The Journal of Emergency Medicine, Vol. 8, pp. 733-741, 1990 Printed in the USA * Copyright 0 1990 Pergamon Press plc

Toxicology

“DESIGNER DRUGS” - A CURRENT PERSPECTIVE

David A. Jerrard, MD

Division of Emergency Medicine, Department of Surgery, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Reprint address: David A. Jerrard, MD, Emergency Medicine, University of Maryland Medical System, 22 South Greene Street, Baltimore, MD 21201

0 Abstract - Since the late 197Os, in an effort to quench the ever burgeoning appetite for pharmacological sub- stances of abuse and to satiate their own need for profit, unscrupulous chemists have set up clandestine laboratories to produce and market new drugs for street sale. Using fairly common industrial chemicals, they have altered or modified preexisting controlled substances such as fenta- nyl, meperidlne, mescaline, amphetamine, and phencycli- dine, producing derivatives of these parent compounds that, up until 1986, were able to temporarily elude the guidelines of the Federal Controlled Substances Act due to their new and unique chemical structures. Unsuspecting users continue to use the drugs recreationally. This article will present a comprehensive review of these “Designer Drugs” looking at historical data, pharmacokinetics, treat- ment, abuse trends, and some of the more recent additions to the social pharmacopoeia.

0 Keywords - Designer drugs; clandestine laboratories; analogues; DEA; drug abuse

INTRODUCTION

The term “designer drug” was first coined in 1980 by a California pharmacologist to describe the private synthe- sis of drugs slightly different from parent compounds that, by design, render them temporarily immune from the control of the Drug Enforcement Agency (DEA) (1). The loophole was that until a drug was isolated, studied,

and scheduled, no laws could apply to it. Using well- known drugs such as fentanyl, phencyclidine, mesca- line, amphetamine, and meperidine as a nucleus, chemical manipulation has given birth to such drugs as 3,4- methylene dioxymethamphetamine (MDMA), l-methyl- 4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), and numer- ous phencyclidine and fentanyl derivatives (2). Emer- gency physicians have had to deal with overdoses and symptoms, the characteristics of which they may not have seen before. Until the derivatives underwent appro- priate chemical identification, analysis, and exhaustive testing, these drugs could be sold on the street without fear of prosecution (3). While this is no longer possible under the Controlled Substances Analogue (CSA) En- forcement Act of 1986, “designer drugs” continue to appear on the street and pose a serious health risk (4). Most recently, in the late fall of 1988, 18 people died as a result of a “China White” (fentanyl derivative) out- break in the city of Pittsburgh (5).

PHENCYCLIDINE

Illicit use of PCP (phencyclidine) begin in 1967 in the Haight Ashbury district of San Francisco, where it was known as the “peace pill.” By the late 197Os, coincid- ing with lay publications outlining simple inexpensive methods for the production of PCP, synthetic PCP analogues began to appear on the streets (6). For the

= Toxicology-one of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Ku@, MD, of the Rocky Mountain Poison Center.

RECEIVED: 4 December 1989; FINAL SUBMISSION RECEIVED: 7 May 1990; 0736-4679/90 $3.00 + .OO ACCEPTED: 17 May 1990

733

David A. Jerrard

most part, these analogues showed the same pharmaco- logical and physical properties of the parent compound and, in some instances, even enhanced toxicity (7,8). High doses or chronic use of PCP or its analogues may lead to the development of acute psychosis, hyperther- mia, rhabdomyolysis with secondary renal failure and respiratory depression. PCP or its analogues may be packaged in a liquid, crystal, paste, or paper form (9). Purity may run from 10% to a high of 80% to 100% found in angel dust (10). Presently, there have been over 30 analogues of PCP illicitly synthesized, including phenylcyclohexyl-pyrrolidine (PHP), ketamine, includ- ing 1-piperidinocyclohexane-carbonitrile (PCC), cyclo- hexamine (PCE) , and ( 1 -[ l -(2&ienyl)cyclohexyl]pi- peridine) (TCP) .

Smoking PCP-laden marijuana cigarettes, the most popular form of use, leads to roughly a 33% absorption rate. Heat degrades phencyclidine into 1 -phenylcyclo- hexane and piperidine (11). Oral bioavailability approx- imates 50% to 90% (12). Studies in hairless mice have suggested a percutaneous route of absorption (13). The half-life .of the drug is usually on the order of 21 hours, although half-lives of 11 and 51 hours, respectively, have been reported as well (14). Renal clearance of unchanged drug approaches 10% (12). Hydroxylation is the principal method of phencyclidine breakdown (15). Renal excretion of phencyclidine may be increased by 50% with urinary acidification (pH of 7.4 to 6.1) (16). Urine samples may remain positive for an average of 2 weeks after ingestion (17).

Initial emergency department diagnoses may include such diverse entities as intoxication, catatonia, head trauma, and heat stroke. Classically, PCP and its ana- logues have produced hyperthermia, marked elevations in blood pressure, nystagmus, psychological abnormal- ities, and seizure (18). Generalized tonic-clonic seizures may occur with mild (l-10 mg), moderate (5-20 mg) or high doses (100-1000 mg) (19). Systolic and diastolic elevations have approached 250 mmHg and 150 mmHg, respectively, and may be manifest to some degree in nearly 50% of users (9). Core temperatures have been recorded as high as 42 “C, although most elevations are mild (20). Nystagmus has been found to be present in one series 60% of the time (21). Minor psychological disturbances include euphoria, lethargy, agitation, and bizarre and violent behavior (21). Chronic use or high doses may lead to increased violence (22). Unlike minor psychological disturbances, major toxicity syndromes require hospitalization. Coma (lasting from 30 minutes to 7 days), catatonic syndrome, and acute toxic psycho- ses all merit hospitalization (21). Acute toxic psychosis includes distorted body images, disorganized thought patterns, and hallucinations in the presence of behav-

Table 1. Clinical Patterns of PCP lntoxlcatlon

Major Patterns Coma Catatonic syndrome Toxic psychosis Acute brain syndrome

Minor Patterns Lethargy/Stupor Bizarre behavior Violent behavior Agitation Euphoria Asymptomatic

Adaptation of McCarron M, Schulze &Thompson G, et al. Acute phencyc- lidine intoxication: clinical patterns, complications and treatment. Ann Emerg Med. 1991; 10291. Used with permission.

ioral abnormalities excluding catatonia (9). McCarron et al have proposed a classification system

for PCP intoxication to allow a more effective treatment in the emergency department and to make the decision regarding ultimate disposition more easily approachable. Table 1 reveals the differentiating features of major and minor patterns of PCP intoxication. Those patients exhibiting major patterns of toxicity can become violent and unpredictable at a moment’s notice and may exhibit medical complications such as cardiac arrest, hyperten- sion, and status epilepticus (21). Patients exhibiting a major pattern of toxicity should be chemically restrained with an initial dose of 5 to 10 mg of intramuscular (IM) haloperidol (23). Four-point restraints should be applied as well. Observation of these individuals for 24 hours or longer is a necessity since delayed intoxication has been reported (9). Those patients exhibiting minor patterns of toxicity are usually fully awake and neurologically normal 4 to 6 hours after ingestion (24). Violence may be manifested by these individuals as well and may be similarly controlled. Most often, for minor patterns, a quiet dark environment will suffice as a method to settle the agitated patient (9). These patients may be dis- charged after 4 hours of observation if they manifest no medical or psychiatric findings. Some reports elucidate a post PCP intoxication depression state and recommend close follow-up (25).

Individuals manifesting lethargy should receive D, and naloxone, as with any altered mental status patient. Patients experiencing seizures should receive intrave- nous diazepam (upwards of 20 mg in 5 mg increments) and be loaded with phenytoin (21,24). If hypertension persists (diastolic > 120 torr) despite settling of agita- tion, nifedipine (10 mg sublingual bite and swallow), and even nitroprusside may be considered if monitoring capabilities are readily available (9). Dystonic reactions to the ingested drug or to the haloperidol used to treat combativeness may be reversed with intravenous (IV) or lM diphenhydramine (25-50 mg) (26). Hyperthetmia

Designer Drugs 735

secondary to seizures or severe agitation may be con- trolled with ice, cooling blankets, fans, and control of the precipitating event (26). Comatose individuals should be intubated .

The most common medical complication of PCP intoxication, secondary to increased muscle activity as a result of combativeness, agitation, or seizures, is that of rhabdomyolysis and myoglobinuric renal failure (26). Occult hematuria with few or no red blood cells seen on magnification of spun urine and elevated creatine phos- phokinase (CPK) is diagnostic of rhabdomyolysis. Once volume depletion is corrected, a liter bag of D,W containing 25 g of mannitol and 100 mBq of sodium bicarbonate should be run at 250 cc/h. This should be continued until myoglobinuria disappears, assuming a flow rate of 40 cc/h. Hyperkalemia should be monitored for and hemodialysis strongly considered with worsen- ing renal function.

Ion trapping of PCP in an acidic environment has been touted as a method to enhance elimination. How- ever, urinary acidification has never been shown to lessen morbidity or mortality (21,26). Also, acidifica- tion increases precipitation of myoglobin in renal tu- bules , exacerbating myoglobinuric renal failure (9).

MEPERIDINE COGENERS (“DESIGNER DRUG” DISASTER)

Clinicians may recall an outbreak of “street demerol” use in 1982 in San Jose, California, with devastating consequences for many of the individuals who used it. MPTP ( 1 -methyl-4-phenyl- 1,2,5,6 tetrahydropyridine) is a commercially available compound that is sold as a chemical intermediate (27). A by-product of the mepe- ridine derivative, MPPP, MPTP was unknowingly pro- duced with MPPP (25 times as potent as demerol, 3 times as potent as morphine) during the “laboratory” synthesis and sold as “synthetic heroin,” resulting in several dozen individuals developing irreversible Par- kinsonism (28). A key link in the ultimate determination and isolation of the offending agent involved a graduate student who had synthesized his own MPPP in 1976 (29). After deciding to take “shortcuts” in the manu- facturing process (higher temperatures, shorter reaction times) and injecting the product that resulted, he soon developed Parkinsonian-like symptoms. After retracing his new synthetic method, it was felt he had concocted a mixture of MPPP and MPTP (30).

The clinical observation of this young individual revealed a strikingly similar picture to that of Parkin- son’s disease. The neuropathological process wasn’t fully realized until his death, by cocaine overdose, two

years after first synthesizing his own drugs. Autopsy revealed extensive destruction within the substantia ni- gra, confirming earlier notions of selective uptake in this portion of the brain (3 1). It is now felt that MPTP neurotoxicity is as a result of its conversion in the brain by monoamine oxidase B to 2,3 M MPDP+, which is further oxidized to MPP+ (32,33). MPP+ is a com- pound commercially marketed as an herbicide under the name of cyberquat (34). MPP+ and MPTP structurally resemble paraquat. This metabolite shows high dopa- minergic cytotoxicity in the pars compacta of the sub- stantia nigra (35,36).

The initial symptoms commonly included visual hal- lucinations and extremity jerking. Of particular note was the time lag before the onset of the remaining symp- toms. Generalized slowing and difficulty moving was experienced by all users from 4 to 14 days after initial drug use. In at least one individual, evolution of these symptoms continued for days. Examination of each of the hospitalized patients revealed “en bloc” turning, fixed stare, “pill-rolling,” bradykinesia, and lack of facial expression (37).

In January 1985, the Centers for Disease Control (CDC) and the National Institute of Drug Abuse began a large scale search for those individuals who may have been exposed to MPTP and MPPP. The study found over 400 exposures, with 50 of that number manifesting Parkinsonian symptoms to various degrees (38). As with the naturally occurring Parkinson’s disease, the MPTP- induced variety remains irreversible, although it can be tempered with such medications as Sinemet@ and bro- mocriptine. Pretreatment with nonspecific MAO inhibi- tors such as pargyline has completely prevented Parkin- sonism in primates exposed to MPTP (39).

FENTANYL DERIVATIVES

Fentanyl citrate is a safe, short-acting narcotic analgesic used in about 70% of all surgical procedures today (40). Pharmacologically, it is similar to morphine, although fentanyl is 150 times as potent (41). It has a number of legal derivatives that are used in human (sufentanil- cardiac surgery) and veterinary (carfentanil - capturing large wild animals) medicine. Since 1980, however, ten illicit analogues have been identified by the DEA (42). Marketed under exotic and alluring names that had been formerly reserved for high grade heroin, the sale of “ChinaWhite, ” “PersianWhite,” and “MexicanBrown” has been brisk. In the early part of the 198Os, it was felt that a number of alleged drug overdose fatalities in California were attributable to an unidentified drug as evidenced by a history of drug abuse and the presence of

736 David A. Jerrard

Table 2. Fentanyl Analogues

Analogue (Year of Appearance) Minimal lethal dosage

alpha-methyl fentanyl (1979) benzyl fentanyl (1982) p-fluoro fentanyl (1981) alpha-methyl acetyl fentanyl (1983) alpha-methyl acryl fentanyl (1983) 3-methyl fentanyl (1984)

3-methyl thienyl fentanyl (1985) thienyl fentanyl (1985) beta-hydroxy-thienyl fentanyl (1985) beta-hydroxy-(3-methyl)-thienyl

fentanyl (1985)

125 i4 unknown 250 pg unknown unknown a few pg (8000 x potency

morphine) unknown unknown unknown

unknown

Adapted from Henderson G. “Designer drugs”. J of Forensic Sci. 1988; 32589-72. Copyright ASTM. Used with permission.

needles still in the arms of some victims (43). Despite negative toxicological analysis of body fluids, a com- mon link was that drug dealers were supplying and overdose victims were buying “China White,” a name theretofore reserved for pure heroin emanating from the “Golden Triangle” of Burma, Laos, and Thailand (42). The drug was ultimately identified as alpha-methyl fentanyl by the DEA’s laboratory in McClean, Virginia (44). Though twice as potent as morphine, it was technically a new drug, not a restricted drug, and was, therefore, still legal. In 1982, it was placed in Schedule I (45). In 1984, 3 methyl-fentanyl was synthesized, having 6000 times the potency of morphine (cis isomer) (46). Street samples have been found to contain both isomers (47).

Since 1981, there have been over 100 deaths in California alone due to fentanyl and its analogues. According to Frank Sapienza, a chemist at DEA head- quarters in Washington, D.C., a $2000 investment in chemicals and glassware can be turned into a kilogram of 3-methyl fentanyl worth about $l,OOO,OOO,OOO (1 billion) on the street. As a result of the tremendous fiscal potential with “designer drugs,” the phenomenon is unlikely to be short-lived. As a result, emergency department physicians need to be well versed with respect to treatment of intoxication.

In addition to “China White,” 9 other known illicit fentanyl derivatives have been produced through the mid-1980s. Table 2 reveals the year of appearance of the analogue and the minimal lethal dosage (estimated).

The drug generally makes up less than 1% of the sample, with the majority being composed of lactose and mannitol. In some cases, the pseudonym is derived from the cutting agent, lactose turning brown when it is heated (ie, “Mexican Brown”). Depending on the purity of the substance and the amount of cutting agent of diluent, the “high” experienced is commensurate. As

of 1987, all deaths attributable to fentanyl analogues had occurred in California, with the exception of two in Portland, Oregon, one in Tempe, Arizona, and one in Reno, Nevada (42). During 1985 and 1986, two well- trained organic chemists were arrested for synthesizing 3-methyl-fentanyl in East Coast laboratories. In the late fall of 1988 in the city of Pittsburgh, 18 deaths were recorded as a result of a “China White” outbreak. Figure 1 reveals the geographical locations where known deaths attributable to fentanyl analogues have occurred.

The half-life of these derivatives is on the order of 10 minutes. Due to a high lipophilic nature, maximal CNS concentration is attained anywhere from 60 to 90 sec- onds after use of the drug. Half of the drug is excreted in the urine with the remainder appearing in the bile (51). Stoeckel and co-workers have found that fentanyl is excreted in the gastric juice, with reabsorption taking place in the alkaline environment of the small bowel (52). This mechanism has been cited as the possible explanation for some patients experiencing severe respi- ratory depression hours after their apparent recovery from anesthesia that included fentanyl (biphasic respira- tory depression) (53).

The “high” that results from fentanyl and its deriv- atives is often compared to heroin and can be achieved by sniffing, smoking, or by intravenous use with doses as little as 25 to 50 pg. Generally, onset is within one to two minutes. Many of the effects are less desirable and may include nausea, vomiting, and, with high doses, chest wall rigidity (54). Hemodynamically, hypotension and bradycardia may be seen (55). Respiratory depres- sion, which is dose dependent, may last for 30 min- utes (42).

Fentanyl derivatives have all the properties of opiates and opioids but are chemically unrelated, and they do not cross react with any of the reagents used in opiate screening tests. Similarly confounding and elusive to

Designer Drugs 737

Figure 1. Areas where known fentanyl analogue-related deaths have occurred.

most hospital screening tests are the small concentra- on the pu receptor (57). Upwards of 2 to 10 mg of

Orange County, California San Diego, California Portland, Oregon Tempe, Arizona Reno, Nevada Pittsburgh, Pennsylvania

tions of the drug that are usually found in body fluids, generally on the order of 1 to 10 ng/mL. Radioimmu- noassay has proven extremely helpful (42,56). The basic tenet of care still involves maintaining adequate vital signs via the ABCs or resuscitation. Secondly, the early and aggressive use of naloxone is mandated in a sus- petted narcotics overdose. Fentanyl works specifically

Narcan@ may be needed to compete at the opiate receptor and effect reversal (43). Natcan@ should be administered 2 mg at a time every 2 to 3 minutes until a response is noted (Ed Krenzelok, PharmD, Director of Pittsburgh Poison Center, personal communication). Early naloxone administration will give a clue as to opioid involvement. Impressive response to naloxone, despite

Table 3. Structurally Related Amphetamlne Hallucinogens

Common name

Amphetamine

DOM, STP

DOB

Chemical name Street terminology

B-(phenylisopropyl)amine

4-Methyl-2,5- dimethoxyamphetamine

4-Bromo-2,5- dimethoxyamphetamine

Bennies, speed

Serenity, tranquility

Golden eagle, tile, LSD- 25, MOA, common adulterant

Mescaline

Methamphetamine

MDA

PMA

MMDA

MDMA

Methylenedioxy- amphetamine

p-Methoxyamphetamine hydrochloride

SMethoxy-4,5- methylenedioxyamphetamine

3,CMethylene dioxymethamphetamine

Speed

Love pill, “speed for lovers”

Adam, ecstasy

Adapted from Bowen J, Davis G, Kerney T, et al. Diffuse vascular spasm associated with 4.Bromo-2,5-dimethoxy amphetamine ingestion. JAMA. 1993; 249:1479. Copyright 1993, American Medical Association. Used with permission.

738 David A. Jerrard

negative narcotic panel screens, may signify fentanyl analogue overdose. It is possible to precipitate narcotic withdrawal using such high doses of Natcan@‘; however, this is not felt to be life threatening. It is unknown whether any of the derivatives exhibit a biphasic respi- ratory depression pattern that has been seen with fenta- nyl. If suspicion warrants, continued observation in the emergency department for a number of hours after presentation is merited, since elimination of the drug may lead to fluctuating serum concentrations.

AMPHETAMINE DERIVATIVES

Amphetamine derivatives have also experienced wide- spread illicit production and abuse. Most recently, MDMA, methamphetamine (smokeable) and, to a lesser extent, MDEA, have supplanted earlier hallucinogenic amphetamines. Table 3 lists a number of structurally related amphetaminemescaline hallucinogens (3,4). Methylenedioxymethamphetamine, also known as MDMA, XTC, Adam, and Ecstasy, is a ring substituted metham- phetamine derivative that is chemically related to am- phetamines and hallucinogens (mescaline) (58). It was used as an adjunct to psychotherapy in the 1970s and 1980s by a few psychiatrists in the Santa Fe and New England areas (59). According to these psychiatrists, therapeutic communication is enhanced and propagated as patients “gain insight into themselves” without psy- chotic or visual disturbances (60,61). In the mid-1980s, it has been used primarily as a drug of abuse or recreation by college age students who pay $10 to $40 for a 100 mg dose (62). An informal 1987 study at Stanford University gave strong evidence for nearly 40% of its undergraduate population as having tried or experimented with MDMA (63). The increasing recre- ational use of this drug is of importance because of its neurotoxic effects in rats and nonhuman primates and some human deaths attributed to its use (64-67).

MDMA had been on the scene nearly 40 years (first marketed as an appetite suppressant in the early part of the century) before the first thorough study of its toxicity and pharmacology was conducted at the University of Michigan in 1953-1954 under the financial auspices of the Army Chemical Center (investigated as a psy- chotoxic drug). Not until 1973 were the results pub- lished, 4 years after declassification. In these studies, using 5 species from mice to monkeys, MDMA proved to be less toxic than MDA but more so than mescaline (68). MDMA has a duration of action of 4 to 6 hours (69). Excretion is primarily renal, with metabolites and unchanged drug appearing in the urine within 24 hours.

The effects are primarily sympathomimetic in nature. The majority of acute or chronic users state that the

effects, initially at least, are pleasurable. Users usually progress through three stages, beginning with disorien- tation, moving onto tingling and spasmodic jerking, and ending with “happy sociability” (70). Psychiatrists feel that communication is enhanced and anxiety and de- fenses are eliminated with patients in their clinical practice (69,70). Some of the less desirable effects are bruxism, jaw clenching, and myalgias. Confusion, de- pression, and anxiety have been reported by some users for several weeks after a single dose (71). High doses have contributed to dysphoria, paranoia, and rarely, hallucinations (72). There is also a “hangover” phe- nomenon causing students to skip use the night before an examination (59).

Illicitly produced methamphetamine, the N-methyl homologue of amphetamine, is the newest “designer drug” on the street, Known as “ice,” “crank,” “zip,” or “&sty” on the street, it appears to be methamphet- amine freebase or methamphetamine hydrochloride upon analysis (73). The current surge of methamphetamine use appears to have begun in Japan in the middle 1980s. Currently, Hawaii and California are experiencing the most illicit use in the United States (Office of Substance Abuse Studies, School of Pharmacy at University of Maryland at Baltimore, personal communication). Legal methamphetamine takes on the appearance of a white, odorless, crystalline powder. Therapeutic uses of methamphetamine include hyperactivity in children and obesity. Trade names of the legal drug include Meth- edrine@ (Burroughs Wellcome), Methampexe (Lem- mon) and Desoxyne (Abbott) (73). Illegally, the drug resembles crystals or chunks. Whereas the illegal methamphetamine prior to 3 or 4 years ago was of a racemic nature, methods to isolate the o-isomer have been perfected (Office of Substance Abuse Studies, School of Pharmacy at University of Maryland at Balti- more, personal communication). “Ice” users tend to be more combative and to experience more dysphoria than other amphetamine users and this is felt to be due to the predominance of the o-isomer (74) (Howard McKinney, Toxicologist, San Francisco, Bay Area Regional Poison Center, personal communication). Methamphetamine has a powerful central nervous system (CNS) stimulant action, which some describe as similar to an intense orgasm. Side effects may include nervousness, irritabil- ity, hypertension, and palpitations (73). The “high” lasts anywhere from 8 to 24 hours (74). Chronic methamphetamine usage in rhesus monkeys has led to decreased serotonin and dopamine in caudate and other brain regions (75).

N-demethylation of methamphetamine produces the active metabolite amphetamine. Within 24 hours, the kidney excretes about 45% of the drug unchanged, 15% as p-hydroxy methamphetamine, and 7% as amphet-

Designer Drugs 739

amine (76). With a pKa of 9.4, metabolism and renal excretion are urine pH dependent and similar to amphet- amine (77).

Table 3 lists a number of amphetamine/mescaline- related hallucinogens that have been illicitly synthe- sized.

Changes in behavior associated with amphetamine (analogue) use can run the gamut from mild agitation to a full-blown amphetamine psychosis (paranoid delu- sions, hallucinations). Due to the sympathomimetic effects of amphetamine and its analogues, a fatal hyper- pyrexic syndrome may be seen, characterized by hyper- thermia, coma, seizures, hyperpyrexia, hypertension, and mydriasis (78). Simultaneous ingestion of amphet- amines with MAO inhibitors has also been noted to produce marked hypertension (79). Leukemoid reac- tions, DIC (especially in association with rhabdomyoly- sis and hyperpyrexia), and azotemia have been reported after large acute ingestions of amphetamines and injec- tions of methamphetamine (80,81). Rhabdomyolysis with consequent myoglobinuria, though rare, may de- velop after large oral or parenteral doses of amphet- amines and analogues associated with severe agitation or seizures. Laboratory changes include elevated serum muscle enzymes (creatine kinase aldolase), hyperkale- mia, myoglobinuria, hyperphosphatemia, hyperurice- mia, hypokalemia, and hypocalcemia. Acute renal failure may develop secondary to acute tubular necrosis (ATN) hypotension , or rhabdomyolysis . Premature ventricular contractions (PVCs) are quite common in overdose situations. Hypotension, refractory to treatment, has been described as well (77). Atria1 and ventricular dysrhythmias have been documented as a result of amphetamine toxicity (82,83). Crystal methamphetamine has also been noted to cause acute pulmonary edema (84). Choreoathetoid movement disorders have also been seen after use of amphetamine like drugs (85).

With no specific antidote available for amphetamine overdose, supportive care is the key. Efforts to empty the stomach 4 hours after ingestion are probably not efficacious despite upwards of a 40% delay in gastric emptying induced by amphetamines. Activated charcoal may be used to effect absorption. Diazepam, 5 mg initially, may be used to treat mild agitation. Haloperi-

do1 in an initial dose of 2-5 mg may be used to treat moderate and severe agitation. Some studies suggest that both diazepam and haloperidol work equally as well in controlling agitation (86). However, Derlet et al suggest that in rats haloperidol alone or in combination with propranolol goes much further to reduce the inci- dence of amphetamine-induced death than does diaz- epam (87,88). Reassurance and a calm environment can be helpful as well in settling the agitated patient. Fulminating amphetamine psychosis (chronic users) re- quire hospitalization since suicidal ideation is prominent during withdrawal (77). The toxicity in overdose situa- tions is short lived (“ice” users are experiencing longer periods of toxicity), although hypertension, hyperther- mia, and seizures may need to be dealt with at some point during the “cool down” period (89). Hyperten- sion may be controlled with sodium nitroprusside (S-8 mg/kg/min) (7790). Hyperthermia, with a core temper- ature of 42°C being a poor prognostic indicator, needs to be treated aggressively with the standard measures. Seizures can be treated with Valium. Phenytoin, 18 mg/kg, or 1 g total load, can be used for refractory seizures. Acute renal failure and any consequent electro- lyte abnormalities may require hemodialysis. Rhabdo- myolysis may be treated with urinary alkalinization and diuresis. Repeat physical examinations are vital to as- sess for these complications as well as for intracranial bleeds and the development of ARDS. Elimination enhancement or ion-trapping through urinary acidifica- tion remains controversial and is absolutely contraindi- cated in the presence of rhabdomyolysis and myo- globinuria (77).

SUMMARY

Designer drugs result from the synthesis of derivatives of present compounds. They represent an important source of “street” drugs and pose a serious health risk.

Acknowledgmenr - The author wishes to acknowledge Dr. Edward Krenzelok, Phartn.D., Director of Pittsburgh Poison Center, for his careful review of the article.

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