86: Phencyclidine and Ketamine

Phencyclidine (PCP) was discovered in 1926 but was not developed as a general anesthetic until the 1950s. At that time, the Parke Davis drug company was searching for an ideal intravenous (IV) anesthetic to rapidly achieve analgesia and anesthesia with minimal cardiovascular and respiratory depression.³⁷ PCP was marketed under the name Sernyl because it rendered an apparent state of serenity when administered to laboratory monkeys. Its surgical use began in 1963, but was rapidly discontinued when a 10% to 30% incidence of postoperative psychoses and dysphoria was documented over the subsequent 2-year period.⁸⁶ By 1967 the use of PCP was limited exclusively to veterinary medicine as a tranquilizer marketed under the name Sernylan.

Simultaneously, in the 1960s, PCP emerged as a street drug in San Francisco called “the PeaCe Pill.”⁷⁰ Numerous street names have been given to phencyclidine; on the West Coast, it was called “angel dust,” PCP, “crystal,” and “crystal joints” (CJs); in Chicago it was called “THC” or “TAC”; and those on the East Coast opted for “the sheets,” “Hog,” or “elephant tranquilizer.”¹³² Ironically, PCP was initially unpopular with drug users because of its dysphoric effects and unpredictable oral absorption.¹⁷³ However, with time its use spread in a similar geographic pattern to that of marijuana and lysergic acid diethylamide (LSD), from the coastal United States to the Midwest region.⁷⁰

PCP abuse became widespread during the 1970s.^26,200 The relatively easy and inexpensive synthesis coupled with the common marketing of PCP as LSD, mescaline, psilocybin, cocaine, amphetamine, and/or “synthetic THC” (tetrahydrocannabinol) added to its allure and consumption.¹³² By the late 1970s PCP abuse had reached epidemic proportions.⁸ The Drug Abuse Warning Network (DAWN) reported that the number of PCP-related emergencies and deaths had more than doubled from 1975 to 1977. In 1978 the National Institute of Drug Abuse reported that 13.9% of young adults (18–25 years old) had used PCP.⁵³ The manufacture of PCP was ultimately prohibited in 1978 when it was added to the list of federally controlled substances. Classifying PCP as a Schedule II drug led to its decrease in availability and, consequently, a decrease in its use. Although the 1980s brought about a cocaine epidemic that eclipsed PCP, PCP has remained consistently available, primarily regionalized to large cities in the northeastern United States and in the Los Angeles area,¹¹¹ where PCP use continues to rise and fall with societal trends. Because many of the PCP congeners made during the manufacturing process were being abused in place of PCP, the Controlled Substance Act of 1986 made these derivatives illegal and established that the use of the precursor of PCP, piperidine, necessitated mandatory reporting. With this new law in place, those possessing similar but not identical illegal substances could be prosecuted. This led to a further decline in the popularity of PCP. Beginning in 1984, the overall use of PCP declined sharply, reaching a nadir in 1994.²⁰³ However, during the 8 years that followed, there was a small resurgence in reported PCP use, but never reaching the epidemic proportions of the 1970s. Peak use reached an annual prevalence rate of 2.6% in 1996 among 12th graders. DAWN reported that the highest number of PCP related emergencies occurred in Washington, DC, Philadelphia, Los Angeles, Chicago, and Newark, NJ.^204,207,208 Since 2003, the use of PCP has declined and its prevalence has remained low. During these years the National Survey on Drug Use and Health reports that the annual prevalence rate for the use of PCP for young adults has fluctuated between 0.6% and 0.1% with the latest report of 0.3% in 2011. Lifetime prevalence use of PCP is highest among adults aged 23 to 30 years (3.3%).¹¹³

Laboratory investigation of phencyclidine derivatives led to the discovery of ketamine, a chloroketone analog. Ketamine was introduced for general clinical practice in 1970 and was marketed as Ketalar, Ketaject, and, for veterinary use, Ketavet. Because ketamine has approximately 5% to 10% of the potency of PCP and a much shorter duration of action, it provides greater control in clinical use. Thirty-five years of clinical experience have established that ketamine provides adequate surgical anesthesia, a rapid recovery, and less prominent emergence reactions than PCP.^{60,83,176,222} Because of the simplicity and efficacy of its use, it is regularly used in operating rooms, emergency departments (EDs), and throughout the developing world where little clinical monitoring is available during surgical and emergency procedures.^{57,82,83,85,86,177,221}

Abuse of ketamine was first noted on the West Coast in 1971.¹⁸⁹ During the 1980s there were reports of its abuse internationally, including physicians.^4,72 The nonmedical use of dissociative anesthetics has continued to increase throughout the 1990s and into the 2000s, in spite of the common complications associated with their use.²⁰² Unfortunately, it is those same pharmacologic qualities that make ketamine more popular than PCP clinically that are responsible for its nonmedical popularity. Ketamine is regularly consumed at all-night “rave parties” and in nightclubs because of its “hallucinatory” and “out-of-body” effects, relatively inexpensive price, and short duration of effect: a single insufflation lasts between 15 and 20 minutes.^{12,47,100,104,223}

The use of ketamine is not limited to the inner city. In the past decade, the media reported police arrests in affluent suburban communities for possession and sale of ketamine, which is coupled to more in-depth and frequent reporting of its toxicity among users.^{47,100,174,223} By contrast to PCP, ketamine is not manufactured illegally, but rather, it is diverted from legitimate medical, dental, and veterinary sources. Additionally, with the advent of the Internet, its availability has dangerously grown nationwide; a sham “biotech” Internet company was seized by the New York City Police Department in 2000 for selling so-called date rape drugs, including ketamine.¹⁴⁵

Adverse reactions do occur, although there are few reports of fatalities secondary to ketamine, even during this period of increased use.^{76,122,126,151} Because of its abuse potential, ketamine was placed in Schedule III of the Controlled Substance Act in 1999.¹⁷⁶ DAWN reported that there was a more than 2000% increase of ketamine related ED visits between 1994 and 2001. Despite any clear reason, after peaking in 2001, there was a decline in ketamine related ED visits in 2002.²⁰⁵ The use of ketamine has remained very low since 2006,¹⁸⁸ with an annual prevalence rate at or below 1.3% for high school students and 0.8% for young adults.^112,113,206

Chemistry

The chemical name, 1-(1-phenylcyclohexyl)piperidine, provided the basis for its street abbreviation, PCP. During its unlawful chemical synthesis, numerous analogs are made that have similar effects on the central nervous system (CNS) and have been used as PCP substitutes. These “designer” ­arylcyclohexylamines are aliphatic- or aromatic-substituted amines, ketones, or halides, and appear similar to the parent compound. More than 60 psychoactive analogs are known. The following salient points of the five most prevalent compounds are worth mentioning: 1-[1-(2-thienyl)cyclohexyl] piperidine (TCP) and 1-piperidino-cyclohexanecarbonitrile (PCC) are piperidine derivatives. Piperidine, the synthetic precursor, was formerly easily purchased for the manufacture of PCP and its derivatives. TCP, a thiophene analog, produces even more intense effects than PCP. An intermediate of PCP synthesis, PCC was a constituent of up to 22% of illicit xenobiotic preparations analyzed for phencyclidine. This most likely resulted from a poor manufacturing process.^15,188 PCC degrades to piperidine, which is ­recognizable by its strong fishy odor. The presence of its carbonitrile group adds to its toxicity by generating cyanide when smoked.^{13,15,195,196} The ­pyrrolidine derivative, phencyclohexylpyrrolidine (PHP), is clinically comparable to PCP and is not detected by many of the available drug-screening methods.^28,95 More potent than PCP, 1-phenyl-cyclohexylethylamine (PCE) was commonly available on the street as a white powder indistinguishable from PCP.¹⁸⁸ TCP, PCE, and PHP are classified as Schedule I drugs, and PCC is classified as Schedule II drug.

Ketamine and tiletamine, two legal analogs of PCP, are used clinically for sedation and anesthesia. In larger quantities, both are also used in veterinary medicine for animal sedation. Tiletamine, in combination with zolazepam (Telazol), is commonly used for animal procedures in veterinary medicine. Ketamine is the only dissociative anesthetic product manufactured for human use for the purpose of anesthesia, conscious sedation, and the treatment of bronchospasm. The development of a mechanistic approach to pain therapy in the last 20 years has brought a renewed interest in the use of ketamine as an adjuvant to multimodal pain treatment. Ketamine is used prophylactically and therapeutically in children and adults in the management of postoperative pain. For the treatment of pain ketamine is administered intravenously (median dose: 0.4 mg/kg; range: 0.1–1.6), orally, intramuscularly, rectally, subcutaneously, intraarticularly, caudally, epidurally, transdermally, intranasally, or added to a patient-controlled analgesia device.^{65,87,96,117,179} Currently, the rapid antidepressant effect of ketamine is being studied clinically. A common single study dose of 0.5 mg/kg administered intravenously (IV) for 40 to 60 minutes to patients with refractory major depressive disorder provides a 14% to 70% antidepressant response lasting 72 hours postinfusion. Presently randomized control trials are underway to explore dosing, maintenance of response, mode of delivery, and adverse effects.¹

The molecular structure of ketamine [2-(ortho-chlorophenyl)-2-methylaminocyclohexanone] contains a chiral center, producing a racemic mixture of two resolvable optical isomers or enantiomers, the d(+)-isomer and l(–)-isomer. Commercially available preparations of ketamine contain equal concentrations of the two enantiomers. These two molecules differ in their pharmacodynamic effects. In a randomized, double-blind evaluation of patients undergoing surgery, the d(+)-isomer of ketamine was a more effective anesthetic but manifested a higher incidence of psychotic emergence reactions than the l(–)-isomer. In other studies, the d(+)-isomer caused a greater increase in both blood pressure and pulse than the l(–)-isomer, and also had more bronchodilatory effects.^177,222

Pharmacokinetics and Toxicokinetics

Phencyclidine is a white, stable solid readily soluble in both water and ethanol. It is a weak base with a pK_a between 8.6 and 9.4 and a high lipid-to-water-partition coefficient. It is rapidly absorbed from the respiratory and the gastrointestinal tracts; as such, it is typically self administered by oral ingestion, nasal insufflation, smoking, or intravenous and subcutaneous injection.

The effects of PCP are dependent on routes of delivery and dose. Its onset of action is most rapid from the IV and inhalational routes (2–5 minutes) and slowest (30–60 minutes) following gastrointestinal absorption.^45,46 Sedation is commonly produced by doses of 0.25 mg intravenously, whereas oral ingestion typically requires 1 to 5 mg to produce similar sedation. Signs and symptoms of toxicity usually last 4 to 6 hours, and large overdoses generally resolve within 24 to 48 hours, but effects may persist in a chronic user.^{17,58,61,131,158,173} However, in the PCP-poisoned patient, the relationships between dose, clinical effects, and serum concentrations are not reliable or predictable.

There are several explanations for the protracted CNS effects of PCP. Its large volume of distribution of 6.2 L/kg^45,229 and high lipid solubility account for its entry and storage in adipose and brain tissue. Also, on reaching the acidic cerebrospinal fluid (CSF), PCP becomes ionized, producing CSF concentrations approximately six to nine times greater than those of serum.¹⁴⁸

PCP undergoes first-order elimination over a wide range of doses. It has an apparent terminal half-life of 21 ± 3 hours under both control and overdose settings.^45,103 Ninety percent of PCP is metabolized in the liver and 10% is excreted in the urine unchanged. PCP undergoes hepatic oxidative hydroxylation into two monohydroxylated and one dihydroxylated metabolites.⁴⁶ All three compounds are subsequently conjugated to form the more water-soluble glucuronide derivatives and then excreted in the urine.

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 ± 0.48 L/h to 2.4 ± 0.78 L/h.⁴⁵ If the urine pH is decreased to less than 5.0, then even higher renal clearance (8.04 ± 1.56 L/h) is noted.¹¹ Although this may account for a 23% increase in the renal clearance, it only represents a 1.1% increase of the total clearance.

Similarly, ketamine is water soluble but also has a high lipid solubility (Log D = 2.01) that enables it to distribute to the CNS readily. It has a pK_a of 7.5 and a volume of distribution of 1.8 ± 0.7 L/kg. Ketamine has approxi­mately 10% of the potency of PCP.^83,105 Human trials demonstrate that, similar to PCP, the clinical effects of ketamine are both route and dose dependent.^49,52,60,197 Peak concentrations occur within 1 minute of IV admin­is­tra­tion and within 5 minutes of a 5 mg/kg intramuscular (IM) injection.^222,233 Ketamine distributes immediately into the CNS with the duration of its hypnotic and anesthetic effects decreased by its redistribution from the brain to other tissues.²²² Recovery time averages 15 minutes for IV administration, but may require 30 to 120 minutes following IM administration. Oral or rectal doses are not well absorbed and undergo substantial first-pass metabolism.^177,222 In contrast to oral administration of ketamine where effects last 4 to 8 hours, after nasal administration they last for 45 to 90 minutes.

Ketamine is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzyme CYP2B6 and to a lesser extent by CYP3A4 and CYP2C9.²³¹ Its biotransformation is complex with numerous metabolites described.^3,177,222 The major pathway involves its N-demethylation to norketamine, a metabolite with one-third the anesthetic potency of ketamine. Norketamine is hydroxylated at different sites within its hexanone ring, producing varying second chiral centers. Most of these diastereoisomers are glucuronidated to more water-soluble derivatives that are then excreted in the urine.^83,177 Ketamine also undergoes ring hydroxylation prior to N-demethylation as a minor metabolic pathway. The elimination half-life, which reflects both metabolic and excretory phases, is 2.3 ± 0.5 hours and is prolonged when xenobiotics requiring hepatic metabolism are coadministered.¹²⁸ Because of the enzymatic metabolism, both tolerance and enzyme induction are reported following chronic administration.^83,177

Available Forms

PCP is available on the street in a variety of forms, including powder, liquid, tablets, leaf mixtures, and rock crystal. Because of its uncontrolled illegal manufacture, the contents of PCP vary considerably, with powder often the purest form. A typical dose consumed contains approximately 5 mg.¹⁷² Leaf mixtures are made by sprinkling approximately 1 to 10 mg of phencyclidine onto parsley, oregano, mint, tobacco, or marijuana. A typical PCP joint (known as “crystal joint,” “KJ,” or “supergrass”) is developed for smoking and contains about 1 mg per 150 mg of plant product.⁷ Mentholated cigarettes dipped into liquid PCP are known as “supercools.”

PCP is included in the US Federal Controlled Substance Act of 1970, reducing its availability for incorporation into marijuana cigarettes. There are reports of marijuana cigarettes being adulterated with PCP and sold on the street under varying names like “Illy” in Connecticut, “Hydro” in New York City, “Dip” in New Jersey, “Wet” in Philadelphia, and “Fry” in Texas.⁹⁸

The cigarettes are purportedly treated with “embalming fluid,” which allegedly enhances the euphoric effects of the drug. Rather, the embalming fluid, or another organic solvent, is used as a medium to allow a uniform distribution of PCP in these cigarettes.⁹⁸ Furthermore, the organic solvent may be the remnant of the organic solvent used in the synthesis of PCP or one of its analogs. In either case, the ability to smoke the cigarette prior to drying after dipping in the solvent/PCP (nonaqueous) mixture accounts for its various names. In most cases, this “enhanced” mixture appears to be purchased intentionally rather than having the PCP placed in these cigarettes surreptitiously.

On the street and on the Internet, ketamine is known as “vitamin K,” “Special K,” “Super K,” “Ket,” or simply “K.” It is available in a liquid form that is dried into a pure-white crystalline powder and is typically self-administered by ingestion or insufflation in a fashion similar to PCP. It is rarely injected IV or IM in aqueous form.

When used by injection, there is an observed demographic and behavioral difference among those who initiate drug injection use with ketamine and those who initiate injection use with another xenobiotic and later transition into ketamine injection.¹²⁵

Ketamine is primarily sold as tablets, capsules, or powder. These formulations are often adulterated with caffeine, methylenedioxymethamphetamine (MDMA), ephedrine, methamphetamine, heroin, and cocaine (a mixture known as CK or Calvin Klein).^63,180 In fact, in addition to alcohol, MDMA (39%), heroin (17%), and cocaine (14%) are the most frequently mentioned xenobiotics used with ketamine.²¹¹ Exemplifying the commercial growth of ketamine, some of the tablets are even found to contain a “K” logo.⁶³ Common sedating doses are 75 to 300 mg orally (30–75 mg for insufflation). Higher doses, ranging between 300 and 450 mg orally (100–250 mg for insufflation), result in substantial CNS adverse effects. These manifestations are similar to the clinical “emergence reactions” that patients experience during ketamine anesthesia.

More recently, abuse of a ketamine analogue, methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino) cyclohexanone) is reported. This designer drug is a means of evading drug enforcement. Sold through the Internet internationally as a white powder, it may be ingested, insufflated, or injected. Its market is mostly in the United Kingdom and is referred to by various names, including M-ket, Kmax, and Mexxy. Case reports indicate that the clinical symptoms of patients with methoxetamine toxicity are similar to those reported from ketamine.^97,218,228

The arylcyclohexylamines, of which PCP and ketamine are prototypes, are a group of anesthetics that functionally and electrophysiologically “dissociate” the somatosensory cortex from higher centers.^49,221 The precise mechanisms by which PCP and ketamine achieve these effects are complex and not fully understood; however, investigation of the nature of PCP-induced psychosis has led to a substantial identification of the various sites of PCP activity.

Most studies demonstrate that PCP and ketamine bind with high affinity to sites located in the cortex and limbic structures of the brain.¹³⁴ They block the NMDA receptors at serum concentrations encountered clinically.^215,234 Analogs of PCP (TCP, PCE, PHP, and ketamine) and dizocilpine (MK-801) also interact with the NMDA receptor in a dose-response manner that corresponds appropriately to their neurobehavioral effect.^27,185,224 These xenobiotics bind to the NMDA receptor at a site independent of glutamate.^{105,110,134,226} As such, they antagonize the action of glutamate on this channel and noncompetitively block Ca²⁺ influx (Fig. 14–14).

PCP and ketamine bind to the biogenic amine reuptake complex with 10% to 20% of the affinity to which they bind to the NMDA receptor. Binding occurs at physiologic concentrations that normally take place after subanesthetic doses.^5,168 This weak inhibition of the catecholamine reuptake accounts for the respective sympathomimetic and psychomotor effects. An increase in blood pressure and heart rate is induced. Rapid IV infusion produces a more pronounced effect than by IM injection, with the d(+)-isomer having a greater effect than the l(–)-isomer.²²²

In significant overdoses, PCP and ketamine also stimulate sigma receptors at concentrations generally associated with coma, although with lower affinity than NMDA receptors.^198,225 Both D₂ and sigma receptors have an inhibitory effect on the cholinergic receptor pathways.²²⁵ At the higher concentrations, typically associated with death, PCP and ketamine also bind to the nicotinic, opioid, and muscarinic cholinergic receptors.²¹⁴

NMDA antagonists produce effects on behavior, sensation, and cognition that resemble aspects of endogenous psychoses, particularly schizophrenia.^106,165 These behavioral abnormalities were first observed in studies in the late 1950s when PCP, administered to healthy volunteers, generated a form of organic psychosis that mimicked schizophrenia. When PCP was administered to schizophrenic patients, it uniformly intensified their primary symptoms of profound disorganization, and some of these symptoms lasted for weeks.¹³¹ PCP psychosis is so similar to schizophrenia that many psychiatrists cannot distinguish them without a prior indication of drug abuse history.¹⁹⁴ The multireceptor action of PCP and its link to schizophrenia is made more intriguing as various antipsychotics (eg, phenothiazines, thioxanthenes, butyrophenones) are also α receptor agonists.⁸⁰

Current interest in the role of excitatory neurotransmitter systems in the pathophysiology of schizophrenia has led to similar observations in patients after ketamine administration. Subanesthetic doses of ketamine administered to both healthy and schizophrenic volunteers induced a mild, dose-related, short-lasting increase in psychotic symptoms. Although the normal and schizophrenic volunteers had different levels of baseline psychosis, the magnitude, time course, and dose-response changes in positive symptoms were similar across the two populations. Both groups experienced thought disorganization, such as concreteness and loose association, hallucinations, and delusions of varying intensity.^{120,122, 123, and 124}

There is a connection between PCP psychosis and sensory processing. PCP and ketamine inhibit sensory perception in a dose-dependent manner. This processing in sensory information corresponds to their relative affinities to the NMDA receptor and not to the sigma receptor.^7,168 Clinically, the impairment of sensory input produced by PCP resembles that of patients who are deprived of sensory stimulation.¹⁴¹ When external stimulation was reduced by environmental sensory deprivation, the psychotomimetic effects of PCP were diminished,⁴³ giving credence to the theory that it may not be anxiety that causes perceptual dysfunction in schizophrenia, but the converse.

Many of the NMDA antagonists, including PCP and ketamine, have a negative effect on cognition and memory. Repeated administration of PCP and ketamine in many animal models results in cognitive and memory impairement.^93,108 Both impair concentration, recall, learning, and retention of new information.^{14,31,56,58,77,92, 93, and 94,120,138,150,161} In human volunteers, ketamine selectively impairs explicit,⁷⁶ episodic,^55,154 and procedural memory,¹⁵⁴ and disrupts frontal cortical function, as measured by the Wisconsin Card Sorting Task and verbal fluency,^120,138 in a dose-dependent manner. Learning and memory impairments in volunteers who were administered subanesthetic doses of ketamine (0.65 mg/kg) are independent of the user’s attention and related psychosis.¹³⁸ Testing performed on chronic ketamine users produces similar results that are long lasting and have more marked effects on semantic and episodic memory.^{55,56,156,157} Accordingly, it is presumed that the acute and repeated NMDA receptor antagonism interferes with those functions that integrate interoceptive and exteroceptive input in which goal-directed action becomes possible, similar to the organic psychosis in schizophrenia. Because the rapid antidepressant effects of ketamine have the potential for either continuous and/or repeated dosing, current research may attend to its long-term adverse effects.

Hypofunction of the NMDA receptor causes neuroanatomic and neurobehavioral effects. Animals exposed to NMDA antagonists such as PCP and dizocilpine transiently demonstrated neuronal vacuolar degeneration in the retrosplenial cortex and the posterior cingulate areas of the brain.^163,164 The major function of cingulate cortical neurons is to mediate affective responses to pain.²¹⁶ Single high doses or repeated exposures to NMDA receptor antagonists are associated with a higher incidence of cellular death.^48,66,67,163 This injury seems to be related to the induction of selective expression of individual heat shock proteins in this anatomical area.¹⁸⁷ Excitatory amino acids are neurotransmitters responsible for mediating seizure activity in the brain. Although NMDA inhibitors, the anticonvulsant properties of PCP and ketamine are not demonstrated. Animals administered PCP or PCP analogs progress through dose-related clonic activity followed by tonic–clonic convulsions, as is typical of classic convulsant compounds.¹⁶⁸ Animal research also demonstrates wide interspecies variability of the electroencephalographic (EEG) effects of PCP.⁶¹ In a murine seizure model, ketamine possessed selective anticonvulsant properties.³² In addition, ketamine preserves learning proficiency in rats when administered shortly after onset of status epilepticus, an effect that may prove useful in the clinical setting when combined with conventional antiepileptic medications.¹⁹⁹

In humans, although these dissociative xenobiotics induce excitatory activity in the thalamus and limbic areas, they do not affect cortical regions.^51,52,60,73 Excitation, muscle twitching, posturing,¹⁴⁹ and tonic–clonic motor activity with or without EEG changes are reported with these subcortical EEG alterations.^35,50,73,149 In the clinical setting, many report ketamine to possess anticonvulsant properties at clinically relevant doses and may be explained by an NMDA inhibitory effect.^35,50 This effect was employed to treat patients with refractory status epilepticus in the critical care setting.²¹⁰

The NMDA receptor is also responsible for the development of the neuronal organization of the central nervous system.^{101,102,190,191} It is linked to hypoxic–ischemic brain injury by mediating calcium influx, a final pathway in cell death. The uninhibited firing of NMDA afferent neurons secondary to brain injury causes their death, as well as the death of efferent neurons downstream. In neonatal rats, ketamine increases the rate of neuronal apoptosis.¹⁸⁵ NMDA antagonists such as PCP block hypoxic brain injury from stroke and trauma.^18,130 In a rat model of ischemic stroke, PCP had a protective effect on the brain, demonstrated by a decreased rate of seizure activity.¹⁸ This effect is transient and has not been studied in humans.

PCP induces modest tolerance in rats and squirrel monkeys. The development of tolerance is mostly secondary to the pharmacologic effects of PCP rather than to biodispositional changes. Dependence was also observed in monkeys who self-administered PCP (10 mg/kg/d to serum concentrations of 100–300 ng/mL) over one month by the appearance of dramatic withdrawal signs when access was denied. Signs included vocalizations, bruxism, oculomotor hyperactivity, diarrhea, piloerection, difficulty remaining awake, tremors, and in one case convulsions.¹⁶ These signs appeared within 8 hours of abstinence and were most severe at about 24 hours. When either PCP or ketamine (2.5 mg/kg/h) was readministered to the animals, PCP withdrawal symptoms were reversed, indicating cross-dependence from PCP to ketamine.^21,107,193

Physiologic dependence in humans has not been formally studied. It is implied to occur by the observation that chronic PCP users developed depression, anxiety, irritability, lack of energy, sleep disturbance, and disturbed thoughts after one day of abstinence from drug use.¹⁷⁵ In addition, neonates whose mothers used PCP developed jitteriness, vomiting, and hypertonicity that lasted for at least 2 weeks.²⁰¹ These symptoms may represent PCP withdrawal or intrinsic teratogenic effects on neurologic development.^81,101 Although there are no controlled studies observing the physiologic symptoms of withdrawal in humans who chronically use PCP or ketamine, there is a definite psychological dependence on the sensations experienced during recreational use of the drugs.¹⁸⁹ There are a few cases of ketamine tolerance where patients report a need to use an increased quantity of drug to get the same effect.^54,152,169 In a study of ketamine abstinence, patients characterized their withdrawal symptoms as anxiety, shaking, sweating, and palpitations.¹⁵⁵ In addition, ketamine impairs response inhibition, which is found to be related to increases in subjective ratings of desire for the drug.¹⁵⁴

The reported signs and symptoms of patients presenting to the ED with PCP and ketamine toxicity are variable. The variations are a result of differences in dosage, the multiple routes of administration, concomitant xenobiotic use, and other associated medical conditions. In accordance with their pharmacologic effect, ketamine toxicity produces signs and symptoms similar to PCP with a shorter duration of action. In addition, individual differences in xenobiotic susceptibility, the development of tolerance in chronic users, as well as contaminants in the drug manufacture, may account for erratic clinical findings.

Vital Signs

Body temperature is rarely affected directly by PCP and ketamine. In one large series, only 2.6% of patients demonstrated hyperthermia (> 101.8°F {38.8°C}).¹⁴² In an experimental animal model, PCP failed to increase body temperature.^37,61 When hyperthermia does occur, all the known complications, including encephalopathy, rhabdomyolysis, myoglobinuria, acute kidney failure, electrolyte abnormalities, and liver failure, occur (Chap. 30).^9,20,42,170

Most PCP and ketamine toxic patients demonstrate mild sympathomimetic effects. PCP consistently increases both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a dose-dependent fashion.^37,61 Doses of 0.06 mg/kg of IV PCP increase the SBP and DBP by 8 mm Hg, whereas 0.25 mg/kg produce a 26 and 19 mm Hg increase in SBP and DBP, respectively. PCP also increases the heart rate, although it does so inconsistently.⁹⁰ Likewise, ketamine produces mild increases in blood pressure, heart rate, and cardiac output via this same mechanism.^{52,133,197,212,222} In fact, tachycardia was the most common finding on physical examination in a case series of ketamine abusers presenting to the ED.²²⁰

Cardiopulmonary

Cardiovascular catastrophes are rarely encountered in PCP toxicity.^64,143 These complications may result from direct vasospasm,^6,36 causing severe systemic hypertension, pulmonary edema, hypertensive encephalopathy,⁶⁵ and cerebral hemorrhage.²³ Hypertension, along with abnormal behavior, miosis, and nystagmus in children, strongly suggest toxicity due to a dissociative anesthetic.¹¹⁵

The effect of PCP and ketamine on cardiac rhythm is controversial. Dysrhythmias are only observed in animals poisoned with very large doses of PCP. Ketamine both enhances and diminishes epinephrine-induced dysrhythmias in animals.^22,62,91,116 The considerable experience in the use of ketamine anesthesia on humans undergoing surgery or cardiac catheterization has not demonstrated prodysrhythmic effects.^69,159

As these dissociative anesthetics were designed to maintain normal ventilation, hypoventilation is uncommon. In clinical studies, PCP increased the minute ventilation, tidal volume, and respiratory rate of volunteers.⁹⁰ Clinically, in PCP-toxic patients, irregular respiratory patterns develop as tachypnea much more often than as bradypnea.^9,142 Hypoventilation, when present, is usually secondary to the use of particularly high doses of PCP. Acute respiratory distress syndrome secondary to respiratory depression is also a rare occurrence. Large doses of PCP (20 mg/kg) administered to laboratory animals produced respiratory depression.³⁷ Although respiratory depression in humans is an extremely rare event, it has been reported with fast or high-dose infusions of ketamine.^84,222 In fact, ketamine has been successfully used to prevent intubation in patients with refractory asthma. Ketamine relaxes bronchial smooth muscles, decreases mean airway pressure and Paco₂, and increases Pao₂.^{75,178,202,222}

Neuropsychiatric

Most patients with PCP and ketamine toxicity brought to medical attention manifest diverse psychomotor abnormalities.^{13,19,29,72,108,220} As dissociative anesthetics, these xenobiotics impair response to external stimuli by separating various elements of the mind. Consciousness, memory, perception, and motor activity appear dissociated from each other. This dissociation prevents the user from attaining cognition and properly assembling all this information to construct a reality. Clinically, the person may appear inebriated, either calm or agitated, and sometimes violent. In large overdoses, the anesthetic effect causes patients to develop stupor or coma. In recreational use, “dissociatives” are not taken for these effects, but rather for so-called out-of-body experiences. In addition patients often have disordered thought processes (including disorientation as to time, place, and person) or amnesia, paranoia, and dysphoria.⁷¹

The manifestations of PCP and ketamine toxicity are better illustrated by the results of their effects in controlled human studies. Volunteers who took oral doses of up to 7.5 mg/day of PCP or 0.1 mg/kg of ketamine exhibited clinical inebriation, but higher doses (PCP > 10 mg/day; ketamine 0.5 mg/kg) generally caused a more severe impairment of mental function.^61,120 IV doses of 0.1 mg/kg of PCP^{17,58,131,158,181} and 0.5 mg/kg of ketamine^120,168 cause diminution in all sensory modalities (pain, touch, proprioception, hearing, taste, and visual acuity) in a dose-dependent fashion. Both xenobiotics also cause feelings of apathy, depersonalization, hostility, isolation, and alterations in body image.^{17,58,74,109,137,156} The deficits in sensory modalities are evident prior to the development of the psychological effects of PCP, with pain perception disappearing first. This alteration in analgesic perception is caused by a blocking action on the thalamus and midbrain (Fig. 86–1).¹⁵⁸

Abnormal stereognosis and proprioception occur in a dose-­dependent manner. This disturbed perception results in body image distortions described as “numbness,” “sheer nothingness,” and “depersonalization.” The decrease of proprioceptive sensation to gravity probably gives the sensation of “tripping” or “flying.” Because all sensory modalities are affected, visual, auditory, and tactile illusions and delusions are common. Hallucinations are typically auditory rather than visual, which are more common with LSD use. The hallucinogenic effects of ketamine on healthy human volunteers are linearly related to steady-state concentrations between 50 and 200 ng/mL.²⁴ Most ketamine users report experiencing a “k-hole,” a slang term for the intense psychological and somatic state experienced while under the influence of ketamine. This experience varies with the individual, but can include buzzing, ringing or whistling sounds, traveling through a dark tunnel, intense visions, and out-of-body or near-death sensations.⁵⁹

The reaction to the misperceived or disconnected reality may result in unintentional actions and violent behavior. 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. The true extent and incidence of violence is probably less than previously suggested.²⁵

Typically, neurologic signs include horizontal, vertical, and/or rotatory nystagmus, ataxia, and altered gait. Initially, except for ataxia, motor movement is not impaired until the patient becomes unconscious. On physical examination, use of dissociative anesthetics typically produces relatively small pupils, nystagmus, and diplopia. In the largest case series reported to date, nystagmus and hypertension were noted in 57% of patients who had taken PCP.¹⁴² Smaller and more limited studies have found an incidence of nystagmus approximating 89%.¹⁹ In comparison, nystagmus was only found in 15% of patients with ketamine abuse.²⁰⁰ Other cerebellar manifestations were also encountered, most notably dizziness, ataxia, dysarthria, and nausea. A pooled data compilation of 35 reports demonstrated that emesis occurred 8.5% of the time.⁸⁴ In fact, Internet chat groups devoted to substance abuse commonly direct users to “mix dissociatives with marijuana” for its antiemetic effect.

Larger doses of PCP produce loss of balance and confusion, the latter characterized by inability to repeat a set of objects, frequent loss of ideas, blocking, lack of concreteness, and disordered linguistic expression.^{55,61,120,131,181} Similarly, ketamine users report a high incidence of incoordination, confusion, unusual thought content, and an inability to speak.⁵⁹ In general, dissociative anesthetics stimulate the CNS but seizures rarely occur, except at high doses. The largest case series of PCP-toxic patients detected a 3.1% incidence of seizures.¹⁴²

Although PCP and ketamine toxic patients also present with motor disturbances, it is unclear to what extent PCP and ketamine are actually responsible for these manifestations. The most common of the reported disturbances are dystonic reactions: opisthotonos, torticollis, tortipelvis, and risus sardonicus (facial grimacing). Myoclonic movements, tremor, hyperactivity, athetosis, stereotypies, and catalepsy also occur.^13,30,72,142 A slight increase in muscle tone results from a dopaminergic effect.¹³¹ Laryngospasm requiring intubation has been reported after the use of ketamine anesthesia. The incidence of this complication is less than 0.017%.⁸³ By comparison, the incidence of laryngospasm following traditional general anesthesia is 2%.¹⁵⁰

Urological and Hepatobiliary

Intense abdominal and pelvic pain is regularly reported in habitual ketamine users.^160,232 In the majority of cases, the etiology is urologic. The first case series describing ketamine-associated urological dysfunction was reported in 2007. The patients’ symptoms consisted of severe lower urinary tract syndrome (LUTS): dysuria, frequency, urgency, urge incontinence, and painful hematuria (Fig. 86–2). When investigated by cystoscopy, patients with hematuria were frequently found to have ulcerative cystitis.¹⁸⁴

Subsequent reports have established LUTS as a complication in both recreational ketamine users as well as in a patient receiving ketamine therapeutically for chronic regional pain syndrome.^39,89,103 The incidence of ketamine-induced urologic dysfunction is not well established. Studies from the United Kingdom report an incidence of 20%, whereas a study from Hong Kong reports the incidence of 32% and 92% in acute and chronic ­ketamine users respectively.^139,227,232

The symptoms of ketamine–induced urologic dysfunction are secondary to an inflammatory process that reduces bladder size. Initial urinalyses are typically sterile. Patients develop diminished voiding capacity of 20 to 200 mL, decreased bladder compliance, and detrusor overactivity as measured by urodynamic testing. A thickened bladder wall, a small bladder volume, and perivesicular stranding are usually detected by ultrasonography and computerized tomography (CT) of the lower urologic tract.¹³⁹ Cystoscopy demonstrates an erythematous bladder mucosa with various degrees of ulcerations. Bladder biopsies confer epithelium denudation and ulcerative cystitis. There is a marked lymphocytic infiltration with a variable number of eosinophils and fibrosis as well as squamous metaplasia and nephrogenic metaplasia. The exact mechanism by which ketamine or one of its metabolites causes the destruction of the urinary tract remains unknown.^{39,40,227,232}

The pathology of ketamine-induced urologic dysfunction is not confined to the lower urinary tract. Upper urinary tract involvement is variable. A lower incidence of 13% has been reported in the United Kingdom ­compared with 51% in Hong Kong. The lower incidence is thought to be due to patients in the United Kingdom seeking medical attention earlier than those living in Hong Kong. IV urography and urography by CT reveal unilateral or bilateral ureteric narrowing. Bilateral hydronephrosis was reported in 44% to 50% of patients, and renal impairment has also been described.^139,147 Biopsy of the ureter in a patient who underwent right nephrectomy with an ileal conduit anastomosis to the left renal pelvis demonstrated nephrogenic metaplasia throughout the ureter extending to the renal pelvis as well as ulceration with associated inflammatory changes, as described the bladder biopsies.⁹⁹

Intense abdominal pain in frequent ketamine users is also suggested to be hepatobiliary in nature. Case series of patients who used ketamine illicitly or therapeutically report abnormal liver function tests and biliary tract abnormalities.^129,162,183 CT revealed common bile duct dilation with a smooth tapered end, a condition that mimics benign cystic dilation of the bile ducts. Endoscopic retrograde cholangiopancreatography and hepatobiliary iminodiacetic acid studies concur with these findings, suggesting gallbladder wall dyskinesia. These biliary abnormalities are noted to subside with cessation of ketamine use.¹²⁸

Emergence Reaction

The acute psychosis observed during the recovery phase of PCP ­anesthesia limits its clinical use. This bizarre behavior, characterized by confusion, vivid dreaming, and hallucinations, is termed an “emergence ­reaction.” These reactions occur most frequently in middle-aged men, with a reported incidence of 17% to 30%.^90,114 The most violent emergence reactions ­follow an IV dose of approximately 0.25 mg/kg of phencyclidine.⁶¹ The ­mildest degrees of agitation produced by PCP resemble the effects of ethanol intoxication.

These same postanesthetic reactions also limit the clinical use of ketamine. The incidence of emergence reactions following ketamine administration may approximate 50% in adults and 10% in children.⁸³ Patients older than 10 years of age, women, persons who normally dream frequently, have a prior personality disorder, or both, premorbid denial of presence of illness or anosognosia (denial of the presence of an illness), and paranoia incur the greatest risk.^83,144 The incidence of the occurrence of emergence reactions appears to be exacerbated when dissociative anesthetics are rapidly IV administered, as well as in patients exposed to excessive stimuli during recovery. Although it has not been proved in a controlled study, reducing external stimuli during the recovery phase might reduce emergence reactions.

Ironically, the very characteristics thought to make PCP ideal for anesthesia—the preservation of muscle tone and cardiopulmonary ­function—magnify the difficulties in managing an individual who manifests dysphoria after an overdose. The course of delirium, stupor, and coma associated with PCP and ketamine is extremely variable, although the manifestations are much milder and shorter acting following ketamine use.

Cholinergic and Anticholinergic Effects

Both cholinergic and anticholinergic clinical manifestations occur in the PCP- or ketamine-toxic patient. Miosis or mydriasis, blurred vision, profuse diaphoresis, hypersalivation, bronchospasm, bronchorrhea, and urinary retention may occur.^{13,19,127,141,142} Clinically, ketamine stimulates salivary and tracheobronchial secretions, both of which are equally and effectively inhibited by atropine and glycopyrolate.¹⁵² Furthermore, in a randomized, double-blind trial, after infusion of 1.5 mg/kg of ketamine in healthy volunteers, physostigmine decreased nystagmus, blurred vision, and the time to recovery. However, nausea and vomiting were more frequent.²¹¹

If it is necessary to confirm the suspicion of PCP usage, then urine is most commonly used as a matrix for analysis, although serum, and possibly gastric contents, can also be used. Rarely is it essential to make this determination. Most hospital laboratories do not perform quantitative analysis of PCP, but many can perform a qualitative urine test for the presence of the drug. Qualitative testing is more important than a quantitative determination as serum concentrations do not correlate closely with the clinical effects. PCP is qualitatively detected by an enzyme immunoassay at a sensitivity of 10 ng/mL. High-affinity antibodies were once studied as specific PCP antagonists to reverse PCP-induced toxicity.^167,213 Thus, the detection of PCP is dependent on the concentration of PCP in the body fluid tested and the affinity of the antibody for the PCP molecule. As such, the immunoassay antibody binding to a molecule similar to PCP can produce false-positive reactions. Metabolites of PCP, such as PCE, PHP, TCP, and its pyrrolizidine derivative TCPy, cross-react with the immunoassay at concentrations 30 times higher than those used to detect PCP. Because of its similar structure to PCP, dextromethorphan and its metabolite dextrorphan also cross-react with Syva enzyme-multiplied immunoassay and fluorescence polarization PCP assays (Chap. 6).^100,219

Although nonspecific, laboratory findings resulting from PCP use can include leukocytosis, hypoglycemia, and elevated concentrations of muscle enzymes, myoglobin, BUN, and creatinine.¹⁴² The EEG reveals diffuse slowing with θ and δ waves, which may return to normal before the patient improves clinically.

There is no commercially available quantitative immunoassay for ketamine. When necessary, ketamine is detected by gas chromatography/mass spectroscopy. The increase in popularity in ketamine use in certain parts of the world has led to the development of rapid-detection urine assays that are sensitive, specific, and accurate.^38,217 There is anecdotal evidence that ketamine also cross-reacts with the urine PCP immunoassay because of their structural similarity.¹⁸⁶ Other authors, including the manufacturer that tests the reactivity of the commercially available PCP immunoassay with ketamine, do not find such results.^33,220

Agitation

Conservative management is indicated for PCP and ketamine toxicity and includes maintaining adequate respiration, circulation, and thermoregulation. The psychobehavioral symptoms observed during acute dissociative reactions and during the emergence reaction are similar. To treat the symptoms of agitation and alteration of mental status of acutely toxic PCP patients, it is helpful to recognize that both pharmacologic^{2,34,41,44,68,82,83,135,140} and behavioral^43,44,83,121 modalities have been used to diminish agitation and emergence phenomena during conscious sedation with ketamine. To prevent self-injury, a common form of PCP-induced morbidity and mortality, the patient must be safely restrained, initially physically, and then chemically. An IV line should be inserted and blood drawn for electrolytes, glucose, BUN, and creatinine concentrations. The use of 0.5 to 1.0 g/kg of body weight of dextrose and 100 mg IV thiamine HCl should be considered as clinically indicated.

Although body temperature is directly affected by PCP and ketamine, hyperthermia may occur secondary to psychomotor agitation and should be rapidly identified. Treatment should be accomplished immediately with adequate sedation to control motor activity. At presentation, placing the patient in a quiet room with low sensory stimuli will help achieve this goal. Physical restraint should only be used temporarily, if necessary, until chemical sedation is achieved. Rapid immersion in an ice water bath may be necessary because body temperatures greater than 106°F (41.1°C) place the patient at a great risk for end-organ injury. These patients will need volume repletion and electrolyte supplementation because hyperthermia increases fluid loss from sweat.

In the pharmacologic treatment of emergence reactions, benzodiazepines have been used with great success. A benzodiazepine such as diazepam, administered in titrated doses of up to 10 mg intravenously every 5 to 10 minutes until agitation is controlled, is usually safe and effective. Numerous studies demonstrate the benefits of benzodiazepines, although under certain conditions^41,83 they may prolong recovery time. Midazolam may be more effective than diazepam under certain circumstances.^34,140 Additionally, in a double-blind placebo-controlled study, lorazepam reduced the anxiety associated with ketamine without antagonizing the cognitive or psychotomimetic effects of ketamine.¹¹⁹ By contrast, phenothiazines may lower the seizure threshold, and both phenothiazines and butyrophenones may cause acute dystonic reactions. Phenothiazines may also cause significant hypotension due to their α-adrenergic blocking effects on the vasculature, worsen hyperthermia, and exacerbate any anticholinergic effects from these drugs.

Some behavioral modalities have also been implemented in the treatment. Early studies demonstrated that the psychotomimetic effects of PCP were diminished when external stimulation was reduced by environmental sensory deprivation.⁴³ The practice of placing patients in a quiet room with minimal sensory stimulation is recommended by many, but has never been formally studied in a double-blind, controlled trial, nor is it functionally feasible in most clinical settings. Conversely, it is observed in patients undergoing ketamine anesthesia that emergence reactions are less violent when patients are talked to or when music is played.^121,192

Although it is always important to ask the patient the names, quantities, times, and route of all xenobiotics taken, the information obtained may be unreliable. Even when the patient is trying to cooperate and give an accurate history, many street psychoactive xenobiotics are mixtures whose contents are unknown to the patient. Consequently, pharmacologic management is complex and often sign or symptom dependent. Although some authors have attempted to define the appropriate therapy for specific PCP congeners and for ketamine-induced psychosis, no single approach has been consistently efficacious.^{77,78,118,136}

Cystitis

The objectives of the management of ketamine-induced cystitis are in mak­ing the diagnosis, decreasing symptoms and in maintaining kidney ­function. Urinalysis should be obtained on all symptomatic patients in order to exclude urinary tract infection and a serum creatinine should be ­obta­ined to evaluate kidney function. For patients whose symptoms are mild, abstinence from ketamine use may be sufficient to reverse symptoms and pathology. ­Several therapeutic regimens have been tried with little success. They include antibiotics, nonsteroidal antiinflammatory drugs (NSAIDs), steroids, anticholiner­gics. Urologic evaluation and follow-up will be necessary.¹⁴⁷

Moderate and severe symptoms of LUTS are defined as a daytime frequency of more than six, nighttime frequency of one or more than one, regular urgency on voiding, and moderate bladder or pelvic pain. For those patients with these symptoms, urologic consultation and repeated kidney function monitoring are essential. Ultrasonography and urography by CT assist in detecting lower and upper tract abnormalities. Urodynamic studies may further quantify bladder voiding capacity and detrusor activity. Invasive procedures may need to be undertaken in patients with impaired kidney function and deterioration. Cystoscopy will aid in visualizing the bladder and excluding other causes of hematuria and LUTS. During this procedure, a bladder biopsy may be performed. Injury to the upper urologic tract may be imaged with urography by CT Nephrostomy insertions may be necessary in patients who present with impaired kidney function secondary to ureteric narrowing. Refractory cases may need to undergo urinary diversion.^40,99,139

Decontamination

Patients with a history of recent oral use of PCP or ketamine are candidates for gastrointestinal decontamination. Although there is rarely, if ever, an indication for orogastric lavage, aggressive decontamination may be indicated if potentially lethal coingestants are suspected. Activated charcoal (1 g/kg) should be administered as soon as possible and may be repeated every 4 hours for several doses. Activated charcoal will effectively adsorb PCP and increase its nonrenal clearance; even without prior gastric evacuation this approach is usually adequate.¹⁷⁴

Theoretically, xenobiotics that are weak bases, such as PCP, can be eliminated more rapidly if the urine is acidified. Although urinary acidification with ammonium chloride was previously recommended,¹⁰ we do not recommend this approach. The risks associated with acidifying the urine—simultaneously inducing a systemic acidosis, thereby potentially increasing urinary myoglobin precipitation—outweigh any perceived ­benefits (Chap. 10).

As opposed to the problems in applying ion trapping to renal excretion, ion trapping results in the active mobilization of PCP into gastric secretions. PCP is in a substantially ionized (and therefore non–lipid-soluble) form in the acid of the stomach and can be absorbed only when it reaches the more alkaline intestine. As a result, gastric suction can remove a significant amount of the drug, as well as interrupt the gastroenteric circulation by which the xenobiotic is secreted into the acid environment of the stomach only to be reabsorbed again in the small intestine.¹⁰ However, continuous gastric suction is unnecessary and can also be dangerous. It should be considered only in comatose patients. Continuous suction may result in trauma to the patient as well as in fluid and electrolyte loss, which can further complicate management and possibly interfere with the efficacy of activated charcoal. For these reasons, the administration of single- or multiple-dose activated charcoal rather than continuous nasogastric suction appears to be the safest and most effective way of removing ion-trapped drug from the stomach in severely poisoned patients.

Most patients rapidly regain normal CNS function anywhere from 45 minutes to several hours after its use. However, those who have taken exceedingly high doses or who have an underlying psychiatric disorder may remain comatose or may exhibit bizarre behavior for days, or even weeks, before returning to normal. Those who rapidly regain normal function should be monitored for several hours and then, after a psychiatric consultation, should receive drug counseling and any additional social support available. Patients whose recovery is delayed should be treated supportively and monitored carefully in an intensive care unit.

Many patients become depressed and anxious during the “post-high” period, and chronic users may manifest a variety of psychiatric disturbances.²³⁰ These individuals typically present with repeated drug use, hospitalizations, and poor psychosocial functioning in the long term.

The major toxicity of PCP appears to be behaviorally related: self-inflicted injuries, injuries resulting from exceptional physical exertion, and injuries sustained as a result of resisting the application of physical restraints are frequent. Patients appear to be unaware of their surroundings and sometimes even oblivious to pain because of the dissociative anesthetic effects. In addition to major trauma, rhabdomyolysis and resultant myoglobinuric acute kidney injury account in large measure for the high morbidity and mortality associated with PCP intoxication. If significant rhabdomyolysis^42,170 has occurred, early fluid therapy should be used to avoid deposition of myoglobin to the kidneys. Urinary alkalinization as part of the treatment regimen for rhabdomyolysis would potentially increase PCP reabsorption and deposition in fat stores, but this is only theoretical.

Although the clinical experience with recreational use of ketamine is limited, toxic manifestations appear to be similar yet milder and shorter lived when compared with PCP. In a study of 20 patients who presented with acute ketamine toxicity, all were treated conservatively and successfully with intravenous hydration, and sedation with benzodiazepines.²²⁰

• PCP and ketamine produce an “out-of-body experience” with seemingly hallucinatory effects.

• The action of these xenobiotics is largely mediated by the NMDA receptor.

• The neuropsychiatric toxicity is managed by supportive care.

• The popularity of ketamine may be related to its lesser toxicity and milder distortion of the personality.

• A chronic effect of ketamine abuse is cystitis and bladder dysfunction.

References