AN OVERVIEW ON PHARMACOVIGILANCE
Mechanism of type A ADRs
A drug suspected to have caused an adverse drug reaction in one patient may not necessarily cause the similar adverse drug reaction in another patient. This is due to inter individual variability, which may predispose an individual to an ADR. Any type A reaction, which occurs in an individual, may be attributed to any one or more of the following mechanism27.
* Pharmaceutical cause
* Pharmacokinetic cause
* Pharmacodynamic cause
The possible pharmaceutical causes which might be attributed to occurrence of type A adverse drug reaction includes changes in the drug quantity present in a particular product, and also changes in its drug release properties. For examples, there are several reported reactions of gastrointestinal bleeding and hemorrhage due to a rate-controlled preparation of indomethacin. This may be due to irritant effects of high concentrations of indomethacin on a localized area of gastrointestinal mucosa. Another example is the corrosive effects on the esophagus caused are certain doxycycline salts. By changing to another salt, the risk may be reduced dramatically. To avoid such reactions, the drug regulatory authorities have laid down stringent requirements for marketed drug products28.
Alterations in the absorption, distribution, metabolism and elimination of drugs may alter drug effects by changing the concentration of drug present at site of action. The change in the drug effect due to alterations in pharmacokinetics parameters may be experienced as either therapeutic failure or toxicity.
Absorption: Alterations in the rate and extent of drug absorption may result in adverse drug effects. The plasma concentration of drug is partly determined by the rate at which the drug is absorbed after ingestion or injection. The plasma concentration of an orally administered drug in turn depends greatly on the gastric emptying rate. Similarly, the extent of drug absorption (the total amount of drug reaching the general circulation) also plays an important role in altered in response. Following oral administration, many factors may influence the extent of drug absorption including drug formulation, gastrointestinal motility, and first pass metabolism, concomitant administration of other drugs and the absorptive capacity of gastrointestinal mucosa. Any absorption may result in either therapeutic failure or toxicity.
Distribution: There are several factors, which determine in the extent of distribution of a drug including regional blood flow, membrane permeability and protein and tissue binding. Changes in drug distribution may predispose to adverse drug reactions, where the clinical significance of such mechanisms is yet to be proved.
Metabolism: The drug handling capacity of an individual can greatly affects the drug effect. In an individual who has a reduced metabolic rate, accumulation of drug in the body may be higher, leading to increased risk of adverse drug reactions especially type A reaction, while therapeutic failure may occur in an individual who has an enhanced metabolic rate. These changes are due to inter-individual variations in drug metabolizing capacity, which in turn is greatly influenced by genetic, environmental and other factors. For example, slow acetylators are highly prone to develop type A reaction to drugs which are metabolized by acetylation, such as isoniazid, dapsone, hydralazine and procainamide. Also differences in then rate of oxidation by cytochrome P450 system are of clinical importance.
Elimination: The major routes of excretion for many drugs are the kidneys (excretion through urine) and liver (yields metabolites which are then excreted by the kidneys). One of the most important causes of type A adverse drug reaction is a change in the drug elimination rate. Drug accumulation due to reduced elimination may predispose to adverse drug reactions as a result of increased drug concentration in plasma and tissue. Conversely, reduced concentration of drug in plasma and tissue due to enhanced drug elimination may lead to therapeutic failure.
Increased sensitivity of target tissues or organs may predispose a person to adverse drug reactions. The reasons why different individuals react differently to drugs are still not clear, evidence is accumulating to suggest that target tissue or organ sensitivity is influenced by the drug receptors themselves, by homeostatic mechanisms and by disease.
Drug receptors: Most drugs elicit their response by combining with receptors. These receptors are either protein molecules or enzymes. The amount and sensitivity of receptors of an individual may differ from another individual. Some individuals may have fewer specific drug receptors while others may have a higher number of less active receptors. This inter variability between different individuals can greatly affects the drug effect, when the drug acts through these specific receptors.
Homeostatic mechanisms: Many physiological factors may determine the extent of a drug’s effect in an individual as drug affects occur within the environment of the body’s physiological mechanisms. For examples, intravenous atropine produces a variable increase in heart rate and some individuals develop tachycardia of 160 beats per minutes at a dose which is almost ineffective in others. The magnitude of the observed effects is dependent on the balance between parasympathetic and sympathetic cardiac tone, which appears to be under genetic control.
Disease: The pharmacological effects of a drug which are not apparent in a healthy individual may be unmasked by intercurrent diseases. An example is an asthmatic patient who develops bronchoconstriction while taking non-selective beta-blockers such as propranolol.
Mechanism of type B ADRs
The type B adverse drug reactions are aberrant in terms of the normal pharmacology of the drug and they are a heterogeneous group of unpredictable adverse effects. By definition, type B reactions are unrelated to the pharmacology. The major sources for type B reactions includes decomposition of the active ingredient, the effects of the non-drug excipients (additives, preservatives, coloring and solubilising agents) and synthetic byproducts of active constituents. In the majority of cases the use of decomposed drug products may result in therapeutic failure. In some instances, though not all, the decomposed product may be highly toxic and lethal. Deaths have been reported due to decomposition of paraldehyde and its subsequent oxidation to acetic acid. There is a clear recognition of adverse drug reaction caused by excipients. Many additives including propylene glycol and carboxymethylcellulose may cause hypersensitivity reactions. The eosinophilia myalgia syndrome associated with L-tryptophan may be related to the use of preparations containing a contaminant, although a genetic factor may also be involved1,4, 29.
The metabolism of a drug to unusual reactive metabolites may give rise to type B reactions either by a direct or though an immune mediated mechanism. Examples of such reactions include phenacetin-induced methemoglobinemia and carbamazepine induced hypersensitivity reactions. Individuals whose specific bio-inactivation pathways are either more active or less active and with immunological characteristics which render them highly responsive to immunogens and haptogens are more susceptible. The reasons for the occurrence of type B reactions in a particulars individual are not clear30.
The importance of reporting ADR
Not all the hazards can be known before a medicine is marketed. Patient’s consumers and indeed some healthcare professionals may have expectations that medicinal products available are “safe” and may be surprised when regulatory action is taken to restrict the use or withdraw medicines as a result of previously unrecognized safety concerns. Information collected during the pre-marketing phase of medicinal products is inevitably incomplete with regard to complete safety profile of a product because
* Animal testing is insufficiently predictive of human safety
* Data from clinical trials is limited by their size and duration
* Patients in clinical trials are selected and the conditions of use differ from those in clinical practice
* Informations are rare but serious adverse reactions, chronic toxicity, and use in special groups such as pediatrics, geriatrics and in pregnancy) or drug interactions is often incomplete or not available and will only manifest after drug is released, may be after several years.
The effects of ADRs
All medicines have the potential to cause ADRs. Prevention of ADRs helps in order to minimize the harmful effects resulting from ADRS, harmful effects includes
* ADRs are estimated that 2-6% of all admissions to hospitals are due to ADRs
* ADRs contribute to an increased attendance to primary care and may complicate hospital in-patient stay in as many as 10% to 20% of patients
* ADRs may be responsible for deaths (Possibly as high as the 4th commonest cause of death)
* ADRs may increase the length of hospital stay and increase the cost of patient care
* ADRs may adversely affect patient quality of life and may cause patients to lose confidence in doctors
* ADRs may also mimic disease and result in unnecessary investigations and/or delay in treatment.
* ADRs are a major economic burden.
* Occurrence of toxicity in a minority of patients might preclude use of the drug in the majority of patients, if risk factors cannot be identified and appropriate regulatory measures implemented.
Pre marketing studies
The safeties of new medicines are tested in animal models. A great deal of risk information may be obtained from such tests, for examples the level of acute toxicity, which organs will be affected in case of toxicity and dose dependency of such tissue injuries. Specific animal tests for carcinogenicity, teratogenicity and mutogenicity are also available. Animals can only serve as approximately models for humans. We do not have sufficient knowledge to extrapolate information collected from animal studies directly into risks in humans. The predictive value of the different animals tests do not reveal particularly worrying results, safety tests precede onto testing in humans in clinical trial programs.
Clinical trials are carried out in three different phases prior to the submission of a marketing authorization application, with a stepwise increase in the number of individuals being exposed. Prior to the general release of a new product, not more than 4000 individuals have normally been exposed to the new drug. This implies that clinical trials, normally, only have the power to identify adverse reactions of a frequency greater that 0.5-1.0 percent. Clinical trial programs are designed to maximize the chance of demonstrating a therapeutic effect in relation to a control group. Children and the elderly are normally actively excluded from the studies. Once the drug is used in clinical practice, children and elderly, and patients with much more complicated diseases situations can be treated. For cost reasons clinical trials often have a very short duration, which means they cannot generate information about long term adverse effects31-34.
The consequence of the above is that at the time of general marketing of a new medicine, only the most common, dose related (type A) adverse reactions will be known.
The most sensitive, powerful and cost effective system for identification of unknown drug related risks are spontaneous adverse reaction reporting. Every healthcare practitioner should see it as a part if his/her professional duty unexpectedly causing a risk situation for a patient under his/her cares. Pharmacovigilance should not be limited to the reporting of classical adverse effects. It should also be concerned with identification of product defects, unexpected insufficient therapeutic effects, intoxications and misuse abuse situation.
An important outcome of spontaneous adverse reaction reporting programs is the creation of signals of previously unknown or insufficiently documented problems. To verify the hypothesis of a causal link between drug exposure and an adverse outcome, it may be necessary to employ epidemiological techniques. With such techniques it is also possible to quantify the risk which is not possible through spontaneous reporting.
The two epidemiological methods that are most commonly used are cohort studies and case-control studies. In Cohort studies, patient exposed to a particular drug are followed up regularly and adverse reactions in them are compared to a matched control population. Case-control studies involve studying patients who have been affected by an adverse reactions and linking it with drug used prior to the reaction. Case control studies are particularly useful for the study of rare adverse reactions5.
In the hospital setup, healthcare professionals should be very vigilant in detecting ADRs. The possibility of an ADR should always be considered during differential diagnosis. ADRs may be detected during wards rounds with the medical team or during review of the patient’s chart. Patient counseling, medication history interview and communicating with other healthcare professionals may provide additional clues which may be useful in the detection of ADRs7.
To assist the detection of ADRs, healthcare professionals should closely monitor patients who are at risk. These includes
* Patients with renal or hepatic impairment
* Patient taking drugs which have potential to cause ADRs
* Patients who have had previous allergic reactions
* Patients taking multiple drugs
The first step in the detection of ADRs is collection of data. The data to be collected includes patient’s demographic data, presenting complaints, past medication history, drug therapy details including over the counter drugs, current medications and medication on admission, and lab data such as hematological, renal and hepatic function test. Details of the suspected adverse reaction such as time of onset and duration of reaction, nature and severity of reaction, details of the suspected drugs including dose, frequency, time of administration, duration of treatment, plasma concentration of drug, previous report on reported reaction, data on any other causes including risk factors and predisposing factors are useful11.
All the above stated relevant data can be obtained from the following sources of information
* Patient’s case notes and treatment chart
* Patient interview
* Laboratory data sources
Communication with other healthcare professionals
6. Method of Pharmacovigilance
a. Passive Surveillance
A spontaneous report is an unsolicited communication by health care professionals or consumers to a company, regulatory authority or other organization (e.g., WHO, Regional Centers, Poison Control Centre) that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection scheme.
Spontaneous reports play a major role in the identification of safety signals once a drug is marketed. In many instances, a company can be alerted to rare adverse events that were not detected in earlier clinical trials or other pre-marketing studies1-5.
Spontaneous reporting systems; yellow card scheme
The yellow card scheme was established in 1964 as a result of the thalidomide tragedy. Since then, the system has become one of the major international pharmacovigilance resources. The yellow card scheme is run jointly by the MCA (the regulatory agency) and the CSM (an expert advisorycommittee to the MCA).Since 1991, the yellow card scheme has been enhanced by a new computer system, the ADROIT (Adverse Drug Reaction Online Information Tracking) system. ADROIT is different from other databases. Not only does it store the details of the report, but also the image of the yellow card in the optical system. Multiple users can view any yellow card on screen at the same time. The MCA receives approximately 20,000 yellow cards each year. The reports are prioritized so that serious adverse drug reactions receive early attention. The yellow cards are classified into seven priorities by a member of the scientific staff according to the drugs and the nature of the ADR. Priority 1 reports receive the earliest attention
Fig. 3: Adverse drug reaction online information tracking and yellow card system
Sources of data
Fig. 4: Different sources of data for Pharmacovigilance
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