Instructions for use KATADOLON® (KATADOLON)
Non-opioid analgesic of central action. Flupirtine is the prototype of a new class of substances SNEPCO (Selective Neuronal Potassium Channel Opener - selective activators of neuronal potassium channels). Refers to non-opioid analgesics of central action that do not cause dependence or addiction.
Flupirtine has analgesic, muscle relaxant and neuroprotective effects based on indirect antagonism of NMDA (N-methyl-O-aspartate) receptors, activation of descending mechanisms of pain modulation and GABAergic processes. At therapeutic concentrations, flupirtine does not bind to α1-, α2-, 5HT1-, 5HT2-, dopamine, benzodiazepine, opioid, central m- or n-cholinergic receptors.
Analgesic effect
Flupirtine in therapeutic doses activates (opens) voltage-independent potassium channels, which leads to stabilization of the membrane potential of the nerve cell. In this case, the activity of NMDA receptors is inhibited and, as a consequence, blockade of neuronal calcium ion channels, a decrease in the intracellular current of calcium ions, and inhibition of neuron excitation in response to nociceptive stimuli (analgesia). As a result of these processes, the formation of nociceptive sensitization (pain sensitivity) and the “wind up” phenomenon (“winding up” - an increase in the neuronal response to repeated painful stimuli) is inhibited, which prevents pain from increasing, its transition to a chronic form, and in case of existing chronic pain syndrome leads to a decrease in its intensity. The modulating effect of flupirtine on the perception (sensitivity) of pain through the descending noradrenergic system has also been established.
Muscle relaxant effect
The antispastic effect on muscles is associated with blocking the transmission of excitation to motor neurons and interneurons, leading to the relief of muscle tension. This effect of flupirtine occurs in many chronic diseases accompanied by painful muscle spasms (musculoskeletal pain in the neck and back, arthropathy, tension headaches, fibromyalgia).
Neuroprotective effect
The neuroprotective properties of the drug determine the protection of nervous structures from the toxic effects of high concentrations of intracellular calcium ions, which is associated with its ability to cause blockade of neuronal calcium ion channels and reduce the intracellular current of calcium ions.
Katadolon
Non-opioid analgesic of central action. Flupirtine is a representative of selective activators of neuronal potassium channels.
Flupirtine activates G protein-coupled neuronal inward rectifier potassium channels. The release of potassium ions causes stabilization of the resting potential and a decrease in the excitability of neuronal membranes. The result is indirect inhibition of NMDA receptors (N-methyl-D-aspartate), since the blockade of NMDA receptors by magnesium ions persists until depolarization of the cell membrane occurs (indirect antagonistic effect on NMDA receptors).
At therapeutically significant concentrations, flupirtine does not bind to α1-, α2-adrenergic receptors, 5HT1(5-hydroxytryptophan)-, 5HT2-serotonin, dopamine, benzodiazepine, opioid, central m- and n-cholinergic receptors.
This central action of flupirtine leads to the implementation of 3 main effects.
Analgesic effect
As a result of the selective opening of voltage-gated neuronal potassium channels with the concomitant release of potassium ions, the resting potential of the neuron is stabilized. The neuron becomes less excitable.
Flupirtine's indirect antagonism of NMDA receptors protects neurons from the influx of calcium ions. In this way, the sensitizing effect of increasing the intracellular concentration of calcium ions is mitigated.
Consequently, when the neuron is excited, the transmission of ascending nociceptive impulses is inhibited.
Muscle relaxant effect
The pharmacological effects described for the analgesic effect are functionally supported by an increase in the uptake of calcium ions by mitochondria, which occurs at therapeutically significant concentrations. The muscle relaxant effect results from the concomitant inhibition of impulse transmission to motor neurons and the corresponding effects of interneurons. Thus, this effect manifests itself mainly in relation to the entire musculature as a whole.
Effect of chronification processes
Chronification processes should be considered as processes of neuronal conduction due to the plasticity of neuronal function.
Through the induction of intracellular processes, the elasticity of neuronal functions creates conditions for the implementation of “inflating” type mechanisms, in which the response to each subsequent impulse is strengthened. NMDA receptors (gene expression) are largely responsible for triggering such changes. Indirect blockade of these receptors by flupirtine leads to suppression of these effects. Thus, unfavorable conditions are created for clinically significant chronic pain, and in the case of previously present chronic pain, for “erasing” pain memory through stabilization of the membrane potential, which leads to a decrease in pain sensitivity.
Pharmacokinetics
Suction
After oral administration, it is almost completely (up to 90%) and quickly absorbed from the gastrointestinal tract.
The concentration of the active substance in the blood plasma is proportional to the dose.
Metabolism
Metabolized in the liver (up to 75% of the dose taken) with the formation of the active metabolite M1 (2-amino-3-acetamino-6-[4-fluoro]-benzylaminopyridine) and M2. The active metabolite M1 is formed as a result of hydrolysis of the urethane structure (phase 1 of the reaction) and subsequent acetylation (phase 2 of the reaction). This metabolite provides on average 25% of the analgesic activity of flupirtine. Another metabolite (M2 - biologically inactive) is formed as a result of the oxidation reaction (phase 1) of para-fluorobenzyl followed by conjugation (phase 2) of para-fluorobenzoic acid with glycine.
Studies have not been conducted on which isoenzyme is predominantly involved in the oxidative pathway of destruction. Flupirtine should be expected to have only minor potential for interaction.
Removal
T1/2 is about 7 hours (10 hours for the main substance and metabolite M1), which is sufficient to provide an analgesic effect.
Excreted mainly by the kidneys (69%): 27% is excreted unchanged, 28% is excreted as metabolite M1 (acetyl metabolite), 12% is excreted as metabolite M2 (para-fluorohippuric acid) and 1/3 of the administered dose is excreted in in the form of metabolites with unknown structure. A small part of the dose is excreted from the body with bile and feces.
Pharmacokinetics in special clinical situations
In elderly patients (over 65 years old), compared with young patients, there is an increase in T1/2 (up to 14 hours with a single dose and up to 18.6 hours when taken for 12 days) and Cmax, respectively, in the blood plasma is 2-2.5 higher times.
Katadolon® forte
Flupirtine is a representative of drugs “selective activators of neuronal potassium channels” (“Selective Neuronal Potassium Channel Opener” - SNEPCO) and is a non-narcotic analgesic of central action that does not cause addiction or dependence.
Flupirtine activates G protein-coupled neuronal inward rectifying K+ channels. The release of K+ ions causes stabilization of the resting potential and a decrease in the excitability of neuronal membranes. The result is indirect inhibition of NMDA receptors (N-methyl-D-aspartate), since the blockade of NMDA receptors by Mg2+ ions persists until depolarization of the cell membrane occurs (indirect antagonistic effect on NMDA receptors).
At therapeutically significant concentrations, flupirtine does not bind to alpha1, alpha2, 5HT1(5-hydroxytryptophan)-, 5HT2-serotonin, dopamine, benzodiazepine, opioid, central m- and n-cholinergic receptors.
This central action of flupirtine leads to three main effects.
Analgesic effect
Due to the selective opening of voltage-gated K+ channels of neurons with the concomitant release of K+ ions, the resting potential of the neuron is stabilized.
The neuron becomes less excitable. Flupirtine's indirect antagonism of NMDA receptors protects neurons from the entry of Ca2+ ions. Thus, the sensitizing effect of increasing the intracellular concentration of Ca2+ ions is mitigated. Consequently, when the neuron is excited, the transmission of ascending nociceptive impulses is inhibited.
Muscle relaxant effect
The pharmaceutical effects described for the analgesic effect are functionally supported by an increase in the uptake of Ca2+ ions by mitochondria, which occurs at therapeutically significant concentrations. The muscle relaxant effect results from the concomitant inhibition of impulse transmission to motor neurons and the corresponding effects of interneurons. Thus, this effect occurs mainly in relation to local muscle spasms, and not in relation to the entire musculature as a whole.
Effect of chronification processes Chronification processes should be considered as processes of neuronal conduction, due to the plasticity of neuron functions. Through the induction of intracellular processes, the elasticity of neuronal functions creates conditions for the implementation of “inflating” type mechanisms, in which the response to each subsequent impulse is strengthened. NMDA receptors (gene expression) are largely responsible for triggering such changes. Indirect blockade of these receptors by flupirtine leads to suppression of these effects. Thus, unfavorable conditions are created for clinically significant chronic pain, and in the case of previously present chronic pain, for “erasing” pain memory through stabilization of the membrane potential, which leads to a decrease in the pain threshold of sensitivity.
Catadolon capsules 100 mg 30 pcs.
Flupirtine is a member of the Selective Neuronal Potassium Channel Opener (SNEPCO) class of drugs. In terms of its pharmacological effects, the drug is a non-opioid analgesic of central action, which does not cause dependence or addiction; in addition, it has a muscle relaxant and neuroprotective effect. The action of flupirtine is based on the activation of voltage-independent potassium channels, which leads to stabilization of the membrane potential of the neuron. The effect on the current of potassium ions is mediated by the effect of the drug on the regulatory G-protein system. The analgesic effect is based both on indirect antagonism towards NMDA (N-methyl-D-aspartate) receptors, and through modulation of pain mechanisms associated with the effect on GABAergic systems. At therapeutic concentrations, flupirtine does not bind to alpha1-, alpha2-adrenergic receptors, serotonin 5HT1, 5HT2 receptors, dopaminergic, benzodiazepine, opiate, central muscarinergic or nicotinergic receptors. The central action of flupirtine is based on 3 main effects: Analgesic effect. Flupirtine activates (opens) voltage-independent potassium channels, which leads to stabilization of the membrane potential of the nerve cell. In this case, the activity of NMDA receptors is inhibited and, as a consequence, the blockade of neuronal calcium ion channels and a decrease in the intracellular current of calcium ions occurs. Due to the developing suppression of neuron excitation in response to nociceptive stimuli, inhibition of nociceptive activation, an analgesic effect is realized. In this case, the growth of the neuronal response to repeated painful stimuli is inhibited. This action prevents pain from intensifying and becoming chronic, and in case of existing chronic pain syndrome, it leads to a decrease in its intensity. The modulating effect of flupirtine on the perception of pain through the descending noradrenergic system has also been established. Muscle relaxant effect. The antispastic effect on muscles is associated with blocking the transmission of excitation to motor neurons and interneurons, leading to the relief of muscle tension. This effect of flupirtine occurs in many chronic diseases accompanied by painful muscle spasms (musculoskeletal pain in the neck and back, arthropathy, tension headaches, fibromyalgia). Neuroprotective effect. The neuroprotective properties of the drug determine the protection of nervous structures from the toxic effects of high concentrations of intracellular calcium ions, which is associated with its ability to cause blockade of neuronal calcium ion channels and reduce the intracellular current of calcium ions.
