Clout over Adverse Drug Reactions

Even before the days of Hippocrates Adverse Drug Reactions (ADR) has been studied. However they came into the forefront only after the Thalidomide Disaster. In the modern day practice where secondary/supernumerary infections and combination therapy consisting of multi-drug regimes seem to be the norm ADR monitoring assumes special significance. Rising costs of patient care, increasing awareness of patients towards the untoward effects of drugs and the rise in the frequency of cases of litigation against doctors and hospitals has entailed the need of a comprehensive ADR monitoring. The paper briefly reviews the various aspects of ADR -its importance, incidence and prevalence under various settings, problems with pharmaco-vigilance and ADR monitoring techniques.


Adverse Drug Reactions are as old as drugs themselves. Ancient medicine has references to noxious effects of drugs much before the days of Hippocrates. Even the very ancient Ayurveda of Indian origin places great emphasis on the processing of herbs and herbo-minerals to prevent harmful effects of drugs.

However it was the thalidomide disaster in 1963 which ultimately brought the issue to forefront in the current world. Ever since then multiple definitions of ADR has come up. The definition perhaps used most widely today is the WHO which states that an adverse drug reaction is “Any 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 physiological function.”1. This definition therefore excludes effects of wrong drug, medication errors e.g. overdose, and defective drug i.e. product not conforming to specifications.

Adverse drug reactions (ADR’s) are a necessary evil accompanying all drugs. Whenever a drug is administered a risk is to be taken in the way of ADR’s. Thus calculation of the magnitude of this risk is an integral part of the treatment provided. In other words a clinician must assess the cost/benefit ratio in that particular situation – where benefits will be measured in terms of the efficacy of the drug and the cost in terms of the side effect liability that use of the drug entails 1 .

Information on adverse reactions is always incomplete when a drug is first introduced into the market. The full range of adverse reactions may not be known until a drug has been used in thousands of people (with varied genetic make-up, underlying illness and from varied backgrounds and using/used a plethora of medicines along with it) or in some cases after exposure for prolonged periods or only long after exposure to the drug.

Magnitude of the problem:

The true incidence and prevalence of ADRs is not known, largely because formalized ADR reporting systems were in place in only a few countries till recently. Even if a very well organized ADR reporting system does exist, it is likely that the reported estimates are far less than true extent because mild ADRs tend to go unreported, Many drug effects are highly subjective and a large fraction of the total ADR burden in the community may not be recognized as iatrogenic events but rather attributed to the underlying or a new illness.

Lazarou et al found ADR’s to be the fourth to sixth leading cause of death in the United States and serious ADR’s accounting for 6.7% of hospitalized admissions 2. Pirmohamed et al in the largest prospective study on 1882 among patients in UK found a prevalence of only 6.5 % 3. A study by Ramesh et al in India carried out in a tertiary referral center in South India showed that admissions due to ADRs accounted for 0.7% of total admissions and deaths due to ADRs accounted for 1.8% of total ADRs 4.

With all limitations of ADR reporting in mind it has been estimated that :

#Up to 30 percent of hospitalized patients suffer one or more ADRs,3 percent will have an ADR of considerable severity and 0.3 percent may die in consequence. Incidences are higher in patient groups (e.g. HIV/AIDS patients) likely to be on multiple interacting medications

# Up to 6.5 percent of hospital out-patients may require hospitalization to prevent or manage ADRs, a large proportion of these being avoidable ADR’s 5.

Most of the doctors are serious about ADR is relation to in-patients , most probably due to the potential medico-legal issues involved. However ADR among out patients are an important problem as well. A meta-analysis in 1994 suggested that more than 1million outpatients in USA experienced ADR which lead to them being hospitalized and that 4.7% of admissions were caused by drugs.2 Estimates of out-patients in the US have varied from 5% to 35%. In contrast to in-patients out patients are responsible for both obtaining and administering drugs. The process is much less controlled. The physician also has much less contact with the out-patients and is also less likely to hear about their problem 6. This is more so the case in a crowded government hospital where there is always a rush to ‘clear’ away patients and mild cases might be overlooked.

Evaluation of ADR:

Evaluation of ADRs can proceed at different levels. The first and most important is patient-specific evaluation. Healthcare professionals must differentiate between effects of the suspect drug, other medications being used by the patient, the patient’s disease, and the influence of lifestyle factors, such as tobacco and alcohol use, or substance abuse. Whenever a patient experiences adverse symptoms, the possibility that the symptom might be drug induced should be included in the differential diagnosis. It is important to recognize reactions in their initial, mild states to avoid progression to more severe morbidity or mortality. If the causality can be established reasonably well, management can proceed with discontinuation or dose modification of the offending drug and administration of remedial or symptomatic therapy as appropriate. Recognition that the reaction is drug related is also important in that such problems can be avoided in future in the affected patient as well as in patients with similar characteristics.5 Specific requirements for an ADR report from a healthcare professional therefore includes information about the patient, event, and drug. Patient demographic information, diagnoses, medications, indications, dose and duration of use of the offending drug and nature of the reaction should be documented, along with the lot number of product, name of manufacturer, clinical and time course of the reaction, dechallenge / rechallenge outcomes, and sequelae, as far as feasible. The clinician needs to be particularly careful about serious and unexpected ADR (Table 1)

ADRs should also be evaluated at the system level.7Once a reaction is identified as drug related and the patient receives appropriate treatment, the reaction should be documented in the patient records and included in the institution’s database of adverse reactions. System-wide evaluation of ADRs will help to identify areas

(a) for improvement in order to reduce the risk of errors in the future,

(b) for continuing education in therapeutics for all healthcare professionals,

(c) with insufficient information in order to develop research hypotheses.

An inherent problem in pharmaco-vigilance is that most case reports concern suspected adverse drug reactions. Adverse drug effects are rarely specific for the drug, diagnostic tests usually absent and a re-challenge is rarely ethically justified. In practice few adverse reactions are “certain” or “unlikely”; and most somewhere between two extremes, i.e. probable or possible. In an attempt to solve the problem many systems have been developed for a structured and harmonized assessment of causality 8.

For causality assessment the WHO-UMC causality assessment system(Table 2) is internationally recognized. The system is basically a combined assessment taking into account the clinical pharmacological aspects of the case history and the quality of documentation of the observation.9 This system besides having the advantage of being internationally recognized and also other criteria like previous knowledge and statistical chance playing a less prominent role. Since by far the most frequent categories in drug reaction case reports are ‘Possible’ and ‘Probable’, the usual approach to using the system is to choose one of these categories (depending on the impression of the assessor) and to test if the various criteria fit with the content of the case report. The WHO UMC system also enables assessing the actor drug, which influences the kinetics or dynamics of the other drug (which has usually been taken over a longer period), in the clinical context of the patient in case of drug-drug interactions.

The adverse drug reactions are graded according to their severity commonly into:

ü Minor/mild: No therapy , antidote or normal life style of patient not disturbed

ü Moderate: Requires change in drug therapy, specific treatment but normal life style of patient not disturbed

ü Severe:potentially dangerous and normal life style of patient disturbed.

However this system of grading is quite subjective and authorities worldwide need to reach a consensus and formulate a common guideline for ADR Severity Gradation.

The main sources of ADR data are:

(a) Spontaneous reporting by doctors, pharmacists nurses etc;

(b) ADR monitoring schemes in hospitals

(c) Clinical trials (all phases including post-marketing surveillance)

(d) Vital statistics (mortality, morbidity registers,birth registers for congenital defects)

(e) Special studies (case control studies, cohortstudies)

However it should be stressed that there is no single effective, fool-proof method for the collection of ADR data. Clinical experience has demonstrated that alert clinicians reporting their observations without hesitation have been repeatedly proven correct, and have prevented many disasters.10

Conclusion :

In the current scenario where secondary/supernumerary infections and combination therapy consisting of multi-drug regimes seem to be the norm ADR monitoring assumes special significance. This is more so the case for developing Asian nations where multi-national pharma houses often try to sell drugs which has been banned in other developed economies . The introduction of a large number of potentially toxic chemicals as drugs has been noted even by the World Health Organization. Although some ADR’s are idiosyncratic and unpredictable, many can be anticipated based on knowledge of a medication’s clinical pharmacology.


Rising costs of patient care, increasing awareness of patients towards the untoward effects of drugs and the rise in the frequency of cases of litigation against doctors and hospitals have made clinicians, hospital administrators and health care planners aware of the necessity of closely monitoring adverse drug reaction.

ADR monitoring will have to become a part and parcel of the comprehensive health care provided to patients to prevent drugs from becoming Frankenstein’s Monster.

To get the references and tables Read the Complete Article by Dr. Soumyadeep B. at : Asian Students Medical Journal

(Asian Student Medical Journal is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License)

Image Courtest :  Albert Bridge and licensed for reuse under this Creative Commons Licence.


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