Preventable Adverse Drug Reactions
| Recognize health care costs associated with Adverse Drug Reactions (ADRs) | |
| Recognize importance of reporting ADRs and medication errors | |
| Outline contribution of drug interactions to overall burden of preventable ADRs | |
| Identify mechanisms for specific clinically relevant drug interactions | |
| Identify methods and systems approaches to predict and prevent drug interactions |
| Sample Case | |
| ADRs: Prevalence and Incidence | |
| Types of Drug Interactions | |
| Drug Metabolism | |
| ADR Reporting | |
| Preventing Drug Interactions |
Ventricular Arrhythmia (Torsades de Pointes)
Occurring in Association with Terfenadine Use
| 39 y.o. female with 2-day Hx of intermittent syncope | |
| Rx with terfenadine 60 mg bid and cefaclor 250 mg tid ´ 10 d | |
| Self-medicated with ketoconazole 200 mg bid for vaginal candidiasis | |
| Palpitations, syncope, torsades de pointes (QTc 655 msec) |
Why Learn about
Adverse Drug Reactions (ADR)?
| Over 2 MILLION serious ADRs yearly | |
| 100,000 DEATHS yearly | |
| ADRs 4th leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths | |
| Ambulatory patients ADR rate—unknown | |
| Nursing home patients ADR rate— 350,000 yearly |
|
| $136 BILLION yearly | |
| Greater than total costs of cardiovascular or diabetic care | |
| ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients | |
| Mean length of stay, cost and mortality for ADR patients are DOUBLE that for control patients | |
| Two-thirds of patient visits result in a prescription |
|
| 2.8 BILLION outpatient prescriptions (10 per person in the United States) filled in 2000 |
|
| ADRs increase exponentially with 4 or more medications |
Characterization of New Drug’s Safety Profile Before Marketing
| Most drugs approved by FDA with average of 1500 patient exposures | |
| Some drugs have rare toxicity profiles (bromfenac hepatotoxicity 1 in 20,000 patients) | |
| For drugs with rare toxicity, more than 100,000 patients must be exposed to generate a signal i.e. after drug is marketed | |
Misconceptions
about ADR Reporting
| All serious ADRs are documented by the time a drug is marketed | |
| It is difficult to determine if a drug is responsible | |
| ADRs should only be reported if absolutely certain | |
| One reported case can’t make a difference | |
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 |
Primary Worries in Primary Care:
1008 Patients
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 number of ER visits and hospital admissions |
Systems Interventions and
Their Limitations
| Systems interventions | ||
| Electronic prescription entry and bar-coding | ||
| Computerized medication records | ||
| Drug interaction software | ||
| Limitations | ||
| Fragmented healthcare delivery and prescription filling | ||
| Information not uniformly translated into practice | ||
| Message | ||
| Can’t rely completely on technology | ||
| Need basic knowledge of clinical pharmacology of drug interactions |
||
Prescribing to Avoid
Adverse Drug Reactions
| Interactions can occur before or after administration | ||
| Pharmacokinetic interactions | ||
| GI tract | ||
| Plasma | ||
| Liver | ||
| Kidney | ||
| Pharmacodynamic interactions | ||
| Target organ | ||
Interactions Before Administration
| Phenytoin precipitates in dextrose solutions (e.g. D5W) |
|
| Amphotericin precipitates in saline | |
| Gentamicin is physically/chemically incompatible with most beta-lactams, resulting in loss of antibiotic effect | |
| Sucralfate, some milk products, antacids, and oral iron preparations | |
| Omeprazole, lansoprazole, H2-antagonists |
|
| Didanosine (given as a buffered tablet) |
|
| Cholestyramine |
| Protein “bumping” interactions in the serum are a test-tube phenomenon without clinical relevance |
Spectrum of Consequences
of Drug Metabolism
| Inactive products | |
| Active metabolites | |
| Similar to parent drug | |
| More active than parent | |
| New action | |
| Toxic metabolites |
| Cytochrome P450 | |
| Flavin mono-oxygenase (FMO3) |
| Phase I | ||
| Oxidation/Reduction/Hydrolysis | ||
| Phase II | ||
| Conjugation | ||
Drug Interactions Due to Hepatic Metabolism
| Nearly always due to interaction at Phase I enzymes, rather than Phase II | |
| i.e. commonly due to interaction at cytochrome P450 enzymes…some of which are genetically absent |
| CYP1A2 | |
| CYP3A | |
| CYP2C9 | |
| CYP2C19 | |
| CYP2D6 |
Cytochrome P450 Nomenclature,
e.g. for CYP2D6
| CYP = cytochrome P450 | |
| 2 = genetic family | |
| D = genetic sub-family | |
| 6 = specific gene | |
| NOTE that this nomenclature is genetically based: it has NO functional implication |
| A trait that has differential expression in >1% of the population |
| Responsible for metabolism of: | ||
| Most calcium channel blockers | ||
| Most benzodiazepines | ||
| Most HIV protease inhibitors | ||
| Most HMG-CoA-reductase inhibitors | ||
| Cyclosporine | ||
| Most non-sedating antihistamines | ||
| Cisapride | ||
| Present in GI tract and liver | ||
| Ketoconazole | |
| Itraconazole | |
| Fluconazole | |
| Cimetidine | |
| Clarithromycin | |
| Erythromycin | |
| Troleandomycin | |
| Grapefruit juice |
| Carbamazepine | |
| Rifampin | |
| Rifabutin | |
| Ritonavir | |
| St. John’s wort |
| Absent in 7% of Caucasians, 1–2% non-Caucasians |
||
| Hyperactive in up to 30% of East Africans | ||
| Catalyzes primary metabolism of: | ||
| Codeine | ||
| Many b-blockers | ||
| Many tricyclic antidepressants | ||
| Inhibited by: | ||
| Fluoxetine | ||
| Haloperidol | ||
| Paroxetine | ||
| Quinidine | ||
| Absent in 1% Caucasians and African-Americans |
||
| Primary metabolism of: | ||
| Most NSAIDs (including COX-2) | ||
| S-warfarin (the active form) | ||
| Phenytoin | ||
| Inhibited by: | ||
| Fluconazole | ||
| Absent in 20–30% of Asians, 3–5% Caucasians |
||
| Primary metabolism of: | ||
| Diazepam | ||
| Phenytoin | ||
| Omeprazole | ||
| Inhibited by: | ||
| Omeprazole | ||
| Isoniazid | ||
| Ketoconazole | ||
| Induced by smoking tobacco | ||
| Catalyzes primary metabolism of: | ||
| Theophylline | ||
| Imipramine | ||
| Propranolol | ||
| Clozapine | ||
| Inhibited by: | ||
| Many fluoroquinolone antibiotics | ||
| Fluvoxamine | ||
| Cimetidine | ||
| Liver disease | |
| Renal disease | |
| Cardiac disease ( hepatic blood flow) | |
| Acute myocardial infarction? | |
| Acute viral infection? | |
| Hypothyroidism or hyperthyroidism? |
| Tetracycline and milk products | |
| Warfarin and vitamin K-containing foods | |
| Grapefruit juice | |
Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.
| St. John’s wort with indinavir | |
| St. John’s wort with cyclosporin | |
| St. John’s wort with digoxin | |
| ? Many others |
Mean plasma concentration time course of indinavir.
"FDA program initiated in 1993"
| FDA program initiated in 1993 | ||
| Four main goals of the program | ||
| Increase awareness of medical product (drug) induced disease and the importance of reporting |
||
| Clarify what should (and should not) be reported | ||
| Facilitate the ease of reporting | ||
| Provide feedback to health professionals about new safety issues |
||
| www.fda.gov/medwatch or 1-800-FDA-1088 | ||
Drug-Drug Interactions:
A Stepwise Approach
| 1. Take a medication history (AVOID mistakes) | ||
| 2. Remember high risk patients | ||
| Any patient taking 2 medications | ||
| Anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc |
||
| 3. Check pocket reference | ||
| 4. Consult pharmacists/drug info specialists | ||
| 5. Check up-to-date computer program | ||
| Medical Letter Drug Interaction Program* | ||
| Clinical pharmacology (gsm.com)* | ||
| www.epocrates.com* | ||
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? |
| arizonacert.org (drug interactions) | |
| www.drug-interactions.com (P450-mediated drug interactions) |
|
| www.torsades.org (drug-induced arrhythmia) | |
| www.penncert.org (antibiotics) | |
| www.dcri.duke.edu/research/fields/certs.html (cardiovascular therapeutics) | |
| www.sph.unc.edu/healthoutcomes/certs/index.htm (therapeutics in pediatrics) |
|
| www.uab.edu (therapeutics of musculoskeletal disorders) |
Clinical Pharmacology: The Science of Pharmacology and Therapeutics
| For more information on training programs in clinical pharmacology visit the website www.ascpt.org |
| David A. Flockhart, MD, PhD |
|
| Director, Division of Clinical Pharmacology Indiana University School of Medicine |
|
| Sally Usdin Yasuda, MS, PharmD |
|
| Assistant Professor Department of Pharmacology Georgetown University School of Medicine |