Phencyclidine and related compounds

Historical background

Phencyclidine (PCP) was first developed as a dissociative anaesthetic in the 1950s, but its use was mainly confined to veterinary anaesthesia after it had been established that it caused delirium and hallucinations in patients undergoing anaesthesia. A closely related congener, ketamine, is however still used clinically, especially in children, as a dissociative anaesthetic, as such psychotomimetic effects are minimal. Both drugs produce intense analgesia, amnesia and finally anaesthesia after intravenous administration. Recovery from ketamine-induced anaesthesia is nevertheless often accompanied by nightmares and occasionally hallucinations, many patients also experiencing delirium and excitement.

Phencyclidine has been favoured as an illicit drug of abuse for some 20 years, but such a use appears to have declined recently owing to the availability of relatively inexpensive cocaine. The drug has the street names of "PCP", ''angel dust' and ''crystal''. The structures of phencyclidine and ketamine are shown in Figure 15.7.

Both phencyclidine and ketamine are arylcyclohexylamines with stimulant, depressant, hallucinogenic and analgesic properties. In man, small doses produce signs of intoxication, as shown by staggering gait, slurred speech and nystagmus. Higher doses also cause sweating, a catatonic rigidity and disorientation; drowsiness and apathy may also be apparent. Such a state is sometimes accompanied by physical aggression. As such drugs are potent amnestic agents, the individual may be unaware of violent acts on recovering from the effects of the drug. Increasing doses lead to anaesthesia and eventually coma. Heart rate and blood pressure are elevated and the individual shows hypersalivation, fever and muscular rigidity. Convulsions may occur at high doses. The effects of a single dose may last 4 to 6 hours; perceptual disturbances, disorientation and intense anxiety commonly occur.

Mode of action

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (a1 and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors.

Considerable attention is now being paid to the way in which phencyclidine and ketamine block the ion channel controlled by the NMDA receptor. This prevents the movement of calcium ions in particular into the cell which, in the case of the NMDA receptors situated in the hippocampus, inhibits long-term potentiation and thereby blocks memory

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Figure 15.7. Structures of the psychotomimetic compound phencyclidine and the structurally related dissociative anaesthetic ketamine.

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Figure 15.7. Structures of the psychotomimetic compound phencyclidine and the structurally related dissociative anaesthetic ketamine.

formation. These drugs can also exhibit a neuroprotective effect against nerve cell damage arising from cerebral hypoxia. Such an action is of potential importance in the future development of drugs to prevent brain damage that arises as a consequence of stroke.

The pronounced effects of phencyclidine on locomotor activity in both animals and man, and the psychotomimetic effects in man, may be a consequence of its facilitatory effects on dopaminergic transmission, particularly in mesolimbic regions of the brain. This is unlikely to be due to a direct effect of the drug on dopamine receptors, but is probably due to its action on NMDA heteroceptors on dopaminergic terminals in these brain regions.

After chronic use, the drug appears to have an extended half-life of up to 3 days. This is due to the extensive enterohepatic circulation combined with the increased concentration of its metabolites, some of which are pharmacologically active.

Tolerance and dependence

Tolerance to the effects of phencyclidine develops in both animals and man. A slight physical dependence has been reported in man, characterized by a craving for the drug, persistent amnesia, slurred speech and difficulty in thinking, which may last up to 1 year after discontinuing the drug. Severe personality changes have also been reported.

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