Drugs

Drug-related neutropenia generally falls into two categories: direct drug toxicity and immunological. Drugs causing neutropenia by direct toxicity can be further subdivided into those that have a predictable dose-dependent effect on the myeloid precursors and those with an idiosyncratic and dose-independent response.

Dose-dependent mechanism

If given in sufficient dosage, certain drugs will consistently cause neutropenia and also suppress other hemopoietic elements. They act mainly, if not entirely, by interfering with cell division in the following manner:

1. inhibition of purine or pyrimidine biosynthesis or incorporation into DNA (e.g. mercaptopurine, 6-thioguanine, hydroxyurea);

2. cross-linkage of DNA, thereby impeding RNA formation (e.g. nitrogen mustard, chlorambucil);

3. disruption of the microtubules of the mitotic spindle (vinblastine).

For the most part these agents are used in the treatment of malignant diseases. The degree and reversibility of neutropenia is determined by the dose and type of drug.

Idiosyncratic mechanism

An ever-growing list of drugs cause neutropenia unpredictably and in only a few patients exposed to them. These include chloramphenicol, carbimazole, and phenothiazines. Typically, neutropenia becomes evident 1 to 2 weeks following initial exposure. The basis of the drug reaction is unclear, but it is probably due to a genetic aberration in enzymatic responsiveness. Treatment consists of immediate withdrawal of the implicated drugs and aggressive management of any underlying infection. Hemopoietic recovery usually follows within 1 to 2 weeks.

Immunogenic mechanism

Although rarely used, aminopyrine remains historically important as the prototype for immunogenic neutropenia. Other drugs recently implicated include phenytoin, chlorpropamide, levamisole, and clozapine. The mechanisms involve development of an antibody to a complex between the drug and specific neutrophil proteins. Administration of the drug to a sensitized individual results in massive leukoagglutination and removal of neutrophils from the circulation. Neutropenia is reversible within 1 to 2 weeks upon withdrawal of the drug.

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