Phencyclidine (PCP; Figure B.11), an arylcyclohexylamine, was developed in the 1950s as a dissociative anaesthetic, where the patient feels detached from themselves and their surroundings. PCP acts at the glutamate-binding NMDA receptor as a non-competitive antagonist. It had a potent analgesic effect, but at clinically effective doses it did not depress respiration or the cardiovascular system, which is highly desirable clinically. Although initially promising, the drug was withdrawn in the early 1960s after patients experienced extremely unpleasant hallucinations and agitation when they emerged from anaesthesia. Later in that decade, the drug began to be abused, although its effects were so unpredictable and often horrible, it never gained mass popularity. Once it was discovered it could be sprayed onto tobacco or cannabis and smoked to exert some rudimentary control of its effects, it gained more adherents, although it remains confined to some large cities in the US, notably Los Angeles and Philadelphia.
The drug is effective orally as well as through smoking PCP oil-soaked tobacco. The ‘oil’ is an ether extract of the drug when illicitly manufactured, which in the right circumstances is explosive and has been known to demolish buildings. In the pure form PCP is a white crystalline powder, but the street drug can be anything from a powder or pill to a brownish syrupy gum.
Figure B.11 Major metabolites of PCP in man; CYP2B6 K262R cannot form the reactive species which inactivates the enzyme.
The powdered form of the drug (‘Angel Dust’) is virtually pure PCP and is so lipophilic it can be absorbed through the skin in pharmacologically effective quantities. It enters the brain easily and interacts with so many neurotransmitter systems that it exhibits a very wide range of central stimulant and depressant effects, including paranoid delusions, depression and hallucinations. Those suffering from acute intoxication can be diagnosed by their generally bizarre and violent behaviour, nystagmus (eye oscillations and visual impairment) and a positive urine test for the parent drug. It causes seizures and can be lethal at only 1mg/kg, often due to a variety of severe reactions, from strokes, respiratory arrest, status elepticus and hyperthermia. The drug is spectacularly addictive on repeated use and it is said that users often die violently or commit suicide under its influence. Fortunately, for those who consider PCP as wholly inadequate for their recreational requirements, there are several designer analogues available, such as PCEEA and PCMEA, so good luck with that.
PCP Metabolism
PCP is extensively metabolized to several main hydroxylated derivatives, including PCHP (1-(1-phenylcyclohexyl)-4-hydroxypiperidine), PPC (4-phenyl-4-(1-piperidinyl)-cyclohexanol) and PCAA (5-[N-(1-phenylcyclohexyl)]-aminopentanoic acid; Figure B.11). Another metabolite has also been found, known as 1-phenylcyclohexylamine (PCA). The drug has a long half-life in man and the effects of one dose can last several days in chronic users. The metabolites are difficult to clear, but are eventually eliminated in the urine and faeces, where they can be detected up to 28 days after drug use. PCP appears to be able to affect CYP expression in animals, although it is unknown whether this might occur in man. It seems that early human liver microsome study showed that PPC and PCHP were cleared by CYP3A4, although there was high inter-individual variation in the pattern of its metabolite formation. Interestingly, a reactive species was detected and it was suggested that PCP could inhibit CYP3A4. More recent studies have found the CYP2B6 is probably the main isoform that clears PCP and its designer equivalents. The drug is also capable of forming a mechanism-dependent reactive species that inactivates wild-type CYP2B6 but not the K262R variant,which is probably why PCP is so persistent in heavy users. Interestingly, the K262R variant can form all the dealkylated metabolites the wild–ype can. The wild–ype lysine is not near the active site, but it promotes substrate binding which facilitates reactive species formation. The substitution of the polymorphic arginine prevents this process. The reactive species can be trapped with GSH and is thought to be either a dihydroxylated iminium, or a monohydroxylated epoxide derivative. Hence, the effects of CYP2B6 inhibitors and inducers may depend on the drug user ’ – CYP2B6 expression status. Overall, PCP is something of a ‘Nantucket Sleigh ride’ and is not recommended.
Ketamine
Ketamine, ‘the drug PCP could have been’ was synthesized in 1962 as an alternative to PCP and shares elements of its mode of action (Figure B.12). The drug entered the clinic in 1970 and has a number of desirable properties aside from its dissociative anaesthetic effects, as it is a good analgesic and hypnotic and does not depress respiration.
Figure B.12 Structure of ketamine and its major demethylated derivative norketamine, alongside the structure of PCP
Although induction of anaesthesia is smooth, emergence can be problematic, with confusion and agitation. It is usually used intravenously or intramuscularly, as orally its effects are less predictable, with more of a sedative rather than an anaesthetic effect, unless the doses are high. It is still used clinically for some minor procedures and in Casualty/Emergency rooms. The drug is usually given as a racemate, although the S-isomer is four-fold more potent as an analgesic than the R-isomer. Interestingly, it has shown promise in patients with intractable depression, with one dose yielding a beneficial effect for a week or so. It is more commonly used now on animals, particularly horses, although it is less effective in cows. Ketamine is abused for its hallucinogenic, dissociative and narcotic properties and has been scheduled as a controlled drug in most countries. It appears to detach users successfully from who they are, why they are here and what they are doing, so it is not surprising that it has been said that its properties make it an ‘ideal’ date-rape drug. It is known by a number of street names, such as ‘Special K’, ‘Kit-kat’, ‘wonk’ and ‘boing’. OK, so the last name I made up. Although not conventionally physiologically addictive, it can cause compulsive use and it does not inspire confidence that one of its leading advocates died in his bath while under its influence. Even when used medically, rapid intravenous injection can stop a patient breathing, so it is more than unwise to try this at home, unless your friends are particularly loyal, sober and adept at CPR.
Ketamine metabolism
The drug is cleared in man mostly through N-demethylation to norketamine (N-desmethylketamine), which is thought to have some analgesic action and more than 90 per cent of the dose is cleared in urine in 5 days. CYP2B6 is believed to be the main high affinity low capacity route of clearance, as well as CYP2C9, with some CYP3A4 involvement as the low affinity, high capacity isoform. This is supported by in vitro data where methadone and diclofenac (CYP2B6 and CYP2C9 substrates) are known to inhibit ketamine conversion to norketamine in human microsomes, probably by competition. The clearance of ketamine is likely to be affected by many factors, not least the high variability of CYP2B6 and to a lesser extent, CYP2C9, as well as the effects of inducers and inhibitors of these CYPs.
Were such things here that we do speak about, Or have we eaten on the insane root that takes the reason prisoner?
Act 1, Scene 3, Macbeth, by William Shakespeare
