Basics of Adverse Drug Reactions
Adverse drug reactions (ADRs) – unintended, harmful events attributed to the use of medicines. A careful medication history can assist a prescriber in understanding the patient's previous experiences with drug treatment, particularly in identifying previous ADRs that may preclude re-exposure to the drug.1, 2
History
Since 2012, the definition has included reactions occurring as a result of error, misuse or abuse, and to suspected reactions to medicines that are unlicensed or being used off- label in addition to the authorised use of a medicinal product in normal doses.2 Seminal research undertaken in the late 20th and early 21st century in the USA and the UK demonstrated that ADRs are a common manifestation in clinical practice.3, 4, 5
Medicines that have been particularly implicated in ADR-Fatal ADRs, when they occur, are often attributable to haemorrhage, the most common suspected cause being an antithrombotic/anticoagulant co-administered with a non-steroidal anti- inflammatory drug (NSAID).4
Pharmacovigilance
The term Pharmacovigilance is the science and activities related to the detection, evaluation, understanding and prevention of adverse drug reactions and other related problems. 6 According to WHO, Pharmacovigilance is a set of practices aiming at the identification, understanding and assessment of the risks associated with drugs. 7
Pharmacovigilance has been defined by the WHO (2002) as the ‘science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug -related problems.’ 8 Its main purpose is to reduce the risk of drug-related harm to the patient. It has an important role in the rational use of medicines,as it provides the basis for assessing safety of medicines. 8
The main objective of Pharmacovigilance is to regulate and ensure the safety & efficacy after the entry of the new drug molecule into the market for the treatment of diseases of the general population with different medical conditions. Recently the concern of Pharmacovigilance has been widened to include herbals, medicines, blood products, biological products, medical devices and vaccines 7
Pharmacovigilance support safe and appropriate use of by
Promoting the detection of Previously unknown ADRs and interactions.
Identifying the risk factors for the development of ADRs.
Estimating the quantitative methods /risk analysis.9
Classifiction of Adverse Drug Reaction
Based on frequency of occurrence 10, 11
Table 1
Frequency of occurrence
Based on the type of adverse drug reaction 10, 11
Table 2
Types of adverse drug reaction
|
Sr. no. |
Type |
Description |
Examples |
|
1 |
TypeA (Augmented) |
Predicted, Dose dependent, severity increases with increase in dose. 12 |
Hypotension by beta-blockers & hypoglycaemia caused by insulin . |
|
2 |
TypeB (Bizarre) |
Unpredictable, rare, idiosyncratic, mechanisms are unknown, unrelated to the dose. 13 |
Hepatitis caused by halothane & aplastic anaemia caused by chloramphenicol . |
|
3 |
TypeC (Continuous drug use) |
Irreversible,unexpected, unpredictable. 14 |
Dementia by anticholinergic medications . |
|
4 |
TypeD (Delayed) |
Delayed occurrence of ADRs. |
Ophthalmopathy after chloroquine. |
|
5 |
TypeE (End of Dose) |
Withdrawal reactions. |
Seizures on alcohol or benzodiazepines withdrawal. |
|
6 |
TypeF (Failureof therapy) |
Therapeutic failure of drug. |
Accelerated hypertension because of improper therapy . |
Definition related to the Adverse drug reaction: 15, 16
1. Adverse drug reaction: It is any noxious, unintended and unexpected effect of a drug that occurs at a dose used in humans for prophylaxis, diagnosis, and therapy of a disease. Requires special treatment or decreases in dose.
2. Adverse Effect: It is a noxious and unintended effect that may occurs during the treatment With pharmaceutical product .Not requires treatment.
3. They are related to the use of drugs
4. Drug recall: It is a action taken by firm to remove product from market. 17
5. WHO drug dictionary: It is a International classification of drug providing name of medicinal Product, use in different countries with all active ingredients. 18
Categories of Adverse Drug Reaction
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.
Example: Atropine is used in preanaesthetic medication for its antisecretory action. The same action produces dryness of mouth as a side effect. 8
Secondary effect
These are indirect consequences of a primary action of the drug.
EX: Suppression of bacterial flora by tetracyclines paves the way for superinfections .
Toxic effects
These are the result of excessive pharmacological action of the drug due to overdosage or prolonged use. The manifestations are predictable and dose related.
EX: drug induced tissue damage (hepatic necrosis from paracetamol overdosage). 8, 19
Another action of the drug can also be responsible for toxicity
Intolerance
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.
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.
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.
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 followed by a photobiological reaction resulting in local tissue damage (sunburn-like), i.e. erythema, edema, blistering which have fast onset and shorter duration after exposure ends. This is followed by hyperpigmentation and desquamation.
The lesions may be more severe with larger doses of the drug.
The shorter wave lengths (290–320 nm, UV-B) are responsible for the photoxic reactions.
Example
Drugs involved in acute phototoxic reactions are tetracyclines (especially demeclocycline) and tar products.
Photoallergic
Drug or its metabolite induces a cell mediated immune response which on exposure to light of longer wave lengths (320–400 nm, UV-A) produces a papular or eczematous contact dermatitis like picture that may persist long after exposure. Rarely antibodies mediate photoallergy and the reaction takes the form of immediate flare, itching and wheal on exposure to sun.
Example
Drugs involved are sulfonamides, sulfonylureas, griseofulvin, chloroquine, chlorpromazine, carbamazepine.
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.
Psychological dependence
It is said to have developed when the individual believes that optimal state of wellbeing is achieved only through the actions of the drug. The subject feels emotionally distressed if the drug is not taken.
Physical dependence
It is an altered physiological 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.
Drug abuse
Refers to use of a drug by selfmedication in a manner and amount that deviates from the approved medical and social patterns in a given culture at a given time.
Drug addiction
It is a pattern of compulsive drug use characterized by overwhelming involvement with the use of a drug. Procuring the drug and using it takes precedence over other activities. Even after withdrawal most addicts tend to relapse.
Drug habituation
It denotes less intensive involvement with the drug, so that its withdrawal produces only mild discomfort. Consumption of tea, coffee, tobacco, social drinking are regarded Habituation.
Frequency of Seizures May Increase on Sudden Withdrawal of An Antiepileptic
Teratogenicity
It refers to the capacity of a drug to cause foetal abnormalities when administeredto the pregnant mother. The placenta does not constitute a strict barrier, and any drug can cross it to a greater or lesser extent. The embryo is one of the most dynamic biological systems and in contrast to adults, drug effects are often irreversible.
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 the chromosomes. Covalent interaction with DNA can modify it to induce mutations. Drugs implicated in these adverse effects are—anticancer drugs, radioisotopes, estrogens.
Adverse Drug Reaction Management
Recognition/Identification Of Adverse Drug Reaction
Ensure, medicine received & actually taken by the patient at the dose advised.
Verify the onset of suspected ADR is after taking the drug.
Determine the time interval between drug taken – onset of event.
Evaluate the suspected ADR after discontinuing the drug / reduced dose, monitor status.
Analyse the alternate cause (other than the drug).
Use experienced physician opinion & information PV center.
Report the ADR.
Reporting
Adverse drug reaction reporting helps the drug monitoring system to detect the unwanted effects of those drugs which are already in the market.
ADR Reporting is a process of continuously monitoring of undesirable effect suspected to be associated with use of medical products. ADR reporting covers all pharmaceutical products, biological, herbal drugs, cosmetics and medical devices. 21
What to report
Any undesirable adverse event suspected to be associated with use of drug.
Include - All ADRs as a result of prescription and non-prescription.
All ADRs – irrespective of the used (acc with PI provided by company).
Unexpected reactions - regardless of their nature or severity.
ADRs-in special field – drug abuse, drug use – pregnancy / lactation.
ADRs occurring from overdose or medication error.
Information required for ADR case reporting
Product problems/Adverse effect
Description of event or problem
Date of event
Date of this report
Relevant tests/laboratory data (if available)
Other relevant patient information/history. 22
Suspected medication (s)
Name ( brand name)
Dose, frequency
Route used
Therapy date
Diagnosis for use
Event abated after use stopped or dose reduced
Batch number
Expiration dat
Event reappeared after reintroduction of the treatment.23
WHO Should Report
Doctors
Pharmacists
Assistant medical officers
Clinical officers
Pharmaceutical assistants
Traditional medicine practitioners
Others health care providers
Where to Report
Please return the completed form to the nearest Adverse drug reaction Monitoring Centre (AMC) or to National Coordinating Centre.
The Uppsala Monitoring Centre (Sweden) is the international collaborating centre. In India, the Central Drugs Standard Control Organization (CDSCO) is coordinating the pharmacovigilance programme, under which peripheral, regional and zonal monitoring centres have been set up along with a National Pharmacovigilance advisory committee.
The pharmacovigilance centres collect, communicate and disseminate ADR data by linking with hospitals as well as practitioners and are also expected to provide expertise for assessing causality and severity of ADRs.
The information is submitted to the Steering Committee of PvPI constituted by the Ministry of Health and Family Welfare. The Committee is entrusted with the responsibility to review the data and suggest any interventions that may be required. 21, 26
Prevention of Adverse Drug Reaction
Anticipation by patient monitoring Ex- anemia- due to deficiency of G6PD, check the condition.
Anticipation of dosage reeducation Ex- impaired renal / liver function – dosage should reduce.
Monitoring the serum levels(drug) Ex- theophylline, aminoglycosides.
Monitoring of pharmacological activity (extensive of Pharmacology activity) Ex- diuretics- to promote salt & water loss, but causes electrolyte depletion & dehydration. 27
Minimizing of non-preventable- Idiosyncratic / hypersensitivity not preventable.
Can be done by carful observation / monitoring of patient Ex- patient with meningitis
• Should be with penicillin. Chemotherapy – nausea 28
Management of Adverse Drug Reaction
Confirmation of the ADRs: indicate what assisted in confirming the suspected adverse reactions.
For example
Drug reactions confirmed by disappearance of the reaction after stopping administration of the drug or reducing the doses.
Recovery on withdrawal of suspected drug(s) if no other drug is withdrawn and no therapy given.
Recovery follows treatment of the reaction in addition to withdrawal of drug.
Mention the criteria for regarding the reaction as serious
Mention any treatment given to the patient after experiencing the ADRs.
Outcome: indicate the outcome of the adverse reaction by marking X in the appropriate box with dates. 29
Aim and Objectives
To disclose the quality and frequency of ADRs and to identify the risk factors that can cause the adverse reactions.
To improve patient care and safety in relation to the use of medicines.
To improve public health and safety in relation to the use of medicines.
To identify new reactions, record the frequency with which they are reorted.
To evaluate factors that may increase risk of ADR.
To provide information to prescribers with a view to preventing future ADRs.
To prevent predictable adverse effects and helps in measuring ADR incidence.
To get information about quality and safety of Pharmaceutical products.
To detect, collect, assess, and monitor the adverse effect.
