Tuesday, April 7, 2015

Drug Induced Neutropenia and Agranulocytosis

DEFINATIONS:
  • Neutropenia is defined as an absolute neutrophil count (ANC) <1500/microL
  • Agranulocytosis literally means the absence of granulocytes (ie, ANC of zero), although the term is often used loosely to indicate severe degrees of neutropenia (ie, ANC <100, <200 or even <500/microL)
  • The terms leukopenia and granulocytopenia are generally used interchangeably with neutropenia, although they are somewhat different.
  • Leukopenia refers specifically to a low WBC due to any cause
  • Granulocytopenia refers to a reduced number of granulocytes

CAUSES:
  • Cytotoxic chemotherapy produces neutropenia by destroying dividing myeloid progenitor cells; this is an expected effect directly related to the treatment's primary mechanism of action.
  • Drug-induced neutropenia is more common in patients over 60 years of age, and in women
  • Severe agranulocytosis from a drug reaction is rare (1-10 cases per million population per year) and most frequently associated with clozapine, antithyroid drugs (thionamides), and sulfasalazine.

MECHANISM
Antibody-mediated neutrophil destruction
  • the drug acts as a hapten and stimulates the formation of antibodies, which then mediate the destruction of circulating neutrophils.
  • Aminopyrine, propylthiouracil, penicillin, and gold compounds are the most common drugs associated with hapten formation.

Acceleration of neutrophil apoptosis
  • antipsychotics (e.g., clozapine) produce metabolites, which bind to the neutrophil causing depletion of intracellular glutathione, toxicity, and cell death.

Complement-mediated lysis of neutrophils
  • the drug acts as a hapten and stimulates the formation of antibodies. However, instead of directly attacking neutrophils, the antibodies activate complement, and neutrophils are destroyed by complement-mediated lysis.

Inhibition of haematopoiesis
  • drugs such as the beta-lactam antibiotics and some anticonvulsant drugs (carbamazepine and valproic acid) inhibit the colony-forming units of granulocytes and macrophages in bone marrow.
  • Ticlopidine, sulfasalazine, and chlorpromazine cause suppression of myeloid precursors in the bone marrow.

COMMON CAUSATIVE AGENTS:

REFERENCES:
  1. Drug-induced neutropenia and agranulocytosis. www.uptodate.com
  2. Neutropenia. http://bestpractice.bmj.com/best-practice/monograph/893/overview/aetiology.html
  3. Drug-Induced Neutropenia – Pathophysiology, Clinical Features, and Management. http://www.annclinlabsci.org/content/34/2/131.full




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