Drug Safety Flashcards
What is an adverse drug reaction (ADR)?
An ADR is a noxious and unintended response to a medicinal product, where a causal relationship between the drug and the event is at least a reasonable possibility.
What are the types of adverse drug reactions (ADRs)?
(1) Type A (Augmented): Dose-dependent reactions related to pharmacological actions, e.g., respiratory depression with codeine in CYP2D6 ultra-rapid metabolizers. (2) Type B (Idiosyncratic): Unpredictable and not dose-related, e.g., anaphylaxis with penicillin. (3) Type C (Continuing): Persist long after drug withdrawal, e.g., bisphosphonate-induced osteonecrosis. (4) Type D (Delayed): Appear long after drug use, e.g., secondary cancers after chemotherapy. (5) Type E (End of use): Associated with withdrawal, e.g., seizures after benzodiazepine discontinuation.
What are Type A adverse drug reactions?
Type A reactions are exaggerated pharmacological effects at therapeutic doses, often dose-dependent. Example: Respiratory depression with codeine in CYP2D6 ultra-rapid metabolizers.
What are Type B adverse drug reactions?
Type B reactions are idiosyncratic and unpredictable, often related to genetic or immune responses. Examples include anaphylaxis with penicillin.
What are examples of Type C, D, and E ADRs?
Type C: Bisphosphonate-induced osteonecrosis of the jaw, which persists long after drug withdrawal. Type D: Secondary cancers such as leukemia following alkylating agents in chemotherapy. Type E: Withdrawal symptoms such as seizures after discontinuing benzodiazepines.
What is the ‘risk-benefit’ assessment of a drug?
The risk-benefit assessment evaluates whether the therapeutic benefits of a drug outweigh its risks, considering severity, frequency, and patient-specific factors.
What is an example of a famous idiosyncratic ADR?
Thalidomide caused teratogenic effects, such as phocomelia (limb malformations), when used for morning sickness.
What is abacavir hypersensitivity and its genetic marker?
Abacavir, an HIV reverse transcriptase inhibitor, causes hypersensitivity reactions in ~9% of patients within 6-8 weeks of treatment. This is strongly associated with the HLA-B*57:01 allele.
What is flucloxacillin-induced liver injury and its relevance?
Flucloxacillin, used for staphylococcal infections, is associated with cholestatic hepatitis, typically occurring 1-45 days post-treatment.
What is rhabdomyolysis and an example of a drug causing it?
Rhabdomyolysis is characterized by severe muscle damage and the release of myoglobin, leading to kidney injury. Cerivastatin (Baycol), a lipid-lowering drug, caused rhabdomyolysis, leading to its market withdrawal in 2001.
What is drug-induced liver injury (DILI)?
DILI refers to liver damage caused by drug exposure, involving mechanisms like oxidative stress and immune-mediated responses. Examples include acetaminophen overdose and idiosyncratic reactions with flucloxacillin.
How can ADRs impact drug development?
ADRs can lead to financial losses for pharmaceutical companies, stricter regulatory oversight, and drug withdrawals. Examples include the withdrawal of cerivastatin due to rhabdomyolysis.
What are preclinical toxicity models?
Preclinical toxicity models involve in vitro (cell culture) and animal studies to predict human toxicity. Examples include hepatotoxicity assays using primary hepatocytes.
What is Fialuridine’s significance in ADR prediction?
Fialuridine, a hepatitis B drug, caused fatal liver failure during Phase I trials despite appearing safe in preclinical studies.
What are predictive biomarkers for ADRs?
Predictive biomarkers identify patients at risk of ADRs. For example, HLA-B*57:01 predicts hypersensitivity to abacavir.
