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Abstract
Trimeperidine, a synthetic opioid analgesic, is widely used as a centrally-acting analgesic and sedative. It is commonly prescribed for the management of moderate to severe pain, known for its rapid onset and short duration of action. With a structure similar to meperidine, trimeperidine exhibits enhanced lipophilicity and high affinity for opioid receptors, resulting in a more rapid and intense analgesic effect. Typically administered via intramuscular or intravenous routes, trimeperidine finds application in surgical settings, postoperative pain management, and acute pain management in emergency and trauma cases. However, caution should be exercised in its use due to the potential for respiratory depression, dependence, and abuse, and it should only be administered under the supervision of a qualified healthcare professional. Further research is needed to fully elucidate the pharmacological properties, efficacy, and safety profile of trimeperidine in various clinical settings. Promedol, also known as 1,2,5-trimethyl-4-propionyloxy-4-phenylpiperidine (trimeperidine) hydrochloride, shares similar pharmacological properties with morphine and is widely used in anesthesiology, particularly for multicomponent anesthesia. However, it is also known to be abused by drug addicts for its narcotic effects. This article provides a comprehensive overview of Promedol, including general information, physico-chemical properties, pharmacology in recreational use, effects and symptoms, hepatotoxicity, prices and approximate dosage, dangerous interactions, legal status, synthesis of [(2S,5R)-1,2,5-trimethyl-4-phenylpiperidin-4-yl] propanoate, conclusion, and bibliography, aiming to provide a thorough understanding of this compound.
General Information About Promedol [1-3]
Other synonyms names of Promedol are: Trimeperidine; Isopromedol; Trimeperidina; Trimeperidinum; Dimethylmeperidine
IUPAC Name of Promedol: [(2S,5R)-1,2,5-trimethyl-4-phenylpiperidin-4-yl] propanoate
CAS numbers is 64-39-1
Physico-Chemical Properties of Promedol [1-3]
- Molecular Formula C17H25NO2
- Molar Weight 275.4 g/mol
- Boiling point 348.2±42.0 °C at 760 mmHg
- Melting Point 109.33 °C
- Solubility: Water Solubility at 25 deg C 368.2 mg/L
Structural formula present on Figure 1.
Figures 2 and 3 depict the liquid formulation of Promedol, showcasing its appearance.
General Information of Promedol in Recreational Use and Pharmacology [4-8]
Promedol, similar to morphine, exerts its effects on the central nervous system (CNS) by reducing the perception of pain impulses and inhibiting conditioned reflexes. It shares similarities with other analgesics in reducing the summation ability of the CNS and enhancing the anesthetic action of local anesthetics such as novocaine. It also exhibits sedative effects, primarily through relief of pain syndrome. Compared to morphine, Promedol has lesser effects on depressing the respiratory and vomiting centers, and stimulating the vagus nerve center. It also has moderate spasmolytic action on smooth muscles of internal organs while increasing tone and enhancing contractions of the uterine musculature.
Promedol is commonly used as an analgesic in cases of serious trauma, severe pain associated with various diseases, and in preparation for surgeries and postoperative care. It has shown efficacy in conditions such as gastric and duodenal ulcers, angina, myocardial infarction, intestinal, hepatic, and renal colic, dyskinetic constipation, where pain is associated with spasms of smooth muscles of internal organs and blood vessels. In obstetric practice, it is utilized for pain relief and acceleration of labor, with no adverse effects reported on the mother and fetus at usual doses. Promedol can be administered subcutaneously, intramuscularly, and orally, with parenteral administration showing more pronounced analgesic effects. Intravenous administration may also be employed when necessary.
Trimeperidine’s analgesic effects are attributed to its binding to opioid receptors in the CNS, which inhibits the transmission of pain signals and provides pain relief. Additionally, it exhibits sedative properties that can help alleviate anxiety and promote relaxation in patients experiencing pain.
Hepatotoxicity
There is limited information available on the hepatotoxicity of trimeperidine, as it is not extensively studied or widely known. Like other opioids, trimeperidine is metabolized in the liver through various enzymatic pathways, and prolonged or excessive use of opioids may potentially result in hepatotoxicity, causing liver damage. Hepatotoxicity can be manifested as elevated liver enzyme levels, hepatitis, cholestasis, or in severe cases, acute liver failure. Risk factors for opioid-induced hepatotoxicity may include pre-existing liver disease, concomitant use of other hepatotoxic medications, excessive opioid dosages, and prolonged use. It should be noted that opioids, including trimeperidine, are metabolized in the liver through various enzymatic pathways, and prolonged or excessive use of opioids can potentially result in hepatotoxicity, or liver damage. Hepatotoxicity may manifest as elevated liver enzyme levels, hepatitis, cholestasis, or even acute liver failure in severe cases. Risk factors for opioid-induced hepatotoxicity may include pre-existing liver disease, concomitant use of other hepatotoxic medications, excessive opioid dosages, and prolonged use.
Effects and Symptoms of Promedol Use
However, similar to other opioids, promedol can induce various effects and symptoms, including:
- Analgesia: Promedol is primarily used for its pain-relieving properties, as it binds to opioid receptors and inhibits the transmission of pain signals.
- Sedation: Promedol can cause sedation or drowsiness, leading to decreased alertness, impaired coordination, and reduced cognitive function.
- Respiratory depression: Promedol, like other opioids, can depress the respiratory center in the brain, resulting in reduced respiratory rate and depth. This can be potentially dangerous, especially in high doses or when combined with other central nervous system depressants.
- Nausea and vomiting: Promedol may cause gastrointestinal effects such as nausea and vomiting, which may be more common during the initial stages of treatment or with higher dosages.
- Constipation: Promedol can reduce intestinal motility, leading to constipation and decreased bowel movements.
- Dependence and addiction: Like all opioids, promedol has the potential to cause dependence and addiction with prolonged use, especially in individuals with a history of substance abuse or addiction.
- Other side effects: Promedol may also result in other side effects such as dizziness, headache, dry mouth, sweating, itching, and urinary retention.
Prices and Approximate Dosage
Promedol is not commonly known by street names, as it is not widely prevalent as a street substance. Its official price is $970 per 5 mg for Research Use Only.
The recommended oral dose of promedol for adults is 0.025-0.05 g per intake, and the subcutaneous dose is 1 ml of 1% or 2% solution. In cases of severe pain, such as in patients with malignant tumors or severe injuries, 1-2 ml of 2% solution may be injected. The maximum doses for adults are: oral – a single dose of 0.05 g, and a daily dose of 0.2 g; subcutaneous – a single dose of 0.04 g, and a daily dose of 0.16 g. For children over 2 years of age, promedol may be prescribed at a dose of 0.003-0.01 g per intake (oral and injectable), depending on the age. Promedol is not used in children under 2 years of age. The onset of action of promedol is usually within 10-20 minutes after administration, and the effect can last for 3-4 hours or more after a single dose. For pain associated with smooth muscle spasms, such as angina, hepatic or renal colic, intestinal colic, etc., promedol may be prescribed in combination with anticholinergic and antispasmodic drugs like atropine, metacin, papaverine, etc.
Dangerous Interactions
Promedol can have dangerous interactions with other substances, including:
- Central nervous system (CNS) depressants: Combining Promedol with other CNS depressants like benzodiazepines, sedatives, hypnotics, alcohol, and other opioids can result in excessive sedation, respiratory depression, coma, and even death due to additive or synergistic effects.
- Monoamine oxidase inhibitors (MAOIs): Promedol should not be used together with MAOIs, as it can lead to serotonin syndrome, a potentially life-threatening condition characterized by symptoms such as confusion, agitation, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremors, and in severe cases, seizures and coma.
- Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs): Combining Promedol with these antidepressant medications can increase the risk of serotonin syndrome, as both Promedol and these medications can elevate serotonin levels in the brain.
- Other opioids: Concurrent use of Promedol with other opioids, whether prescription or illicit, can increase the risk of respiratory depression, sedation, and other opioid-related adverse effects.
- Anticholinergic medications: Promedol can have anticholinergic effects, and combining it with other medications that also have anticholinergic properties, such as some antihistamines, tricyclic antidepressants, and antipsychotics, can result in additive anticholinergic effects, including dry mouth, blurred vision, urinary retention, constipation, and increased heart rate.
Legal Status
- Legal status of Promedol (trimeperidine) varies by country:
- European Union (EU) countries: As of September 2021, Promedol is not approved for use in the EU countries, and its legal status may differ from country to country.
- United States (USA): Promedol is not approved by the Food and Drug Administration (FDA) for human use in the USA. It is classified as a Schedule II controlled substance, indicating a high potential for abuse and no accepted medical use.
- Australia (AU): Promedol is classified as a prohibited substance under Schedule 9.
- Canada (CA): Promedol is listed as a Schedule I controlled substance.
- Germany (DE): Promedol is classified as Anlage I, authorized for scientific use only.
- United Kingdom (UK): Promedol is classified as a Class A substance.
- International: Promedol is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in a similar manner as morphine or heroin.
Synthesis of [(2S,5R)-1,2,5-trimethyl-4-phenylpiperidin-4-yl] propanoate [9; 10]
A method for synthesizing Promedol involves the interaction of phenyl lithium and 1,2,5-trimethyl-piperidone-4 in a molar ratio of 1.17:1. The reaction is conducted with vigorous boiling of diethyl ether at approximately 40°C. Subsequently, the reaction mixture is treated with a 1.70 molar excess of propionyl chloride per loaded 1,2,5-trimethyl-piperidone-4. After alkalization and distillation, the reaction mass undergoes repeated acylation with a 0.76 molar excess of propionyl chloride, and then left to stand for 10 hours. The resulting crystalline precipitate is filtered, washed with benzene, recrystallized from isopropyl alcohol, and dried. The synthesis of Promedol is illustrated in Figure 5.
Conclusion
Trimeperidine, an opioid analgesic and analogue of prodine, has four structural isomers, of which the γ isomer (trimeperidine) and the β isomer (isopromedol) are active. It is approximately half as potent as morphine as an analgesic and has been commonly used for pain management. Similar to other opioids, trimeperidine produces analgesia and sedation, but also comes with side effects such as nausea, itching, vomiting, and respiratory depression. It is important to note that trimeperidine can interact dangerously with other substances. While trimeperidine is not widely known by street names and is not prevalent as a street substance, it is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in a manner similar to morphine or heroin.
Bibliography
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- https://www.chemspider.com/Chemical-Structure.16736164.html
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