18th March 2024

Adverse drug reactions

Overview

Adverse Drug Reactions (ADRs) can be defined as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to use of the medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of drug regime or withdrawal of the product.” Important aspects to consider when labelling a reaction as an ADR include a causal relationship between the medication and the effect (which can be difficult to establish, particularly in the context of polypharmacy) and that the effect observed resulted from a dose which is considered safe in humans.

The effects of ADRs are significant at both an individual and organisation level: 6-7% of hospital admissions are related to ADR. The term “pharmacovigilance” relates to the accountability of healthcare professionals to monitor the safety of medications; in the UK the Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) is ultimately responsible. Clinicians should be familiar with the process for reporting concerns and ADRs, specifically via the Yellow Card Scheme.

Classification of adverse drug reactions

ADRs can be classified into six subtypes with the mnemonic:

• Augmented – dose-related: these result from an increased effect of the drug’s pharmacology when given at the usual dose
• Bizarre – non-dose-related: these cannot be predicted from the drug’s pharmacology
• Chronic – time-related and dose-related: the effect may persist for an extended period of time despite withdrawal of the drug
• Delayed – time-related: the observed effect presents a period of time after the administration of the drug (therefore, these reactions can be particularly difficult to relate to the initial drug)
• End of Use – withdrawal: these include withdrawal effect of the drug after discontinuation
• Failure – failure of therapy

Of the ADRs described above, the most common type is an augmented/dose-related; these constitute 80% of ADRs.

In this way, type A may be considered pharmacological and type B immunological:

Type A reactions: These may arise from pharmacokinetic or pharmacodynamic variations. At this point, we can review what is meant by these terms:

Examples of pharmacokinetic causes of ADRs include pharmacogenetic variations. Application of pharmacogenetics within clinical practice is rapidly increasing as genetic variations are identified which affect a particular drug’s pharmacokinetics within an individual: this allows individual assessment of a drug’s safety and efficacy and can advise dosing. A clinical example is checking a patient’s thiopurine S-methyltransferase (TPMT) prior to initiation of azathioprine therapy. Specific genetic variations within the TPMT gene affect the metabolism of azathioprine; patients with genetic mutations that confer a low TPMT activity may be unable to effectively metabolise azathioprine causing build-up and risk of myelosuppression. Conversely, patients with higher TMPT levels may metabolise azathioprine more effectively than others, necessitating a higher dose.

Pharmacodynamic-mediated ADRs may occur when multiple drugs taken in combination have similar, potentiating or competing, antagonistic effects on their specific target site, often at a receptor level. A different example is that of a cutaneous folliculitis associated with endothelial growth factor receptor (EGFR) antagonists. EGFR is a common target in a variety of cancer therapeutics, but its blockade is associated with a rash that is dose-dependent and can limit its use.

Type B reactions: These are non-dose dependent and considered to have an immunological basis. Here, we can consider Gell and Coombs’ classification of hypersensitivity reactions:

Gell and Coombs classification of drug reactions

In the context of drug reactions:

Type I: Drug-induced anaphylaxis is one of the most common causes of anaphylaxis, especially in inpatients and in older populations. Furthermore, when anaphylaxis is secondary to drugs it is associated with a worse prognosis. It can be related to any drug, however non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics (penicillins) are the most common culprits.

Type II: Reactions include heparin induced hypersensitivity. This occurs due to activation of IgG antibodies against heparin-platelet factor 4 complexes.

Type III: A Streptococcal throat infection leading to immune complex deposition in the kidney causing glomerulonephritis usually within 10 to 21 days.

Type IV: Examples of drug-induced delayed hypersensitivity reactions mediated by T cells include: DILI (drug-induced liver injury), DRESS (drug reaction with eosinophilia and systemic symptoms), TEN (toxic epidermal necrolysis), DIA (drug-induced agranulocytosis) and AGEP (acute generalised exanthematous pustulosis).

Severe Cutaneous Adverse Reactions (SCARs)

SCARs comprise of several distinct conditions with overlapping features. They are all T cell-mediated:

• Acute Generalised Exanethematous Pustulosis (AGEP) – a rare pustular drug eruption characterised by superficial pustules which usually develop within two days of exposure to the culprit medication. The rash usually starts on the face or in axillary folds and may be associated with a fever, however patients very rarely deteriorate in contrast to other SCARs
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) – a severe multi-organ drug reaction including pyrexia, morbilliform skin eruption, eosinophilia and hepatic injury. Lymphadenopathy is often a feature. It is particularly associated with anticonvulsant medication. DRESS is slower to develop than AGEP and is usually seen within two to eight weeks of starting the responsible medication. Immediate withdrawal of the culprit drug is warranted and systemic immunosuppression is often required. Many patients require intensive care and this condition is associated with significant morbidity and mortality.
• Toxic Epidermal Necrolysis (TEN) – a very rare adverse drug reaction more commonly seen in drugs with longer washout periods. Timing of presentation can be variable but is usually within four weeks of drug exposure. TEN is more common in patients with Human Immunodeficiency Virus. Appearance of a painful, erythematous, diffuse rash is often preceded by pyrexia and flu-like illness. Mucosal involvement can be extremely severe with ocular, gastrointestinal, genital, urinary and respiratory tract pathology. Shock and multiple organ failure can develop rapidly.

Important adverse drug reactions

References

• Edward IR, Aronson JK. Adverse drug reactions: definitions, diagnosis and management. Lancet 2000;356(9237):1255-1259
• National Institute for Clinical Excellence: Adverse Drug Reactions, last reviewed March 2017: https://cks.nice.org.uk/topics/adverse-drug-reactions/
• World Health Organisation. Collaborating Centre for International Drug Monitoring, Safety Monitoring of Medicinal Products, Guidelines for setting up and running a Pharmacovigilance Centre. Uppsala: World Health Organisation; 2000
• Böhm R, Proksch E, Schwarz T, Cascorbi I. Drug Hypersensitivity. Dtsch Arztebl Int. 2018 Jul 23;115(29-30):501-512
• Gauba V, Saldanha M, Vize C, Saleh GM. Thiopurine methyltransferase screening before azathioprine therapy. Br J Ophthalmol. 2006 Jul;90(7):923-4