Adverse drug reactions: what they are and how to manage adverse effects
Adverse effects: Unwanted drug reactions can be considered a form of toxicity; however, the concept of toxicity is most commonly applied to effects due to overdose (accidental or intentional) or to elevated plasma levels or increased drug effects that occur during appropriate use (e.g. when the metabolism of the drug is temporarily inhibited by a disease or another drug)
For information on the toxicity of specific drugs see table Symptoms and treatment of specific poisons.
The term side effects is imprecise and is often used to refer to unexpected effects of the drug that occur during the use of therapeutic doses.
Adverse effects, some key points
Because all drugs have the potential to cause adverse reactions, risk-benefit analysis (which analyses the likelihood of the drug’s benefit versus the risk of adverse reactions) is necessary when a drug is prescribed.
In the United States, 3 to 7% of all hospitalisations are due to adverse drug reactions.
Adverse drug reactions occur in 10-20% of hospitalised patients and about 10-20% of these are severe.
These statistics do not include the number of adverse drug reactions occurring in outpatients and nursing homes.
Although the exact number of adverse drug reactions is uncertain, they represent a serious public health problem that, for the most part, is preventable (1, 2).
The incidence and severity of adverse drug reactions may vary due to patient characteristics (e.g. age, gender, ethnicity, co-existing diseases, genetic or geographical factors) and pharmacological factors (e.g. type of drug, route of administration, duration of therapy, dose, bioavailability).
The incidence is higher with advanced age and polypharmacy. Adverse drug reactions are more severe in elderly patients, although age per se may not be the primary cause.
The extent to which prescribing errors and lack of patient compliance contribute to the incidence of adverse drug reactions is unclear.
Adverse drug reactions: aetiology
Most adverse drug reactions are dose-related; others are allergic or idiosyncratic.
Dose-related adverse drug reactions are generally predictable.
Adverse drug reactions that are not dose-related are usually unpredictable.
Dose-related adverse drug reactions are of particular concern when the drugs have a narrow therapeutic index (e.g. bleeding from oral anticoagulants).
Adverse drug reactions may result from decreased drug clearance in patients with impaired renal or hepatic function or from drug-drug interactions.
Allergic adverse drug effects are not dose-related and require prior exposure
Allergies develop when a drug acts as an antigen or allergen.
After a patient is sensitised, subsequent exposure to the drug produces one of several types of allergic reaction.
History and appropriate skin tests can sometimes help to predict unwanted allergic drug reactions.
Idiosyncratic adverse drug reactions are unexpected adverse drug reactions that are neither dose-related nor allergic in nature.
They occur in a small percentage of patients taking a drug.
Idiosyncrasy is an imprecise term, and has been defined as a genetically determined abnormal response to a drug, but not all idiosyncratic reactions recognise a pharmacogenetic cause.
The term may become obsolete as the specific mechanisms of adverse drug reactions become known.
Symptomatology of diseases related to adverse drug effects
Adverse drug reactions are generally classified as mild, moderate, severe or fatal.
Serious or life-threatening adverse drug reactions may be specifically mentioned in black box warnings in the manufacturer’s prescribing information.
Symptoms may occur immediately after the first intake or only after chronic use.
Some undesirable drug reactions are easily attributable to the use of drugs, others consist of mild manifestations that are difficult to identify as a consequence of taking a drug.
In the elderly, adverse drug reactions, even mild ones, can cause functional impairment, changes in mental status, growth difficulties, loss of appetite, confusion and depression.
Allergic adverse drug reactions typically occur immediately after taking a drug, but generally do not occur after the first dose; typically, they occur when the drug is administered after a previous exposure.
Symptoms include itching, rash, drug rash, oedema of the upper or lower respiratory tract with difficulty breathing and hypotension.
Idiosyncratic adverse drug reactions can occur with virtually any symptom or sign and usually cannot be predicted.
Diagnosis of adverse drug effects
Usually, symptoms occurring immediately after taking a drug are easily related to the use of the drug.
However, the diagnosis of symptoms due to chronic drug use requires significant diagnostic suspicion and is often complicated.
Deciding to discontinue a drug is sometimes necessary but difficult if the drug is essential and there is no acceptable substitute.
If the evidence of a relationship between drug and symptoms is high, the possibility of re-administration of the drug should be considered, except in the case of severe allergic reactions.
In the United States, physicians must report the most suspicious symptoms of adverse drug reactions to MedWatch (the FDA’s [Food and Drug Administration] adverse drug reaction surveillance programme), which is an early warning system.
Only through such reports can unexpected adverse drug reactions be identified and investigated.
MedWatch also monitors changes in the nature and frequency of adverse drug reactions.
Online reporting of adverse drug reactions is recommended.
Forms for reporting adverse drug reaction information are available in the Physicians’ Desk Reference and the FDA (Food and Drug Administration) News Daily Drug Bulletin, as well as at www.fda.gov (MedWatch: The FDA Safety Information and Adverse Event Reporting Program); forms can also be obtained by calling 800-FDA-1088.
Nurses, pharmacists, and other health care professionals should also report adverse drug reactions.
The FDA’s Adverse Event Reporting System (FAERS) is a research tool that improves access to data on adverse drug reactions (1).
The incidence of serious or life-threatening adverse drug reactions is very low (typically < 1 in 1000) and may not be evident during clinical trials, which are generally not sized to detect low incidence adverse drug reactions.
Thus, these adverse drug reactions may only be detected after a drug is released to the public and is in widespread use.
Physicians should not assume that, as soon as a drug is on the market, all adverse drug reactions are known.
Post-marketing surveillance is extremely important for monitoring adverse drug reactions at low incidence.
- Dosage modification
- Discontinuation of the drug, if necessary
- Switching to another drug
For dose-dependent adverse drug reactions, dose modification or elimination/reduction of triggers may be sufficient.
Increasing the rate of elimination of the drug is rarely necessary.
In the case of undesirable reactions to allergic and idiosyncratic drugs, it is usually necessary to discontinue the drug and avoid administering it again.
Switching to a different drug class is often necessary in the case of allergic adverse reactions and sometimes necessary for dose-related ones.
For example, opioid-induced constipation can be improved by the use of an opioid receptor antagonist such as lubiprostone.
Adverse drug effects: prevention
Prevention of adverse drug reactions requires knowledge of the drug and potential reactions to it.
Analyses should be carried out with appropriate software to check for potential drug interactions; analyses should be repeated each time drugs are changed or added.
In the elderly, drugs and starting doses should be chosen carefully.
If patients develop non-specific symptoms, undesirable drug reactions should always be considered before starting symptomatic treatment.
Several genes have been identified as having an association with adverse drug reactions.
For example, multiple liver enzymes affecting cytochrome P450 metabolism have been characterised, and many are affected by single nucleotide polymorphisms, leading to clinically significant effects on a wide range of commonly prescribed drugs.
Therefore, pharmacogenomics can help predict, reduce and minimise adverse drug reactions (1, 2).
However, only a limited number of such tests are used in routine clinical practice (e.g. genotype-guided warfarin therapy ).