Epileptogenic Potential of Carbapenem Agents

Mechanism of Action, Seizure Rates, and Clinical Considerations

April D. Miller, Pharm.D.; Amanda M. Ball, Pharm.D.; P. Brandon Bookstaver, Pharm.D.; Emily K. Dornblaser, Pharm.D.; Charles L. Bennett, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2011;31(4):408-423. 

In This Article

Mechanism of Carbapenem-induced Seizure

The carbapenem antibiotics represent a newer class of agents that derive their structure from the classic β-lactam ring and share similar neurologic adverse effects as penicillins and cephalosporins. It is believed that the seizure-inducing potential of these agents may be directly related to the similarity of the β-lactam ring to the structure of the γ-aminobutyric acid (GABA) neurotransmitter and antagonism at the GABA receptor site.[12,13] Imipenem is also formulated with cilastatin, which boosts plasma levels in a probenecid-like effect. However, studies indicate that cilastatin itself is not epileptogenic.[14]

The GABA neurotransmitter mediates inhibitory neurotransmission by agonism at the GABAA receptor complex. This receptor functions as a ligand-gated chloride ion channel composed of multiple subunits, with the benzodiazepine, barbiturate, and GABA binding sites being most clinically relevant.[12] Agonism at GABA's binding site opens the chloride channel, resulting in an influx of chloride ions into the postsynaptic nerve terminal and a hyperpolarization of the membrane potential. Hyperpolarization results in decreased postsynaptic nerve terminal response to stimuli and an inhibition of neuronal firing.[4] Conversely, antagonism of GABA binding leads to increased membrane potential and an excitatory state that more readily depolarizes in response to stimuli. There is also some evidence of an increased excitatory effect on the N-methyl-Daspartic acid receptors by imipenem-cilastatin, but research in this pathway has been minimal.[15]

Early studies on properties of penicillin and its derivatives show that they possess an affinity for the GABAA receptor, and it is hypothesized that antagonism of the GABA binding site by β-lactams, including the carbapenem class, is responsible for their epileptogenic potential.[16] Furthermore, it is believed that the intact β-lactam ring is needed for antagonism to occur.[13] The range of epileptogenic potential of the carbapenems is most likely related to increases in the basicity of the C2 side chain.[17] The basicity of the C2 side chain is influenced by Nacetylation or N-methylation of the C2 cyclopentene ring, and the presence of either substitution effectively decreases seizure potential by decreasing basicity. The C2 side chain of imipenem is most basic. Meropenem and ertapenem possess less basic C2 side chains than imipenem, which is likely responsible for the reduced neurotoxicity seen with these agents. The C2 side chain of ertapenem is differentiated from meropenem only by a meta-substituted carboxylic acid on a benzoic ring.[18] The two compounds would be expected to have similar basicity resulting in a similar epileptogenic profile, although this has not been specifically described. To our knowledge, in vitro studies comparing the basicity of doripenem's C2 side chain to that of other carbapenems have not been published, making qualitative comparison difficult at this time. However, animal data indicate that doripenem has a lower binding affinity for the GABA receptor than imipenem, meropenem, and panipenem-betamipron.[19]

Pharmacokinetics and pharmacodynamics can also play a role in the epileptogenic potential of individual agents. Free, unbound plasma concentrations are of concern when evaluating the epileptogenic potential of individual agents. High unbound concentrations and low protein binding increase the seizure propensity. As described above, a variety of pharmacologic factors influence epileptogenic potential, but comparisons of protein binding may provide insight.

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