Toxicity idiosyncratic reactions

R. H. Lavey, and J. K. Penny (eds.), Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanism of Toxicity, Raven Press, New York, 1991, pp. 19-24. 

This statement is somewhat at odds with the conventional view that idiosyncratic toxicology is dose-size independent. Idiosyncratic reactions are thought to result from an immune-mediated cell injury triggered by previous contact with the drug. The toxicity may appear after several asymptomatic administrations of the com-... 

Whilst this may explain potentially explain many cases, this does not represent the full mechanism which is undoubtedly more complex as not all reactions appear to be immunological. For example, paracetamol is known to form reactive intermediates but yet is not involved in idiosyncratic reactions. Indeed, with some notable exceptions such as the penicillins, many drugs involved in idiosyncratic reactions do not mediate their toxicity through a immune response. 

A variety of idiosyncratic reactions may be seen shortly after therapy has begun. Skin rashes, usually morbilliform in character, are most common. Exfoliative dermatitis or toxic epidermal necrolysis (Lyellis syndrome) has been observed but is infrequent. Other rashes occasionally have been reported, as have a variety of blood dyscrasias and hepatic necrosis. 

There are many examples of human subjects showing idiosyncratic reactions to the pharmacological or toxicological actions of drugs. In some cases, the genetic basis of such reactions has been established, and these cases underline the need for an understanding and appreciation of genetic factors and their role in the causation of toxicity. 

Gastrointestinal side effects of diarrhea, nausea, and vomiting are observed in one third to half of patients. A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Idiosyncratic reactions including thrombocytopenia, hepatitis, angioneurotic edema, and fever are observed rarely. 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

Idiosyncratic toxicity Immunoallergic reaction No No 1-5 weeks Any Fever, rash, eosinophilia, arthralgias, hepatitis Halothane Carbamazepine... 

A second, more serious, type of bone marrow depression consists of aplastic anemia. Considered an idiosyncratic reaction rather than a toxic reaction, aplastic anemia occurs most commonly weeks to months after completion of therapy and is not dose related. In the most severe form of aplastic anemia, pancytopenia with an aplastic marrow is present. Prognosis is very poor because the anemia is usually irreversible. 

Kamik AM, Al-Shamah MA, Fenech FF. A case of ocular toxicity to ethambutol—an idiosyncratic reaction Postgrad Med J 1985 61(719) 811-13. 

Primidone can cause various idiosyncratic reactions, including systemic lupus erythematosus, a sjmdrome resembling diabetes insipidus, lymphadenopathy, toxic epidermal necrolysis, thjroid enlargement, and edema. 

Biotransformation and generation of reactive intermediate metabolites are associated with a variety of toxicities and idiosyncratic reactions.37 Toxicologists should always consider how drug disposition and fate contribute to toxicity, as target organ dosimetry, biotransformation, and detoxification reactions can be important determinants of toxicity. In all cases, understanding how biotransformation may differ across species, with emphasis on human metabolism, is an important component in determining whether preclinical effects are predictive of and relevant for human safety evaluation. 

Chronic toxic effects are dose related and typically involve cerebellar and vestibular functions (nystagmus and ataxia). Nausea, dizziness, diplopia, behavioral changes, gingival hyperplasia, hirsutism, hyperglycemia, osteomalacia, pancytopenia, and skin eruptions are reported complications of chronic therapy. Hypersensitivity (idiosyncratic) reactions, including hepatic necrosis and Stevens-Johnson syndrome, can occur and are potentially fatal. 

While in the hospital she also developed symptoms of neuritis and bilateral cataracts, which were not present on admission. Hematological tests were normal except for a slight secondary anemia. This individual may have had an idiosyncratic reaction to 2,4-DNP, dermal reactions in other patients were reversed when 2,4-DNP was discontinued. Oral exposure to 2,4-DNP at 0.01 mg/kg/day would be unlikely to result in effects on ATP production in the mitochondria, which is the mechanism of action for 2,4-DNP-induced toxicity. 

Drug-induced liver disease occurs as several different clinical presentations idiosyncratic reactions, allergic hepatitis, toxic hepatitis, chronic active toxic hepatitis, toxic cirrhosis, and liver vascular disorders. 

Centrolobular necrosis is often a dose-related, predictable reaction secondary to drugs such as acetaminophen however, it also can be associated with idiosyncratic reactions, such as those caused by halothane. Also called direct or metabolite-related hepatotoxic-ity, centrolobular necrosis is usually the result of the production of a toxic metabolite (see Fig. 38-1). The damage spreads outward from the middle of a lobe of the liver. 

Such indices are of most value when toxicity represents an extension of the pharmacologic actions of a drug. They do not predict idiosyncratic reactions or drug hypersensitivity. 

In 2003, Shenton et al. reported a novel animal model of a drug-induced idiosyncratic reaction nevirapine-induced skin rash in the female Brown Norway rat. This animal model does not reproduce severe skin rashes such as TEN and SJS, nor does it reproduce the liver toxicity observed in some nevirapine-treated patients. However, the skin rash that develops in nevirapine-treated rats closely resembles the mild erythematous rash observed in patients (Shenton et al. 2003). 

Several drugs marketed currently have exhibited problems with toxicity or tetratoge-nicity. Hepatotoxicity, aplastic anemia, Stevens-Johnson syndrome, and neurotoxicity have been concerns cited frequently. Idiosyncratic reactions involving hematologic and dermatologic systems have proved fatal in a few cases. Considerable research effort has been directed toward identifying novel pharmaceutical moieties with a broad spectrum of efficacy and fewer side effects. 

Reports of acute liver toxicity associated with consumption of chaparral surfaced from 1990 through 1997, leading to the issuance of a warning by the FDA to cease consumption of chaparral (FDA 1992). The American Herbal Products Association (AHPA) initiated a review of four cases (Watt et al. 1994) and found the reported toxicity to be due to idiosyncratic reactions in persons with preexisting liver conditions. The authors concluded, and AHPA recommended in 1995, that products containing chaparral should be labeled with the following cautionary statement Seek advice from... 

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