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Learning Objectives

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

Learning Module

Sample Case
ADRs: Prevalence and Incidence
Types of Drug Interactions
Drug Metabolism
ADR Reporting
Preventing Drug Interactions

Torsades de Pointes

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)

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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

Costs Associated with ADRs

$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

Why Are There So Many ADRs?

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
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

In the GI Tract

Sucralfate, some milk products, antacids, and oral iron preparations
Omeprazole, lansoprazole,
H2-antagonists
Didanosine (given
as a buffered tablet)
Cholestyramine

Interactions in the Serum

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

Microsomal Enzymes

Cytochrome P450
Flavin mono-oxygenase (FMO3)

Phases of Drug Metabolism

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

Phase I Drug Oxidation

Cytochrome P450 Isoforms

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

CYP450

Polymorphic Distribution

A trait that has differential expression
in >1% of the population

Cytochrome P450 3A

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

CYP3A Inhibitors

Ketoconazole
Itraconazole
Fluconazole
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice

CYP3A Inducers

Carbamazepine
Rifampin
Rifabutin
St. John’s wort

Cytochrome P450 2D6

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

Cytochrome P450 2C9

Absent in 1% Caucasians and
African-Americans
Primary metabolism of:
Most NSAIDs (including COX-2)
S-warfarin (the active form)
Phenytoin
Inhibited by:
Fluconazole

Cytochrome P450 2C19

Absent in 20–30% of Asians,
3–5% Caucasians
Primary metabolism of:
Diazepam
Phenytoin
Omeprazole
Inhibited by:
Omeprazole
Isoniazid
Ketoconazole

Cytochrome P450 1A2

Induced by smoking tobacco
Catalyzes primary metabolism of:
Theophylline
Imipramine
Propranolol
Clozapine
Inhibited by:
Many fluoroquinolone antibiotics
Fluvoxamine
Cimetidine

www.drug-interactions.com

Drug-Disease Interactions

Liver disease
Renal disease
Cardiac disease (   hepatic blood flow)
Acute myocardial infarction?
Acute viral infection?
Hypothyroidism or hyperthyroidism?

Drug-Food Interactions

Tetracycline and milk products
Warfarin and vitamin K-containing foods
Grapefruit juice

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Drug-Herbal Interactions

St. John’s wort with indinavir
St. John’s wort with cyclosporin
St. John’s wort with digoxin
? Many others

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"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?

This completes the ADR learning module. 
Please check the following web sites for more learning tools.

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

Acknowledgements

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