FIRST DO NO HARM: PREVENTION, DETECTION & MANAGEMENT … · Drug-Induced Diseases in Hospitalized...

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

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

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.

PATIENT CASE

5

•  Discharged from the hospital 8 days prior to this presentation after receiving treatment of osteomyelitis of the left hip

HPI


PMHx •  Hypertension •  Chronic stable angina •  Systemic lupus erythematosus •  Penicillin allergy

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


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


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


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:


PATIENT CASE

10

•  Received MgSO4 2g IV •  Arrhythmia terminated, patient regained

consciousness



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



PATIENT CASE

12

•  3:50 pm: o ECG again showed TdP o Patient found pulseless o Patient underwent defibrillation, sinus rhythm

restored



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



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:


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

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.

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

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.

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.

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.

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.

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

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.

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.

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

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%

Drugs Implicated in Drug-Induced Diseases in Hospitalized Patients

28

Drug Class %

AnC-‐infecCves 17%


AnCneoplasCc 15%

Analgesics/anC-‐inflammatory 15%

Psychotropic 5.5%

All others 32%

Ann Pharmacother 2000;34:1373-1379.

Drugs Implicated in Drug-Induced Diseases in Hospitalized Cardiac Patients

29 Am J Cardiol 2007;100:1465-1469.

Drug Class %

AnCcoagulants 28.5%


Analgesics and sedaCves 11.3%

AnCbioCcs 10.6%

Electrolytes 4.7%

AnCplatelet 3.6%

All others 13.1%

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%

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%

PHOTOTOXICITY INDUCED BY DEMETHYCHLORTETRACYCLINE

32 Koehler JM. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases. Prevention, Detection and Management, 2nd ed, 2010.

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


34




35

•  Demographic factors o Age o Ethnicity o Sex


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.


37

Demographic Factors


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


38

Demographic Factors


Risk Factor Drug-‐Induced Disease for Which Risk is Increased

White race SLE-‐like syndrome

Black race ACE-‐inhibitor-‐induced cough


39




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


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


42




43

•  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


44

•  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)


45




46

•  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


47




48

•  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.


49



Drug-Induced Disease

50

•  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

FIRST DO NO HARM: PREVENTION, DETECTION & MANAGEMENT … · Drug-Induced Diseases in Hospitalized...

Documents

Transcript of FIRST DO NO HARM: PREVENTION, DETECTION & MANAGEMENT … · Drug-Induced Diseases in Hospitalized...