Tapentadol
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Mechanism of action
Tapentadol is a centrally-acting synthetic analgesic. Although their clinical relevance is unclear, tapentadol is believed to have two main mechanisms of action. Tapentadol is a selective mu-opioid receptor (MOR) agonist: it binds to MOR with an affinity greater than or equal to ten-fold affinity compared to delta- and kappa-opioid receptors. Tapentadol also inhibits noradrenaline reuptake, thereby increasing noradrenaline levels and activating alpha-2 receptors to promote analgesia. Tapentadol is a weak serotonin reuptake inhibitor; however, this action does not contribute to its analgesic effect.
Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerable side effects. The right central nucleus of the amygdala (CeA) is critical for the lateral spinal ascending pain pathway, regulates descending pain pathways and is key in the emotional-affective components of pain. Few studies have investigated the pharmacology of limbic brain areas in pain models. Here we determined the actions of systemic tapentadol on right CeA neurones of animals with neuropathy and which component of tapentadol contributes to its effect. Neuronal responses to multimodal peripheral stimulation of animals with spinal nerve ligation or sham surgery were recorded before and after two doses of tapentadol. After the higher dose of tapentadol either naloxone or yohimbine were administered. Systemic tapentadol resulted in dose-dependent decrease in right CeA neuronal activity only in neuropathy. Both naloxone and yohimbine reversed this effect to an extent that was modality selective. The interactions of the components of tapentadol are not limited to the synergy between the MOR and a2-adrenoceptors seen at spinal levels, but are seen at this supraspinal site where suppression of responses may relate to the ability of the drug to alter affective components of pain.
Pharmacodynamics
Tapentadol is an opioid agonist that exerts physiological effects commonly caused by the opioid drug class. These effects include miosis, reduced gastrointestinal motility, and peripheral vasodilation. Tapentadol produces respiratory depression by reducing the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tapentadol has a high potential for misuse and abuse, which can lead to the development of substance use disorder. Abuse of tapentadol poses a risk of overdose and death, which increases with alcohol or other central nervous system depressants.
Pharmacokinetics
Half-life
The terminal half-life is about four hours after oral administration.
The average terminal half-life of tapentadol is 4 hours following oral administration.
Absorption
The mean absolute bioavailability after single-dose administration of tapentadol in a fasted state is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing. Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range. A multiple (every 6 hours) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol- O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite. The AUC and Cmax increased by 25% and 16%, respectively, when tapentadol was administered after a high-fat, high-calorie breakfast. Tapentadol may be given with or without food.
Tapentadol and its metabolites are 99% excreted via the kidneys.
Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (V<sub>z</sub>) for tapentadol is 540 ± 98 L.
The total clearance is 1530 ± 177 mL/min.
Following oral administration, approximately 70% of a dose is excreted in urine as glucuronide or sulfate conjugates and only 3% is excreted unchanged. Tapentadol and its inactive metabolites are eliminated primarily by the kidneys (99%).
Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. ... The total clearance is 1530 +/- 177 mL/min.
Metabolism
In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized by Phase II pathways, and only a small amount is metabolized by Phase I oxidative pathways; thus, drug metabolism mediated by cytochrome P450 system is of less importance than phase II conjugation. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration, approximately 70% of the drug, of which 55% is the O-glucuronide metabolite and 15% is the sulfate metabolite, is excreted in urine. About 3% of the dose was excreted in urine as the unchanged parent drug. Tapentadol can also undergo CYP2C9- and CYP2C19-mediated demethylation to form N-desmethyl tapentadol, which accounts for 13% of the dose. About 2% of tapentadol can also undergo CYP2D6-mediated hydroxylation to form Hydroxy tapentadol. N-desmethyl tapentadol and Hydroxy tapentadol can further be glucuronidated. Metabolites of tapentadol do not contribute to the pharmacological activity of tapentadol.
Tapentadol is a novel, centrally acting analgesic combining mu-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. Nine metabolites, including the major metabolite tapentadol-O-glucuronide, had no analgesic effects in the tail-flick test in mice. In the phenylquinone writhing test in mice, only 5 of these metabolites showed analgesic effects. The absence or presence of analgesia correlated with moderate activity (0.5 uM < K(i) < 1.1 uM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.
In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. None of the metabolites contribute to the analgesic activity. Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys.
Protein binding
The plasma protein binding is approximately 20%.
External links
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