safe use of medicines in patients with renal diseases · nephrotoxicity’!physical assessment...
TRANSCRIPT
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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