Adverse drug reactions: A guide for general practice nurses

What is an adverse drug reaction?

An adverse drug reaction (ADR) can be defined as:

• An unwanted or harmful reaction, which occurs after administration of a drug or drugs and is suspected or known to be due to the drug(s).
• A response to a drug that is noxious, unintended, and occurs at doses normally used for prophylaxis, diagnosis, or treatment of disease, or for modification of physiological function.

An ADR may be a known effect of the drug, or a new and previously unrecognized effect.

There are other terms that should be distinguished:

• The terms 'adverse reaction' and 'adverse effect' are interchangeable but reflect different points of view: a drug has an adverse effect, whereas a person experiences an adverse reaction
• These terms are preferred to other terms, such as 'toxic effect' or 'side effect', because they encompass all unwanted effects. They make no assumptions about mechanism, evoke no ambiguity, and avoid the risk of misclassification.

Subtypes of adverse drug reaction

Type A reactions (pharmacological/augmented reactions) result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose (for example respiratory depression with opioids or bleeding with warfarin). These are dose dependent reactions and are therefore usually reversible on reducing the dose of (or withdrawing treatment with) the drug. Type A reactions also include those that are not directly related to the desired pharmacological action of the drug (for example, dry mouth with tricyclic antidepressants).

Type B reactions (idiosyncratic/bizarre reactions) cannot be predicted from the known pharmacology of the drug (for example, anaphylaxis with penicillin and skin rashes with antibiotics).

Type A adverse reactions are more common than Type B reactions and account for more than 80% of all reactions. Type B reactions may only be discovered for the first time after a drug has already been made available for general use.

Other categories of ADRs include:

Type C reactions (continuing reactions) — these persist for a relatively long time (for example, osteonecrosis of the jaw with bisphosphonates).

Type D reactions (delayed reactions) — these become apparent some time after the use of a drug, thereby making them more difficult to detect (for example, leucopenia starting six weeks following some chemotherapeutic drugs).

Type E reactions (end-of-use reactions) — these are associated with the withdrawal of a drug (for example, insomnia, anxiety, and perceptual disturbances following the withdrawal of benzodiazepines).

Type F reactions (unexpected failure of therapy) — these are often caused by drug interactions (for example, oral contraception failure when used with an enzyme inducer) or resistance to antimicrobial drugs.

How common are ADRs?

The precise numbers of ADRs that occur cannot be determined, given the difficulties in assessing causality and the low proportion of ADRs that are reported.

Most research has tried to quantify ADRs by evaluating hospitalised patients, and admissions in particular.

• The percentage of hospital admissions due to ADRs in the UK has been estimated to be 6–7%. One systematic review found 3.73% (range 1.36–15.42) of hospital admissions to be preventable and drug-related.
• ADRs are thought to occur in 10–20% of hospital in-patients. In one study, over 2% of people admitted with an ADR (approximately 0.15% of all people admitted) died.
• A systematic review estimated that the overall impact of ADRs in England was four out of 100 hospital bed-days, or about fifteen to twenty '400-bed hospital equivalents' at a cost of about £380 million a year to the NHS in England.
• A meta-analysis assessed the percentage of patients with preventable ADRs as well as the preventability of ADRs. For outpatients (n = 48,797 emergency visits/hospital admissions), the evidence showed that 2% had preventable ADRs, and 52% of ADRs present at the time of hospitalisation/emergency visit were assessed as preventable. For inpatients (n = 24,128 inpatients), the results showed that 1.6% had preventable ADRs during hospital stay, and 45% of ADRs were assessed as preventable.

Which reactions are most common?

The most common adverse reactions are nausea, itch and dizziness.

Other common non-specific symptoms are vomiting, headache and pyrexia.

Cutaneous reactions are also common and include rash, erythema and urticaria.

There is a variance between doctors’ and patients’ reporting of ADRs, with doctors more likely to report serious or life-threatening reactions.

Which drugs are most commonly involved?

A large study in Germany (involving 345,662 participants) found that antithrombotic agents were the most common therapeutic subgroup of drugs associated with ADRs, which included thrombocytopaenia, gastrointestinal (GI) haemorrhage and other bleeding phenomena.

Other groups associated with ADRs included:

• Antibacterials (diarrhoea, skin rash, pruritis)
• Antipsychotics (drug dependence, leukopenia, fever); antidepressants (nausea, dizziness, headache)
• Antineoplastic agents e.g. protein kinase inhibitors (dyspnoea, fever, thrombocytopenia)
• Anti-inflammatory drugs e.g. diclofenac, rofecoxib (hypertension, nausea, stroke)
• Analgesics (nausea, drug dependence, agranulocytosis)
• Anti-epileptics e.g. lamotrigine, cabamazepine (seizure, dizziness, hyponatraemia);
• ACE inhibitors, angiotensin receptor blockers (ARBs) (angioedema, cough, dizziness);
• Hormonal contraceptives (pulmonary embolism, deep vein thrombosis, pregnancy).

What else might it be?

Other possible causes of symptoms include:

• Manifestation of the person's underlying illness or another disease.
• Other medications (including self-medication and herbal remedies) could be responsible.

Consider the possibility of drug interactions (including with food and drinks).

How should I assess a person with a suspected adverse drug reaction?

Assess the nature and severity of the reaction.

This will determine whether urgent action is required or whether the person can be managed in primary care. For example, a cough due to an ACE inhibitor can be troublesome but not life threatening, but an anaphylactic reaction is a medical emergency.

The nature of the presenting condition may strongly suggest that it is an adverse drug reaction (ADR). For example, the following conditions are often ADRs:

• Acute dystonias (movement disorders)
• Blood disorders
• Skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis
• Neuroleptic malignant syndrome

How do I manage it?

Take a history of the presenting symptoms, including:

• When it started:
  • The time from when use of the drug was started to when the reaction develops may be characteristic of the reaction (for example anaphylaxis usually develops within a few minutes of parenteral drug administration).
  • If the drug was stopped, the time it took for the reaction to abate will often be related to the known duration of action of the drug.
• Relationship to dose
  • DRs are often dose related and may be minimised by reducing the dose of the drug. If the symptoms resolve when the drug is withdrawn, they may have been associated with the drug, although it could still have been coincidental. If a drug is reintroduced and symptoms recur, the drug is most probably responsible for the adverse reaction. However, deliberate re-challenge is only very rarely justified (clinically and ethically) after serious ADRs, because of the risks involved.
• Consider the drug history, and review any history of allergy or previous ADRs.
• Take a complete drug history, including when the drug was started, what dose is being taken, what other drugs are being taken, and whether the person is also taking over-the-counter (OTC) or herbal medicines.
• Check whether the person has ever had similar symptoms or presentation in the past with other drugs (from the same or a different drug class) or has a history of atopy or of ADRs with different presentation(s).
• Be aware that even if a drug was stopped some time before the ADR, it may have been responsible if it has a very long duration of action (for example, amiodarone).

How do I manage it?

Review the adverse effect profile of the drug and consider:

• Whether the signs and symptoms are in keeping with the documented adverse effect profile of the drug.
• Whether the ADR been reported before. This can be checked in the readily available sources of information, including:
  • The British National Formulary
  • The electronic Medicines Compendium www.medicines.org.uk
  • Interactive Drug Analysis Profiles (iDAPs) – a complete listing of suspected ADRs for individual drugs that have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA) through the Yellow Card scheme by health care professionals, members of the public, and pharmaceutical companies.

Regional and district medicine information services. Details of regional centres and other useful contacts can be found in the front of the BNF and BNF for Children (or online). Local services can found by contacting the medicines information department or the hospital pharmacy in major hospitals.

• Consider the need for further examination and investigations, if necessary. These may include specific investigations and laboratory tests, for example liver or renal function tests; assessing for further complications of the ADR, such as gastrointestinal bleeding; drug monitoring, for example checking serum digoxin concentrations in a person with suspected toxicity.

Following an initial assessment

• Arrange emergency hospital admission if the adverse drug reaction (ADR) is serious or life threatening.
• Assess whether the ADR can be managed in primary care.
• Consider seeking specialist advice.

If the ADR can be managed in primary care, review and discuss treatment options with the person. These may include:

• Stopping the suspected drug if the ADR is serious, or at the request of the individual, and avoiding its use in future.
• Considering alternative drug treatment if treatment of the original condition is still required.
• Considering altering the dose or temporarily stopping drug treatment if the benefit-to-harm balance of drug treatment is favourable.
• Considering the effects of concurrent treatments (drug interactions).
• Considering the possibility of withdrawal effects if drug treatment is stopped suddenly.

Manage symptoms of the ADR as appropriate

• Explain the benefits and harms if another drug is prescribed to treat the ADR.
• Record the ADR in the person's health record.

Who else might I tell?

You may wish to consider discussing the ADR with a specialist responsible who initiated the drug for this patient.

Additionally, you should also inform the MHRA.

The Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) are responsible for monitoring the safety of all medicines marketed in the UK.

Despite extensive research for specific medicines, some ADRs may not be seen until a very large number of people have used the medicine. It is therefore vital that the safety of all medicines is monitored throughout their marketed life, through a process known as pharmacovigilance.

Pharmacovigilance is the process of:

• Monitoring the use of medicines in everyday practice to identify previously unrecognized adverse effects or changes in the patterns of adverse effects.
• Assessing the risks and benefits of medicines to determine what action, if any, is necessary or needed to improve their safe use.
• Providing information to health care professionals and patients to optimize safe and effective use of medicines.
• Monitoring the effect of any action taken.
• Spontaneous ADR reporting schemes are important information sources for pharmacovigilance.

The UK's ADR reporting scheme, called the Yellow Card Scheme, is run by the MHRA and the Commission on Human Medicines (CHM).

The scheme receives voluntary reports of suspected ADRs from health professionals and members of the public. It assists in alerting the MHRA and CHM to new signals (or potential safety concerns), such as previously unrecognized ADRs or ADRs related to a specific drug. It also helps to confirm a signal of an ADR with limited information from an alternative data source, such as the literature or post-marketing studies, and also in evaluating comparative risks of related drugs. Information collected through the Yellow Card Scheme is vital in helping the MHRA and CHM monitor medicine safety.

Yellow Card reports are evaluated, alongside other information and evidence on medicine safety, to determine whether any regulatory action is required to allow medicines to be used more safely and effectively.

The MHRA works closely with other European regulatory authorities on pharmacovigilance matters.

Data from the Yellow Card Scheme underpins the process of pharmacovigilance in the UK. However, the UK pharmacovigilance system does not rely solely on ADR reporting. Other data sources regularly used in the monitoring of drug safety in the UK include clinical and epidemiological studies, worldwide published medical literature, pharmaceutical companies, worldwide regulatory authorities, and morbidity and mortality databases.

Pharmacovigilance and reporting of ADRs are important because the information collected during the pre-marketing phase of drug development is inevitably incomplete with regard to possible ADRs.

This is because :

• Tests in animals are insufficient to predict human safety.
• Participants in clinical trials are selected and limited in number; the conditions of actual use differ from those in clinical trials, and trials have limited duration.
• Exposure of fewer than 5,000 human subjects to a drug allows only the more common ADRs to be detected before the drug is licensed.
• At least 30,000 people need to be treated with a drug to be sure that at least one person with an ADR that has an incidence of 1 in 10,000 exposed persons is not missed.
• Information about rare but serious adverse reactions, long-term effects, use in special groups (such as children, elderly people, or pregnant women), or drug interactions is often incomplete or not available.
• It permits detection of less common but sometimes very serious ADRs.

Additional monitoring of ADRs is undertaken in the UK by other research organizations independent of the MHRA, such as:

The Drug Safety Research Unit (DSRU) in Southampton www.dsru.org

The Tayside Medicines Monitoring Unit (MEMO) www.dundee.ac.uk/memo

The Health Improvement Network (THIN) in London https://www.the-health-improvement-network.co.uk/

QResearch www.qresearch.org

Learning points

During this module you have learnt

• The definition of an adverse drug reaction (ADR)

• How common they are

• Which drugs are most commonly involved

• The range of differential diagnoses

• How to manage ADR

• Who to discuss or tell about ADRs including yellow card reporting

Suggested activity

Run a report on all patients coded as having suffered an adverse drug reaction, fixed drug reaction or drug allergy in the past 12 months.

How were the drug reactions classified, by severity, by system affected (GI, skin, CNS etc)?

How many required treatments, and of what type? Stopped medication? Reduced medication? Started different medication? Investigations? Admission to hospital or secondary care referral?

How many had a yellow card report? What percentage of the ADRs had a yellow card report?

Repeat the audit in 6 months to report on any increase in yellow card reporting.

References

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Aronson JK. (Eds.) Meyler's side effects of drugs. The international encyclopedia of adverse drug reactions and interactions. Oxford: Elsevier; 2006

Bandolier. Adverse drug reactions in hospital patients. A systematic review of the prospective and retrospective studies; 2002. Bandolier. www.medicine.ox.ac.uk/bandolier

BMA Board of Science. Reporting adverse drug reactions: a guide for healthcare professionals; 2006.

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MHRA. Monitoring the safety of medicines. https://yellowcard.mhra.gov.uk/monitoringsafety/

MHRA. New guidance on reporting suspected adverse drug reactions in children; 2014. https://www.gov.uk/drug-safety-update/new-guidance-on-reporting-suspected-adverse-drug-reactions-in-children

MHRA (2015b) The Yellow Card Scheme: guidance for healthcare professionals, patients and the public. https://www.gov.uk/guidance/the-yellow-card-scheme-guidance-for-healthcare-professionals

Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK. (1998) Adverse drug reactions. BMJ 1998;316(7140):1295-1298.

Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18820 patients. BMJ 2004;329(7456):15-19.

Rawlins MD, Thompson JW. Textbook of adverse drug reactions. In: Davies,D.M. (Eds.) Pathogenesis of adverse drug reactions. 1977; Oxford: Oxford University Press

Schatz SN, Weber RJ. Adverse Drug Reactions https://www.accp.com/docs/bookstore/psap/2015B2.SampleChapter.pdf

Smith CC, Bennett PM, Pearce HM, et al. (1996) Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. Br J Clin Pharmacol 1996;42(4): 423-429

Tan K, Petrie KJ, Faasse K, et al. Unhelpful information about adverse drug reactions. BMJ 2014; 349:g5019

WHO. Safety of medicines. A guide to detecting and reporting adverse drug reactions. Why health professionals need to take action; 2002. https://apps.who.int/iris/handle/10665/67378