1、,Centers for Education & Research on Therapeutics,Preventable Adverse Drug Reactions: A Focus on Drug Interactions,C L I N I C A L P H A R M A C O L O G Y E D U C A T I O N A L M O D U L E 1 (2009 revision),Preventable Adverse Drug Reactions,Centers for Education & Research on Therapeutics,Arizona C
2、enter for Education and Research on Therapeutics - Critical Path Institute and The U.S. Food and Drug Administration Center for Drug Evaluation and Research,Developed By,This project was supported by grant numbers U18HS10385 and U18HS017001 from the Agency for Healthcare Research and Quality (AHRQ).
3、 The content is solely the responsibility of the authors and does not represent the official views of the AHRQ or the U.S. Food and Drug Administration.,Learning Objectives,Recognize the human and health care costs associated with Adverse Drug Reactions (ADRs) Recognize the importance of reporting A
4、DRs Outline the contribution of drug interactions to the overall burden of preventable ADRs Identify known mechanisms for specific, clinically relevant drug interactions Identify methods and systems approaches to predict and prevent drug interactions,Learning Module,Example Cases ADRs: Prevalence an
5、d Incidence Types of Drug Interactions Drug Metabolism ADR Reporting Preventing Drug Interactions,Definitions and Terms,Side Effects: unintended, usually detrimental, consequences Adverse: untoward, unintended, possibly causing harm AE: Adverse Event, Effect or Experience ADE (AE associated with a D
6、rug): an AE which happens in a patient taking a drug ADR (Adverse Drug Reaction): an ADE in which a causal association is suspected between the drug and the event Unfortunately, these terms are frequently used interchangeably,Monahan BP et al. JAMA 1990;264(21):27882790.,Case 1: Torsades de Pointes,
7、Monahan BP et al. JAMA 1990;264(21):27882790.,Ventricular Arrhythmia (Torsades de Pointes) with Terfenadine Use,39-year-old female Rx with terfenadine 60 mg bid and cefaclor 250 mg tid 10 d Self-medicated with ketoconazole 200 mg bid for vaginal candidiasis 2-day Hx of intermittent syncope Palpitati
8、ons, syncope, torsades de pointes (QTc 655 msec),Monahan BP et al. JAMA 1990;264(21):27882790.,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,Day of Administration,Terfenadine,Cefaclor,Ketoconazole,Medroxyprogesterone,Symptomatic,H,Ketoconazole,Adapted from: Sinoway L, Li J. J Appl Physiol 2005;99:522.,Case
9、2: Rhabdomyolysis,Kahri J et al. Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol 2005;60:905907.,Rhabdomyolysis: Atorvastatin & Fluconazole,76-year-old male with Hx of chronic atrial fibrillation and aortic stenosis Initial prescription medications:,Bisoprolo
10、l Digoxin Warfarin Doxicycline Fucidic acid,Prednisolone Esomeprazole Pravastatin Fluconazole,Kahri J et al. Eur J Clin Pharmacol 2005;60:905907,Rhabdomyolysis in Association with Atorvastatin and Fluconazole Use,Pravastatin dosage increased from 40mg to 80mg/day Pravastatin changed to Atorvastatin
11、40mg After 7 days Extreme fatigue After 3 weeks Hospitalized for dyspneaCreatinine 1.36CK 910 I.U.Dx: Renal Failure and DEATH,Weeks,Fluconazole,Pravastatin 80mg,Pravastatin 40 mg,Atorvastatin,Fatigue,Dyspnea & CK 910,Death,Fatal Rhabdomyolysis,Why Learn about Adverse Drug Reactions (ADR)?,Over 2 MIL
12、LION serious ADRs yearly 100,000 DEATHS yearly Up to 10% of hospital admissions ADRs are the 4th leading cause of death Ambulatory patients ADR rate unknown Nursing home patients ADR rate 350,000 yearly,Costs Associated with ADRs,$136 BILLION yearly Greater than total costs of cardiovascular or diab
13、etic care ADRs cause injuries or death in 1 of 5 hospital patients Length of stay, cost, and mortality for hospital patients with an ADR are 2X,Why Are There So Many ADRs?,Two-thirds of patient visits result in Rx 3 BILLION outpatient Rx per year Specialists give 2.3 Rx per visit Medicare Patients (
14、2003, before drug benefit)89.2% take a prescription medicine daily46.1% take 5 prescriptions chronically53.6% take meds Rxed by 2 or more doctors5% obtain an Rx from Canada/Mexico ADRs increase exponentially with 4 Rx,Friedman MA et al. JAMA 1999;281(18):17281734.,Premarket Drug Safety Profile,Most
15、new drugs have only 3000 short-term patient exposures Some drugs have rare toxicity (e.g., bromfenac hepatotoxicity, 1 in 20,000 patients) To detect such rare toxicity, more than 60,000 patients must be exposed after the drug is marketed,Misconceptions about ADRs and Reporting,All serious ADRs are d
16、ocumented by the time a drug is marketed It is difficult to determine if a drug or another clinical cause is responsible ADRs should be reported only if absolutely certain One reported case cant make a difference,Drugs Removed from or Restricted in the U.S. Market Because of Drug Interactions,Terfen
17、adine (Seldane) February 1998 Mibefradil (Posicor) June 1998 Astemizole (Hismanal) July 1999 Grepafloxacin (Raxar) October 1999 Cisapride (Propulsid) January 2000 Cerivastatin (Baycol) August 2001 Levomethadyl (Orlaam) August 2003,*,* Restricted,Primary Worries in Primary Care: 1,008 Patients,Source
18、: American Society of Health Systems Pharmacists. ASHP Patient Concerns National Survey Research Report, 1999.,Leape LL et al. JAMA 1995;274(1):3543. Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959963.,Contribution of Drug Interactions to the Overall Burden of Preventable ADRs,Drug interacti
19、ons represent 35% of preventable in-hospital ADRs Drug interactions are an important contributor to the number of ER visits and hospital admissions,MessageOne cant rely completely on technologyKnowledge of clinical pharmacology of drug interactions is valuable,Importance of Systems Interventions Lim
20、itations,Prescribing to Avoid Adverse Drug Reactions,Interactions can occur before or after administration of drugs Pharmacokinetic interactions GI tract Plasma Liver Kidney Pharmacodynamic interactionsCan occur at target organCan be systemic (e.g., blood pressure),Interactions before Administration
21、,Phenytoin precipitates in IV dextrose solutions (e.g., D5W) Amphotericin precipitates in IV saline Gentamicin is physically/chemically incompatible when mixed with most beta-lactam antibiotics, resulting in loss of both antibiotics effects,They Can Occur in the GI Tract,Sucralfate, some milk produc
22、ts, antacids, and oral iron preparations Omeprazole, lansoprazole, H2-antagonists Didanosine (given as a buffered tablet) Cholestyramine,Block absorption of quinolones, tetracycline, and azithromycin Reduce absorption of ketoconazole, delavirdine Reduces ketoconazole absorption Binds raloxifene, thy
23、roid hormone, and digoxin,Interactions in the Plasma,To date, most protein “bumping” interactions described are transient and lack clinical relevance The transient increase in free drug is cleared more effectively,Spectrum of Consequences of Drug Metabolism,Inactive products Active metabolitesSimila
24、r to parent drugMore active than parentNew action unlike parent Toxic metabolites,Microsomal Enzymes,Cytochrome P450Flavin mono-oxygenase (FMO3),Phases of Drug Metabolism,Phase I Oxidation Reduction Hydrolysis Phase II Conjugation,Interactions Due to Drug Metabolism,Nearly always due to interaction
25、with Phase I enzymes, rather than Phase IICommonly due to cytochrome P450 enzymes which have highly variable activity and, in some cases, are genetically absent or over-expressed,Phase I - Drug Oxidation,Cytochrome P450 Nomenclature, e.g., for CYP2D6,CYP = cytochrome P4502 = genetic familyD = geneti
26、c sub-family 6 = specific geneNOTE: This nomenclature is genetically based; it does not imply chemical specificity,Major Human CYP450 Isoforms,CYP2D6CYP2E1CYP3A4CYP3A5CYP3A6,CYP1A2CYP2B6CYP2C8CYP2C9CYP2C19,Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.,CYP3A,CYP2D6,CYP2C,CYP1A2,CYP2E1,Relati
27、ve Importance of P450s in Drug Metabolism,CYP3A,CYP2C,CYP1A2,CYP2E1,?,CYP2D6,Relative Quantities of P450s in Liver,CYP450 Activity in the Liver,Number of Subjects,Increasing Metabolic Capacity,EM,PM,URM,Polymorphic Distribution,Multiple groups of traits in which each constitutes 1% of the population
28、,91%,9%,Cytochrome P450 3A,Responsible for metabolism of: Most calcium channel blockers Most benzodiazepines Most HIV protease inhibitors Most HMG-CoA-reductase inhibitors Most non-sedating antihistamines CyclosporinePresent in GI tract and liver,CYP3A Inhibitors,Ketoconazole Itraconazole Fluconazol
29、e Cimetidine Clarithromycin Erythromycin Troleandomycin Grapefruit juice,NOT Azithromycin,CYP3A Inducers,Carbamazepine Rifampin Rifabutin Ritonavir St. Johns Wort,Aklillu E et al. J Pharmacol Exp Ther 1996;278(1):441 446.,Cytochrome P450 2D6,Absent in 7-9% of Caucasians, 12% of non-CaucasiansOver-ex
30、pressed in up to 30% of East AfricansCatalyzes primary metabolism of:Codeine Many -blockersMany tricyclic antidepressantsInhibited by:Fluoxetine HaloperidolParoxetine Quinidine,Cytochrome P450 2C9,Absent in 1% of Caucasians and African-AmericansPrimary metabolism of: Most NSAIDs (including COX-2) S-
31、warfarin (the active isomer) PhenytoinInhibited by fluconazole,Cytochrome P450 2C19,Absent in 2030% of Asians, 35% of Caucasians Primary metabolism of:Diazepam PhenytoinOmeprazole Clopidogrel Inhibited by:Omeprazole IsoniazidKetoconazole,Cytochrome P450 1A2,Induced by smoking tobacco Catalyzes prima
32、ry metabolism of:Theophylline ImipraminePropranolol Clozapine Inhibited by:Many fluoroquinolone antibioticsFluvoxamine Cimetidine,www.drug-,Drug Transporters,P-Glycoprotein and others Pump drugs out of cells, which alters distribution Found in the following tissues: Gut Gonads Kidneys Biliary system
33、 Brain (blood-brain barrier) Placenta,Marchietti S, et al. Clinical relevance of drug-drug and herb-drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). The Oncologist 2007;12:927-41.,P - Glycoprotein Tissue Distribution,Bauer B, Hartz AM, Fricker G, Miller D. Modulation o
34、f p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine Feb. 2005;230:118-27.,P-Glycoprotein (PGP) Substrates,Digoxin and PGP,Digoxin is a PGP substrate Increased digoxin plasma conc. when combined with:Quinidine VerapamilTalinolol ClarithromycinErythromycin
35、 ItraconazoleRitonavir,Both PGP and CYP3A4,Inhibitors Verapamil Clarithromycin Erythromycin Itraconazole Ritonavir Cyclosporine,Inducers Rifampicin St. Johns Wort Phenobarbital Reserpine,Liver disease Renal disease Cardiac disease ( hepatic blood flow) Acute myocardial infarction? Acute viral infect
36、ion? Hypothyroidism or hyperthyroidism?,Drug-Disease Interactions,Drug-Food Interactions,Tetracycline and milk productsWarfarin and vitamin K-containing foodsGrapefruit juice,Dresser GK, et al. Clin Pharmacol Ther 2000;68(1):2834.,Hours after Dose,Hours after Dose,Effects of grapefruit juice on felo
37、dipine pharmacokinetics and pharmacodynamics.,Grapefruit Juice and Felodipine,Drug-Herbal Interactions,St. Johns Wort with: Indinavir Cyclosporine Digoxin Tacrolimus Possibly many others,After St. Johns Wort,Mean plasma concentration time course of indinavir.,FDA program initiated in 1993 Four main
38、goals of the program: Increase awareness and the importance of reporting adverse events Clarify what should be reported Facilitate reporting Provide feedback to health professionals www.fda.gov/medwatch or 1-800-FDA-1088,*These programs are not endorsed by the FDA,Drug-Drug Interaction Prevention: A
39、 Stepwise Approach,1. Take a medication history(AVOID Mistakes mnemonic) 2. Remember high-risk patients Any patient taking 2 medications Patients Rxed anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc. 3. Check pocket reference or PDA 4. Consult pharmacists or drug info specialists 5.
40、 Check up-to-date computer program Medical Letter Drug Interaction Program* * and others,A Good Medication History: AVOID Mistakes,Allergies? Vitamins and herbs? Old drugs and OTC? (as well as current) Interactions? Dependence? Do you need a contract? Mendel: Family Hx of benefits or problems with a
41、ny drugs?,These web sites are not endorsed by the FDA,This completes the ADR learning module. Please check the following web sites for more learning tools.,www.arizonacert.org (drug interactions)www.drug- (P450-mediated drug interactions)www.QTdrugs.org (drug-induced arrhythmia)www.C-Path.org (drug
42、development),Clinical Pharmacology: The Science of Pharmacology and Therapeutics,For more information on training programs in clinical pharmacology, visit these websites:http:/www.ascpt.org/education/training.cfm http:/www.accp1.org http:/ to the first edition,David A. Flockhart, MD, PhDDirector, Cl
43、inical Pharmacology, Indiana University School of Medicine Sally Yasuda, MS, PharmDSafety Team Leader, Neurology Products, U.S. Food and Drug Administration Peter Honig, MD, MPH Executive Vice-President, Merck Research Laboratories Curtis Rosebraugh, MD, MPH Director, Office of New Drugs II, U.S. Fo
44、od and Drug Administration Raymond L. Woosley, MD, PhD President and CEO, Critical Path Institute,Klaus Romero, MS, MD Clinical Pharmacologist and Assistant Program Director, Critical Path Institute Dennis L. Vargo, MD Senior Clinical Scientist, Critical Path Institute Raymond L. Woosley, MD, PhD Pr
45、esident and CEO, Critical Path Institute,Contributors to the second edition,Centers for Education & Research on Therapeutics,Developed by,Arizona Center for Education and Research on Therapeutics - Critical Path Institute and The U.S. Food and Drug Administration Center for Drug Evaluation and Research,This project was supported by grant numbers U18HS10385 and U18HS017001 from the Agency for Healthcare Research and Quality (AHRQ). The content is solely the responsibility of the authors and does not represent the official views of the AHRQ or the U.S. Food and Drug Administration.,
