Introduction
An adverse drug reaction (ADRs) is an unwanted, undesirable effect of a medication that occurs during usual clinical use. Adverse drug reactions occur almost daily in health care institutions and can adversely affect a patient’s quality of life, often causing considerable morbidity and mortality.
Adverse drug reactions may cause patients to lose confidence in or have negative emotions toward their physicians and seek self-treatment options, which may consequently precipitate additional ADRs.
Around 5% of all hospital admissions are the result of an ADR, and around 10%– 20% of inpatients will have at least one ADR during their hospital stay (Kongkaew 2008; Lundkvist 2004; Pirmohamed 1998).
This article discusses methods of ADR detection and classification and associated treatment strategies.
Defining ADRs
The definition of an ADR is often confused with that of an adverse drug event (ADE). The World Health Organization (WHO) defines an ADE as
“Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment” (WHO 2005).
The WHO defines an ADR as “a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.”
Classification of ADRs
Adverse drug reactions were originally classified into two subtypes.
Type A ADRs are dose-dependent and predictable; they are augmentations of known pharmacologic effects of the drug, such as orthostatic hypotension with antihypertensive medications.
Type B ADRs are uncommon and unpredictable, depending on the known pharmacology of the drug; they are independent of dose and affect a small population, suggesting that individual patient host factors are important (Pirohamed 2003; Edwards 2000).
Hypersensitivity (allergic) reactions to drugs are examples of type B ADRs. Type A reactions were later called augmented, and type B reactions, bizarre.
Two further types of reactions were eventually added: chronic reactions, which relates to both dose and time (type C), and delayed reactions (type D).
Withdrawal later became the fifth category (type E), and most recently, unexpected failure of therapy became the sixth (type F) (Rohilla 2013; Edwards 2000).
| Type of Reaction (Mnemonic) | Features | Examples | Management |
| A: Dose related (Augmented) | Common Related to the pharmacologic action of the drug – exaggerated pharmacologic response Predictable Low mortality | Dry mouth with tricyclic antidepressants, respiratory depression with opioids, bleeding with warfarin, serotonin syndrome with SSRIs, digoxin toxicity | Reduce dose or withhold drug Consider effects of concomitant therapy |
| B: Non–dose related (Bizarre) | Uncommon Not related to the pharmacologic action of the drug Unpredictable High mortality | Immunologic reactions: anaphylaxis to penicillin Idiosyncratic reactions: malignant hyperthermia with general anesthetics | Withhold and avoid in future |
| C: Dose related and time related (Chronic) | Uncommon Related to the cumulative dose | Hypothalamic-pituitary-adrenal axis suppression by corticosteroids, osteonecrosis of the jaw with bisphosphonates | Reduce dose or withhold; withdrawal may have to be prolonged |
| D: Time related (Delayed) | Uncommon Usually dose related Occurs or becomes apparent sometime after use of the drug | Carcinogenesis Tardive dyskinesia Teratogenesis Leucopenia with lomustine | Often intractable |
| E: Withdrawal (End of use) | Uncommon Occurs soon after withdrawal of the drug | Withdrawal syndrome with opiates or benzodiazepines (e.g., insomnia, anxiety) | Reintroduce drug and withdraw slowly |
| F: Unexpected failure of therapy (Failure) | Common Dose related Often caused by drug interactions | Inadequate dosage of an oral contraceptive when used with an enzyme inducer Resistance to antimicrobial agents | Increase dosage Consider effects of concomitant therapy |
Populations at Greatest Risk Due To ADRs
Pediatrics
Adverse drug reactions are common in the pediatric population. Developmental changes affect the pharmacodynamics and pharmacokinetics of many of the drugs used in neonates, infants, and children.
For example, gastric emptying is delayed in neonates and infants, resulting in longer absorption time and potentially increasing the risk of an ADR.
The volume of distribution also differs, compared with adults, as does protein-binding capacity, phase I and II metabolic pathways, and glomerular filtrate rate. Therefore, extrapolation of pediatric dosages from adult dosages should be avoided (Fabiano 2012).
Geriatrics
The WHO defines elderly as individuals 60 years and older. The percentage of people in this age category continues to rise and the total is expected to reach 2 billion by 2050 (Brahma 2013).
As the number of drugs increases, the risk of medication nonadherence also increases, further increasing the risk of an ADR. By examining the patient’s medication record and evaluating for duplicate therapies or medications being used to potentially treat ADRs caused by other medications, pharmacists can help reduce unnecessary prescribing and optimize the patient’s drug therapy regimen.
Detecting and preventing ADRs in the older adult population remains a challenging, yet important part of good clinical practice. Tools available to assist in evaluating potentially inappropriate prescribing in older adults include the Beers Criteria, IPET (Improved Prescribing in the Elderly Tool), MAI (Medication Appropriateness Index), and STOPP (Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions) (Petrovic 2012).
Renal and Hepatic Impairment
Most drugs are metabolized by the liver and excreted by the kidneys. Impairment or failure of either of these organs can affect drug absorption, distribution, bioavailability, CYP metabolism, and clearance. Monitoring the laboratory values and adjusting the doses of drugs using these metabolic and excretory pathways can prevent an ADR.
Special consideration should be given to identifying and, if possible, avoiding drugs that undergo extensive hepatic first-pass metabolism in patients with hepatic impairment. Pharmacovigilance can be used to assist prescribers with dosing or alternative drug selection in these patients.
Conclusion
As medication experts, pharmacists are a vital part of the treatment team, especially when an ADR occurs. Treating an ADR consists mainly of supportive therapy with symptom management.
Furthermore, additional steps should be taken to determine the cause of the patient’s symptoms and whether they can be attributed to the use of a drug. Begin by evaluating the nature of the event. Thoroughly review the medical history available in the patient’s chart. Identify and document the clinical reaction, including the patient’s subjective report of symptoms.
Review the patient’s medication list, and then use references such as product inserts, MedWatch reports, and published literature to evaluate whether the reaction is known to occur with any of the drugs the patient has taken. Classify the severity of the reaction.
A severe reaction is fatal or life-threatening; the drug should be discontinued and not rechallenged. A moderate reaction requires an antidote, a medical procedure, or hospitalization. In many cases, this may mean discontinuing the drug. Mild reactions have symptoms that often require therapy discontinuation.
It is possible that the therapy can be reinitiated with an adjustment in dosage if the management of the disease state warrants continuation. Incidental reactions have mild symptoms; patients can choose whether to discontinue treatment, depending on their tolerability of the ADR.