Ziconotida

Ziconotida Uses, Dosage, Side Effects, Food Interaction and all others data.

Ziconotida (also known as SNX-111) is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds. Other such peptides, collectively termed conotoxins, exist, and some have shown efficacy in binding specific subsets of calcium channels; ziconotide is used in part because it can be synthesized without loss of proper bond formation or structural elements. Ziconotida is used to manage severe chronic pain refractory to other methods, through its ability to inhibit N-type calcium channels involved in nociceptive signalling.

Ziconotida was granted FDA approval on December 28, 2004 for marketing by TerSera therapeutics LLC. under the name Prialt. To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA.

Ziconotida inhibits N-type calcium channels involved in nociceptive signalling, primarily in the dorsal horn of the spinal cord. Although binding is reversible, careful dosing is required to ensure therapeutic effects while minimizing adverse effects, and ziconotide has been described as possessing a narrow therapeutic window. Patients taking ziconontide may experience cognitive and neuropsychiatric symptoms, reduced levels of consciousness, and elevated serum creatine kinase levels. In addition, ziconotide may increase the risk of infection, including serious cases of meningitis. Patients who withdraw from opiates for ziconotide initiation are advised to taper off the dose.

Ziconotida
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Ziconotida
Availability	Prescription only
Generic	Ziconotide
Ziconotide Other Names	Ziconotida, Ziconotide
Related Drugs	Buprenex, Subutex, aspirin, acetaminophen, tramadol, duloxetine, naproxen, Tylenol, oxycodone, Cymbalta
Type
Protein binding	Ziconotide is roughly 50% bound to human plasma proteins.
Groups	Approved
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Ziconotida is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics.

Ziconotida is indicated for the management of severe chronic pain in patients refractory to other treatments, and for whom intrathecal therapy is warranted.

Ziconotida is also used to associated treatment for these conditions: Severe, Chronic Pain

How Ziconotida works

Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels. Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia.

Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception. In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain.

Ziconotida belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail Conus magus which are capable of inhibiting N-type VGCCs. Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane. Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met¹²

Toxicity

Symptoms of overdose include neurological effects such as ataxia, nystagmus, stupor, sedation, speech difficulties, dizziness, nausea, and vomiting, and may also cause other effects such as hypotension; overdose is not associated with respiratory depression. In case of overdose, symptom-related supportive care up to and including hospitalization is recommended. Ziconotida has no known antidote, but the withdrawal of ziconotide generally allows patients to clear the drug and recover within 24 hours. As ziconotide does not bind to opiate receptors, opioid antagonists are not effective at ameliorating overdose effects.

Food Interaction

Avoid excessive or chronic alcohol consumption. Ingesting alcohol may increase the CNS depressive effects of ziconotide.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Ziconotida Drug Interaction

Moderate: duloxetine, hydromorphone, morphine, acetaminophen / hydrocodone, paroxetine, carbidopa / levodopaUnknown: fexofenadine / pseudoephedrine, amoxicillin / clavulanate, roflumilast, glucose, tamsulosin, formoterol, isosorbide mononitrate, potassium chloride, furosemide, esomeprazole, acetaminophen, clopidogrel, budesonide, tiotropium

Ziconotida Disease Interaction

Major: infection, psychosis

Volume of Distribution

In patients administered 1-10 mcg intrathecal ziconotide over one hour, the apparent volume of distribution was calculated as 155 ± 263 mL; this value is roughly equivalent to the expected CSF volume. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an apparent volume of distribution of 30,460 ± 6366 mL.

Elimination Route

Ziconotida administered intrathecally over one hour in doses between 1 and 10 mcg produced calculated AUC values between 83.6-608 ng*h/mL and C_max between 16.4-132 ng/mL; these values are approximately dose-proportional. Given the intrathecal administration and low membrane permeability due to its size, ziconotide is expected to remain primarily in the CSF; plasma levels, where detected, remain constant up to nine months following administration.

Half Life

In patients administered 1-10 mcg intrathecal ziconotide over one hour, the elimination half-life was calculated as 4.6 ± 0.9 hr. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an elimination half-life of 1.3 ± 0.3 hr.