Pentoxyverine

Identification

Summary

Pentoxyverine is a medication used to suppress a cough in the common cold, flu, bronchitis, and sinusitis.

Generic Name

Pentoxyverine

DrugBank Accession Number

DB11186

Background

Pentoxyverine, also referred to as carbetapentane, is a non-opioid central acting antitussive with antimuscarinic, anticonvulsant ⁴, and local anesthetic properties. It is an active ingredient in over-the-counter cough suppressants in combination with guaifenesin and H1-receptor antagonists ¹. Pentoxyverine acts on sigma-1 receptors, as well as kappa and mu-opioid receptors.

The FDA withdrew the use of all oral gel drug products containing pentoxyverine citrate.⁹ Other forms of pentoxyverine citrate continue to be marketed.

Type

Small Molecule

Groups

Approved, Investigational, Withdrawn

Structure

Similar Structures

Weight: Average: 333.472
Monoisotopic: 333.230393862
Chemical Formula: C₂₀H₃₁NO₃

Synonyms

Carbetapentane
Pentoxyverine

Pharmacology

Indication

Indicated as a cough suppressant to relieve cough caused by the common cold, flu, bronchitis, and sinusitis ¹.

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Pentoxyverine induces an antitussive action. In animal studies, intraperitoneal administration of pentoxyverine inhibited citric-acid-induced cough in guinea-pigs in vivo ². Some mice and rat studies suggest that pentoxyverine may also exert anticonvulsant activities without inducing a protective effect from NMDA-induced lethality ^4,5. Protective effects against maximal electroshock-induced seizures in a dose-related fashion was also observed following either intraperitoneal or oral administration ⁵. In hERG-transfected cells, pentoxyverine inhibited the outward current of the hERG ion channel with half-maximal inhibition concentrations (IC50) of 3.0 µM ³. In rats receiving intrathecal administration, pentoxyverine exhibited dose-dependent spinal blockade with a more sensory-selective action over motor blockade ⁶. It induced a spinal blockade with a more sensory/nociceptive-selective action over motor blockade compared to lidocaine ⁶.

Mechanism of action

While the mechanism of antitussive action of pentoxyverine is not fully understood, it is thought to be mediated via sigma-1 receptors expressed in the central nervous system ¹. Pentoxyverine acts as an agonist at sigma receptors with the Ki of 75±28 nM, as demonstrated in a competitive binding assay ². The function of sigma receptors on cough suppressant activities is unclear, however these receptors are highly expressed in the nucleus tractus solitarius (NTS) of the brainstem where the afferent fibres first synapse ². NTS is located very close to the cough centre in the brainstem thus may function as a ‘gate' for the cough reflex and allow sigma-1 receptor agonists to modulate afferent activity prior to reaching the cough center ². It is suggested that highly lipophilic sigma-1 agonists may penetrate the CNS following systemic administration. When administered as aerosols, sigma-1 receptor agonists may temporarily act in the periphery to modulate cough by acting activate sigma receptors expressed in the lungs ². However there is limited evidence of peripheral localization of the sigma agonists following aerosol administration and the ruling out of systemic exposure ². The local anesthesia action of pentoxyverine may occur through inhibition of voltage-gated Na(+) currents ⁶.

Target	Actions	Organism
ASigma non-opioid intracellular receptor 1	agonist	Humans
UPotassium voltage-gated channel subfamily H member 2	inhibitor	Humans
UVoltage-gated sodium channel alpha subunit	inhibitor	Humans
UKappa-type opioid receptor	agonist	Humans
UMu-type opioid receptor	antagonist	Humans

Absorption

In humans, maximum plasma concentrations are achieved 1.2 hours after oral dosing ¹.

Volume of distribution