Does not require weight as a variable

•  More accurate for patients whose GFR is less than 90 mL/min

Other Methods: CKD-EPI, Cystatin, etc…

NEEDS  IT  FACILITY!!!  

4. STAGES OF CHRONIC KIDNEY DISEASE ACCORDING TO NKF-KDOQI GUIDELINES

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5. DOSE REQUIREMENT IN PATIENT WITH CKD  

DRUGS   Usual dosage   GFR>50   GFR10TO50   <10  

Captopril   25mg tds   100%   75%   50%  Furosemide   no adjustment  Fluconazole   100 to200mg/d   100%   100%   50%  Ertapenem   1g/d   100%   100%   50%  Ceftriaxon   No adjustment  Ceftazidime   1to2g tds   8 to 12h   12 to 24h   24 to 48h  Clarithromycin   250 to 500mgbd   100%   50 to 100%   50%  Erythromycin   No adjustment  Ciprofloxacin   500mgbd   100%   75to50%   50%  Doxycyclin   No adjustment  Allopurinol   300mg/d   75%   50%   25%  

6. PATHOGENESIS OF DRUGS NEPHROTOXICITY

1. GLOMERULAR INJURY MECHANISMS

Ø  AlteraFons  to  the  renin-­‐angiotensin      system/prostaglandin  synthesis  

Ø   Podocyte  injury,  possibly  immune  (T-­‐cell)  mediated  

Ø   Podocyte    injury,  phenotypic  alteraFons  

Ø  InhibiFon  of  lysosomal  enzyme  Ø  ANCA    Ø  Endothelial  damage  

DISEASE/DRUGS

Ø  FuncFonal/hemodynamic  effect  NSAIDS/CNIs    

Ø MCD/  NSAIDS  

Ø  FSGS/Pamidronate  

Ø  Phospholiposis/  Chloroquine  Ø  CrescenFc/necroFzingGN/

Infliximab,  propylthiouracil  Ø  TMA/CNI/Bevacisumab    

 

 

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PATHOGENESIS OF DRUGS NEPHROTOXICITY    2.      VASCULAR INJURY

MECHANISMS Ø  Endothelial,  myocyte  damage      Ø  Cell  or  anFbody  mediated      Ø  Capillary/ischaemic  damage    

DISEASE/DRUGS Ø  TMA/CNI      Ø  Inflamatory  vasculites/Various  

anFbioFcs  

Ø  Analgesic  nephropathy/Analgesics  

 

PATHOGENESIS OF DRUGS NEPHROTOXICITY CTND

3 TUBULOINTERSTITIAL INJURY Mechanism  Ø  Immune mediated

Ø Direct cellular toxicity

Ø Cast formation obstructing tubules

Ø Crystal deposition/Calcification

Disease/Drug  Ø  Acute or chronic tubulointerstitial

nephritis/AB, NSADS Ø  ATN/Nephrogenic diabetes

insipidus Cisplatin/Lithium Ø  Tubulointerstitial nephritis/ATN

Various drugs/Sirolimus

Ø  Tubulointerstitial nephritis/ATN/ Diethylene glycol/Indinavir/Oral sodium

Ø  Nephrocalcinosis phosphate purgative

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COMMON MEDICATIONS ASSOCIATED WITH ELECTROLYTE/ACID–BASE ABNORMALITIES.  

Ø Hyponatremia    increased  ADH      secreFon  and  sensiFvity)  

Ø Hypokalemia/hypomagnesemia  (increased  urinary  excreFon)    

Ø     Hyperkalemia      anFaldosterone  

         or  anFadrenergic  effect;            blocking  sodium  channels)    Ø Renal  tubular  acidosis      

 

Ø     Thiazide  diureFcs,  vincrisFne,cyclophosphamide  Ø     Gentamicin,  cisplaFn,  

diureFcs,  carboplaFn  

Ø   ACE  inhibitors,  β-­‐blockers,  heparin,      NSAIDs,  K+-­‐sparing  diureFcs,  trimethoprim,  

ciclosporin,  pentamidine    Ø     Amphotericine,  Lithium        

7. NSAIDs

Ø Injure kidneys directly –  Induce acute kidney injury (AKI) from “pre-renal”

or ATN

–  Interstitial nephritis

– Nephrotic syndrome

Ø Decrease kidney potassium excretion → hyperkalemia

Ø Decrease sodium excretion → HTN, edema

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NSAIDs

Ø Avoid  in  paFents  with:  – CKD – Conditions that could lead to

“pre-renal physiology” or dehydration ü CHF ü Cirrhosis ü Renal artery stenosis ü RAAS-blockade

GADOLINIUM

Ø  Linked to nephrogenic systemic fibrosis (NSF) –  Rare, but painful debilitating

fibrosing disease –  Primarily in extremities but

may involve lung and heart i.  Increased risk w/ decreased

kidney function (AKI, CKD, post-transplant)

ii.  Avoid gadolinium in patients w/ eGFR <30 ml/min

ü  Contraindication in PD ü  HD patients require immediate

HD post-exposure x 3 d ü  No effective treatment available

Swaminathan  S  and  Shah  S.  J  Am  Soc  Nephrol.2007.  

Grobner  T  and  Prischl  FC.  Kidney  Int  2007  

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8. MANAGEMENT OF DRUG NEPHROTOXICITY  

Ø Physical assessment should include  :  ü An estimate of the extracellular fluid volume. i.  Edema or ascites increases the distribution

volume of many drugs, while dehydration contracts this volume.

ii.  Evidence of impaired function of other excretory organs should be sought.

iii.  Stigmata of liver disease are clue that the drug dose may need to be altered.

 MANAGEMENT OF DRUG NEPHROTOXICITY Ø  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:

CrCl (ml/min)= (140-age)x (BW in kg)(x0.85if female)

72x Scr(mg/dl)

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9 Prescribing for a Patient with Renal Dysfunction Ø Ascertain level of renal function (estimated GFR/

CCr ) Ø Establish integrity of liver metabolism Ø Establish loading dose Ø Maintenance dose - dose reduction vs. interval

extension Ø Check for drug interactions Ø Decide whether blood level monitoring is indicated      Kidney  Disease:  Improving  Global  Outcomes  www.kdigo.org    

OTHER STRATEGIES PRESCRING MEDICINES IN RENAL DISESASE

Ø Computerized dosing programmes

Ø  Clinical pharmacist

dosing services

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Case Presentation 74 yo W woman with right hip pain. 2 wks earlier Scr was 1.3 mg/dl, eGFR of 43ml/min/1.73m2 Meds: Tramadol 50 mg qd, HCTZ 25 mg qd, irbesartan 300 mg qd. Added Gabapentin 300 mg qd. Pain continued and she took OTC ibuprofen 200 mg qid. Poor po intake. Fell and was admitted. BP 110/60 mmHg, HR 100. Scr ↑1.6 mg/dl Given IVF and discontinued HCTZ . Which other medication(s) would you stop for the AKI?

A. Irbesratan B. Ibuprofen C. Both irbesartan and ibuprofen D. Tramadol

10        KEY POINTS

Ø  Renal injury caused by medication can usually be reversed if detected early

Ø  Drug-induced renal damage can be acute or chronic,

prerenal, intrarenal (vascular,tubular, glomerular or interstitial) or postrenal

Ø  Different drug classes share common mechanisms of

inducing renal injury (e.g. toxic, ischemic, inflammatory, obstructive or volume depletion

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KEY POINTS CNTD

Ø  Electrolyte/acid–base abnormalities are common effects of some medications

Ø  Medications that can cause kidney damage include diuretics, antihypertensives, immunosuppressants, antiplatelet agents, antivirals, chemotherapeutics, antibiotics and radiocontrast agents

KEY POINTS CTND

Ø CKD patients at high risk for drug-related adverse events

Ø Several classes of drugs renally eliminated

Ø Consider kidney function and current eGFR (not just SCr) when prescribing meds

Ø Minimize pill burden as much as possible Ø Remind CKD patients to avoid NSAIDs

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11. CONCLUSION Ø Most important drug-related problems in patients with

chronic kidney disease (CKD) is medication dosing errors.

Ø Adequate renal function is important to avoid toxicity. Ø  The clearance of drugs eliminated primarily by renal

filtration is decreased by renal disease. Ø  Special consideration should be taken when these

drugs are prescribed to patients with impaired renal function.

Ø  Physicians and pharmacists can work together to accomplish safe drug prescribing

QUOTES

"Medicine is a collection of uncertain prescriptions the results of which, taken collectively, are more fatal than useful to mankind“.

 Napoleon Bonaparte(1769-1821)  

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THANKS FOR YOUR ATTENTION QUESTIONS /COMMENTS