LECTURE 6: ADVERSE DRUG REACTIONS (ADR) Flashcards
ADVERSE DRUG EVENT VS ADVERSE DRUG REACTION
Adverse Drug Event (ADE): ‘Any untoward medical occurrence that may present during
treatment with a pharmaceutical product but which does not necessarily have a causal
relationship with this treatment’
Adverse Drug Reaction (ADR): ‘A response to a drug which is noxious and unintended and
which occurs at doses normally used in human for prophylaxis, diagnosis, or therapy or
disease or for the modification of physiologic function’
Side Effect: ‘Any unintended effect of a pharmaceutical product occurring at doses
normally used in humans which is related to the pharmacological properties of the
medicine. Maybe well known or expected and may require little or no change in patient
management.’
ADVERSE DRUG EVENT VS ADVERSE DRUG REACTION
define med error
Adverse drug event – outcome that occurs while taking a drug but not always attributable to it
Ø Adverse drug reaction – outcome attributed to some action of a drug
- ADR is a type of ADE whose cause can be directly attributed to a drug and its
physiologic properties. - ADRs occur despite appropriate prescribing and dosing, whereas ADEs may also
be associated with inappropriate use of the drug or other confounders that occur
during drug therapy but are not necessarily caused by the pharmacology of the
drug itself.
Medication Error - Medication error: any preventable event that may cause or lead to inappropriate
medication use or patient harm while the medication is in the control of the health
care professional, patient or consumer. - A mistake that happens with medical therapy such as wrong dose, wrong person,
missing an allergy
QUESTIONS TO THINK ABOUT REGARDING ADR
Timing
Does response make sense in therapy
Predictable outcome?
Pdt defects?
Something wrong with medicaiton?
Wrong dose, wrong individual
Allerrgies
Comorbidities
age
CLASSIFICATIONS OF ADRS
Type A (dose-dependent and predictable) augmentations of known pharmacological
effects (ie., orthostatic hypotension with antihypertensive drugs)
Type B (uncommon and unpredictable) depending on the known pharmacology,
independent of the dose and affect a small population suggesting individual patient host
factors are important, (ie., hypersensitivity (allergic) reactions to drugs)
- Type A called augmented
- Type B called bizarre/idiosyncratic
- Type C – chronic
- Type D – delayed
- Type E – withdrawal
- Type F – unexpected failure of efficacy
TYPE A (AUGMENTED)
Type of Reaction
- Dose-dependent and predictable,
- Readily reversible by reducing dose or withdrawal
- More common than Type B (>80% of ADR)
Features
- Reactions primarily result from drug pharmacology and represent augmented or
exaggerated effect
- Can result from secondary mechanism (known side-effect)
- Problematic when there is a narrow therapeutic window
Examples
- Hypertension drugs result in hypotensive response
- Non-selective beta blockers
- Warfarin (bleeding), Diazepam (sedation), Insulin (hypoglycemic coma), Respiratory
Depression (Morphine)
TYPE B (BIZARRE)
Type of Reaction
- Unrelated to known pharmacological actions
- Less common than Type A (~20%)
Features
- Often caused by immunological response and pharmacogenetic mechanisms
- Idiosyncratic e.g., genetics – acetylator polymorphisms (slow vs fast acetylator –
isoniazid)
Examples
- Anaphylaxis in response to penicillin
- Aplastic anaemia caused by chloramphenicol
- Malignant hyperthermia in response to anaesthetics
CHARACTERISTICS OF TYPE A VS.B ADVERSE DRUG REACTIONS
Pharmacological predictability
Related to dose
Prevalence of mortality
Prevalence of morbidity
Response to changing dose
Re-administration
ok
ADR - TYPES C, D, E AND F
Type C (Continuing, Chronic)
- Continuing reactions, persist for relatively long period of time, cumulative dose
- Reduce the dose or withhold medicine
- Use of bisphosphonates results in osteonecrosis of the jaw
Type D (Delayed)
- Emerge after patient has begun therapy, uncommon but often intractable
- Adriamycin (doxorubicin) used to treat some cancers can result in cardiomyopathy
~15-20 years post therapy
- Teratogenic effects or carcinogenesis
Type E (End of Use/Withdrawal)
- Occur after patient stops therapy, uncommon, reintroduce and then slowly withdraw
- Stoppage of benzodiazepine therapy used to treat anxiety can result in insomnia,
anxiety and perceptual disturbances
Type F (Unexpected Failure of Therapy)
- Failure of efficacy, common, may dose related or drug interactions
- Resistance to antimicrobial
IMMUNOLOGICAL REACTIONS
(TYPE I –IV HYPERSENSITIVITY)
Type B Adverse Drug Reactions
- Prior exposure to drug leads to sensitization to elicit a reaction is a common feature
to hypersensitivity
- Drug or its metabolite can act as a hapten by interacting with proteins to become
immunogenic
- Necessity of prior exposure to leading to sensitization that elicits a reaction upon
subsequent challenge
IMMUNOLOGICAL REACTIONS
(TYPE I HYPERSENSITIVITY) (Immediate or IgE-mediated hypersensitivity)
- Antibody mediated hypersensitivity
- Acute allergic reaction to stings, pollens, food, drugs
- Evoke release of IgE ie., instead of IgM, IgG or IgA
(e.g., penicillin, streptokinase) - Reexposure after sensitization triggers response
- Local effects - rhinitis, asthma, rash
- Systemic effects – anaphylactic shock
IMMUNOLOGICAL REACTIONS
(TYPE II HYPERSENSITIVITY)
(Non-immediate response)
- Antibody based reaction primarily involving IgG or IgM-mediated response
- Reactions emerge 5 to 21 days, symptoms can be observed 24-48h
- Antigen directed at ‘foreign’ host cells, cells can be made foreign by drugs
- Blood cells and platelets are often targets
- Hemolytic anemia (methyldopa)
- Leukopenia (aminopyrine)
this reaction takes about a week to to 3 weeks to develop again. You’re developing antibodies.
There’s a complement independent cytolysis versus a complement dependent cytolysis.
So in the complement independent Cytolysis, your your antigen is going to bind to a tissue or a cell. Antibody is going to bind IgG directed Antigen against it
against that antigen recruiting, macrophages and nutrients to kill, and in this attack that foreign body
Compleemnt depending - antigen is going to attach to the cell, and it’s going to trigger a compliment in response.
Type III (Non-immediate immune complexmediated hypersensitivity)
- Antibody reactions involve IgG
- Reactions due to elevated levels of
antigen-antibody complexes. - Complexes deposited in e.g. vascular
endothelium to cause inflammatory
responses/tissue injury (1-24h) serum
sickness - Serum sickness syndrome (penicillins,
NSAIDs)
Type IV (T-cell-mediated hypersensitivity)
- Take the longest to develop symptoms (2 to 20 days)
- Reaction involves drug-sensitizing T-cells as opposed to antibody
- Response to antigen release cytokines and T cell proliferation
- E.g. latex gloves or drugs applied topically to skin to cause contact dermatitis and photosensitivity
- Stevens-Johnson syndrome (sulphonamides, carbamazepine)
SUSCEPTIBILITY FACTORS
Age
- Age-related changes impact pharmacokinetic and pharmacodynamics
- Older individuals have increased sensitivity (e., psychotropics, diuretics, NSAIDs)
- Co-morbidities
- ADRs can present in non-specific manner (ie., confusion, constipation)
- Pediatric and neonates differ in how they handle and respond to drugs
Sex
- Sex differences such as hormonal and immunological factors
Pregnancy
- Profound physiological changes during pregnancy
- Fetus and breastfeeding
- E.g., thalidomide, warfarin, antiepileptic drugs
Disease States
- Numerous differences exist, ie., hepatic or renal dysfunction will impact ADR
Genetics
- Pharmacogenetics/Pharmacogenomics impact all aspects of kinetics and dynamics
Polypharmacy
- Many individuals, notably older patients, often taking numerous different medications
N-Acetyltransferase 2
Who has higher cure rates? Who would have more toxicity?
Covalent binding in liver cell
macromolecules leading to
liver damage
Reactive metabolite that’s toxic
Who has higher cure rate: fast acetylators would have reduced benefit, removing therapeutic properties faster
Who has more toxicity: slow acetylators have less toxicity because metabolite is made slower so less AE, fast acetylators have conversion of toxic metabolite faster, more AE
polymorphisms play a role in adverse effects and adverse responses
