Adverse Drug Reactions

Definition

No medicine is risk free, yet the definition of an adverse drug reaction may not be straightforward. The World Health Organization (1972 Technical Report No. 498) defines an adverse drug reaction as “A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function.” One particular problem with this vague definition is that it assumes that all individuals are the same and hence the “normal dose” of a drug is to be comparable within a population. It does not consider differences in pathophysiology within individuals that can alter the way a drug behaves in terms of its pharmacokinetics or pharmacodynamics. Another problem is that it can be difficult to distinguish an adverse drug reaction from what is commonly known as a “side effect.” A side effect can occur within or outside the normal dose of a medication. One particular aspect of a side effect, which may differ from an adverse drug reaction, is that the effect can be beneficial. An example in anesthetic practice is the use of lidocaine as an antiarrhythmic. This drug was originally licensed for its use as a local anesthetic, yet its inhibitory effects on cardiac sodium channels can be used to dampen cardiac conduction. Further confusion with the definition of an adverse drug reaction is when a drug is being researched or is under surveillance after its initial commercial release. The European Medicines Agency good clinical practice guidelines state that “In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.”

The majority of adverse drug reactions can be attributed to a drug interacting with another or several other drugs. The practice of anesthesia involves the coadministration of several drugs alongside any drugs a patient may already be taking. The potential for drug interaction is therefore very high and this topic is covered elsewhere in this book (see Chapter 6 ).

With regard to anesthetic adverse drug reactions, a large analysis of more than 11,000 adverse drug reactions in more than 6600 patients in the United Kingdom showed a mortality of 9% with the largest proportion (>40% of deaths) associated with inhalation anesthetics and the smallest proportion (8% of deaths) from local anesthetics. The most frequently reported adverse drug reactions were associated with the use of intravenous induction agents.

Historically, adverse drug reactions were classified into two distinct categories; type A and type B. Type A reactions were classed as “dose-related” and included pharmocokinetic and pharmacodynamic variations within populations as well as drug interaction. Type B described reactions that were not dose related but idiosyncratic or allergic and often in genetically susceptible individuals. Type A reactions are more common than type B reactions and count for more than 80% of all reactions. This classification has evolved into one described neatly by Edwards and Aronson and a modification is shown in Table 7.1 . This chapter focuses on the general principles of the mechanisms of adverse drug reactions that can be applied to a wide range of drugs used in the practice of anesthesia. For ease, the layout of the chapter reflects the classification as described in Table 7.1 .

Drug Administration Errors

Adverse drug reactions can occur if the drug is incorrectly administered to a patient. Note that this does not fall into the classification described previously. Over the past 2 decades, NHS England (and formally the National Patient Safety Agency [NPSA]) and the Institute of Medicine in the United States have both compiled massive data highlighting that this is a serious and widespread issue in hospitals and drug administration errors are the single most preventable cause of patient harm. Although the majority of these reported errors lead to minimal or no harm, in anesthesia they have the potential to cause devastating effects. A U.K. study of 12,606 reported incidents showed medication errors occurred in 1,120 patients. Of these, only 15 (1.3%) resulted in severe harm or even death. A further 6-month analysis of reports to the NPSA regarding drug errors in intensive care showed of the 2428 incidents reported, 355 different drugs were involved, with morphine, gentamicin, and norepinephrine the most common. A review of anesthetic drug errors states that an error can happen as frequently as every 133 anesthetics. Much work is being done to prevent administration errors and recent evidence suggests that double-checking of drugs with a second person may reduce errors.

Drug errors need not be as late as the administration phase but can occur during the prescription. Illegible handwriting, inaccurate medication history, confusion with the drug name, inappropriate use of decimal points, use of abbreviations, and use of verbal orders have all been implicated in prescribing errors.

For some drugs, inaccurate knowledge of dosing information among prescribers can lead to erroneous dosing. A drug developed in a nonanesthetic context could have its dosing regimen inappropriately applied to the perioperative situation. This applies to some drugs that were introduced into clinical practice at a time when licensing legislation was less vigorous. A good example of this is morphine, for which the traditional quoted dose for severe postoperative pain is 0.15 mg/kg given intramuscularly. This dose was deemed the effective dose for battlefield casualties. However, one can now accept that battlefield casualties are an inappropriate model for postoperative pain as the pain tolerance of those injured in battle is high as a result of the psychological and neurohumoral response to the situation.

Another example is antiemetic medication. None of the currently available antiemetics was developed primarily for perioperative use. Many were first introduced as treatments for motion sickness, vestibular disorders, migraine, or for the treatment of side effects of radiation therapy or cytotoxic chemotherapy. The butyrephenone droperidol was introduced into anesthetic practice as a neuroleptic agent in a dose of approximately 0.1 mg/kg. Neuroleptanesthesia as a technique is now rarely performed; however, it does still demonstrate the antiemetic efficacy of droperidol. This efficacy is maintained at doses 10 times lower than those used for the neuroleptic effect. It may well be that more commonly used antiemetics such as phenothiazines and antihistamines (see Chapter 34 ) are also being used in inappropriately high doses in the perioperative setting with potentially avoidable side effects.

Types of Adverse Drug Reactions

Type A Reactions: Augmented (Dose-Related)

Paracelsus (1493-1541) once noted “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.” Despite the administration of a drug in its intended therapeutic dose range, some patients exhibit an adverse effect. This may occur as a result of variation of an individual's drug response within a unimodal population variation in response. This phenomenon is termed drug intolerance. The causes of drug intolerance are multifactorial with environmental and genetic factors involved. The intolerance of the drug is invariably related to the dose administered and there are numerous examples of these in anesthesia. One example is the intrathecal administration of a local anesthetic that can result in either a desired, low, or high block level dependent on patient characteristics. The most common dose-related reactions seen with anesthetic agents (inhalation or intravenous) are dampening of the normal cardiovascular and respiratory functions, and indeed these reactions are sometimes used for clinical benefit. This relationship between desired effect and unwanted effect remains at the forefront of toxicology.

Conventionally we measure the propensity for adverse effects of drugs by the therapeutic index. In the preclinical testing of new drugs, the therapeutic index provides a ratio of the LD ₅₀ (the dose that causes death in 50% of animals) to the ED ₅₀ (the dose that produces the desired effect in 50% of animals). The LD ₅₀ and ED ₅₀ are calculated from cumulative quantal dose-response curves as illustrated in Fig. 7.1 . Although widely established within toxicology, the therapeutic index does have its limitations. Consider two drugs A and B with the same ED ₅₀ value. If the population variability on response to drug B is greater than drug A ( Fig. 7.2 ), then there will be a larger ED ₉₅ (dose that produces the desired effect in 95% of subjects) value in drug B. Clinically the ED ₉₅ or even the ED ₉₉ is far more useful than the ED ₅₀ as we would want as many patients as possible being treated with a beneficial effective dose, yet the dose must not reach levels that produce important unwanted effects. It also becomes clear that the ED ₅₀ is not an ideal dose for clinical purposes as one would not want to produce an unwanted/lack of effect in 50% of patients. Figs. 7.3 and 7.4 further illustrate this principle. A more useful pharmacologic concept revolves around the certain safety factor . This is the ratio of the dose to produce an unwanted effect in a defined proportion of the population (usually 1%) to the dose to produce a desired effect in a proportion 100 minus that defined. In other words, the certain safety factor is most commonly described as TD ₀₁ /ED ₉₉ , where TD is the toxic dose. The certain safety factor can be adjusted if the unwanted effect of the drug is particularly serious; hence TD _0.1 /ED _99.9 or TD _0.01 /LD _99.99 , and so on could be used.

The doses used in the calculation of the certain safety factor also define the limits of the therapeutic window. Dose-response relationships remain a popular area for anesthetic research. Newer drugs, combinations of drugs, and techniques to administer them are slowly being introduced in all areas of anesthetic practice and each will undoubtedly have the ability to cause harm.