Cameron Grant
Thomas Ertl
Opioid Epidemic: Uses, Abuses, and Innovation: Pethidine
Pethidine,whose structure can be seen in Scheme 1,is a synthetic opioid that has uses similar to that of morphine. Also known as meperidine, pethidine is used to provide relief for moderate to severe pain and is primarily used during labor or dental work.[1] Pethidine was thought to be a safer alternative to morphine witha lower risk for addiction. However, these assumptions were proven to be false. Pethidine carries an equal amount of abusive risk and provides no greater advantage in treatment.[2]Yet, pethidine is unique when compared to morphine. It is known to have a shorter duration and a more rapid onset. This rapid onset is one of the qualities that makes this drug high susceptible to suffer from serious side effects. Table 1 shows an analytical description of pethidine’s ability to provide rapid analysis during clinical monitoring. Injecting the drug too quickly can cause hypotension, respiratory depression, and tachycardia. Its analgesic effects take place after having reacted with the μ-opioid receptors, and pethidine is absorbed effectively through popular routes of administration. A large percentage of pethidine is protein bound and is hydrolyzed by the liver which produces a neurotoxic metabolite callednorpethidine.Norpethidine can be toxic under high concentration. With low pH conditions in the liver, norpethidine is usually excreted safely[3].
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Cameron Grant
Thomas Ertl
Table 1.Potentiometric methods compared to standard procedure methods proved pethidine to be more efficiently absorbed than that of its counterpart
Scheme 1. Structure of Pethidine
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Cameron Grant
Thomas Ertl
Synthesis of pethidine can be relatively long and difficult. A synthesis procedure found on Rhodium Archive Index describes the formation of five intermediates before producing pethidine as a final product. I chose to reference this particular synthesis because it describes the entire procedure from start to finish in thorough detail. Additionally, the procedure gives the reader the option to omit difficult steps, if desired, by recommending the purchase of a pethidine derivative.Synthesis of pethidine begins by creating a slurry of an isonicotinic acid. This slurry is refluxed for 60 hours, vacuum filtered, and reduced with sodium thiosulfate. A second slurry is created to be placed in a column. This column chromatography is meant to elute the previous slurry for the purpose of removing iodine. This eluted solution is recrystallized and then reduced in a high-pressure reaction vessel. From this stage forward, the procedure suggests purchasing 1-methyl-4-carboxypiperidine hydrochloride to surpass the two previous steps.The purchased intermediate is placed in a mixture of acid and refluxed for 6 hours.Unwanted material is removed, and additional solvents are brought in to create another slurry. Several more steps are taken to add reagents and allow for proper mixing, leaving a brown oil left to be fractionally distilled. The fourth intermediate can be prepared by passing chlorine gas into a mixture containing some of the previously product formed. The final intermediate is produced by forming several mixtures, putting it through areflux, and extracting the organic layer with water. Extracts are combined, and pH of the solutionis adjusted. Finally, a hydrochloride salt isrefluxed to produce the final product pethidine[4]whose Raman spectra can be viewed in Figure 2.[5]
Figure 2. Raman shift of Pethidine Hydrochloride after injection in water in various levels of concentration. Each graph will represent the values from the different levels of concentration
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Cameron Grant
Thomas Ertl
Pethidine has become very commonly used to alleviate pain in pregnant women during labor. It is usually administered by injection into some large muscle such as the thigh. Typical dosage for adults is anywhere from 25-100mg about every four hours2. Even with this small dosage recommended by health care professionals, the potency of pethidine can make it have lasting effects. Use can lead to addiction, as well as include possibly severe side effects. Pethidine has even been found to cause depression in respiratory function in newborn babies whose mothers had used the drug[6]. In fact, these babies were observed to have depressed respiratory function for 12-24 hours after birth, even taking 3-6 days for the drug to be fully eradicated from their system. These findings were observed in women who very carefully received the appropriate amounts of pethidine. Table 2 shows the doses of pethidine taken by mothers and its effect on the time to sustained respiration in the newborn in a study to determine the effects of the drug on newborn children. Figure 2 shows the mass spectrum of pethidine.
Table 2. Maternal pethidine dose, pethidine-delivery interval, birthweight, cord blood pH, Apgar score, and time to sustained respiration
Figure 2.Mass spectrum of pethidine.
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Cameron Grant
Thomas Ertl
Pethidine is an effective analgesic for moderate to severe pain, and very effective in providing labor pain relief2. It works relatively fast, and is a very potent pain killer. A simplified mechanism of action can be seen in scheme 2. For these reasons, it is a popular synthetic opioid for use in pain relief in pregnant women in labor. However, there are many side effects and risk of addiction that is evident here as well as for many similar powerful synthetic opioids. Because of the potency of the drug, any prolonged use can cause addiction. Prolonged use during pregnancy can also cause opioid dependence in the baby[7]. Pethidine can also cause depression in respiratory function, which can be life-threatening5. With prolonged use during pregnancy, it can also cause this same depression in respiratory function in the newborn baby, which can be dangerous4. In comparison to similar drugs such as remifentanil, pethidine does have its advantages and disadvantages. Compared to remifentanil, pethidine works slower, and can cause issues with the baby such as depressed respiratory function if taken too close to the birth of the baby. Remifentanil works quicker, and therefore can be taken in very small doses at the patients will when pain is felt, while still having similar side effects as other opioids including pethidine[8]. However, remifentanil may not be as effective at total pain relief, and may be used with other methods to achieve total pain relief.
Scheme 2.Mechanism of pethidine.
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[1] “Pethidine.” Science Direct, The Nervous System (Second Edition) 2018, 2, (Accessed March 5, 2018).
[2] “Pethidine Injection BP 50mg/MI.” Pethidine Injection BP 50mg/MI – Summary of Product Characteristic (SmPC) –(EMC), 1 Sept. 2014, (Accessed March 5, 2018).
[3]Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review.Am J Ther. Pub Med2002, 1, 53-68.
[4]Pethidine (Demerol, Meperidine) Synthesis, Rhodium Chemistry Archive, erowid.org/archive/rhodium/chemistry/pethidine.html. (Accessed March 5, 2018).
[5]Zhang, Mei-Ling & Hasi; Wu-Li-Ji & Lin; Xiang & Zhao; Xiao-Rong & Lou; Xiutao & Han; Si-qin-gao-wa & Lin; Dian-Yang & Lu;Zhi-Wei. Rapid and simple detection of pethidine hydrochloride injection using surface-enhanced Raman spectroscopy based on silver aggregates †. Analytical methods.(2015),7, 8241.
[6]Brice, J. E.; Moreland, T. A.; Walker, C. H. Effects of pethidine and its antagonists on the newborn. Archives of Disease in Childhood1979, 54 (5), 356-361.
[7]Meperidine (Rx) (accessed Mar 7, 2018).
[8]Devabhakthuni, S. Efficacy and Safety of Remifentanil as an Alternative Labor Analgesic. Clinical Medicine Insights: Womens Health2013, 6, 37-49.