Ketobemidone Analgetic - Research Paper Example

Ketobemidone Introduction Ketobemidone is a strong analgesic that has been used as a pain reliever for a verylong period time. The compound is considered to be a pain reliever that is considered to be almost at par with morphine. Ketobemidone has the ability to calm pains that do not respond effectively to other opioids. This property is attributed to NMDA, which originates from its component, metabolite norketobemidone. Ketobemidone remains a vital pain killer during surgeries and also quell severe pain caused by various ailments like cancer and fractures among others. This paper explores the synonyms of Ketobemidone, its chemical structure, its discovery and synthesis, physical and chemical properties as well as its uses. Various Names for the Compound Ketobemidone is a compound with numerous names. The compound is also using other multiple synonyms such as: 1-[4-(3-Hydroxyphenyl)-1-methylpiperidin-4-yl]-1-propanone; Cetobemidone; Ethyl 4-(3-hydroxyphenyl)-1-methylpiperidin-4-yl ketone; Cliradon; Cliradone; Cetobemidon; Cymidon; Hoechst 10720; Ciba 7115; Ketobemidonum; 1-[4-(m-Hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone; 1-Propanone, 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidinyl]-;1-Propanone, 1-[4-(m-hydroxyphenyl)-1-methyl-4-piperidyl]-; NSC 117863; or A 21 Lundbeck1. The Chemical Structure of Ketobemidone The chemical structure of the compound is: How Ketobemidone Was Discovered and Synthesized “The history of synthetic drugs with morphine-like effect is relatively short, dating back only to 1939, when Eisleb produced the now famous 1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester.”2 Eisleb together with his colleagues first synthesized Ketobemidone in 1942 at I.G. Farbenindustrie’s laboratory at Hoechst amidst World War II. However, for many years, research had been on-going to find synthetic substances with the same structure as morphine. Small, Eddy together with their co-workers at the United States Public Health service3 worked tirelessly to find these synthetic substances with morphine-like structure. The experiments were founded on the supposition that morphine’s analgesic effect was intrinsic in dibenzofuran, phenanthrene, dibenzofuran as well as carbazole nucleus, which were identified as components of morphine. Earlier attempts were however futile with no development of any synthetic compound with desirable analgesic effect. Organic chemistry experiments rarely yield expected results and products obtained usually come by chance. The analgesic activity of 4-phenylpiperidines was discovered by chance in 1940s in the course of research by scientists to find antispasmodic characteristics on analogues of cocaine.4 The main focus of Eisleb and Schaumann was to find an alternative compound for atropine. The researchers discovered that the compounds had high levels of analgesic properties apart from their spasmolytic properties. Carboxylic acid exhibited the best outcomes and was later sold in Germany as dolantin, which was wrongly assumed to be non-addictive. As research intensified, several other compounds with structures like morphine were developed including methadone, which was discovered in Germany during the Second World War.5 The initial study of ketobemidone became available in print in 1946 after which it took short duration before being introduced in clinical medicine. In 1954, the Economic and Social Council urged governments to stop producing and trading on ketobemidone arguing that it is a dangerous drug.6 Ketobemidone is synthesized by alkylation of (3-methoxyphenyl) acetonitrile with bis (2-chloroethyl) methylamine, which is then reacted with ethylmagnesiumbromide. The resulting product is then O-demethylated with hydrobromic acid to form ketobemidone. “1-Methyl-4-(m-methoxy)phenyl-4-cyanopiperidine on reaction with ethyl magnesium bromide forms ketone intermediate, which on demethylation with hydrobromic acid affords ketobemidone.”7 Physical and Chemical Characteristics of Ketobemidone Physical Properties Ketobemidone exists in a solid state. Ketobemidone exists as Ketobemidone hydrochloride, a crystalline powder, which is white or almost white. Ketobemidone hydrochloride dissolves freely in water and alcohol, but in methylene chloride, it is sparingly soluble. The boiling Point of ketobemidone is 391.283 °C at 760 mmHg Ketobemidone has a melting point of 156.5 °C. The compound, Ketobemidone, has four freely Rotating Bonds. Ketobemidone has a density of 1.092g/cm3 Chemical Properties Ketobemidone has a chemical formula C15H21NO2. The compound has a molecular weight of 247.3327. Various Uses of Ketobemidone In the United States, Ketobemidone has no authorized use. In other parts of the world, the compound has been used since 1950s to allay pain during surgery as well as pain associated with cancer and other ailments8. Ketobemidone is also used alleviate nervousness before surgery operations9. According to Miller, in Denmark, 1981 to 1993 statistics for overall legal usage of opiates or opioids show that only morphine and methadone surpassed the usage of ketobemidone‘s10. Pain can trigger off vomiting in individuals. As such, ketobemidone, a pain reliever, can also be used to stop vomiting by calming down the pain. The compound can also be used to lower blood pressure11. Additional Useful or Interesting About Ketobemidone Drawbacks in the Use of Ketobemidone Despite the fact that Ketobemidone has been identified as one of the most effective pain reliever, it is associated with numerous side-effects on its users. Unwanted effects include shivering, coughing, nausea, and vomiting12. Another adverse effect of ketobemidone on the users is that it can cause respiratory depression if taken in large dose. Drowsiness together with respiratory depression is aggravated by other substances that repress the central nervous system (CNS). As such, opioids, where Ketobemidone belongs, can pose life-threatening effects when combined with tranquilizers, alcohol or sedatives.13 Pregnancy and Breastfeeding During pregnancy, especially at advanced stages, opioids should be used with a lot of precautions. This is because at advanced stages of pregnancy, the fetus can develop dependence for opioids.14 Because their liver is not completely developed, neonates have very low ability to conjugate morphine-like substances (drugs)15. The metabolism of ketobemidone involves phenolic hydroxyl group conjugation as well as N-desmethylation. As a result, the half-life of the drugs is effectively increased in neonates. Because of increased half-life, the effect of morphine-like drugs, including ketobemidone, tends to last longer in neonates compared to others16. Ketobemidone-A29 diffuses into human milk. In certain cases involving 5,000 micrograms of ketobemidone administered during childbirth, “one study estimated that breast-fed infants would receive under 2 micrograms of ketobemidone from their first day’s milk.”17 Therefore, when analgesia must be used during childbirth, pethidine is preferred because it has a relatively shorter half-life.18 Drug Interactions In a research focused on comparing intravenous pharmaceutical formats, morphine was established to be weaker than “combination of product containing one part ketobemidone and five parts of a drug called A29.”19 A29 is a drug used in fighting seizure. However, this study that was aimed at comparing drug combination with morphine is not a guarantee that if ketobemidone is used alone would be more effective than morphine. A research that involved the use of rats and mice indicated that A29 increases the effect of ketobemidone as a pain reliever. In the same study, it was discovered that when doses were attuned to equivalent strength, the ketobemidone-A29 still proved to be more effective or stronger than morphine in relieving pain.20 Dosing of Ketobemidone Generally, opioids such as ketobemidone among others have low bioavailability when given orally. As such, patients suffering from chronic pain need to be given large doses at frequent intervals so that the drug’s analgesic effect can be maintained. However, when opioids are prescribed in large single dosages, patients are likely to feel the side-effects immediately after administering the drug. This happens when the concentration of the blood plasma hits its peak.21 However, “depot preparations result in a more stable plasma concentration and give a longer duration of analgesia.”22 Abuse of Ketobemidone Ketobemidone has been extensively used and abused in Scandinavian countries23 than any other part of the world. Despite being an important pain reliever, man people have used Ketobemidone inappropriately in various parts of the world. “Ketobemidone has been a prominent substance in the abuse scenes of Scandinavian countries.”24 Illegal drug users usually grind oral tablets made of ketobemidone and inject themselves with the resulting powder. This tradition has been linked with adverse impact on eyesight. Further, injecting the powder has been suspected of causing hardening of skin around injection areas, which become open sore with time. Conclusion Ketobemidone is a strong analgesic compound that was first discovered by Eisleb and his co-workers in 1942. However, the compound was recommended later to clinical medicine in 1946. Ketobemidone is perceived to be having strong analgesic effect as morphine. The compound’s initial clinical experiments on former addicts demonstrated that it is hazardous substance, which led to the ban on its production in the United States. However, there has been extensive use of Ketobemidone in Scandinavian countries where the rate of its abuse is also reported to be highest. Switzerland and Denmark led in the production of Ketobemidone in 1950s. In 1954, the Economic and Social Council called on countries to sun down the production and trade on Ketobemidone. However, Ketobemidone remains one of the strongest pain relievers from chronic ailments and anxiety depressant during surgery. Works Cited D., Sriram and P. Yogeeswari. Medicinal Chemistry. New Delhi: Pearson Education India, 2010. Print. Miller, Richard Lawrence. Drugs of abuse: a reference guide to their history and use. Westport, Conn.: Greenwood Press, 2002. Print. National Intistute of Standards and Technology. Ketobemidone. Viewed on November 13, 2013 Olof, Beck, Stephanson Niclas, Sandqvist Soeren, and Franck Johan, "Detection of drugs of abuse in exhaled breath using a device for rapid collection: comparison with plasma, urine and self-reporting in 47 drug users," Journal of Breath Research, 7.2(2013): 11. Patrick, Graham L. An introduction to medicinal chemistry. Oxford: Oxford University Press, 2013. Print. Salumeh, Bastami, Norling Cecilia, Trinks Cecilia, Holmlund Birgitta, Walz Thomas M., Ahlner Johan, and Uppugunduri Srinivas, "Inhibitory effect of opiates on LPS mediated release of TNF and IL-8," Acta Oncol., 52. 5 (2013):1022-1033. Simonsen, Terje, Jarle Aarbakke and Ian Kay. Illustrated Pharmacology for Nurses. Boca Raton, FL: CRC Press, 2006. S., Lundeberg, Stephanson, N., Stiller, C.-O., and Eksborg, S. “Pharmacokinetics after a single intravenous dose of the opioid ketobemidone in neonates.” Acta Anaesthesiologica Scandinavica, 56.8 (2012):1026-1031. Tomas, Log, Skurtveit, Svetlana, Selmer, Randi, Tverdal, Aage, Furu, Kari, and Hartz, Ingeborg, "The association between prescribed opioid use for mothers and children: a record-linkage study," European Journal of Clinical Pharmacology, 69.1(2013):111-118. UNODC. Development of Synthetic Narcotic Drugs , 1956. Viewed on November 13, 2013 Read More