first do no harm: prevention, detection & management … · drug-induced diseases in...
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FIRST DO NO HARM: PREVENTION, DETECTION & MANAGEMENT OF DRUG-INDUCED DISEASES
James E. Tisdale, PharmD, FCCP, FAPhA, FAHA Professor College of Pharmacy Purdue University & Adjunct Professor School of Medicine Indiana University Indianapolis, IN
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LEARNING OBJECTIVES
2
• Describe the epidemiology of drug-induced diseases and associated morbidity and mortality
• Compare and contrast factors that may increase the risk of drug-induced diseases
• Discuss medications/drug classes most commonly associated with drug-induced diseases
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PATIENT CASE
4
• A 65 year old female presents to the ED with weakness, diminished urine production, and diarrhea
• Admitted to the hospital with: o Acute kidney injury o Urinary tract infection
Chief Complaint
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
5
• Discharged from the hospital 8 days prior to this presentation after receiving treatment of osteomyelitis of the left hip
HPI
Clin Pharmacol Ther 2004;75:242-‐7.
PMHx • Hypertension • Chronic stable angina • Systemic lupus erythematosus • Penicillin allergy
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PATIENT CASE
6
• Ciprofloxacin 500 mg orally twice daily • Vancomycin 1g IV every 8 hours • Ranitidine 150 mg orally twice daily • Lisinopril 40 mg orally once daily • Metoprolol XL 100 mg orally twice daily • HCTZ 25 mg orally once daily • Fexofenadine 60 mg orally twice daily
Medications Prior to Admission
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
7
• Na 143 mmol/L • K 2.9 mmol/L • Mag 0.8 mmol/L • SCr 698 µmol/L • BUN 12.1 mmol/L
Select lab values on admission
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
8
• Ciprofloxacin and vancomycin d/c • Other home meds initiated • KCL • Hydroxyzine 200 mg orally twice daily • Metoprolol 100 mg orally twice daily • Ranitidine 150 mg orally twice daily • Hydroxychloroquine 200 mg orally twice daily • Levofloxacin 250 mg orally once daily
Medications Initiated in the Hospital
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
9
• ECG in the morning found QTc interval = 605 ms
• 12:50 pm – found unresponsive • Placed on ECG monitor, which revealed
torsades de pointes (TdP)
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
10
• Received MgSO4 2g IV • Arrhythmia terminated, patient regained
consciousness
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
11
• 2:30 pm: o ECG revealed TdP again o Patient found pulseless o TdP stopped spontaneously, patients was
intubated and transferred to ICU
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
12
• 3:50 pm: o ECG again showed TdP o Patient found pulseless o Patient underwent defibrillation, sinus rhythm
restored
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
13
• 3:55 pm: o Patient went into ventricular fibrillation o Patient underwent defibrillation x 3, received IV
MgSO4 2g o Sinus rhythm restored
On Day #3 of Hospitalization:
Clin Pharmacol Ther 2004;75:242-‐7.
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PATIENT CASE
14
• Levofloxacin discontinued • K+ and Mg++ replaced aggressively • 24 hours later: QTc = 399 ms • No additional episodes of TdP • Discharged to home on day 9
Outcome:
Clin Pharmacol Ther 2004;75:242-‐7.
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Partial list of Drugs Removed From the US Market
16
Drug Brand Name Class/Indica4on Drug-‐Induced Disease Years on Market
Propoxyphene Darvon Analgesic Cardiovascular 55
DethylsClbestrol DES PrevenCon of miscarriage
Teratogenicity, cancer 31
Pemoline Cylert ADHD/ADD Hepatotoxicity 30
IsotreCnoin Accutane Acne Teratogenicity 27
Fenfluramine Pondimin AppeCte suppressant Valve disease 24
Pergolide Permax Parkinson’s Disease Valve disease 19
AproCnin Trasylol AnCfibrinolyCc Kidney disease, stroke 15
Sibutramine Meridia AppeCte suppressant CV disease, stroke 13
Terfenadine Seldane AnChistamine Torsades de pointes 13
Astemizole Hismanal AnChistamine Torsades de pointes 11
Levasimole Ergamisol AnthelminCc, cancers, RA
Neutropenia 11
Gemtumuzmab Mylotarg AML Thrombosis 10
CerivastaCn Baycol Hyperlipidemia Rhabdomyolysis 3
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Drug-Induced Disease
17
• An unintended effect of a drug that may result in: o Mortality o Morbidity o Symptoms sufficient to prompt a patient to seek
medical attention
Definition
Tisdale JE, Miller DA. Drug-Induced Diseases. Prevention, Detection and Management, 2nd ed. Bethesda; American Society of Health-Systems Pharmacists 2010.
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Medication Use in Canada
18 Statistics Canada June 2014
Age group (yrs) % Taking Rx Meds % Taking 1-‐2 Rx Meds % Taking ≥ 5 Rx Meds
6-‐14 11.7 10.9 -‐-‐
15-‐24 26.2 24.6 -‐-‐
25-‐44 28.0 23.3 1.5
45-‐64 55.1 30.8 11.4
65-‐79 82.7 27.9 29.9
OVERALL 40.5 25.0 7.4
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Impact of Drug-Induced Diseases on Hospital Admissions
19
• 0.2-21.7% of all hospital admissions associated with adverse drug reactions*
• Median: 4.9%* • Canadian study:
o 19% of hospital admissions in patients > 50 years old due to a drug-related adverse patient event¶
*Ann Pharmacother 1993;27:832-840.
¶J Am Geriatr Soc 1988;36:1092-8.
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Impact of Drug-Induced Diseases on Hospital Admissions
20
• ProspecCve mulCcenter study in the Netherlands • Case-‐control design • N=13,000 unplanned admissions in 21 hospitals over 40 days
• 5.6% were medicaCon-‐related
Arch Intern Med 2008;168:1890-1896.
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Impact of Drug-Induced Diseases on ED Visits
21
• ProspecCve, observaConal study • n= 1,017 paCents presenCng to an ER • 4.7% of ER visits were due to adverse drug reacCons
Can Med Assoc J 2008;178:1563-1569.
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Impact of Drug-Induced Diseases on MICU Admissions
22
• Prospective, observational study • n = 281 patients admitted to MICU over 19 weeks • 7.5% were admitted due to adverse drug
reactions • 57% of ADRs were cause by drug interactions –
100% were preventable
Am J Health-Syst Pharm 2007;64:1840-1843.
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Impact of Drug-Induced Diseases on MICU Admissions
23
• 1.9 million ER visits/hospitalizations in 2008 ( 52% from 2004)
• Top 5 drugs associated with ER visits/ hospitalizations: o Unspecified (261,000) o “Pain killers” (118,100) o Antibiotics (95,100) o Tranquilizers and antidepressants (79,300) o Corticosteroids and other hormones (71,400)
Agency for Healthcare Research & Quality 2011
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Drug-Induced Diseases in Hospitalized Patients
24
• Meta-analysis of 39 prospective studies from US hospitals
• Overall incidence of serious drug-induced diseases: 6.7%
• Incidence of fatal drug-induced diseases: 0.32% • Would make this the 4th-6th leading cause of death
in hospitalized patients
JAMA 1998;279:1200-1205.
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Drug-Induced Diseases in Hospitalized Patients
25
• Meta-analysis of 8 prospective studies from hospitals in US, Australia, UK, Canada, New Zealand
• Included a total of 74,485 patients • Overall incidence of in-hospital drug-induced
diseases: 9.2% • Incidence of fatal drug-induced diseases: 0.68% • 43.5% of drug-induced diseases were preventable
Qual Saf Health Care 2008;17:216-223.
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Impact of Drug-Induced Diseases in Hospitalized Patients
26 JAMA 1997;277:301-306.
• Matched, case-control study • n=1580 cases • n=20,197 controls
Extra length of hospital stay abributed to ADEs
1.91 days
p<0.001
Excess cost of hospitalizaCon abributed to an ADE
$2,262 p< 0.001
Increased risk of death among paCents experiencing an ADE
1.88 (95% CI 1.54-‐2.22) p<0.001
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Drugs Implicated in Drug-Induced Diseases Leading to ER Visits
27 Ann Pharmacother 2010;44:641-649.
Drug classes implicated (of n=409 drug-induced diseases) Drug Class %
Cardiovascular 37.4%
Hormone agents (oral hypoglycemics, corCcosteroids, thyroid drugs, insulin, etc)
11.2%
Hematologic 9.8%
GastrointesCnal 9.5%
CNS 7.6%
Vitamins and minerals 4.6%
Musculoskeletal 3.9%
Respiratory 3.9%
AnCmicrobial 3.7%
Cancer chemotherapy 2.7%
Herbal 1.2%
Other 4.4%
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Drugs Implicated in Drug-Induced Diseases in Hospitalized Patients
28
Drug Class %
AnC-‐infecCves 17%
Cardiovascular 16.5%
AnCneoplasCc 15%
Analgesics/anC-‐inflammatory 15%
Psychotropic 5.5%
All others 32%
Ann Pharmacother 2000;34:1373-1379.
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Drugs Implicated in Drug-Induced Diseases in Hospitalized Cardiac Patients
29 Am J Cardiol 2007;100:1465-1469.
Drug Class %
AnCcoagulants 28.5%
Cardiovascular 28.1%
Analgesics and sedaCves 11.3%
AnCbioCcs 10.6%
Electrolytes 4.7%
AnCplatelet 3.6%
All others 13.1%
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Types of Drug-Induced Diseases in Hospitalized Patients
30 Ann Pharmacother 2000;34:1373-1379.
Type of Drug-‐Induced Disease %
GastrointesCnal 24%
Skin 19%
Immunologic 15%
CNS 13%
Hematology 10%
Other 19%
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Types of Drug-Induced Diseases in Hospitalized Cardiac Patients
31 Am J Cardiol 2007;100:1465-1469.
Type %
Elevated laboratory monitoring tests 17.2%
Rash/hives/angioedema 12.0%
Thrombocytopenia 11.3%
OversedaCon/mental status changes 10.2%
Hemorrhage 8.8%
Renal or hepaCc dysfuncCon 6.9%
Electrolyte imbalance 5.8%
Others 27.9%
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PHOTOTOXICITY INDUCED BY DEMETHYCHLORTETRACYCLINE
32 Koehler JM. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases. Prevention, Detection and Management, 2nd ed, 2010.
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Factors Contributing to Drug-Induced Diseases
33
• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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Factors Contributing to Drug-Induced Diseases
34
• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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Factors Contributing to Drug-Induced Diseases
35
• Demographic factors o Age o Ethnicity o Sex
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Factors Contributing to Drug-Induced Diseases
36
Demographic Factors Risk Factor Drug-‐Induced Disease for Which Risk is Increased
Older age SLE-‐like syndrome Ischemic stroke Hemorrhagic stroke Torsades de pointes Movement disorders Delirium Sleep disorders CogniCve disorders Psychosis Bleomycin-‐induced pulmonary fibrosis Glitazone-‐induced heart failure Anthracylcine-‐induced heart failure Hypertension Valve disease Acute kidney injury
From: Tisdale JE and Miller DA. Drug-‐Induced Diseases. PrevenCon, DetecCon and Management, 2nd ed. ASHP 2010.
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Factors Contributing to Drug-Induced Diseases
37
Demographic Factors
From: Tisdale JE and Miller DA. Drug-‐Induced Diseases. PrevenCon, DetecCon and Management, 2nd ed. ASHP 2010.
Risk Factor Drug-‐Induced Disease for Which Risk is Increased
Female sex Allergic cutaneous reacCons Contrast media-‐induced pseudoallergy Torsades de pointes SLE-‐like syndrome Movement disorders Sleep disorders Aspirin-‐induced asthma Valve disease SIADH
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Factors Contributing to Drug-Induced Diseases
38
Demographic Factors
From: Tisdale JE and Miller DA. Drug-‐Induced Diseases. PrevenCon, DetecCon and Management, 2nd ed. ASHP 2010.
Risk Factor Drug-‐Induced Disease for Which Risk is Increased
White race SLE-‐like syndrome
Black race ACE-‐inhibitor-‐induced cough
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Factors Contributing to Drug-Induced Diseases
39
• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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Factors Contributing to Drug-Induced Diseases
40
Comorbid Conditions - Disease Effects on Drug PK/PD
From: MacKichan JJ, Lee MWL. In: Tisdale JE and Miller DA. Drug- Induced Diseases. Prevention, Detection and Management, 2nd ed. ASHP 2010.
Disease Drug Mechanism
Kidney Numerous Reduced renal eliminaCon leading to elevated plasma concentraCons
Liver Midazolam Clearance reduced in moderate-‐to-‐severe cirrhosis
Cardiovascular Lidocaine Digoxin
Clearance reduced in heart failure Enhanced toxicity in cor pulmonale
Hypothyroidism Digoxin Warfarin
Decreased renal excreCon and enhanced sensiCvity to effects Dimished response due to reduced catabolism of vitamin K-‐dependent clolng factors
Electrolyte imbalance
Digoxin Increased suscepCbility to toxicity in paCents with hypokalemia or hypomagnesemia
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Factors Contributing to Drug-Induced Diseases
41
Comorbid Conditions
Tisdale JE and Miller DA. Drug- Induced Diseases. Prevention, Detection and Management, 2nd ed. ASHP 2010.
Disease Drug-‐Induced Disease for Which Risk is Increased HIV Allergic cutaneous reacCons
Peripheral neuropathy Diabetes Hypertension
Peripheral neuropathy
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Factors Contributing to Drug-Induced Diseases
42
• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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Factors Contributing to Drug-Induced Diseases
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• Drug Interactions o InhibiCon of cytochrome P-‐450 enzymes
o See hbp://medicine.iupui.edu/clinpharm/ddis/table.asp
o InhibiCon of drug transporters, including P-‐glycoprotein and OATP
o Decreased organ blood flow (ie NSAIDs decrease renal blood flow, decreasing lithium clearance)
o Increased kidney reabsorpCon (thiazides and lithium) o AddiCve pharmacologic effects
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• Drug-Food Interactions o MAO inhibitors and tyramine-‐containing foods o Grapefruit juice inhibits cytochrome P-‐450 3A4 (lovastaCn, simvastaCn, erythromycin, clarithromycin, fluconazole, many others)
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• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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• Lifestyle Factors o Alcohol
o Exaggerates the CNS effects of benzodiazepines, TCAs, opiates, anCdepressants
o Caffeine o AddiCve sCmulant effects when taken with other sCmulant drugs
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• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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• Genetic Variability o Slow acetylators of N-‐acetyltransferase more likely to develop syndrome resembling SLE associated with hydralazine
o Inherited thiopurine methyltransferase (TMPT) deficiency leads to potenCally fatal hematological toxicity associated with 6-‐mercaptopurine
o HLA allele B*1502 idenCfies paCents at risk of carbamazepine-‐induced Stevens-‐Johnson syndrome (prevalent in Asian paCents)
Pharmacogenomics 2008;9:1543-‐1546.
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• Pharmacokinetic/pharmacodynamic factors o Demographic factors o Comorbid conditions o Drug interactions o Lifestyle factors o Genetic variability
• Adherence to therapy • Medication errors
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Drug-Induced Disease
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• Common cause of ER visits and hospitalizaCons • Occur commonly in hospitalized paCents • Associated with morbidity and mortality • Many factors contribute, parCcularly age, drug-‐interacCons, and increasingly, geneCc polymorphisms
• Many drug-induced diseases are preventable
Summary
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