adverse drug reactions Flashcards
define an adverse drug reaction
A response to a medicinal product, or combination of medicinal products, which is noxious and unintended
Outline the effect of ADRs on patients, healthcare systems and public health.
For patients:
Reduced Quality of life
Poor compliance
Reduced confidence in clinicians and the healthcare system
Unnecessary investigations or treatments
For healthcare systems:
- increased healthcare costs
- resourse strain
- impact on healthcare delivery
public health:
- public health burden (economic strain, high hospitalization and mortality rates)
- impact health disparities, targetting certain groups
what are the 2 methods of classifying ADR?
ABCDEFG
DOTS
outline what the ABCDEFG stands for when classifying ADR.
Augmented
Bizarre
Chronic/continuing
Delayed
End of use/withdrawal
Failure of treatment
Genetic
outline type A (augmented) ADR and give examples.
Most common type of ADR (80%)
Exaggerated effect of drugs pharmacology at a therapeutic dose
Often not life threatening
Dose dependent
reversible upon withdrawing the drug
Examples:
AKI with ACE inhibitors
Bradycardia with betablockers
Hypoglycaemia with gliclazide, insulin
Respiratory depression with opiates
Bleeding with anticoagulants
outline type B (bizarre) ADR and give examples.
- unpredicatable
- Not related to pharmacology of drug
- Not dose related
- Can cause serious illness or mortality
- caused by individual patient-specific factors such as genetic predisp
- Symptoms do not always resolve upon stopping drug
Examples:
Anaphylaxis with penicillins
Tendon rupture with quinolone antibiotics
Steven Johnson Syndrome with IV vancomycin
outline type C (chronic/continuing) ADR and give examples.
ADRs that continue after the drug has been stopped
Examples:
Osteonecrosis of the jaw with bisphosphonates
Heart failure with pioglitazone
outline type D (delayed) ADR and give examples.
ADRs that become apparent some time after stopping the drug
Examples:
Leucopenia with chemotherapy
outline type E (end of use/withdrawal) ADR and give examples.
ADR develops after the drug has been stopped
Examples:
Insomnia after stopping benzodiazepine
Rebound tachycardia after stopping beta-blocker
Nasal congestion after stopping xylometolazine nasal spray
outline type F (failure of treatment) ADR and give examples.
Unexpected treatment failure
Could be due to drug-drug interaction or drug-food interaction
Poor compliance with administration instructions
Examples:
Failure of oral contraceptive pill due to St John’s Wort
Failure of DOAC due to enzyme inducer (eg carbamazepine)
Failure of bisphosphonate due to taking with food
outline type G (genetic) ADR and give examples.
Drug causes irreversible damage to genome
Examples:
Phocomelia in children of women taking thalidomide
outline what the DOTS method of ADR classification is and when is it most useful.
An alternative way to classify ADRs
Dose-relatedness
Timing
Susceptibility
More complex than ABCDE, but provides more detail.
Useful for those working in pharmacovigilance, undertaking research or developing medicines
what are the 3 dose-relatedness classifications according to DOTS and explain them.
Hypersusceptibility: ADRs at subtherapeutic doses (eg anaphylaxis with penicillins)
Collateral effects (side effects): ADRs at therapeutic doses (eg hypokalaemia with loop diuretic)
Toxic effects: ADRs at subpratherapeutic doses (eg liver damage with paracetamol)
outline DOTS timing.
outline DOTS susceptability.
Certain patient groups/populations may have a specific susceptibility to ADRs from a drug
Age (anticholinergics in elderly patients)
Gender (metoclopramide in females)
Disease states (eg diclofenac in CVD)
Physiological states (eg phenytoin in pregnancy)
what are the steps of releasing a drug to the market in which an ADR may be identified?
Pre-clinical testing (computer models, cells and toxicity testing in animals)
Clinical trial data (pre-marketing evaluation)
Post marketing surveillance
Pharmacovigilance
outline what is involved during the clinical trials step of identifying ADRs.
Clinical trials have 3 stages:
- administeration of 1 dose usually to healthy volunteers (sometimes patients)
- administeration of drug to selected populatioms for which the drug will eventually be indicated. dose finding
- randomised controlled trials. any adrs identified have to be included in the SPC
outline what is involved during the pre-clinical trials step of identifying ADRs.
- Computer modelling
animal testing:
- Long term administration in different species
- Toxic doses given to identify likely ‘targets’ of toxic effects
- Recovery studies - identify irreversible ADRs (e.g. carcinogenesis and neurodegeneration)
- Acceptable level of toxicity depends on intended indication
- Findings may halt development of drug or provide focus for future trials
outline the limitations of pre-marketing evaluation.
Low patient numbers
Exclusion of specific patient groups (many at high risk of ADRs):
Elderly, frail
Polypharmacy, multimorbid
Severe organ dysfunction
Neonatal and paediatric population
ADRs with incidence over 1% will generally be identified (most likely Type A)
Less common ADRs (including Type B) are less likely to be identified
outline what is involved during the post marketting surveillance step of identifying ADRs.
Full ADR profile is unlikely to be understood once the drug is in widespread clinical use
Identify groups who may be especially susceptible:
- Drug dose ranges
- Gender
- Age
- Disease state
After product licence is granted by MHRA, medicines are subject to post marketing surveillance (usually at least 5 years)
Additional monitoring to inform risk-benefit profile when used in everyday practice
Established medicines may be placed back under post marketing surveillance if the manufacturer wants to amend licence (eg use for a new indication)
outline what is black triangle medicines.
Medicines subject to post marketing surveillance are indicated by a black triangle:
BNF (under Medicinal Forms section)
SPC
Patient information leaflet (see below)
All ADRs should be reported for Black triangle medicines
- a black traingle is on the packet into showing the medication is still subject to monitoring
outline what is involved during the pharmacovigilance step of identifying ADRs.
- Collect reports of ADRs in everyday use for licensed medicines, unlicensed medicines, herbal medicines, biological products and vaccines
- Monitor known ADRs and identifies previously unknown ADRs
- Assess risk/benefits of the medicine and decide on safest course of action
- Provide information and guidance on identified safety issues to healthcare professionals and public
Q: What is the Yellow Card System for ADRs?
Purpose:
Monitor Drug Safety:
Collect data on ADRs to identify safety concerns with medicines or vaccines.
Prevent Harm:
Allow early detection of rare or severe ADRs, especially for new medicines.
Improve Public Health:
Enable regulatory action (e.g., label changes, safety warnings, drug recalls).
How It Works:
Who Can Report:
Healthcare Professionals (doctors, pharmacists, nurses).
Patients and the general public can also report directly.
What to Report:
Suspected ADRs, including serious, rare, or previously unknown reactions.
Medicine quality issues (e.g., defects, packaging errors).
Submission:
Reports can be made online, via the Yellow Card app, or by paper form.
Importance:
Enhances Drug Safety: By gathering real-world data, the system contributes to safer medicines for the population.
Global Collaboration: Data is shared internationally to improve pharmacovigilance worldwide.
outline the stregnths and weknesses of the yellow card system.
Strengths:
Confidential
No fear of litigation
Quick to submit
Accessible to all (HCPs and patients)
Weaknesses:
Under-reporting (5% of ADRs and 10% of serious are reported)
Relies on HCPs recognising ADR
Data does not indicate incidence
what should you look out for when prescribing drugs to patients to reduce and avoid ADRs?
Patient groups at increased risk of ADRs
Drugs which most commonly cause ADRs
Drugs with potential for serious ADRs
when identifying who is at increased risk of ADRs, what genetic variations could be dangerous.
Genetic variation can increase risk of ADRs
Expression of CYP450 enzymes (altered drug metabolism)
Eg. ultra-fast metabolisers of codeine
Human Leucocyte Antigen (HLA) alleles can increase risk of immune mediated idiosyncratic ADRs
5-7% of patients prescribed abacavir have severe hypersensitivity reactions
NICE requirement for HLA testing has virtually eliminated these reactions
In most cases genomic risk factors will be unknown (for now)
what are high risk drugs for ADR
Drugs with a narrow therapeutic window:
Digoxin
Vancomycin
Carbamazepine
Phenytoin
Gentamicin
Theophylline
Warfarin
Lithium
Sodium valproate
Common causative drugs:
Opiates
Antibiotics
Anticoagulants
Antiplatelets
Cytotoxics/ immunosuppressants
Diuretics/ARB blockers
Antihypertensives
Antidiabetic drugs
outline some actions that prescribers can take to reduce the risk of ADRs.
Rationalise
Stop unnecessary drugs
Thorough and complete DHx
Optimise dose/frequency for individual
Pre-empt ADRs and consider prophylaxis
Patient counselling
How to take
Side effects to expect
Side effects to report
Appropriate monitoring and follow up
Clear and timely communication between care providers
who can have an ADR?
Possibility of an ADR should be considered in differential diagnosis if a patient is taking medication
Thorough and complete drug history (DHx) is essential
Think beyond prescribed medicines…
when should we suspect an ADR?
Symptoms soon after a new drug is started
Symptoms after a dosage increase
Symptoms disappear when the drug is stopped
Symptoms reappear when the drug is restarted (rechallenge)
Patient concerns
when should we report an ADR?
Serious ADRs:
Caused hospitalisation
Prolonged hospitalisation
Life threatening
Causing disability or death
Causing congenital abnormalities
Deemed medically significant
Unlicensed uses:
Unlicensed medicines
Off label uses
Herbal medicines
Illicit drugs
Reactions at unlicensed doses (toxicity)
Any ADR caused by black triangle medicine
What should we do if there is an ADR is suspected?
Assess if ADR requires treatment (reversal, symptom management)
Take a history
Review medication history
Review ADR profile of suspected drug (BNF, SPC)
Modify dose, stop or swap
Document allergy/ADR in patient record (including nature of reaction)
If criteria met…report
how do you complete a yellow card when reporting an ADR and what information is required?
How to complete a Yellow Card:
https://yellowcard.mhra.gov.uk
Paper copy in back of BNF
Smartphone app
Anyone can complete (HCPs and patients)
Quick to complete
Just 4 pieces of information required:
Suspected drug(s)
Suspected reaction(s)
Patient details (initials, Hosp/NHS number)
Reporter details
what processes happen once an ADR has been confirmed to a medication?
Adding ADR to product information (BNF, SPC)
Restrictions in use made to product licence:
Dose, caution in certain patient groups, monitoring
SPC and BNF will be updated with changes
Change in legal classification
GSL to P, P to POM
Increasing monitoring requirements through
Medicine may be withdrawn from market
