First synthesised in 1962 by Calvin L. Stevens, ketamine has had a significant influence on the modern world. It has played an integral role in anaesthesia of both humans and animals for operations, and has a prominent social reputation. Shortly after its approval from the FDA it was the most used anaesthetic in the Vietnam war. For these reasons in 1985 it was added to the World Health Organisation (WHO) Essential Medicines List. Coupled with its medical uses are its social ones. In the early 1970s it became popular as a recreational drug due to a mixture of its anaesthetic and hallucinogenic properties, and it has been popular ever since. Additionally there is more modern research into the potential for ketamine to be used to treat depression and as a neuroprotective post-stroke. This well rounded use is why ketamine can be said to be my favourite drug.
Post synthesis, ketamine gained widespread recognition as a potentially revolutionary anaesthetic firstly in a veterinary setting and later for human use. Testing began on humans in 1964 in the USA and was eventually approved for use in 1970 by the FDA. The main result of this was for Ketamine to become the most used infield anaesthetic of the Vietnam war. It was especially useful in wartime situations as it has a wide safety margin in terms of dosage, additionally it reduced the problems associated with a panic jab (administering the drug in a panicked state and supplying too much). Vietnam was not the only war in which ketamine was used as an anaesthetic, in the Somalia civil war in 1994 and in North Uganda in 1999. A total of 64 operations on patients ranging from 6 weeks to 70 years old were performed, all of which where successful in terms of anaesthesia. During war ketamine is more commonly used as it does not inhibit the heart or lungs function considerably, hence eliminating the need for expensive/implausible in operation monitoring. Moreover ketamine requires but one complimentary drug when used, benzodiazepines in order to reduce the hallucinogenic effects felt by the patient and improve cardiovascular response, making it very popular in initially war and then later in less developed countries (Bonanno, 2002).
Ketamine may be described as a dissociative anaesthetic, this is due to the out of body experiences those who are administered the drug encounter. Upon its creation it became clear that it would most likely replace PCP (Phencyclidine), the sedative effects of ketamine are far less deep coupled with the fact that patients who received PCP would encounter extreme delirium amongst other side effects. Moreover research undertaken in 1989 by Dr. John Olney on rats, illustrated a type of brain damage that would be called Olney lesions. Upon administration of NMDA antagonists lytic breakdown of mitochondria in the vacuoles of cells located in the posterior cingulate and the retrosplenial cortex would be observed, these experiments would examine the different effect of multiple drugs and the effect of their dose. PCP caused Onley lesions at a much lower dose than that of ketamine (1mg/kg for PCP compared to 40mg/kg for ketamine). It is for these reasons that in 1965 PCP (being sold under the trade name sernyl) was removed from the market and limited to only veterinary use. Clearly then compared to its predecessors Ketamine is much safer at higher doses and would achieve a similar effect to that of earlier drugs. Furthermore these types of lesions appeared to be reversible as they would slowly fade from view. Illustrating that the long term effects of ketamine use may not be so significant (Olney, 1989).
As with effectively every drug, the medical and recreational use of ketamine can have many adverse effects. In a medical setting these effects can range from local pain at the site of injection to double vision and skin rashes. It is estimated that 10-20% of patients who receive ketamine as an anaesthetic will experience these symptoms along with the hallucinations/delirium (Strayer, RJ. Nelson, LS. 2008). The most common problems associated with significant recreational use is that of ketamine induced ulcerative cystitis, this encompasses a range of complications related to the bladder and the urinary tract; reduced bladder volume and incontinence to name but a few of many (Middela, S. Pearce, I. 2011). Coupled with this it is know that ketamine can upset the balance of liver enzymes. Admittedly, ketamine does have detrimental effects when overused in a recreational or even medical setting, however the neurological effects differ greatly from the physical ones. In a study focusing on the long term recreational use of ketamine conducted by Morgan, Muetzelfeldt and Curran (2009), it was found that people who used on average 20 days per month experienced depression and decreased memory capacity. However what was interesting in this study was that infrequent users, averaging 3.25 days per month, had no negative repercussions from taking the drug when compared to a control group. This is affirmed by Olney’s experiments in which the lytic breakdown of mitochondria appeared to be a reversible process. So it could be said that for the infrequent social user, the negative effects (if used in moderation) may be minimal.
The metabolised form of ketamine is norketamine, the two have the same structure however norketamine has undergone demethylation so no longer has the methyl group. The process of metabolising ketamine is commenced by the microsomal enzymes of the liver CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) . Norketamine is then itself metabolised by many hydroxylation sequences to dehydroketamine (Sinner, B. Graf, BM. 2008). As ketamine exists as an unionised form, it can be said to be lipid soluble and therefore will diffuse through cell membrane with less resistance and in a shorter period of time. Contrasting significantly with ionised forms which will have high water solubility and will also exhibit electrical resistance when passing through cell membrane, making the process slower and less efficient (Le, 2016). For this reason ketamine has a rapid onset time when administered intravenously, a dosage of 2mg/kg will have effect within 30-60 seconds with the effects lasting for 10-15 minutes (Pharmacology2000.com, 2016). There is large variance however in the bioavailability of ketamine depending on how it is administered, it is 93% for intramuscular (hence why it was so useful on battlefields), 25-50% intranasally, 30% sublingually and 30% rectally (Kolind, 2016).
There is currently ongoing research and debate on the use of ketamine as a neuroprotective. Undertaken by a group of scientists, this is the idea that ketamine will prevent the death of neutrons in ischemic events (periods of inadequate blood supply) such as strokes. This is possible as it is thought that Ketamine can block the neurotransmitters that signal the beginning of apoptosis (Sakowitz et al., 2009). The damaging events that occur in the brain post trauma is known as anoxic depolarisation. This is caused by the loss of neuron membrane permeability, as a result concentration gradients become unbalanced. This in turn causes the concentration of glutamate and aspartate to increase. Both are present in normal excitotoxins however in higher concentrations they can cause apoptosis of neurons (Nilsson, G. Lutz, P. 2004). In Sakowitz et al’s research these depolarisations were present in both cases, with a rate of 1.5/h for case 1 and 0.7/h for case 2. After the introduction of ketamine to the system both patients depolarisations stopped abruptly and did not occur again. The researchers are now calling for more work to be done in order to limit the damage caused post stroke, ketamine could potentially be a breakthrough in stroke treatment.
To conclude, ketamine’s use is widespread and effective. Although there was potential for hallucinations when administered as an anaesthetic, its positive analgesic effects outweighed the negative reactions. Especially in the Vietnam war in which it played a crucial role in treating the injured. The more modern day research into ketamine also indicates that it has a potential to be used in multiple fields of medicine. It’s historical importance along with this current potential to treat neurological conditions is why I have deemed it to be my favourite drug.