adverse drug reactions

Question 1

define an adverse drug reaction

Answer 1

A response to a medicinal product, or combination of medicinal products, which is noxious and unintended

Question 2

Outline the effect of ADRs on patients, healthcare systems and public health.

Answer 2

For patients:
Reduced Quality of life
Poor compliance
Reduced confidence in clinicians and the healthcare system
Unnecessary investigations or treatments

For patients:
Reduced Quality of life
Poor compliance
Reduced confidence in clinicians and the healthcare system
Unnecessary investigations or treatments

Question 3

what are the 2 methods of classifying ADR?

Answer 3

ABCDEFG
DOTS

Question 4

outline what the ABCDEFG stands for when classifying ADR.

Answer 4

Augmented
Bizarre
Chronic/continuing
Delayed
End of use/withdrawal
Failure of treatment
Genetic

Question 5

outline type A (augmented) ADR and give examples.

Answer 5

Most common type of ADR (80%)
Exaggerated effect of drugs pharmacology at a therapeutic dose
Often not life threatening
Dose dependent and reversible upon withdrawing the drug

Examples:
AKI with ACE inhibitors
Bradycardia with betablockers
Hypoglycaemia with gliclazide, insulin
Respiratory depression with opiates
Bleeding with anticoagulants

Question 6

outline type B (bizarre) ADR and give examples.

Answer 6

Not related to pharmacology of drug
Not dose related
Can cause serious illness or mortality
Symptoms do not always resolve upon stopping drug

Examples:
Anaphylaxis with penicillins
Tendon rupture with quinolone antibiotics
Steven Johnson Syndrome with IV vancomycin

Question 7

outline type C (chronic/continuing) ADR and give examples.

Answer 7

ADRs that continue after the drug has been stopped

Examples:
Osteonecrosis of the jaw with bisphosphonates
Heart failure with pioglitazone

Question 8

outline type D (delayed) ADR and give examples.

Answer 8

ADRs that become apparent some time after stopping the drug

Examples:
Leucopenia with chemotherapy

Question 9

outline type E (end of use/withdrawal) ADR and give examples.

Answer 9

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

Question 10

outline type F (failure of treatment) ADR and give examples.

Answer 10

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

Question 11

outline type G (genetic) ADR and give examples.

Answer 11

Drug causes irreversible damage to genome

Examples:
Phocomelia in children of women taking thalidomide

Question 12

outline what the DOTS method of ADR classification is and when is it most useful.

Answer 12

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

Question 13

what are the 3 dose-relatedness classifications according to DOTS and explain them.

Answer 13

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)

Question 14

outline DOTS timing.

Question 15

outline DOTS susceptability.

Answer 15

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)

Question 16

what are the steps of identifiying an ADR?

Answer 16

Pre-clinical testing (computer models, cells and toxicity testing in animals)

Clinical trial data (pre-marketing evaluation)

Post marketing surveillance

Pharmacovigilance

Question 17

outline what is involved during the clinical trials step of identifying ADRs.

Answer 17

Prior to the thalidomide disaster there was no need for manufacturers to demonstrate the efficacy or safety of a drug
MHRA (Medicines Healthcare Regulatory Authority) is responsible for monitoring drug safety (from clinical trial stage and post-marketing)
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

Question 17

outline what is involved during the pre-clinical trials step of identifying ADRs.

Answer 17

Computer modelling
Testing in animals before being given to humans
Long term administration in different species
Toxic doses given to identify likely ‘targets’ of toxic effects
Recovery studies aim to 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

Question 18

outline the limitations of pre-marketing evaluation.

Answer 18

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

Question 19

outline what is involved during the post marketting surveillance step of identifying ADRs.

Answer 19

Full ADR profile is unlikely to be understood once the drug is in widespread clinical use
ADR frequency (including rare ADRs)
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)

Question 20

outline what is black triangle medicines.

Answer 20

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

Question 21

outline what is involved during the pharmacovigilance step of identifying ADRs.

Answer 21

• 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

Question 22

Q: What is the Yellow Card System for ADRs?

Answer 22

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.

Question 23

outline the stregnths and weknesses of the yellow card system.

Answer 23

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

Question 24

what should you look out for when prescribing drugs to patients to reduce and avoid ADRs?

Answer 24

Patient groups at increased risk of ADRs
Drugs which most commonly cause ADRs
Drugs with potential for serious ADRs

Question 25

when identifying who is at increased risk of ADRs, what genetic variations could be dangerous.

Answer 25

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)

Question 26

what are high risk drugs for ADR

Answer 26

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

Question 27

outline some actions that prescribers can take to reduce the risk of ADRs.

Answer 27

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

Question 28

who can have an ADR?

Answer 28

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…

Question 29

when should we suspect an ADR?

Answer 29

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

Question 30

when should we report an ADR?

Answer 30

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

Question 30

What should we do if there is an ADR is suspected?

Answer 30

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

Question 31

how do you complete a yellow card when reporting an ADR and what information is required?

Answer 31

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

Question 32

what processes happen once an ADR has been confirmed to a medication?

Answer 32

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