Ketamine
Taylor Scott
November 5, 2018
Discovery/Development
Ketamine was first discovered as a derivative of phencyclidine. Phencyclidine was first synthesized in 1956 and after animal studies was discovered to be a good anesthetic [2]. Phencyclidine was then given as an anesthetic to people undergoing surgery. Although it was safe to use as an anesthetic, it caused post-surgery emergence delirium, which is psychomotor agitation after coming out of anesthesia. Therefore, phencyclidine was not suitable to use as an anesthetic. Cal Bratton, M.D., Ph.D., Head of Pharmaceutical Research at Parke Davis believed that a short-acting form of phencyclidine would be better, so he approved the synthesis of similar compounds [2]. Calvin Lee Stevens, Ph.D., who was a chemical consultant for Parke Davis, synthesized several compounds similar to phencyclidine in 1962, and after animal studies (mainly on monkeys), it was determined that compound CI-581 (ketamine) was safe, had excellent anesthetic properties, and was short acting (which decreases emergence delirium) [2].
From there, human clinical studies began in 1964 [2]. The first study was ten male volunteers from a prison. The second clinical study used ketamine for anesthesia in 130 patients (71 males), ranging from 6 weeks to 86 years old, for a total of 133 surgical procedures [1]. A side effect of the ketamine included a lot of patients feeling like they were floating in outer space and had no feeling in their arms or legs. It was determined that ketamine could be used as a safe drug for humans because the hallucinogenic side effects were minor. Ketamine was deemed as a “dissociative anesthesia” [2].
After ketamine was approved by the Food and Drug Administration in 1970 [4], it was used as an anesthetic for American soldiers in the Vietnam War [2]. However, ketamine became an abused drug. The occurrence of emergence delirium needed to be reduced. This led to the synthesis of shorter acting anesthetic agents, and now drugs such as midazolam and propofol are used more [2]. As of 1999, ketamine is a Schedule III controlled substance [4]. The main purpose for ketamine today is for veterinary anesthesia because of the hallucinogenic side effects it can have in humans.
Ketamine works as an NMDA receptor antagonist, meaning it inhibits the action of the N-methyl-D-aspartate receptor [4]. The NMDA receptor allows transfer of electrical signals between neurons in the brain and the spinal column. For the signals to pass, the NMDA receptor must be open by having glutamate and glycine bound to it. Ketamine deactivates the NMDA receptor by binding to the ion channel and blocking it [4].
Therapeutic uses for ketamine include as an analgesic, anesthetic, and antidepressant [2]. For its analgesic effects, ketamine can be used for pain relief associated with postherpetic neuralgia, migraine, burns, neuropathies, and fibromyalgia. It can also be used to enhance the analgesic effect of opioids [4]. For antidepressant effects, ketamine was found to be antidepressant in surgical patients during their postoperative periods and reduce the risk of suicide in patients [4]. Ketamine is also quick acting antidepressant, showing significant antidepressant effect in under two hours and was sustained for at least one week in 35% of patients [4]. Ketamine is believed to work in the same way as schizophrenia, which has enabled researchers to gain some insight on the disease [4]. Adverse effects of ketamine include hallucinations, changes in mood, delirium, and confusion. It can cause mild respiratory depression, and when used as an anesthetic, can cause increases in blood pressure and heart rate.
The most compelling reason for the refinement/modification of ketamine was the abuse of the drug. Users modify the drug into powder to snort or a capsule to take orally [3]. It is used as a street drug for its hallucinations of “out-of-body” experience [3]. This led to the modification to drugs like propofol, which are shorter acting and have less dissociative effects [2].
Commercialization
Ketamine is sold under the brand name Ketalar. Par Sterile Products manufactures Ketalar. Par Sterile Products submitted New Drug Application (NDA) 016812 that was approved prior to January 1, 1982 [5]. The NDA specifies Ketalar as an injection with the main physiological effect as general anesthesia [5]. The cost for a Ketalar injectable solution (10 mg/mL) is around $196 for a supply of 200 mL [6]. The generic ingredient in Ketalar is ketamine hydrochloride. There are six suppliers for this generic compound [5].
Because of the dissociative effects and abuse as a recreational drug, ketamine is no longer widely used as an anesthetic for humans but does have a large market in the veterinary sector. Ketamine is one of the most widely used anesthetic medicines in veterinary practice worldwide [7]. Ketamine is a Schedule III controlled substance, but in 2015 the World Health Organization's Expert Committee on Drug Dependence considered making ketamine an even higher controlled substance, which would have limited its availability as an anesthetic agent [8].
Taylor Scott
November 5, 2018
Discovery/Development
Ketamine was first discovered as a derivative of phencyclidine. Phencyclidine was first synthesized in 1956 and after animal studies was discovered to be a good anesthetic [2]. Phencyclidine was then given as an anesthetic to people undergoing surgery. Although it was safe to use as an anesthetic, it caused post-surgery emergence delirium, which is psychomotor agitation after coming out of anesthesia. Therefore, phencyclidine was not suitable to use as an anesthetic. Cal Bratton, M.D., Ph.D., Head of Pharmaceutical Research at Parke Davis believed that a short-acting form of phencyclidine would be better, so he approved the synthesis of similar compounds [2]. Calvin Lee Stevens, Ph.D., who was a chemical consultant for Parke Davis, synthesized several compounds similar to phencyclidine in 1962, and after animal studies (mainly on monkeys), it was determined that compound CI-581 (ketamine) was safe, had excellent anesthetic properties, and was short acting (which decreases emergence delirium) [2].
From there, human clinical studies began in 1964 [2]. The first study was ten male volunteers from a prison. The second clinical study used ketamine for anesthesia in 130 patients (71 males), ranging from 6 weeks to 86 years old, for a total of 133 surgical procedures [1]. A side effect of the ketamine included a lot of patients feeling like they were floating in outer space and had no feeling in their arms or legs. It was determined that ketamine could be used as a safe drug for humans because the hallucinogenic side effects were minor. Ketamine was deemed as a “dissociative anesthesia” [2].
After ketamine was approved by the Food and Drug Administration in 1970 [4], it was used as an anesthetic for American soldiers in the Vietnam War [2]. However, ketamine became an abused drug. The occurrence of emergence delirium needed to be reduced. This led to the synthesis of shorter acting anesthetic agents, and now drugs such as midazolam and propofol are used more [2]. As of 1999, ketamine is a Schedule III controlled substance [4]. The main purpose for ketamine today is for veterinary anesthesia because of the hallucinogenic side effects it can have in humans.
Ketamine works as an NMDA receptor antagonist, meaning it inhibits the action of the N-methyl-D-aspartate receptor [4]. The NMDA receptor allows transfer of electrical signals between neurons in the brain and the spinal column. For the signals to pass, the NMDA receptor must be open by having glutamate and glycine bound to it. Ketamine deactivates the NMDA receptor by binding to the ion channel and blocking it [4].
Therapeutic uses for ketamine include as an analgesic, anesthetic, and antidepressant [2]. For its analgesic effects, ketamine can be used for pain relief associated with postherpetic neuralgia, migraine, burns, neuropathies, and fibromyalgia. It can also be used to enhance the analgesic effect of opioids [4]. For antidepressant effects, ketamine was found to be antidepressant in surgical patients during their postoperative periods and reduce the risk of suicide in patients [4]. Ketamine is also quick acting antidepressant, showing significant antidepressant effect in under two hours and was sustained for at least one week in 35% of patients [4]. Ketamine is believed to work in the same way as schizophrenia, which has enabled researchers to gain some insight on the disease [4]. Adverse effects of ketamine include hallucinations, changes in mood, delirium, and confusion. It can cause mild respiratory depression, and when used as an anesthetic, can cause increases in blood pressure and heart rate.
The most compelling reason for the refinement/modification of ketamine was the abuse of the drug. Users modify the drug into powder to snort or a capsule to take orally [3]. It is used as a street drug for its hallucinations of “out-of-body” experience [3]. This led to the modification to drugs like propofol, which are shorter acting and have less dissociative effects [2].
Commercialization
Ketamine is sold under the brand name Ketalar. Par Sterile Products manufactures Ketalar. Par Sterile Products submitted New Drug Application (NDA) 016812 that was approved prior to January 1, 1982 [5]. The NDA specifies Ketalar as an injection with the main physiological effect as general anesthesia [5]. The cost for a Ketalar injectable solution (10 mg/mL) is around $196 for a supply of 200 mL [6]. The generic ingredient in Ketalar is ketamine hydrochloride. There are six suppliers for this generic compound [5].
Because of the dissociative effects and abuse as a recreational drug, ketamine is no longer widely used as an anesthetic for humans but does have a large market in the veterinary sector. Ketamine is one of the most widely used anesthetic medicines in veterinary practice worldwide [7]. Ketamine is a Schedule III controlled substance, but in 2015 the World Health Organization's Expert Committee on Drug Dependence considered making ketamine an even higher controlled substance, which would have limited its availability as an anesthetic agent [8].
Recently, ketamine has been investigated for its potential use as a rapid treatment for depression. Johnson & Johnson is pursuing a nasal formulation of ketamine to be used as a depression drug [9]. The drug would be the first new drug for depression in 35 years [9]. Johnson & Johnson received breakthrough therapy designation from the FDA in 2016 [9]. This status is designed to help move the drug through the federal approval process. The current market value for depression medications in the US is $4.6 billion a year and expected to grow to $7.3 billion by 2024 [10]. It is expected that the new class of depression drugs, which includes ketamine and opioid-based drugs, will account for $4.15 billion in sales by 2024 (which is almost the size of the current market) [10]. When the nasal formulation is approved for sale it is expected to have initial sales of around $45 million, even though it will be a Schedule III controlled substance [10].
References
1.) Corssen, Guenter, and Edward F. Domino. “Dissociative Anesthesia: Further Pharmacologic Studies and First Clinical Experience with the Phencyclidine Derivative CI-581.” Anesthesia & Analgesia, vol. 45, no. 1, Jan. 1966, pp. 29–40., doi:10.1213/00000539-196601000-00007.
2.) Domino, Edward F. “Taming the Ketamine Tiger.” Anesthesiology, Sept. 2010, doi:10.1097/aln.0b013e3181ed09a2.
3.) National Institute on Drug Abuse. NIDA Research Report Series, Hallucinogens and Dissociative Drugs. U.S. Department of Health and Human Services.
4.) Tyler, Marshall W., et al. “Classics in Chemical Neuroscience: Ketamine.” ACS Chemical Neuroscience, vol. 8, no. 6, 2017, pp. 1122–1134., doi:10.1021/acschemneuro.7b00074.
5.) “Ketalar / Ketamine Hydrochloride NDA 016812 International Drug Patent Coverage, Generic Alternatives and Manufacturers.” Deep Knowledge on Small-Molecule Drugs and the Global Patents Covering Them.
6.) “Ketalar Prices, Coupons & Patient Assistance Programs.” Drugs.com, Drugs.com.
7.) Wedderburn, Pete. “Ketamine: an Essential Veterinary and Medical Drug That Doesn't Need Further Controls.” The Telegraph, Telegraph Media Group, 17 Oct. 2016.
8.) Fiala, Jennifer. “Veterinarians Stress about Ketamine's Future.” Latest News - VIN, 19 Nov. 2015.
9.) Brodwin, Erin. “Ketamine Could Become the First New Depression Drug in More than 30 Years.” Business Insider, Business Insider, 16 Apr. 2018.
10.) Oberhaus, Daniel. “This Nasal Spray Will Totally Change the Antidepressant Market.” Tonic, VICE, 19 Sept. 2017.
References
1.) Corssen, Guenter, and Edward F. Domino. “Dissociative Anesthesia: Further Pharmacologic Studies and First Clinical Experience with the Phencyclidine Derivative CI-581.” Anesthesia & Analgesia, vol. 45, no. 1, Jan. 1966, pp. 29–40., doi:10.1213/00000539-196601000-00007.
2.) Domino, Edward F. “Taming the Ketamine Tiger.” Anesthesiology, Sept. 2010, doi:10.1097/aln.0b013e3181ed09a2.
3.) National Institute on Drug Abuse. NIDA Research Report Series, Hallucinogens and Dissociative Drugs. U.S. Department of Health and Human Services.
4.) Tyler, Marshall W., et al. “Classics in Chemical Neuroscience: Ketamine.” ACS Chemical Neuroscience, vol. 8, no. 6, 2017, pp. 1122–1134., doi:10.1021/acschemneuro.7b00074.
5.) “Ketalar / Ketamine Hydrochloride NDA 016812 International Drug Patent Coverage, Generic Alternatives and Manufacturers.” Deep Knowledge on Small-Molecule Drugs and the Global Patents Covering Them.
6.) “Ketalar Prices, Coupons & Patient Assistance Programs.” Drugs.com, Drugs.com.
7.) Wedderburn, Pete. “Ketamine: an Essential Veterinary and Medical Drug That Doesn't Need Further Controls.” The Telegraph, Telegraph Media Group, 17 Oct. 2016.
8.) Fiala, Jennifer. “Veterinarians Stress about Ketamine's Future.” Latest News - VIN, 19 Nov. 2015.
9.) Brodwin, Erin. “Ketamine Could Become the First New Depression Drug in More than 30 Years.” Business Insider, Business Insider, 16 Apr. 2018.
10.) Oberhaus, Daniel. “This Nasal Spray Will Totally Change the Antidepressant Market.” Tonic, VICE, 19 Sept. 2017.
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