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Adverse Drug Reactions &
Interactions
Seminar 1: MPHM
Learning Objectives
- Understand what an adverse drug
reaction (ADR) is
- Know how to identify & how to manage
ADRs in a clinical situation
- Know how to report an ADR & which
ones should be reported
Learning Objectives
- Understand what an interaction is, how
they can affect a patient’s treatment & how
to manage them in a clinical situation
- Be aware of examples in practice of
common drug interactions
Adverse Drug
Reactions
ADRs – Type A & B
Type A Type B
Pharmacologically predictable
Yes No
Dose-dependent Yes No
Incidence High (usually)^ Low (usually)
Morbidity High (usually)^ Low (usually)
Mortality Low (usually) High (usually)
Management
Dose adjustment may be appropriate
Stop
ADRs – Examples: Type A
- Bradycardia with beta blockers
- Cough with ACE inhibitors
- Carcinogenesis
- Teratogenicity
ADRs – Examples: Type B
- Rash with penicillins (immunological
reaction)
- Aplastic anaemia with chloramphenicol
- Malignant hyperthermia with
anaesthetics
ADRs – Importance
They are common:
- GPs estimated that the presenting symptom of 1.7% of their consultations over a six month period was a manifestation of an ADR Millar JS. Consultations owing to adverse drug reactions in a single practice. Br J Gen Pract 2001;51:130-
- 2 - 6% of hospital admissions are for ADRs (these are probably underestimates) Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK. Adverse drug reactions. BMJ 1998;316:1295-8.
- They can cause death, permanent damage, necessitate withdrawal of drug, etc.
ADRs – Is it one?
(Or how do we know if the drug is to blame)
- This is the major problem with identifying
(& therefore managing) ADRs
- Problems:
- Delayed onset
- Multiple drugs started at the same time
- Are the symptoms indicative of another disease that co-exists in this patient?
- Drugs unknown to the healthcare professional (e.g. OTCs)
- Is the diagnosis correct?
ADRs – Identifying
- Need a full history – especially all drugs/supplements
- Timing of symptoms
- Did the event occur after an appropriate interval?
- Dose
- Is the dose high for this specific patient? (Think about age & interactions)
- Nature of problem
- Is character consistent/inconsistent with pharmacology of drug?
ADRs – Identifying
- Experience
- Has this reaction previously been reported for this drug?
- De-challenge/re-challenge
- Does the reaction stop when the drug is withdrawn & reoccur when restarted?
- Not always advisable
- Alternative aetiologies
- Is another cause of the reaction/problem likely?
- Does the patient have a previous history of these symptoms?
ADR – Identifying
Example algorithm
Was the drug taken prior to development of symptoms?
No (^) Not ADR
Yes
Are symptoms related in time to use of the drug?
No (^) ADR unlikely No Yes
Is the ADR documented in the BNF/SPC/Martindale?
No
4 Is it a^ ▼^ drug?
No
Is there any other evidence of an ADR (e.g. rechallenge, dechallenge, past history)?
Yes Yes^ Yes Consider possible ADR
NOTE: If more than one drug, checkeach one through algorithm
ADRs - Reporting
MHRA
- UK government body
- Principal aim is to protect the public’s health by
making sure that medicines and medical
devices work properly and are acceptably safe
- Introduced yellow cards in 1964
ADRs - Reporting
Yellow Cards
- Allow healthcare professionals AND patients to
report suspected ADRs
- Includes POMs, OTCs & herbal remedies
- Advantages:
- Applicable to whole of drug’s life
- Relatively inexpensive to operate
- Confidential
ADRs - Reporting
- Reporting has led to:
- Withdrawal of benoxaprofen
- Identifying risk of convulsions with
quinolones
- Rosuvastatin, revised dosing instructions
- Dabigatran, contraindications clarified
ADRs – (lack of) Reporting
- Low level of reporting
- Evidence to suggest <15% of hospital doctors & GPs report ADRs meeting criteria
- Reporting by pharmacists is also low
- Reasons?
- Complacency, fear, guilt, ambition, ignorance, diffidence, lethargy
Report!
Do not have to be sure about causality
ADR
Questions
Drug
Interactions
Interaction - Definition
- “ An interaction is said to occur when the
effects of one drug are changed by the
presence of another drug, food, drink or by
some other environmental chemical agent.”
I Stockley, 2007
OR
- “When one medicine falls out with
another…”
Interactions – Serious?
- So, how serious are interactions?
(Or ‘just because it interacts does it mean its worth
doing anything about it?’)
- Not always significant (relatively few pairs of
drugs that should always be avoided)
- Some interactions are useful
E.g. ACE inhibitors & diuretics
- Synergistic interaction for hypertensive patients
Interactions – Serious?
Interactions can:
- Prevent correct treatment E.g. if it prevents use of a drug
- Cause harm/discomfort to patients
- Require (in)expensive tests E.g. Blood level monitoring or blood tests to monitor potential adverse events
- Prolong/cause hospital stay
- Death
Interactions – Mechanisms
- Some drugs interact in unique ways, but
many interact using common mechanisms.
- The same pharmacokinetic &
pharmacodynamic principles that
determine the behaviour of drugs in body
can be applied to drug interactions.
- Many drugs interact by more than one
mechanism (often simplified in texts)
Interactions – Mechanisms
Pharmacokinetics Pharmacodynamics
Absorption
Additive/synergistic interactions & combined toxicity Drug displacement (protein-binding)
Antagonistic/opposing interactions Drug metabolism (induction/inhibition) Changes in drug transport
Changes in excretion
Changes in fluid/electrolyte balances
Interactions – Time course
- Interactions are most likely to occur when the
interacting drug is introduced or stopped
(beware of length of half-lives)
- The effects of interactions will not always appear
immediately:
- some may take a period of time to occur E.g. enzyme inducers may take 1-3 weeks until maximal effect (compare to enzyme inhibitors which usually have an effect within 24 hours)
- some may require a trigger E.g. illness
Interactions - Problems
- BNF 88 pages of interactions – remember them all??
- But, normally few “ • ” (clinically significant) interactions per page
- Disagreement about significance e.g. BNF – Thyroid hormones & Calcium salts – not “ • ” SPC – Avoid by 4hrs
BNF – Bisphosphonates & Calcium salts – not “ • ” Common practice – Change timings…
Interactions - Problems
- Patient variability is very considerable (predisposing / protecting factors) often very difficult to predict which patients will be affected
- Time course information not always known (& often just estimates)
- Food / caffeine / alcohol
- How relevant is it to patient?
- How do you counsel (/“convince”) patient?
Interactions - Management
Seriousness of interaction vs. risk of interaction occurring
- Can do nothing/monitor situation (i.e. wait & see)
- ‘Potential’ interaction may not cause any problems/be clinically significant
- However, may cause a problem & you may not realise until harm has been done
- Can monitor patient/drug levels/markers (e.g INR with warfarin)
- Is effect of interaction potentially beneficial?
E.g. 2 antihypertensives in a patient with raised BP
