They are diagnosed on clinical grounds from the temporal relation between the start and finish of drug treatment and the onset and offset of the reaction
Pharmacological adverse reactions are generally dose-dependent, related to the pharmacokinetic properties of the drug, and resolve when the dose is reduced
Idiosyncratic adverse reactions are not related to the known pharmacology of the drug, do not show any simple dose-response relation, and resolve only when treatment is discontinued
Vigilance by clinicians in detecting, diagnosing, and reporting adverse reactions is important for continued drug safety monitoring
An adverse drug reaction is any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use. In contrast, an adverse drug event is an untoward occurrence after exposure to a drug that is not necessarily caused by the drug. (1)
When a drug is marketed little is known about its safety in clinical use because only about 1500 patients are likely to have been exposed to it. (1,2) Thus drug safety assessment should be considered an integral part of everyday clinical practice since detection and diagnosis often depend on clinical acumen.
In this article we review the current status of adverse drug reactions, briefly describing the complexity of the more bizarre reactions and outlining a strategy to eliminate serious adverse drug reactions.
Methods
We conducted a search on the BIDS ISI database between 1981 and 1997 using key
words such as toxicity and hypersensitivity combined with drug. The references most
relevant to this review were then scanned together with any other relevant references
cited within the articles. We also continuously review the literature because of our
research interests.
Importance of adverse drug
reactions
Adverse drug reactions are a major clinical problem, accounting for 2-6% of all hospital
admissions (box). (3-6) Recent surveys in
the United States have indicated that adverse drug events increase the length of hospital
stay and costs. (5,6)
Types of adverse drug reactions
Adverse drug reactions are type A (pharmacological) or type B (idiosyncratic). (7) Type A reactions represent an augmentation of the pharmacological
actions of a drug. They are dose-dependent and are therefore readily reversible on
reducing the dose or withdrawing the drug. In contrast, type B adverse reactions are
bizarre and cannot be predicted from the known pharmacology of the drug.
Importance of adverse drug reactions
Adverse drug reactions:
- Account for 5% of all hospital admissions
- Occur in 10-20% of hospital inpatients
- Cause deaths in 0.1% of medical and 0.01% of surgical inpatients
- Adversely affect patients' quality of life
- Cause patients to lose confidence in their doctors
- Increase costs of patient care
- Preclude use of drug in most patients, although they may occur in only a few patients
- May mimic disease, resulting in unnecessary investigations and delay in treatment
Pharmacological adverse drug
reactions
Type A adverse drug reactions are more common than type B reactions, (3) accounting for over 80% of all reactions. They can be divided into
those due to the primary pharmacology of the drug-that is, augmentation of the drug's
therapeutic actions-and those due to the secondary pharmacology of the drug-that is, an
action different from the drug's therapeutic actions but still rationalisable from the known
pharmacology of the drug.
Thus, for beta blockers, bradycardia and heart block are primary pharmacological adverse effects while bronchospasm is a secondary pharmacological adverse effect. More emphasis is now placed on the secondary pharmacology of new drugs during preclinical evaluation to anticipate problems that might arise once the drug is given to humans.
Recent experience with fialuridine, an experimental drug for hepatitis B, highlights the need for continued development of appropriate in vivo and bridging in vitro test systems to predict secondary pharmacological adverse effects in humans. In June 1993, during phase II trials, 5 out of 15 patients died while two others required emergency liver transplantation for liver and kidney failure (8); this effect had not been observed in four animal species. On the basis of results from in vitro studies in cultured hepatoblasts, the toxicity may be due to inhibition of mitochondrial DNA polymerase gamma by fialuridine and its metabolites. (9)
Factors predisposing to pharmacological adverse reactions include dose, pharmaceutical variation in drug formulation, pharmacokinetic or pharmacodynamic abnormalities, and drug-drug interactions (* Table 1*). Some drugs, including captopril, were introduced into clinical practice at a dose that was subsequently shown to be associated with an unacceptable frequency of toxicity and for which a lower dose was found to be both safe and effective. Elderly people and patients with diseases such as renal failure which affect drug handling are more likely to have type A reactions. The likelihood of developing an adverse interaction also increases with the number of drugs prescribed-for example, if five drugs are given simultaneously the chance of an adverse interaction occurring is 50%. (10) To date, this has largely been a problem in elderly people but it is becoming increasingly common in younger patients with chronic diseases such as AIDS, who! may be taking 6-10 different drugs. (11)
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- Receptor abnormality-malignant hyperthermia with general anaesthetics
- Abnormal biological system unmasked by drug-primaquine induced haemolysis in patients deficient in glucose 6-phosphate dehydrogenase
- Abnormalities in drug metabolism-isoniazid induced peripheral neuropathy in people deficient in the enzyme N-acetyl transferase (that is, those who are slow acetylators)
- Immunological-penicillin induced anaphylaxis
- Drug-drug interactions-increased incidence of hepatitis when isoniazid is prescribed with rifampicin
- Multifactorial-halothane hepatitis
Idiosyncratic adverse drug reactions
Idiosyncratic adverse reactions are less common than pharmacological adverse reactions,
but they are as important because they are often serious and account for many deaths.
Mechanisms of idiosyncratic adverse effects (12) are listed in the
box.
The body's drug metabolising system has been implicated in the pathogenesis of many idiosyncratic reactions. (13) Drug metabolism is conventionally divided into phase I and phase II (14); it acts as a defence mechanism by facilitating excretion of the parent drug and its metabolites, limiting their ability to accumulate within the body and cause dose-dependent toxicity. Metabolic processes may also prevent accumulation of some drugs within particular cells or cellular compartments, which would eventually lead to toxicity. The best example of this is perhexilene, an antianginal agent, which caused hepatotoxicity and peripheral neuropathy in people deficient in the CYP2D6 (debrisoquine hydroxylase) isoform of cytochrome P- 450. (15)
Paradoxically, drug metabolising enzymes, particularly the phase I cytochrome P-450 enzymes, may also cause the formation of chemically reactive metabolites-a process termed bioactivation. (12,13,16) Such metabolites may be toxic. In most people the formation of chemically reactive metabolites is counter-balanced by detoxification mechanisms-a process termed bioinactivation. In susceptible people the usually favourable balance between bioactivation and bioinactivation may be perturbed by either genetic or host factors such as age, enzyme induction, and disease, all of which allow the toxic metabolites to escape detoxification. Under these circumstances, the toxic metabolites may bind covalently to various cellular macromolecules and cause toxicity. With most drugs, however, the factors which cause this imbalance are unknown, which explains why such reactions continue to occur.
In some cases chemically reactive metabolites will be formed irrespective of the dose. (16) At therapeutic doses any toxic metabolite formed will be detoxified by cellular defence mechanisms, but an imbalance between bioactivation and bioinactivation may result after overdoses. This will lead to the formation of large amounts of chemically reactive metabolite, which will overwhelm cellular detoxification capacity and lead to cell damage.
The clearest example of this occurs in paracetamol overdose, which causes hepatotoxicity and kills about 160 people each year in the United Kingdom. (17) Paracetamol hepatotoxicity should not be classed as an adverse reaction since the hepatic injury occurs when the drug is used inappropriately. However, the occurrence and severity of liver damage with paracetamol is a function not only of the dose but also of various host factors. (13) Indeed, paracetamol hepatotoxicity has been reported with therapeutic drug use. For example, a recent study in 67 alcoholic patients with paracetamol hepatotoxicity showed that 40