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:

• Among the agents that are more commonly associated with agranulocytosis are clozapine, the thionamides (antithyroid drugs), sulfasalazine, andticlopidine. 
• Other classes of agents with multiple reports of agranulocytosis include other antibiotics, ACE inhibitors, H2 blockers, nonsteroidal antiinflammatory drugs, amodiaquine, antiarrhythmic drugs such as tocainide, procainamide, and flecainide, dapsone, and deferiprone 
• the following 11 drugs accounted for more than 50 percent of definite or probable reports: carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin  G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine . 
• A listing of all case reports of agranulocytosis included in this 2007 systematic review is available at: www.adverse-effects.com/agranulocytosis/case_reports.html

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