Adverse Drug Reaction (ADR)
Adverse effect is ‘any undesirable or unintended consequence of drug administration’. It is a broad term, includes all kinds of noxious effect trivial, serious or even fatal. For the purposes of detecting and quantifying only those adverse effects of a drug which are of some import and occur in ordinary therapeutic setting, the term adverse drug reaction (ADR) has been defined as ‘any noxious change which is suspected to be due to a drug, occurs at doses normally used in man, requires treatment or decrease in dose or indicates caution in the future use of the same drug’. This definition excludes trivial or expected side effects and poisonings or overdose.
Another term ‘adverse drug event’ (ADE) has been used to mean ‘any untoward medical occurrence that may present during treatment with a medicine, but which does not necessarily have a causal relationship with the treatment’. The idea is to record all adverse events first, and look for causality only while analyzing pooled data. All drugs are capable of producing adverse effects, and whenever a drug is given a risk is taken.
The magnitude of risk has to be considered along with the magnitude of expected therapeutic benefit in deciding whether to use or not to use a particular drug in a given patient, e.g. even risk of bone marrow depression may be justified in treating cancer, while mild drowsiness caused by an antihistaminic in treating common cold may be unacceptable. Adverse effects may develop promptly or only after prolonged medication or even after stoppage of the drug. Adverse effects are not rare; an incidence of 10–25% has been documented in different clinical settings. They are more common with multiple drug therapy and in the elderly.
Adverse effects have been classified in many ways. One may divide them into:
Predictable (Type A or Augmented) reactions (mechanism based adverse reactions)
These are based on the pharmacological properties of the drug, which means that they are augmented, but qualitatively normal response to the drug; include side effects, toxic effects and consequences of drug withdrawal. They are more common, dose related and mostly preventable and reversible.
Unpredictable (Type B or Bizarre) reactions
These are based on peculiarities of the patient and not on drug’s known actions; include allergy and idiosyncrasy. They are less common, often non-dose related, generally more serious and require withdrawal of the drug. Some of these reactions can be predicted and prevented if their genetic basis is known and suitable test to characterize the individual’s phenotype is performed.
Severity of adverse drug reactions has been graded as:
Minor: No therapy, antidote or prolongation of hospitalization is required.
Moderate: Requires change in drug therapy, specific treatment or prolongs hospital stay by atleast one day.
Severe: Potentially life-threatening, causes permanent damage or requires intensive medical treatment.
Lethal: Directly or indirectly contributes to death of the patient.
Adverse drug effects may be categorized into:
1. Side effects
These are unwanted but often unavoidable pharmacodynamic effects that occur at therapeutic doses. Generally, they are not serious, can be predicted from the pharmacological profile of a drug and are known to occur in a given percentage of drug recipients. Reduction in dose, usually ameliorates the symptoms. A side effect may be based on the same action as the therapeutic effect, e.g. atropine is used in preanaesthetic medication for its antisecretory action. The same action produces dryness of mouth as a side effect. Glyceryl trinitrate relieves angina pectoris by dilating peripheral vasculature which is also responsible for postural hypotension and throbbing headache.
The side effect may also be based on a different facet of action, e.g. promethazine produces sedation which is unrelated to its antiallergic action; estrogens cause nausea which is unrelated to their antiovulatory action.
An effect may be therapeutic in one context but side effect in another context, e.g. codeine used for cough produces constipation as a side effect, but the latter is its therapeutic effect in traveller’s diarrhoea; depression of A-V conduction is the desired effect of digoxin in atrial fibrillation, but the same may be undesirable when it is used for CHF.
Many drugs have been developed from observation of side effects, e.g. early sulfonamides used as antibacterial were found to produce hypoglycaemia and acidosis as side effects which directed research resulting in the development of hypoglycaemic sulfonylureas and carbonic anhydrase inhibitor acetazolamide.
2. Secondary effects
These are indirect consequences of a primary action of the drug, e.g. suppression of bacterial flora by tetracyclines paves the way for superinfections; corticosteroids weaken host defence mechanisms so that latent tuberculosis gets activated.
3. Toxic effects
These are the result of excessive pharmacological action of the drug due to overdosage or prolonged use. Overdosage may be absolute (accidental, homicidal, suicidal) or relative (i.e. usual dose of gentamicin in presence of renal failure). The manifestations are predictable and dose related. They result from functional alteration (high dose of atropine causing delirium) or drug induced tissue damage (hepatic necrosis from paracetamol overdosage).
The CNS, CVS, kidney, liver, lung, skin and blood forming organs are most commonly involved in drug toxicity. Toxicity may result from extension of the therapeutic effect itself, e.g. coma by barbiturates, complete A-V block by digoxin, bleeding due to heparin. Another action of the drug can also be responsible for toxicity, e.g.—
- Morphine (analgesic) causes respiratory failure in overdosage.
- Imipramine (antidepressant) overdose causes cardiac arrhythmia.
- Streptomycin (antitubercular) causes vestibular damage on prolonged use.
It is the appearance of characteristic toxic effects of a drug in an individual at therapeutic doses. It is the converse of tolerance and indicates a low threshold of the individual to the action of a drug. These are individuals who fall on the extreme left side of the Gaussian frequency distribution curve for sensitivity to the drug. Examples are:
- A single dose of triflupromazine induces muscular dystonias in some individuals,
- Only few doses of carbamazepine may cause ataxia in some people.
- One tablet of chloroquine may cause vomiting and abdominal pain in an occasional patient.
It is genetically determined abnormal reactivity to a chemical. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. As such, the type of reaction is restricted to individuals with a particular genotype. In addition, certain bizarre drug effects due to peculiarities of an individual (for which no definite genotype has been described) are included among idiosyncratic reactions, e.g.:
- Barbiturates cause excitement and mental confusion in some individuals.
- Quinine/quinidine cause cramps, diarrhoea, purpura, asthma and vascular collapse in some patients.
- Chloramphenicol produces nondose-related serious aplastic anaemia in rare individuals
6. Drug allergy
It is an immunologically mediated reaction producing stereotype symptoms which are unrelated to the pharmacodynamic profile of the drug, generally occur even with much smaller doses and have a different time course of onset and duration.
This is also called drug hypersensitivity but does not refer to increased response which is called supersensitivity. The target organs primarily affected in drug allergy are skin, airways, blood vessels, blood and gastrointestinal tract.
Allergic reactions occur only in a small proportion of the population exposed to the drug and cannot be produced in other individuals at any dose. Prior sensitization is needed and a latent period of at least 1–2 weeks is required after the first exposure.
It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation.
8. Drug dependence
Drugs capable of altering mood and feelings are liable to repetitive use to derive euphoria, recreation, withdrawal from reality, social adjustment, etc. Drug dependence is a state in which use of drugs for personal satisfaction is accorded a higher priority than other basic needs, often in the face of known risks to health.
9. Drug withdrawal Reactions
Apart from drugs that are usually recognised as producing dependence, sudden interruption of therapy with certain other drugs also results in adverse consequences, mostly in the form of
The first question healthcare providers should ask themselves is “why is it important to learn about ADRs?” The answer is because ADRs are one of the leading causes of morbidity and mortality in health care. The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000 deaths occur annually from medical errors.1 Of this total, an estimated 7,000 deaths occur due to ADRs. To put this in perspective, consider that 6,000 Americans die each year from workplace injuries.