Many factors are responsible for the adverse effects of drugs on patients receiving them. The adverse effects of the drug depend on its dose, duration, toxicity, and other individual factors such as sex, age, genetics, compliance of patients, and the total number of drugs administered. Whether a patient experiences the toxicity of a drug depends on its dose.
The pharmacokinetics of the drug may also affect drug
toxicity. Alteration in the pharmacokinetics of the drug may result in an abnormally
higher concentration of the drug at the receptor site, resulting in an adverse
effect.
The therapeutic index of a drug is also responsible
for the adverse effects. A drug with a small therapeutic index is more prone to
produce adverse effects than one with a large therapeutic index e.g.
therapeutic index of amphotericin B is small while that of acetaminophen is
large. Hence 75% of patients receiving
amphotericin B show the adverse effect while less than 1% of patients receiving acetaminophen show adverse
effects. Infants are more prone to adverse effects because of incomplete
development of the liver enzyme system. Also, the elderly patient shows a higher
incidence of adverse effects.
The common cause of the drug-induced disease is the
excessive pharmacological effects of the drug which is readily predictable
whereas other types of drug-induced disease are more difficult to detect and
quantify (Non-predictable). The various methods are given below:
Spontaneous Case Reports
It is the common method of affecting doubts about drug-related
diseases. A prescriber suspects that a condition arising in a patient may be
drug-related. He, therefore, reports either in a letter to the medical journals
or to the manufacturer of the drug. This means other prescribers are alerted to
the possibility of a drug-disease relationship. “Spontaneous Reporting Agencies” are set up to collect and
gather such case reports. Although the resulting information collected gives no
idea of the frequency with which a given event is caused by a drug, it
indicates that several prescribers feel that the event is possibly
drug-related.
In recent years, national registers have been
established in several countries with the main aim of providing an early
warning that a dug is capable of causing a serious adverse effect. Their
registers in general depend upon the voluntary spontaneous reporting of
suspected adverse drug reactions by doctors. The British registrar of Adverse
Drug Reactions was established in 1964.
Most physicians fail to report many adverse drug
reactions which may be due to the following reasons.
• The misconception that ADR reflects poor therapeutic
agent selection.
• Lack of interest.
• Lack of understanding of what to report.
• Belief that the reaction is unimportant or has been
previously reported in the literature.
Vital Statistics and Record Linkage Studies
The details of the cause of death (as recorded on the death
certificate) or of hospitalization (as recorded on the discharge letter) are
routinely collected and analyzed. It gives early warning of an epidemic of
drug-related disease. Record linkage studies may be used to great effect in the
search for drug-induced disease.
Cohort Studies
The ‘Cohort’ means identifying a group of recipients
of a drug of interest and observing these patients for varying lengths of time
for what happens to them. This type of study is used for short-term clinical
trials of a new drug. Cohort studies involving long-term clinical trials are
more difficult to organize. Thus, this method is of great value for detecting
predictable adverse effects due to excessive pharmacological effects arising
during or immediately after short-term treatment.
Case-Control Studies
It involves the comparison of a group of patients with a disease that is thought to be due to a drug (the ‘cases’) with a group of patients who do not have the disease (the ‘control’). The drug histories of the cases and controls are obtained and compared. If a drug is causing the disease then its use in the cases will be far more than that found in the controls. Case-control studies can be conducted rapidly and efficiently at a relatively low cost. However, it must be conducted correctly, and the resulting data must be interpreted correctly. The following precautions should be taken while conducting case-control studies:
• The cases must be selected carefully. The disease
must be defined clearly, precisely, and accurately. The disease under study
must have a reasonable risk of being drug-induced.
• The controls obtained should be from a similar
population of cases with the exception that controls do not have the disease of
interest. Controls are usually hospitalized, patients. They should not include
patients admitted for conditions that are indications of a drug of interest or
which are caused or prevented by the drug of interest.
• The method used to describe drug use must be
identical in cases and controls.
• Interpretation of results must be accurate.