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Recognize health care costs associated with Adverse Drug Reactions (ADRs) |
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Recognize importance of reporting ADRs and medication errors |
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Outline contribution of drug interactions to overall burden of preventable ADRs |
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Identify mechanisms for specific clinically relevant drug interactions |
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Identify methods and systems approaches to predict and prevent drug interactions |
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Sample Case |
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ADRs: Prevalence and Incidence |
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Types of Drug Interactions |
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Drug Metabolism |
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ADR Reporting |
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Preventing Drug Interactions |
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39 y.o. female with 2-day Hx of intermittent syncope |
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Rx with terfenadine 60 mg bid and cefaclor 250 mg tid ´ 10 d |
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Self-medicated with ketoconazole 200 mg bid for vaginal candidiasis |
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Palpitations, syncope, torsades de pointes (QTc 655 msec) |
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Over 2 MILLION serious ADRs yearly |
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100,000 DEATHS yearly |
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ADRs 4th leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths |
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Ambulatory patients ADR rate—unknown |
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Nursing home patients ADR rate—
350,000 yearly |
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$136 BILLION yearly |
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Greater than total costs of cardiovascular or diabetic care |
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ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients |
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Mean length of stay, cost and mortality for ADR patients are DOUBLE that for control patients |
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Two-thirds of patient visits result in
a prescription |
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2.8 BILLION outpatient prescriptions
(10 per person in the United States) filled
in 2000 |
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ADRs increase exponentially with
4 or more medications |
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Most drugs approved by FDA with average of 1500 patient exposures |
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Some drugs have rare toxicity profiles (bromfenac hepatotoxicity 1 in 20,000 patients) |
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For drugs with rare toxicity, more than 100,000 patients must be exposed to generate a signal i.e. after drug is marketed |
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All serious ADRs are documented by the time a drug is marketed |
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It is difficult to determine if a drug is responsible |
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ADRs should only be reported if absolutely certain |
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One reported case can’t make a difference |
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Terfenadine (Seldane®) February 1998 |
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Mibefradil (Posicor®) June 1998 |
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Astemizole (Hismanal®) July 1999 |
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Grepafloxacin (Raxar®) October 1999 |
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Cisapride (Propulsid®) January 2000 |
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Drug interactions represent 3–5% of preventable in-hospital ADRs |
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Drug interactions are an important contributor to number of ER visits and hospital admissions |
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Systems interventions |
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Electronic prescription entry and bar-coding |
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Computerized medication records |
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Drug interaction software |
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Limitations |
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Fragmented healthcare delivery and prescription filling |
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Information not uniformly translated into practice |
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Message |
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Can’t rely completely on technology |
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Need basic knowledge of clinical pharmacology
of drug interactions |
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Interactions can occur before or after administration |
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Pharmacokinetic interactions |
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GI tract |
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Plasma |
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Liver |
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Kidney |
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Pharmacodynamic interactions |
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Target organ |
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Phenytoin precipitates in dextrose solutions
(e.g. D5W) |
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Amphotericin precipitates in saline |
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Gentamicin is physically/chemically incompatible with most beta-lactams, resulting in loss of antibiotic effect |
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Sucralfate, some milk products, antacids, and oral iron preparations |
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Omeprazole, lansoprazole,
H2-antagonists |
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Didanosine (given
as a buffered tablet) |
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Cholestyramine |
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Protein “bumping” interactions in the serum are a test-tube phenomenon without clinical relevance |
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Inactive products |
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Active metabolites |
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Similar to parent drug |
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More active than parent |
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New action |
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Toxic metabolites |
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Cytochrome P450 |
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Flavin mono-oxygenase (FMO3) |
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Phase I |
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Oxidation/Reduction/Hydrolysis |
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Phase II |
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Conjugation |
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Nearly always due to interaction at Phase I enzymes, rather than Phase II |
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i.e. commonly due to interaction at cytochrome P450 enzymes…some of which are genetically absent |
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CYP1A2 |
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CYP3A |
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CYP2C9 |
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CYP2C19 |
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CYP2D6 |
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CYP = cytochrome P450 |
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2 = genetic family |
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D = genetic sub-family |
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6 = specific gene |
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NOTE that this nomenclature is genetically based: it has NO functional implication |
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A trait that has differential expression
in >1% of the population |
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Responsible for metabolism of: |
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Most calcium channel blockers |
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Most benzodiazepines |
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Most HIV protease inhibitors |
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Most HMG-CoA-reductase inhibitors |
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Cyclosporine |
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Most non-sedating antihistamines |
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Cisapride |
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Present in GI tract and liver |
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Ketoconazole |
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Itraconazole |
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Fluconazole |
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Cimetidine |
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Clarithromycin |
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Erythromycin |
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Troleandomycin |
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Grapefruit juice |
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Carbamazepine |
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Rifampin |
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Rifabutin |
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Ritonavir |
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St. John’s wort |
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Absent in 7% of Caucasians,
1–2% non-Caucasians |
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Hyperactive in up to 30% of East Africans |
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Catalyzes primary metabolism of: |
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Codeine |
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Many b-blockers |
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Many tricyclic antidepressants |
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Inhibited by: |
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Fluoxetine |
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Haloperidol |
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Paroxetine |
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Quinidine |
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Absent in 1% Caucasians and
African-Americans |
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Primary metabolism of: |
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Most NSAIDs (including COX-2) |
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S-warfarin (the active form) |
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Phenytoin |
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Inhibited by: |
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Fluconazole |
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Absent in 20–30% of Asians,
3–5% Caucasians |
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Primary metabolism of: |
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Diazepam |
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Phenytoin |
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Omeprazole |
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Inhibited by: |
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Omeprazole |
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Isoniazid |
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Ketoconazole |
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Induced by smoking tobacco |
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Catalyzes primary metabolism of: |
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Theophylline |
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Imipramine |
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Propranolol |
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Clozapine |
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Inhibited by: |
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Many fluoroquinolone antibiotics |
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Fluvoxamine |
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Cimetidine |
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Liver disease |
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Renal disease |
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Cardiac disease ( hepatic blood flow) |
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Acute myocardial infarction? |
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Acute viral infection? |
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Hypothyroidism or hyperthyroidism? |
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Tetracycline and milk products |
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Warfarin and vitamin K-containing foods |
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Grapefruit juice |
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St. John’s wort with indinavir |
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St. John’s wort with cyclosporin |
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St. John’s wort with digoxin |
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? Many others |
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FDA program initiated in 1993 |
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Four main goals of the program |
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Increase awareness of medical product
(drug) induced disease and the importance
of reporting |
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Clarify what should (and should not) be reported |
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Facilitate the ease of reporting |
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Provide feedback to health professionals about
new safety issues |
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www.fda.gov/medwatch or 1-800-FDA-1088 |
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1. Take a medication history (AVOID mistakes) |
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2. Remember high risk patients |
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Any patient taking 2 medications |
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Anticonvulsants, antibiotics, digoxin,
warfarin, amiodarone, etc |
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3. Check pocket reference |
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4. Consult pharmacists/drug info specialists |
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5. Check up-to-date computer program |
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Medical Letter Drug Interaction Program* |
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Clinical pharmacology (gsm.com)* |
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www.epocrates.com* |
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Allergies? |
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Vitamins and herbs? |
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Old drugs and OTC? ….as well as current |
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Interactions? |
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Dependence? Do you need a contract? |
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Mendel: family Hx of benefits or problems with any drugs? |
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arizonacert.org (drug interactions) |
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www.drug-interactions.com
(P450-mediated drug interactions) |
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www.torsades.org (drug-induced arrhythmia) |
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www.penncert.org (antibiotics) |
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www.dcri.duke.edu/research/fields/certs.html (cardiovascular therapeutics) |
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www.sph.unc.edu/healthoutcomes/certs/index.htm
(therapeutics in pediatrics) |
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www.uab.edu
(therapeutics of musculoskeletal disorders) |
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For more information on training programs in clinical pharmacology visit the website www.ascpt.org |
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David A. Flockhart,
MD, PhD |
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Director, Division of Clinical
Pharmacology
Indiana University School
of Medicine |
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Sally Usdin Yasuda,
MS, PharmD |
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Assistant Professor
Department of Pharmacology
Georgetown University School
of Medicine |
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Notes
