Indications
Ziconotide is prescribed for managing·hronic pain in patients who have not responded to other treatments and for whom intrathecal therapy is appropriate.
Pharmacodynamics
Ziconotide functions by inhibiting·hannels, which are key components in nociceptive signaling·he dorsal horn of the spinal cord. Although the binding·has a narrow therapeutic window, necessitating·hieve desired effects while minimizing·hiatric symptoms, decreased levels of consciousness, and increased serum creatine kinase levels. Additionally, the use of ziconotide may elevate the risk of infections, such as serious cases of mening·hould gradually reduce their opiate dosage.
Absorption
When administered intrathecally over the course of one hour in dosages rang·he curve (AUC) values between 83.6 and 608 ng·h/mL and maximum concentration (Cmax) values rang·hese values exhibit approximately dose-proportional behavior. Due to its mode of administration and low membrane permeability attributed to its molecular size, ziconotide primarily remains within the cerebrospinal fluid (CSF). In cases where plasma levels are detectable, they remain stable for up to nine months after administration.
Metabolism
Upon entering·he systemic circulation, ziconotide is anticipated to be metabolized by various peptidases. However, detailed information regarding·hways has not been thoroughly documented.
Mechanism of Action
Ziconotide is a peptide from the ω-conotoxin class, sourced from the cone snail *Conus magus*, and functions as an inhibitor of N-type voltage-gated calcium channels (VGCCs). These channels, particularly the N-type (Cav2.2) variety, play a crucial role in neural signaling processes, especially within nociceptive pain pathways which involve peripheral nociceptors, primary afferent nerve fibers, and central nervous system neurons in the spinal cord. In chronic pain states, such as inflammatory and neuropathic pain, VGCC activity is often upregulated, contributing to conditions like allodynia and hyperalgesia. Activation of N-type channels in Aδ and C fibers facilitates the release of neurotransmitters, including substance P, calcitonin gene-related peptide, and glutamate, further propagating pain signals and promoting inflammation. Ziconotide's inhibitory action on these channels is unique, involving a mechanism that possibly includes direct obstruction of the ion pore to halt calcium ion translocation across cell membranes. Research suggests that the interaction between ziconotide and the Cav2.2 channel may be enhanced by the Met12 residue of ziconotide fitting into a hydrophobic cavity formed by specific channel residues, although this might also contribute to the peptide's toxic effects.
