Definition Of Adverse Drug Effect
Adverse effect is any undesirable or unintended consequence of drug administration. It is a broad term, includes all kinds of noxious effects – Trivial, serious or even fatal.
Adverse Drug reaction (ADR) –
- It excludes trivial or expected side effects and poisonings or overdose.
- Another term ‘Adverse drug event’ – Any untoward (unexpected and inappropriate or inconvenient) medical occurrence that may present during treatment with a medicine but which does not necessarily have a casual relationship with the treatment.
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 are 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, which means that they are augmented, but qualitatively normal response to the drug; includes side effects, toxic effects and consequences of the drug withdrawal. They are more common, dose related and mostly preventable and reversible.
- Unpredictable (Type B or Bizarre) reactions (adverse effects unrelated to the known pharmacological action of the drug) 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.
Another Classification –
Adverse drug effects may be categorized into :
- Side effects : These are unwanted but often unavoidable pharamacodynamic effects that occur at therapeutic doses. They 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 generally 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. But the same action produces dryness of mouth as a side effect. Side effect may also be based on different facet of action, E.g. promethazine produces sedation which is unrelated to its antiallergic action.
- Secondary effects : These are indirect consequences of a primary action of the drug, e.g. corticosteroids weaken host defence mechanisms so that latent tuberculosis gets activated.
- Toxic effects : These are the result of excessive pharmacological action of the drug due to overdosage or prolonged use. Overdosage maybe absolute (accidental, homicidal, suicidal) or relative (I.e. usual dose of gentamicin in presence of renal failure). The effects are predictable or dose related. E.g. High dose of atropine causing delirium, morphine (analgesic) causes respiratory failure in overdosage.
Note : The CNS, CVS, kidney, liver, lung, skin and blood forming organs are most commonly involved in drug toxicity.
Poisoning : May result from large doses of drugs because ‘it is the dose which distinguishes a drug from a poison’. Where poison is a ‘substance which endangers life by severely affecting one or more vital functions’.
- Intolerance : It is the appearance of characteristic toxic effects of a drug in an individual at therapeutic doses. Tolerance = a person’s diminished response to a drug that is the result of repeated use. Therefore, higher dose is required to produce initial normal effect. (Diazepem) E.g. One tablet of choloroquine may cause vomiting and abdominal pain in a occasional patient.
- Idiosyncrasy : 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. E.g. Barbiturates is a CNS depressant, but in some people the cause CNS stimulation (excitement and mental confusion).
- Drug Allergy : It is an immunologically mediated reaction producing stereotype (sample) symptoms that are unrelated to pharmacodynamic profile of the drug, generally occur even with much smaller dosage and have a different time course of onset and duration. Allergic reactions occur only in a small proportion of the population exposed to the drug and cannot be produced in another individuals in any dose.
Mechanism and types of allergic reaction :
B) Cell mediated
Refer to another article on Mechanism and types of allergic reaction for detail.
- Photosensitivity : It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation. The reactions are of two types:
(a) Phototoxic : Drug or its metabolite accumulates in the skin, absorbs light and undergoes a photochemical reaction resulting in local tissue damage (sunburn-like), i.e. erythema, edema, blistering followed by hyperpigmentation and desquamation. The shorter wave lengths (290-320 nm, UV-B) are responsible. E.g. Sulfonamides, thiazides, nalidixic acid…
(b) Photoallergic : Drug or its metabolite induces a cell mediated immune response which on exposure to light to light of longer wave lengths (320-400 nm, UV-A) produces a papular or eczematous contact dermatitis like picture. E.g. Chloroquine, chlorpromazine.
- Drug dependence : Drug dependence is a stage in which use of drugs for personal satisfaction is accorded a higher priority that other basic needs, often in the face of known risks to health.
(A) Psychological Dependence : It is a state that involves emotional-motivational withdrawal symptoms, where the individual believes that optimal state of well-being is achieved only through the actions of drug. E.g. People tend to feel that the treatment of any small problem can be achieved only after professional medical attention.
(B) Physical Dependence : It is a state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. Since the essence of the drug, it has been called ‘neuroadaptation’. E.g. Alcohol, opioids, barbiturates.
- Drug withdrawal reactions : It is a state in which symptoms occur upon cessation of repeated drug use. E.g. Worsening of agina pectoris, preciptation of mycocardial infraction may be result from stoppage of Beta-Blockers.
- Teratogenicity : It is the ability of the drug to produce foetal abnormalities when administrated to the pregnant mother. E.g. Thalidomide disaster (1958-61) – Phocomelia.
Drugs can affect the foetus at 3 stages –
(i) Fertilization and implantation – Conception to 17 days – failure of pregnancy which often goes unnoticed.
(ii) Organogensis – 18 to 55 days of gestation – most vulnerable period, deformities are produced.
(iii) Growth and development – 56 days onwards – developmental and functional abnormalities can occur, e.g. ACE inhibitors can cause hypoplasia of organs, specially lungs and kidneys; NSAIDs may induce premature closure of ductus arteriosus.
- Mutagenicity and Carcinogenicity : It refers to capacity of a drug to cause genetic defects and cancer respectively. Usually oxidation of the drug results in the production of reactive intermediates which affect genes and may cause structural changes in chromosomes. If the modified DNA sequences code for factors that regulate cell proliferation/growth, i.e. are protooncogenes, or for proteins that inhibit transcription of protooncogenes, a tumor (cancer) may be produced. Drugs implicated in these adverse effects are anticancer drugs, radioisotopes, estrogen, tobacco.
- Drug induced diseases : These are also called Iatrogenic (physician induced) diseases, and are functional disturbances (disease) caused by drugs which persist even after the offending drug has been withdrawn and largely eliminated, e.g.:
- Peptic ulcer by salicylates and corticosteroids.
- Parkinsonism by phenothiazines and other antipsychotics.
- Hepatitis by isoianzid.
- DLE by hydralazine.
Severity of Adverse Drug Reactions
- 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.
Prevention of Adverse Effects to Drugs
Adverse drug effects can be minimized but not altogether eliminated by observing the following practices:
- Avoid all inappropriate use of drugs in the context of patient’s clinical condition.
- Use appropriate dose, route and frequency of drug administration based on patient’s specific variables.
- Elicit and take into consideration previous history of drug reactions.
- Elicit history of allergic diseases and exercise caution (drug allergy is more common in patients with allergic diseases).
- Rule out possibility of drug interactions when more than one drug is prescribed.
- Adopt correct drug administration technique (e.g. intravenous infection of vancomycin must be slow).
- Carry out appropriate laboratory monitoring (e.g. prothrombin time with warfarin, serum drug levels with lithium).
Pharmacovigilance has been defined by the WHO as the ‘science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems’. The information generated by pharmacovigilance is useful in educating doctors about ADRs and in the official regulation of drug use. It has an important role in rational use of medicines, as it provides the basis for assessing safety of medicines. The activities involved in pharmacovigilance are:
- Postmarketing surveillance and other methods of ADR monitoring such as voluntary reporting by doctors (e.g. yellow card system of UK), prescription event monitoring, computerized medical record linkage and other cohort/case control studies as anecdotal case reports by doctors.
Voluntary reporting depends on the initiative and willingness of the health professionals. It is minimal in India, while even in the developed counties only ~10% ADRs are reported voluntarily. Generally, immediately occuring reactions and those that are dramatic are reported. Though even rare reactions can be detected by this method, it does not provide incidence of the reaction.
- Dissemination of ADR data through ‘drug alerts’, ‘medical letters’, advisories sent to doctors by pharmaceuticals and regulatory agencies (such as FDA in USA, committe on safety of medicines in UK).
- Changes in the labeling of medicines indicating restrictions in use or statuary warnings, precautions, or even withdrawal of the drug.
Thank you for reading our article on Adverse Drug effect, we hope you got all the information on the topic. If you have any doubt, please comment and we will be glad to help you.
Reference taken from Essentials of medical Pharmacologoy – Tripathi.
Do not forget to read our article on Drug Discovery and Drug Development.