1	Preventable Adverse Drug Reactions
2	Developed By
3	Learning Objectives Recognize the human and health care costs associated with Adverse Drug Reactions (ADRs) Recognize the importance of reporting ADRs 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
4	Learning Module Example Cases ADRs: Prevalence and Incidence Types of Drug Interactions Drug Metabolism ADR Reporting Preventing Drug Interactions
5	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 Drug): 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
6	Case 1: Torsades de Pointes
7	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 Palpitations, syncope, torsades de pointes (QTc 655 msec)
8	Ketoconazole
9	Case 2: Rhabdomyolysis
10	Rhabdomyolysis: Atorvastatin & Fluconazole Bisoprolol Digoxin Warfarin Doxicycline Fucidic acid 76-year-old male with Hx of chronic atrial fibrillation and aortic stenosis Initial prescription medications:
11	Rhabdomyolysis in Association with Atorvastatin and Fluconazole Use
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13	Why Learn about Adverse Drug Reactions (ADR)? Over 2 MILLION 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
14	Costs Associated with ADRs $136 BILLION yearly Greater than total costs of cardiovascular or diabetic 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
15	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 (2003, before drug benefit) 89.2% take a prescription medicine daily 46.1% take ≥5 prescriptions chronically 53.6% take meds Rxed by 2 or more doctors 5% obtain an Rx from Canada/Mexico ADRs increase exponentially with ≥4 Rx
16	Premarket Drug Safety Profile Most 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
17	Misconceptions about ADRs and Reporting All serious ADRs are documented 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 can’t make a difference
18	Drugs Removed from or Restricted in the U.S. Market Because of Drug Interactions Terfenadine (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
19	Primary Worries in Primary Care: 1,008 Patients
20	Contribution of Drug Interactions to the Overall Burden of Preventable ADRs Drug interactions represent 3–5% of preventable in-hospital ADRs Drug interactions are an important contributor to the number of ER visits and hospital admissions
21	Importance of Systems Interventions …Limitations Message One can’t rely completely on technology Knowledge of clinical pharmacology of drug interactions is valuable
22	Prescribing to Avoid Adverse Drug Reactions Interactions can occur before or after administration of drugs Pharmacokinetic interactions GI tract Plasma Liver Kidney Pharmacodynamic interactions Can occur at target organ Can be systemic (e.g., blood pressure)
23	Interactions before Administration 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
24	They Can Occur in the GI Tract Sucralfate, some milk products, antacids, and oral iron preparations Omeprazole, lansoprazole, H2-antagonists Didanosine (given as a buffered tablet) Cholestyramine
25	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
26	Spectrum of Consequences of Drug Metabolism Inactive products Active metabolites Similar to parent drug More active than parent New action unlike parent Toxic metabolites
27	Microsomal Enzymes Cytochrome P450 Flavin mono-oxygenase (FMO3)
28	Phases of Drug Metabolism Phase I Oxidation Reduction Hydrolysis Phase II Conjugation
29	Interactions Due to Drug Metabolism Nearly always due to interaction with Phase I enzymes, rather than Phase II Commonly due to cytochrome P450 enzymes which have highly variable activity and, in some cases, are genetically absent or over-expressed
30	Phase I - Drug Oxidation
31	Cytochrome P450 Nomenclature, e.g., for CYP2D6 CYP = cytochrome P450 2 = genetic family D = genetic sub-family 6 = specific gene NOTE: This nomenclature is genetically based; it does not imply chemical specificity
32	Major Human CYP450 Isoforms CYP2D6 CYP2E1 CYP3A4 CYP3A5 CYP3A6
33	CYP450 Activity in the Liver
34	Polymorphic Distribution Multiple groups of traits in which each constitutes >1% of the population
35	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 Cyclosporine Present in GI tract and liver
36	CYP3A Inhibitors Ketoconazole Itraconazole Fluconazole Cimetidine Clarithromycin Erythromycin Troleandomycin Grapefruit juice
37	CYP3A Inducers Carbamazepine Rifampin Rifabutin Ritonavir St. John’s Wort
38	Cytochrome P450 2D6 Absent in 7-9% of Caucasians, 1–2% of non-Caucasians Over-expressed in up to 30% of East Africans Catalyzes primary metabolism of: Codeine Many b-blockers Many tricyclic antidepressants Inhibited by: Fluoxetine Haloperidol Paroxetine Quinidine
39	Cytochrome P450 2C9 Absent in 1% of Caucasians and African-Americans Primary metabolism of: Most NSAIDs (including COX-2) S-warfarin (the active isomer) Phenytoin Inhibited by fluconazole
40	Cytochrome P450 2C19 Absent in 20–30% of Asians, 3–5% of Caucasians Primary metabolism of: Diazepam Phenytoin Omeprazole Clopidogrel Inhibited by: Omeprazole Isoniazid Ketoconazole
41	Cytochrome P450 1A2 Induced by smoking tobacco Catalyzes primary metabolism of: Theophylline Imipramine Propranolol Clozapine Inhibited by: Many fluoroquinolone antibiotics Fluvoxamine Cimetidine
42	www.drug-interactions.com
43	Drug Transporters P-Glycoprotein and others Pump drugs out of cells, which alters distribution Found in the following tissues: Gut Gonads Kidneys Biliary system Brain (blood-brain barrier) Placenta
44	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.
45	Bauer B, Hartz AM, Fricker G, Miller D. Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine Feb. 2005;230:118-27.
46	Digoxin and PGP Digoxin is a PGP substrate Increased digoxin plasma conc. when combined with: Quinidine Verapamil Talinolol Clarithromycin Erythromycin Itraconazole Ritonavir
47	Both PGP and CYP3A4 Inducers Rifampicin St. John’s Wort Phenobarbital Reserpine Inhibitors Verapamil Clarithromycin Erythromycin Itraconazole Ritonavir Cyclosporine
48	Drug-Disease Interactions Liver disease Renal disease Cardiac disease ( hepatic blood flow) Acute myocardial infarction? Acute viral infection? Hypothyroidism or hyperthyroidism?
49	Drug-Food Interactions Tetracycline and milk products Warfarin and vitamin K-containing foods Grapefruit juice
50	Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.
51	Drug-Herbal Interactions St. John’s Wort with: Indinavir Cyclosporine Digoxin Tacrolimus Possibly many others
52	Mean plasma concentration time course of indinavir.
53	"FDA program initiated in 1993" FDA program initiated in 1993 Four main 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
54	Drug-Drug Interaction Prevention: A 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. Check up-to-date computer program Medical Letter Drug Interaction Program* www.epocrates.com* and others
55	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 any drugs?
56	This completes the ADR learning module. Please check the following web sites for more learning tools. www.arizonacert.org (drug interactions) www.drug-interactions.com (P450-mediated drug interactions) www.QTdrugs.org (drug-induced arrhythmia) www.C-Path.org (drug development)
57	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://www.accp.com/education.index.aspx http://www.nigms.nih.gov/training/
58	Contributors to the first edition David A. Flockhart, MD, PhD Director, Clinical Pharmacology, Indiana University School of Medicine Sally Yasuda, MS, PharmD Safety 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. Food and Drug Administration Raymond L. Woosley, MD, PhD President and CEO, Critical Path Institute
59	Contributors to the second edition
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