Proparacaine Hydrochloride

Proparacaine hydrochloride significantly decreased the potential difference and short-circuit current in isolated toad skin, indicating an inhibition of active ion transport. X-ray diffraction analyses demonstrated that proparacaine interacted directly with dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) bilayers, causing marked structural perturbations particularly in DMPC, the phospholipid class located in the outer monolayer of cell membranes. Fluorescence spectroscopy of large unilamellar DMPC vesicles at 18°C confirmed this membrane-disrupting effect.
Scanning electron microscopy of human erythrocytes revealed characteristic morphological changes induced by the drug. The mechanism of action involved a dual interaction: proparacaine altered epithelial sodium channels through perturbation of the surrounding lipid matrix while also interacting with channel protein residues. This combined effect on both membrane lipids and channel proteins explained how proparacaine limited sodium ion permeability, thereby blocking action potential generation and producing its rapid local anesthetic effect.

Fig. 1 SEM images of human erythrocytes. (A) Control, 2900X; (B) incubated with 3 mm proparacaine, 2000X. (Suwalsky M.; et al. 2002)

Proparacaine hydrochloride demonstrated a robust antiepileptic effect in a pilocarpine-induced mouse model of epilepsy by blocking the Nav1.3 sodium channel. Chronic treatment with proparacaine hydrochloride completely terminated spontaneous recurrent seizure activity without causing significant cytotoxicity, neuropsychiatric effects, hepatotoxicity, or genotoxicity as assessed by whole-genome transcriptomic analyses. However, high-dose administration (50 mg/kg) produced a mild prolongation of the QRS interval on electrocardiography.
To mitigate this cardiotoxicity concern, a liposomal hydrogel formulation was developed using a thermosensitive chitosan-based hydrogel containing liposome-encapsulated proparacaine. Subcutaneous implantation of this novel formulation provided immediate and long-lasting remission from spontaneous recurrent seizures in epileptic mice without affecting the QRS interval. This liposomal hydrogel strategy enabled sustained drug release while eliminating the cardiac safety liability. The study proposed that proparacaine could be repurposed as a transdermal patch for epilepsy treatment, avoiding the severe toxicities associated with current antiepileptic drugs.

Fig. 2 Illustration of the Proparacaine-liposome hydrogel preparation. (Taleb A.; et al. 2021)