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Local anesthetic activity and disopyramide toxicity.

A Malavé, M P Holsapple, G K Yim

    Archives Internationales De Pharmacodynamie Et De Therapie
    |June 1, 1983
    PubMed
    Summary

    Disopyramide (DIP) exhibits weak local anesthetic properties, with an irreversible nerve block at higher concentrations. Its toxicity is not attributed to local anesthetic effects, as evidenced by lack of prevention of seizures in mice.

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    Area of Science:

    • Pharmacology
    • Neuroscience
    • Toxicology

    Background:

    • Disopyramide (DIP) is an antiarrhythmic drug with potential toxic effects.
    • The local anesthetic properties of DIP and its metabolite MIP have not been fully elucidated.
    • Understanding DIP's mechanism of toxicity is crucial for clinical management.

    Purpose of the Study:

    • To investigate the local anesthetic activity of disopyramide (DIP) and its metabolite MIP.
    • To determine if DIP's local anesthetic action contributes to its toxicity.
    • To compare the nerve blocking potency of DIP and MIP with known local anesthetics like lidocaine and procaine.

    Main Methods:

    • Isolated frog sciatic nerve preparation to determine IC50 concentrations for nerve block.
    • Electrically stimulated rat ventricular strip assay to assess drug reversibility.
    • In vivo studies in mice to evaluate the efficacy of anticonvulsants against DIP-induced toxicity.

    Main Results:

    • Disopyramide (DIP) demonstrated weak local anesthetic activity with an IC50 of 11.9 mM, significantly higher than lidocaine (0.34 mM) and procaine (0.62 mM).
    • The mono-demethylated metabolite of DIP (MIP) showed even weaker activity (IC50: 52.8 mM).
    • DIP-induced nerve block was irreversible, unlike lidocaine block, but DIP-induced cardiac depression was reversible.
    • Anticonvulsants did not prevent seizures or death in mice treated with DIP, suggesting local anesthetic action is not the primary cause of toxicity.

    Conclusions:

    • Disopyramide possesses weak local anesthetic properties that are unlikely to significantly contribute to its overall toxicity.
    • The irreversible nature of DIP-induced nerve block warrants further investigation.
    • The primary mechanisms of disopyramide toxicity likely lie in pathways other than local anesthesia.

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