Type B Or Idiosyncratic Adverse Drug Reactions

Idiosyncratic adverse reactions are less common than the pharmacological adverse reactions, but are as important, if not more so, because they are often more serious, and account for many drug-induced deaths. The possible mechanisms of idiosyncratic adverse effects (Park et al., 1992) are listed in Table 6.5. The toxic reactions may affect many organ systems either in isolation or in combination (Table 6.6).

Type B adverse drug reations have been characterized as being dose-independent (Table 6.2), or rather, there is no simple relationship between dose and the occurrence of toxicity (Park et al., 1998). Certainly, evaluation of patients with and without hypersensitivity to a particular compound shows very little difference in doses received, and indeed in the patients with hypersensitivity, the doses may have been lower since the drug had to be withdrawn. Furthermore, even within the hypersensitive group, there is little relationship to the occurrence and severity of toxicity and the dose administered.

Table 6.5. The mechanisms of type B or idiosyncratic adverse drug reactions.


Pharmaceutical variation

Receptor abnormality

Abnormal biological system unmasked by drug

Abnormalities of drug metabolism


Drug - drug interactions


Adapted from Park et al. (1992).


Eosinophilia-myalgia syndrome with L-tryptophan

Malignant hyperthermia with general anaesthetics

Primaquine-induced haemolysis in patients with G6PD deficiency

Isoniazid-induced peripheral neuropathy in slow acetylators

Penicillin-induced anaphylaxis

Increased incidence of isoniazid hepatitis with concomitant administration of rifampicin

Halothane hepatitis

METABOLIC MECHANISMS Table 6.6 Examples of organs affected by type B or idiosyncratic adverse drug reactions.

Organ system

Generalized reaction Generalized reaction Skin Liver

Haematological system

Central nervous system




Reproductive toxicity

Type of reaction



Toxic epidermal necrolysis


Aplastic anaemia



Guillain-Barre syndrome Interstitial nephritis Pneumonitis Cardiomyopathy Etretinate

Drug examples












Various foetal abnormalities

However, intuitively there must be some kind of dose-response relationship since if the patient had not received the drug they would not have developed the hypersensitivity reaction. Since many type B adverse drug reations are thought to be mediated by the formation of chemically reactive metabolites through metabolism by P450 enzymes (a process termed bioactivation) (Park et al., 1998), perhaps a relationship exists with the ''internal dose'', i.e. the concentration of the toxic metabolite formed in the body. However, since these metabolites by definition are unstable, it has not been possible with the currently available technologies to evaluate the dose-response relationship. The situation is further compounded by the fact that the different sources of variation in the human body may all have a different dose-response relationship. Nevertheless, evidence for the existence of such a dose-response relationship can be gleaned from clinical situations where different doses have to be given to the same group of patients in different circumstances. For example, in HIV-positive patients, the anti-infective agent co-trimoxazole has to be given at low doses for prophylaxis against Pneumocystis carinii pneumonia (PCP) (960 mg once daily), while for acute treatment of PCP, much higher doses (up to 8 g/day) may be administered. The frequency of hypersensitivity reactions is lower with the prophy lactic dose (30%) than with the acute dose, where rates as high 80% have been reported (Carr and Cooper, 1995; Pirmohamed and Park, 1995).

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