Anticonvulsant Hypersensitivity Syndrome: Implications for Pharmaceutical Care

Abstract

Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000-10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40-80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.

Pathogenesis and Clinical Approaches to Anticonvulsant Hypersensitivity Syndrome: Current State of Knowledge

“…The toxic intermediaries in the metabolism of anticonvulsant drugs, arene oxides, can accumulate and directly bind to macromolecules, causing subsequent cell death as well as acting as prohaptens that bind to T cells, initiating a T-cell immune response and systemic reactions (12).…”

“…Drug eruption occurs in approximately 90-100% (3,10,12,(33)(34)(35)(36) of patients with AHS and can range from an exanthematous eruption to more serious reactions like SJS or TEN (9). Desquamation occurs with resolution (8).…”

“…The main haematological abnormalities in patients with AHS consist of: leukocytosis (28-75%), with atypical lymphocytes (50-71%), eosinophilia (42-73%) and lymphocytosis (11-71%) (3,12,(34)(35)(36); less frequently leukopenia (35), anemia, positive rheumatoid factor, antinuclear antibodies, antidouble-stranded DNA smooth muscle antibodies, cold agglutinin, hypo/hypergammaglobulinaemia (6).…”

“…Patients need to be informed that they may have the same type of reaction to other anticonvulsant drugs (not in the same drug class as the original drug) and about the dangers of rechallenging (3), considering that there is a 40%-80% incidence of cross-sensitivity between the different aromatic anticonvulsants (14,40). Cross-sensitivity is significant among PHT, CBZ, and PB, which obviously contain the aromatic structure (12). CBZ, OXC, PHT, LTG and PB have a 20-30% chance of cross-reacting.…”

Acute Hypersensitivity Syndrome Caused by Valproic Acid: A Review of the Literature and a Case Report

“…Because cross-reactivity can be as high as 75%, they recommended that physicians be taught not to use these agents in such situations, but to instead use VPA, benzodiazepine, lamotrigine, and gabapentin. 8,9 Alldredge et al 10 reported that before the onset of symptoms, physicians for 3 of 4 patients with acute hypersensitivity syndrome (AHS) switched their medications to an anticonvulsant with an aromatic ring in the structure. They also reported that the symptoms subsided after the interruption of the medication and that all patients recovered.…”