PCP is metabolized mainly in the liver. Oxidative hydroxylation to the inactive monohydroxypiperidine is followed by glucuronidation to a more water-soluble, conjugated derivative that is then excreted in the urine as the major form of metabolism. Significant first-pass liver metabolism also occurs when the drug is ingested orally, as opposed to being smoked or injected. Approximately 10% of drug is excreted unchanged un the urine.
Abuse Liability: A bioassay procedure ... demonstrated that eight structurally related analogs of PCP were self administered by the dog. The thienyl-substituted analog was the most potent, followed by PCP, N-substituted alkyl analogs, monohydroxylated metabolites, and ketamine.
IDENTIFICATION AND USE: Phencyclidine (PCP) is a white, crystalline powder. It is a Schedule II Controlled Substance. PCP was formerly used as a preinduction anesthetic and as an animal tranquilizer. It has no current medical indications, although it is still used illegally as a hallucinogen. HUMAN STUDIES: PCP causes distortion of perception and produces a feeling of detachment of dissociation from the user's surroundings and self. It is not a classic hallucinogen but better described as a dissociative agent or anesthetic. The hallmark of PCP toxicity is the recurring delusion of superhuman strength and invulnerability resulting from both its anesthetic and dissociative properties. There are case reports of patients presenting with trauma either from jumping from high altitudes, fighting large crowds or the police, or self-mutilation. Children have become intoxicated by ingesting the butts of used PCP-impregnated cigarettes or from passive inhalation of sidestream smoke. Children aged 5 years and younger often present with lethargy, severe depression of consciousness, ataxia, nystagmus, and staring episodes. Presenting signs may also include apnea, seizures, opisthotonos, and choreoathetosis. Miosis may be present. In children, unexplained stupor or coma, seizures, ataxia, nystagmus, strange behavior, staring spells, or unusual posturing can indicate possible PCP intoxication. Patients may present with various combinations of CNS stimulation and depression, cholinergic and anticholinergic effects, and adrenergic effects. The most common physical findings are nystagmus (horizontal, vertical, or rotatory) and hypertension. Respiratory depression and aspiration may also occur. Some patients display evidence of nystagmus, ataxia, loss of muscle coordination, and vital sign abnormalities without obvious signs of behavioral toxicity. Irritability, hypertonicity, poor feeding, and abnormal neurobehavior have been reported in newborns of phencyclidine abusing mothers. ANIMAL STUDIES: Subchronic PCP treatment induces schizophrenic-like behavior in rodents, including cognitive deficits and increased locomotor sensitivity towards acute administration of PCP. Perinatal PCP administration in rat blocks the N-methyl D-aspartate receptor and causes symptoms reminiscent of schizophrenia in human. Animals exposed to PCP during the neonatal period have fewer GABAergic interneurons in the corticolimbic area, including the hippocampus, and exhibit abnormal behaviors after attaining maturation. In developmental studies 25 to 30 mg/kg of PCP was injected into rats on gestational days 6 through 15 and produced skeletal dysplasias and cleft palates in the offspring. Growth retardation and delay in reflexes was found in the offspring of mice exposed to 5 to 20 mg/kg of PCP.
Phencyclidine is no longer used medically and its production is outlawed. Nevertheless, phencyclidine remains an agent of abuse, used for its hallucinogenic effects. At low doses, phencyclidine appears to have little effect on the liver. However, high doses of phencyclidine have been associated with malignant hyperthermia which can trigger acute hepatitis necrosis and liver failure. Patients generally present with seizures and coma followed by severe hyperthermia, rhabdomyolysis and renal failure. The liver injury arises 1 to 2 days after the overdose with marked, rapid elevations in serum ALT, AST and LDH, with minimal increases in alkaline phosphatase and delayed rises in bilirubin (Case 1). Coma arises early along with prolongation of the prothrombin time, hyperammonemia and metabolic acidosis. The abnormalities resolve almost as rapidly as they develop and with suitable life support, survival is not uncommon (Case 1). The clinical syndrome is that of acute hepatic necrosis and resembles the acute liver injury that occurs with heat shock, severe hypoxia and hepatic ischemia. Liver biopsy shows severe centrilobular necrosis with mild inflammation.
Likelihood score: C[HD] (probable cause of clinically apparent acute liver injury but only when given in high doses).
Mechanism of Injury
The mechanism of acute liver injury by phencyclidine is probably hyperthermia, hypoxia and hypotension, and the clinical course and outcome resembles that associated with shock or severe hypoxia.
◉ Summary of Use during Lactation:A single case of phencyclidine use has been reported in which a small amount of phencyclidine was detected in breastmilk over 6 weeks after use of an unknown quantity of the drug. Effects on the breastfed infant are unknown.
The Academy of Breastfeeding Medicine suggests that women who have abused phencyclidine generally should not breastfeed unless they have a negative maternal urine toxicology at delivery, have been abstinent for at least 90 days, are in a substance abuse treatment program and plan to continue in it during the postpartum period, have the approval of their substance abuse counselor, have been engaged and compliant in their prenatal care, and have no other contraindications to breastfeeding.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0 mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances.
The aim of the study was to determine the effects of early postnatal PCP treatment on the sensitivity of pubertal and adult rats to lindane proepileptogenic effects. Rat pups were treated with NaCl (0.9%) or PCP (10 mg/kg) at postnatal days 2, 6, 9 and 12. One control (NaCl-35) and one experimental (PCP-35) group have received lindane (4 mg/kg) at postnatal day 35, while others received lindane at postnatal day 65 (NaCl-65 and PCP-65). One week prior to lindane treatment three gold-plated EEG electrodes were implanted. Pubertal rats had significantly shorter latency time. After lindane, a prompt increase in power spectral density seen in PCP-treated groups vs. control was evident earlier in PCP-65 rats. The theta waves were significantly increased in PCP-35 and alpha rhythm in PCP-65 rats, when compared with corresponding controls. Postnatal PCP treatment increases the synchronization of brain electrical activity, thus contributing to the increased susceptibility to lindane.
/Monkeys/ maintained a state of continuous intoxication which was sustained when the dose /of PCP/ was increased to 0.5 mg/kg. Substitution of saline after 58 days of exposure resulted in the appearance of numerous abstinence signs and symptoms including increased vocalizations, bruxism, oculomotor hyperactivity, diarrhea, refusal of preferred food, piloerection, and tremors. Less common signs included ear and facial twitches, priapism, abdominal contractions, emesis, and convulsions. The time course of withdrawal was characterized by an initial recovery from the PCP-induced intoxication at about 4 hr after saline substitution. Onset of hyper-responsive behaviors became evident at 8-12 hr, with the maximum number of symptoms occurring 12-15 hr post-substitution. The syndrome dissipated over 24 hr, however, and all withdrawal signs were immediately reversed by PCP (0.25 g/kg, iv). This study also showed that PCP blood levels were in the 105-280 mg/mL range during self administration, and declined to 0-12 mg/mL with saline substitution.
/Phencyclidine/ is rapidly absorbed from the respiratory and the gastrointestinal tracts; as such, it is typically self-administered by oral ingestion, nasal insufflation, smoking, or IV and subcutaneous injection.
Urine pH is an important determinant of renal elimination of PCP. In acidic urine, PCP becomes ionized and then cannot be reabsorbed. Acidification of the urine increased renal clearance of PCP from 1.98 + or- 0.48 L/hr to 2.4 + or - 0.78 L/hr. Additional studies have found a much higher renal clearance (8.04 + or- 1.56 L/hr) if the urine pH was decreased to less than 5.0. Although this may account for a 23% increase in the renal clearance, it only represents a 1.2% increase of the total clearance.
