Phencyclidine, PCP, or 1-(1-phenylcyclohexyl) piperidine is an arylcyclohexamine with structural similarities to ketamine. It is a lipophilic weak base with a pKa of 8.5. Phencyclidine was originally synthesized and marketed under the trade name Sernyl®, by Parke-Davis for use as an intravenously administered anaesthetic agent in humans. Distribution began in 1963 but was discontinued in 1965 due to a high incidence (10 to 20%) of post-operative delirium and psychoses. However, its use continued as a veterinary tranquilizer for large animals until 1978, when all manufacture was prohibited and PCP was placed in Schedule II of the federal Controlled Substances Act (1970).

Illicit use of PCP as a hallucinogenic agent was first reported in San Francisco in 1967.1 It was first abused in oral form but then gained popularity in the smoked form as this mode of drug delivery allowed better control over dose. Because illicit synthesis is relatively easy and inexpensive, abuse became widespread in the 1970s and early 1980s. Today, use of PCP tends to be highly regionalized and located in certain areas of the U.S., notably, the Washington D.C./Baltimore corridor, New York City, and Los Angeles.2 Pharmacology

Phencyclidine binds with high affinity to sites located in the cortex and limbic structures of the brain. Binding results in blockade of N-methyl-D-aspartic acid (NMDA)- type glutamate receptors. The actions of glutamate and aspartate at the NMDA receptor allow movement of cations across the cell membrane. PCP exerts its action by binding to the glutamate receptor, thus preventing the flux of cations.3 PCP is also known to exert effects on catecholamines, serotonin, gamma-hydroxy butyric acid, and acetylcholine neurotransmitter release, but its role is incompletely defined. Due to its action on several systems, the physiological and behavioral effects of PCP are varied and depend on not only the dose, but the route of administration and user's previous experience. Absorption

Phencyclidine is typically self-administered by the oral, intravenous, or smoked routes. After oral administration to healthy human volunteers, the bioavailability was found to vary between 50 to 90%.4 In this study, peak plasma concentrations were achieved after 1.5 h and appeared to correlate with the time to reach maximum pharmacological effects. However, because there have been no comprehensive clinical controlled studies of phencyclidine, a correlation between PCP blood concentrations and pharmacological effects has not been definitively documented. Maximum serum PCP concentrations ranged between 2.7 and 2.9 ng/mL after 1 mg PCP administered orally.4

PCP is commonly self-administered by the smoked route. Liquid PCP is soaked in parsley flakes and rolled as a cigarette; powdered PCP is sprinkled over a marijuana joint or the end of a tobacco cigarette is dipped in liquid PCP and then smoked. Cook et al.5 studied the pharmacokinetic properties of PCP deposited on parsley cigarettes. Upon smoking, PCP is partially volatilized to 1-phenylcyclohexene (PC). These investigators found that 69 ± 5% of the PCP available in the cigarette was inhaled, 39% as PCP and 30% as PC.5 The pharmacological and toxicological properties of PC have not been established. Peak plasma concentrations of PCP were reached within 5 to 20 min. In 80% of the subjects, a second peak was observed in plasma PCP concentrations, occurring 1 to 3 h after the end of smoking. This may have been due to trapping of PCP in the mouth, where it could be released and absorbed by the G.I. tract or, alternatively, it could be due to absorption by the lung and bronchial tissue with slower release into the systemic circulation.6 Long-term users of PCP report feeling the effects of the drug within 2 to 5 min of smoking, with a peak effect after 15 to 30 min and residual effects for 4 to 6 h.7 Distribution

Plasma protein binding of PCP in healthy individuals remains relatively constant between 60 to 70% over the concentration range of 0.007 to 5000 ng/mL.5 PCP binding to serum albumin accounts for only 24% of the binding6 which suggests binding to another protein may occur to a significant extent. When studied in vitro, a^Acid glycoprotein was also found to bind phencyclidine.6 The volume of distribution has been shown to be large, between 5.3 to 7.5 L/kg,8 providing evidence of extensive distribution to extravascular tissues.

Wall et al.9 administered 1.3 ug/kg of 3H-PCP intravenously to human volunteers and collected blood samples for 72 h. Data from this study suggested a two compartment pharmacokinetic model with a plasma half life for PCP of 7 to 16 h. Domino et al.10 further analyzed the data from Wall et al. and developed a more complex three compartment PK model. The reported half-lives for each compartment were 5.5 min, 4.6 h, and 22 h. The specific tissues and organs represented by the multicompartment model were not identified. Half-lives of greater than 3 days have been reported in cases of PCP overdose.11 Metabolism and Excretion

PCP is metabolized by the liver through oxidative hydroxylation. Unchanged PCP, two monohydroxylated, and one dihydroxylated metabolite have been identified in urine after oral and intravenous administration.12 The monohydroxlyated metabolites have been identiifed as 4-phenyl-4-(1-piperidinyl)-cyclohexanol (PPC) and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (PCHP). These metabolites are pharmacologically inactive in humans and PPC is present in both cis- and trans-isomeric forms. The cis/trans ratio was found to be 1:1.4 in human urine.5 The dihydroxylated metabolite was identified as 4-(4-hydroxypiperidino)-4-phenylcyclohexanol (HPPC). These metabolites are present in urine as glucuronide conjugates in addition to their unconjugated forms.8

Approximately 30 to 50% of a labeled intravenous dose is excreted over a 72-h period in urine as unchanged drug (19.4%) and 80.6% as polar metabolites, mainly 4-phenyl-4-(1-piperidinyl) cyclohexanol.5 Only 2% of a dose is excreted in feces.10 After 10 days, an average of 77% of an intravenous dose is found in the feces and urine.9 Green et al.12 reported urine PCP concentrations between 40 to 3400 ng/mL in ambulatory users.

Urine pH is an important determinant of renal elimination of PCP. In a study in which urine pH was uncontrolled (6.0 to 7.5), the average total clearance of PCP was 22.8 ± 4.8 L/ h after intravenous administration.4 In the same study, renal clearance was 1.98 ± 0.48 L/h. When the urine was made alkaline, the renal clearance of PCP was found to decrease to 0.3 ± 0.18 L/h. If the urine was acidified (pH 6.1) in the same subjects, renal clearance increased to 2.4 ± 0.78 L/h.13 Aronow et al.14 determined that if the urine pH was decreased to < 5.0, renal clearance increases significantly to 8.04 ± 1.56 L/h. There is disagreement about the utility of urine acidification in the treatment of PCP overdose, even though excretion may be increased by as much as 100-fold.15 It should be noted that acidification may increase the risk of metabolic complications.16

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