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Toronto Notes 2019
Therapeutic Drug Monitoring
Clinical Pharmacology CP9
100%
50%
Efficacy
TD50
Toxicity
Log Dose
100%
50%
10%
Efficacy
TI
Drug A Toxicity
log(Dose)
Efficacy
TI
Drug B Toxicity
TI
ED50
The therapeutic index (TD50/ED50) is a measure of the margin of safety of a given drug
Figure 9. ED50, TD50, and the therapeutic index
Drug A has a much narrower therapeutic index than Drug B. The dose of Drug A required to achieve a 100% therapeutic response will be toxic in 50% of patients. For Drug B, this is only 10%
Therapeutic Drug Monitoring
• definition:usingserumdrugconcentrationdatatooptimizedrugtherapy(e.g.doseadjustment, monitor compliance) serum drug samples are usually taken when the drug has reached steady state (after approximately 5 half-lives)
• TDMisoftenusedfordrugsthathave:narrowTIs,unpredictabledose-responserelationships, significant consequences associated with therapeutic failure or toxicity, and wide inter-patient PK variability
• examplesofdrugsthatrequiretherapeuticdrugmonitoringinclude: ■ vancomycin
■ aminoglycosides (gentamicin, tobramycin) ■ digoxin
■ phenytoin
■ warfarin
Adverse Drug Reactions
• adversedrugevents(ADEs)areeventsthatoccurwhileapatientisonadrugateitherappropriateor inappropriate doses. A causal relationship is not required
• adversedrugreactions(ADRs)arereactionstodrugsthatoccurwhenadrugisusedfortheappropriate indication at normal therapeutic doses
Table 2. Characteristics of Type A-E Adverse Drug Reactions
Classification
A (Augmented)
B (Bizarre)
See Rheumatology section for Gell and Coombs classification of hypersensitivity reactions
C (Chronic)
D (Delayed) E (End of use)
Definition
Dose related
Non-dose related
Dose and time related
Time related Withdrawal
Characteristics
Predictable extension of drug’s pharmacologic effect (e.g. β-blockers causing bradycardia) >80% of all ADRs
Reactions unrelated to the known pharmacological actions of the drug
Examples include: drug hypersensitivity syndromes, immunologic reactions (penicillin hypersensitivity), and idiosyncratic reactions (malignant hyperthermia)
Related to cumulative doses
Effects are well-known and can be anticipated (e.g. atypical femoral fracture from bisphosphonates)
Occurs some time after use of drug (e.g. carcinogen) May also be dose-related
Occurs after cessation of drug use (e.g. opiate withdrawal)
Tips to Reduce Drug-Related Adverse Events in the Elderly
• Be mindful of longstanding medications
that have never been adjusted for patient
age or renal or hepatic function
• Consider whether medications initiated
during hospital admission are needed long-term (and whether the discharge dose is appropriate for maintenance)
• Avoid polypharmacy by decreasing the dose of or discontinuing medications that are causing side effects
• Verify adherence to medications before automatically increasing the dose of subtherapeutic treatment
• When prescribing medications, use those with a wide therapeutic window
• Review the patient’s problem list and reconcile current medications to avoid duplication or inappropriate dosing/ frequency
Approach to Suspected Adverse Drug Reactions
• historyandphysicalexam:signsandsymptomsofreaction(e.g.rash,fever,hepatitis,anaphylaxis), timing, risk factors, detailed medication history including all drugs and timing, de-challenge (response when drug is removed), and re-challenge (response when drug is given again, if applicable)
• differentiatebetweendrugtherapyvs.diseasepathophysiology
• treatment:stopthedrug,supportivecare,symptomaticrelief.Specificinterventions(eg.steroids,
immunosuppressants) used for some ADRs
• resources: check recent literature, Health Canada, and FDA; contact the pharmaceutical company; call
Poison Control (1-888-268-9017) if overdose or poisoning suspected; check with Motherisk (www.
motherisk.org) in cases involving pregnant or breastfeeding women
• reportallsuspectedADRsthatare:1)unexpected,2)serious,or3)reactionstorecentlymarketeddrugs
(on the market <5 yr) regardless of nature or severity
■ Canadian Adverse Drug Reaction Monitoring Program available for online reporting
Response
Response