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Amphetamines
Amobarbital see Barbiturates
Amphetamines EM Pallasch, Illinois Poison Center, Chicago, IL, USA M Wahl, Illinois Poison Center, Chicago, IL, USA and Northshore University Healthsystems, Evanston, IL, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Michael Wahl, volume 1, pp 108–109, Ó 2005, Elsevier Inc. l l l
l l l
Name: Amphetamines Chemical Abstracts Service Registry Number: 300-62-9 Synonyms: Phenethylamine; racemic b-phenylisopropylamine (Figure 1). Phenethylamines are a large group of structurally similar agents that includes the amphetamines, hallucinogenic tryptamines, and the cathinones. Amphetamines and cathinones have similar activities, but are technically subsets of phenethylamines. Slang terms for this group of stimulants include uppers, meth, speed, ice, dexies, and crank. Chemical/Pharmaceutical/Other Class: Central nervous system stimulant Molecular Formula: C9H13N Chemical Structure:
History The first amphetamine was originally developed in 1887 by Edeleano, a Romanian chemist working in Germany. It became available in the form of an inhaler for use as a nasal decongestant under the name Benzedrine in the 1930s. It was marketed for the treatment of narcolepsy and appetite suppression and was also used off-label for schizophrenia, morphine addiction, alcoholism, and behavioral issues in children. In the 1940s, methamphetamine and amphetamine were used by soldiers during World War II to fight combat fatigue and amphetamine is currently permitted for use to promote wakefulness in battle. Amphetamines were readily available over the counter and by prescription until the dangers of use, abuse, and addiction such as palpitations, convulsions, and psychosis were recognized. The drug was classified as a schedule II substance under the federal Controlled Substances Act in 1970. Amphetamines
Figure 1 Structures of methamphetamine and selected other psychostimulants. Source: Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J.T., Haggerty, D.A. 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Disease-a-Month 58 (2), 33–92.
212
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00692-8
Amphetamines
remained a popular drug of abuse leading to illegal production and criminal activity. Motorcycle gangs would conceal methamphetamine in the crankcases of their bikes, leading to the popular slang term ‘crank.’ Methamphetamine abuse resurged in the 1980s and 1990s along with ‘designer drugs’ such as methylenedioxymethamphetamine (MDMA). These drugs were popularized in clubs and ‘rave’ parties, prompting the Methamphetamine Control Act of 1996. In 2005 a federal law was enacted to regulate the sale of the precursors of methamphetamine (pseudoephedrine, ephedrine). The law limits the purchaser to a maximum of 3.6 g of pseudoephedrine per day and requires identification and the signature of the purchaser at the pharmacy counter. Newer designer drugs known as ‘bath salts’ comprised of amphetamine-like chemicals, cathinone derivatives (e.g., methylenedioxypyrovalerone and mephedrone) are emerging drugs of abuse prompting lawmakers to create and amend regulations prohibiting the manufacture and sale of these amphetamine-like compounds.
Uses Amphetamines are advocated for use in a wide variety of conditions but are medically approved for the treatment of attention-deficit hyperactivity disorder, narcolepsy, and weight loss. Amphetamines are also popular drugs of abuse available in several forms for different routes of abuse.
Environmental Fate and Behavior Physicochemical Properties Amphetamine is a clear to colorless liquid in freebase or white crystalline substance as a salt. As a liquid it slowly volatilizes and has a characteristic amine odor. Amphetamine base is slightly soluble in water, soluble in alcohol and ether. The melting point of amphetamine is 300 C with some decomposition occurring.
Exposure Routes and Pathways Amphetamines are most commonly administered orally when prescribed. Certain amphetamines of abuse (i.e., methamphetamine) are injected, smoked, or snorted (insufflations) as well. Exposure to methamphetamine can occur through environmental contamination as well and children and other individuals on-site at a methamphetamine production center (including a ‘mom-and-pop’ lab in a house) can be exposed through the environment at a clandestine lab. In fact 15% of children simply around individuals who use methamphetamine will test positive for the drug and nearly 100% of children in a clandestine lab environment will have methamphetamine detectable in their system. Therapeutic dosing for amphetamine ranges from 5 to 60 mg per day in adults and 5–40 mg per day in children of 6 years of age and older. Peak plasma concentrations are dependent on the route of exposure. Absorption from the gastrointestinal tract is rapid producing peak concentrations in approximately 2–3 h vs 30 min when used intravenously or intramuscularly. Delayed
213
release preparations will take longer time to reach peak concentrations. Absorption into the lungs via smoking reaches the brain within 7 s. More than 50% of a dose undergoes hepatic metabolism, and about 30% is excreted unchanged in urine. The amount of nonmetabolized drug recovered in urine is greater with acidic urine. The half-life ranges from 8 to 30 h.
Toxicokinetics Amphetamines are generally well absorbed from the gastrointestinal tract in therapeutic doses. Several commercially available amphetamines are formulated as sustained or delayed release products. Peak steadystate serum levels are expected within 30 min after intravenous injection and within 2–3 h after ingestion of immediate release products. In overdose and with exposure to sustained release products, delays in absorption are expected. Amphetamines have a volume of distribution of approximately 3–5 l kg 1 with low protein binding. These agents are extensively metabolized through hepatic and renal pathways via cytochrome P450 enzymes. Cytochrome CYP2D6 may be responsible for some amphetamine-related drug toxicity. Substrate competition or inhibition at this metabolic site may increase the half-life of amphetamines. Many metabolites have amphetamine activity. Elimination can vary greatly. Some amphetamines have primary renal elimination with the rate of elimination depending upon the urine pH (e.g., amphetamine). With others, less than 1% of the parent compound is renally excreted (e.g., methylphenidate). Halflives vary as well with intravenous methylphenidate at 1–2 h and chlorphentermine at 5 days.
Mechanism of Toxicity Amphetamines are indirect acting sympathomimetics, producing their effects by inhibiting the transporters of dopamine, norepinephrine, and serotonin at the presynaptic nerve terminal (Figure 2). This increases the release of norepinephrine, dopamine, and serotonin and increased norepinephrine levels at central synapses, which further stimulates alpha and beta receptors. Some amphetamines also inhibit monoamine oxidase, preventing the breakdown of catecholamines. These mechanisms combine to produce the sympathomimetic and central nervous system (CNS) effects seen with amphetamine abuse.
Acute and Short-Term Toxicity (or Exposure) Animal Amphetamine toxicity in animals manifests itself in a similar way as humans. Expected signs and symptoms include hypertension, tachycardia, seizures, coma, and hyperthermia. Rhabdomyolysis may also result and leads to renal failure if not treated aggressively.
Human Toxicity in humans will follow the expected sympathomimetic toxidrome. CNS effects include hypervigilance, agitation,
214
Amphetamines
Figure 2 Mechanism of action of methamphetamine on dopamine neurotransmission. MA, methamphetamine; DA, dopamine; DAT, dopamine transporter; VMAT, vesicular monoamine transporter-2. Source: Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J.T., Haggerty, D.A. 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Disease-a-Month 58 (2), 33–92.
restlessness, decreased appetite, irritability, stereotyped repetitive behavior, and insomnia with low doses. Patients may develop psychosis due to dopaminergic effects. With larger exposures, confusion, panic reactions, aggressive behavior, hallucinations, seizures, delirium, coma, and death can occur. Intracranial bleeding can result from untreated hypertension. Trauma is common secondary to behavior changes and impaired judgment. Frequent use results in fatigue, paranoia, and depression. Cardiovascular effects include tachycardia, hypertension, chest pain, myocardial ischemia or infarction, dysrhythmias, cardiovascular collapse, and death. Other effects include rhabdomyolysis, increased respiratory rate, flushing, diaphoresis, and dilated pupils. Hyperthermia may lead to multisystem organ failure. Serotonin syndrome is also possible in overdose of certain amphetamines alone or in combination with other serotonergic agents. Symptoms include altered mental status, hyperthermia, rigidity, and autonomic instability.
has been no increased carcinogenic activity in rats and mice fed varying doses of amphetamine over studies as long as 2 years.
Chronic Toxicity (or Exposure)
Reproductive Toxicity
Animal Animal models describe changes in behavior with toxicity and withdrawal. Chronic dosing of animals leads to stereotypic, compulsive behaviors of searching and examining in higher animals, sniffing and biting movements in lower animals. There
Human Chronic use may result in paranoia, psychosis, bruxism, compulsive behavior, and cardiomyopathy. Acute withdrawal may lead to headache, anxiety, and depression.
In Vitro Toxicity Data Several amphetamines have been shown to have monaminergic neurotoxic properties. Recent studies of PC12 dopaminergic cells have shown increased activity of capsase-3 and mitochondrial cytochrome c release. These findings suggest that amphetamines (particularly substituted amphetamines) may induce apoptosis, possibly via a mitochondrial pathway.
Amphetamines do not appear to cause congenital abnormalities when taken during pregnancy; however, intrauterine growth retardation, premature delivery, and maternal and fetal morbidity is significantly increased when abuse of amphetamines occurs during pregnancy. A mild withdrawal syndrome has also
Amphetamines
been reported after delivery with amphetamine use during pregnancy. Most studies of long-term follow-up of children exposed to amphetamines during pregnancy have found no significant chronic behavioral changes. Adverse effects in utero to the vasoconstrictive effects of amphetamines have been reported including cerebral injury. Poor outcomes occurring during amphetamine exposure during pregnancy may also be due to factors other than the drug itself including multiple drug use, poor maternal health, socioeconomic factors, and other lifestyle variables.
215
Exposure Standards and Guidelines Amphetamine is a Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) hazardous substance and subjects to the release reporting requirement of CERCLA section 103, 40 CFR parts 302 and 355. It is an extremely hazardous substance and subjects to reporting requirements when stored in amounts of 1000 lbs or greater (the threshold planning quantity).
Miscellaneous Genotoxicity
Drug Screening
Amphetamines are not thought to be mutagenic.
Qualitative tests such as immunoassays may have false positive results for products containing ephedrine and pseudoephedrine. Other substances, such as labetalol and ranitidine, may cross-react with antiamphetamine antibodies, giving a false positive test result as well. Selegiline, a selective monoamine oxidase inhibitor type B, is partially metabolized to amphetamine and thus will give a positive result by most analytical methods. Additionally some newer designer drugs such as MDMA may not react with antiamphetamine antibodies and will result in a negative test. Limitations such as these may make clinical interpretations more difficult and imprecise. A confirmatory test, such as gas chromatography– mass spectrometry, offers greater specificity and sensitivity and may be the best choice in avoiding false positives and false negatives.
Carcinogenicity Amphetamines are not carcinogenic in humans. Some amphetamines have been shown to have beneficial effects in the treatment of certain cancers, in particular hematologic malignancies.
Clinical Management After assessment of airway, breathing, and circulation with necessary supportive care, decontamination of the gastrointestinal tract should be undertaken for substantial recent ingestions. If patients present within an hour of ingestion or have taken a modified release product, consider activated charcoal; a 10:1 ratio of activated charcoal per gram of ingested substance may be administered to patients who are awake and alert and can protect their airway. Gastric lavage may be recommended in potentially life-threatening ingestions that present within 60 min of ingestion. Determination of specific toxic doses is difficult in chronic users of amphetamines due to the development of tolerance. Oxygen and benzodiazepines should be administered as needed for agitation, shortness of breath, or chest pain. Increased blood pressure can be managed with benzodiazepines. Although vasodilators such as nitroprusside have been recommended, reflex tachycardia is a common result. Beta blockers are not recommended for use in overdose due to possible unopposed alpha adrenergic effects, which may lead to exacerbation of symptoms, i.e., worsening hypertension. Benzodiazepines may be necessary for agitated or combative patients. Benzodiazepines, cooling, and rehydration are standard treatments for patients with increased temperature and rhabdomyolysis. Hyperthermia is a poor prognostic sign and should be aggressively treated.
Clinical Management and Suggested Diagnostic Tests Electrolytes, urinalysis, complete blood count, urine toxicology screen, creatine kinase, and cardiac enzymes are helpful laboratory tests for evaluation. In patients with severe toxicity monitor arterial blood gas (ABG), liver function tests, coagulation studies and disseminated intravascular coagulation panel.
See also: Drugs of Abuse; Benzodiazepines; Methylenedioxymethamphetamine; Poisoning Emergencies in Humans.
Further Reading Baselt, R.C., 2002. Disposition of Toxic Drugs and Chemicals in Man, sixth ed. Biomedical Publications, Foster City, CA. 64–66. Biaggioni, I., Robertson, D., 2009. Adrenoceptor agonists & sympathomimetic drugs (Chapter 9). In: Katzung, B., Masters, S.B., Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, eleventh ed. McGraw-Hill (Access Medicine). Blanckaert, P., van Amsterdam, J., Brunt, T., van den Berg, J., Van Durme, F., Maudens, K., Van Bussel, J., 2013. 4-methyl-amphetamine: a health threat for recreational amphetamine users. J. Psychopharmacol. 27 (9), 817–822. Chiang, W., 2010. Amphetamines. In: Flomenbaum, et al. (Eds.), Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill, New York, NY, pp. 1078–1090. German, C.L., Fleckenstein, A.E., Hanson, G.R., 2013. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci.. S0024-3205(13) 00424–4. Kraemer, T., Maurer, H.H., 2002. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine and their N-alkyl derivatives. Ther. Drug Monit. 24 (2), 277–289. McCann, U.D., Ricaurte, G.A., 2004. Amphetamine neurotoxicity: accomplishments and remaining challenges. Neurosci. Biobehav. Rev. 27, 821–826. POISINDEX® System: Amphetamines. Klasco, R.K. (Ed.), POISINDEX® System. Thomson Reuters, Greenwood Village. Colorado Edition Expires (04/2012). Prosser, J.M., Nelson, L.S., 2012. The toxicology of bath salts: a review of synthetic cathinones. J. Med. Toxicol. 8 (1), 33–42. Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J., Haggerty, D.A., 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Dis. Mon. 58 (2), 33–92.
216
Amphetamines
Relevant Websites http://emedicine.medscape.com/article/812518-overview – Amphetamine toxicity – Medscape reference an online resource on diagnosis, mechanism of toxicity, clinical management and treatment of amphetamine toxicity. http://health.utah.gov/meth/index.html – Utah Department of Health Methamphetamine. http://www.drugabuse.gov/sites/default/files/drugfacts_bath_salts_final_0_1.pdf – National Institute on Drug Abuse (NIDA) information on bath salts (cathinones).
http://www.aiha.org/aihce06/handouts/po118vandyke.pdf – National Jewish Medical Center power point resource on methamphetamine particle size and persistence after methamphetamine cook. http://www.dtsc.ca.gov/SiteCleanup/ERP/upload/OEHHA_Memo-Nov2007.pdf – Office of Environmental Health Hazard Assessment for children’s exposure to methamphetamine surface residue in use and clandestine laboratory environment. www.erowid.org/ – Online resource for intoxicating plants and drugs – information and resources including journal articles, timelines, media, prohibition sites, harm reduction, subjective user reports and chemical information.
Amphetamines EM Pallasch, Illinois Poison Center, Chicago, IL, USA M Wahl, Illinois Poison Center, Chicago, IL, USA and Northshore University Healthsystems, Evanston, IL, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Michael Wahl, volume 1, pp 108–109, Ó 2005, Elsevier Inc. l l l
l l l
Name: Amphetamines Chemical Abstracts Service Registry Number: 300-62-9 Synonyms: Phenethylamine; racemic b-phenylisopropylamine (Figure 1). Phenethylamines are a large group of structurally similar agents that includes the amphetamines, hallucinogenic tryptamines, and the cathinones. Amphetamines and cathinones have similar activities, but are technically subsets of phenethylamines. Slang terms for this group of stimulants include uppers, meth, speed, ice, dexies, and crank. Chemical/Pharmaceutical/Other Class: Central nervous system stimulant Molecular Formula: C9H13N Chemical Structure:
History The first amphetamine was originally developed in 1887 by Edeleano, a Romanian chemist working in Germany. It became available in the form of an inhaler for use as a nasal decongestant under the name Benzedrine in the 1930s. It was marketed for the treatment of narcolepsy and appetite suppression and was also used off-label for schizophrenia, morphine addiction, alcoholism, and behavioral issues in children. In the 1940s, methamphetamine and amphetamine were used by soldiers during World War II to fight combat fatigue and amphetamine is currently permitted for use to promote wakefulness in battle. Amphetamines were readily available over the counter and by prescription until the dangers of use, abuse, and addiction such as palpitations, convulsions, and psychosis were recognized. The drug was classified as a schedule II substance under the federal Controlled Substances Act in 1970. Amphetamines
Figure 1 Structures of methamphetamine and selected other psychostimulants. Source: Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J.T., Haggerty, D.A. 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Disease-a-Month 58 (2), 33–92.
212
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00692-8
Amphetamines
remained a popular drug of abuse leading to illegal production and criminal activity. Motorcycle gangs would conceal methamphetamine in the crankcases of their bikes, leading to the popular slang term ‘crank.’ Methamphetamine abuse resurged in the 1980s and 1990s along with ‘designer drugs’ such as methylenedioxymethamphetamine (MDMA). These drugs were popularized in clubs and ‘rave’ parties, prompting the Methamphetamine Control Act of 1996. In 2005 a federal law was enacted to regulate the sale of the precursors of methamphetamine (pseudoephedrine, ephedrine). The law limits the purchaser to a maximum of 3.6 g of pseudoephedrine per day and requires identification and the signature of the purchaser at the pharmacy counter. Newer designer drugs known as ‘bath salts’ comprised of amphetamine-like chemicals, cathinone derivatives (e.g., methylenedioxypyrovalerone and mephedrone) are emerging drugs of abuse prompting lawmakers to create and amend regulations prohibiting the manufacture and sale of these amphetamine-like compounds.
Uses Amphetamines are advocated for use in a wide variety of conditions but are medically approved for the treatment of attention-deficit hyperactivity disorder, narcolepsy, and weight loss. Amphetamines are also popular drugs of abuse available in several forms for different routes of abuse.
Environmental Fate and Behavior Physicochemical Properties Amphetamine is a clear to colorless liquid in freebase or white crystalline substance as a salt. As a liquid it slowly volatilizes and has a characteristic amine odor. Amphetamine base is slightly soluble in water, soluble in alcohol and ether. The melting point of amphetamine is 300 C with some decomposition occurring.
Exposure Routes and Pathways Amphetamines are most commonly administered orally when prescribed. Certain amphetamines of abuse (i.e., methamphetamine) are injected, smoked, or snorted (insufflations) as well. Exposure to methamphetamine can occur through environmental contamination as well and children and other individuals on-site at a methamphetamine production center (including a ‘mom-and-pop’ lab in a house) can be exposed through the environment at a clandestine lab. In fact 15% of children simply around individuals who use methamphetamine will test positive for the drug and nearly 100% of children in a clandestine lab environment will have methamphetamine detectable in their system. Therapeutic dosing for amphetamine ranges from 5 to 60 mg per day in adults and 5–40 mg per day in children of 6 years of age and older. Peak plasma concentrations are dependent on the route of exposure. Absorption from the gastrointestinal tract is rapid producing peak concentrations in approximately 2–3 h vs 30 min when used intravenously or intramuscularly. Delayed
213
release preparations will take longer time to reach peak concentrations. Absorption into the lungs via smoking reaches the brain within 7 s. More than 50% of a dose undergoes hepatic metabolism, and about 30% is excreted unchanged in urine. The amount of nonmetabolized drug recovered in urine is greater with acidic urine. The half-life ranges from 8 to 30 h.
Toxicokinetics Amphetamines are generally well absorbed from the gastrointestinal tract in therapeutic doses. Several commercially available amphetamines are formulated as sustained or delayed release products. Peak steadystate serum levels are expected within 30 min after intravenous injection and within 2–3 h after ingestion of immediate release products. In overdose and with exposure to sustained release products, delays in absorption are expected. Amphetamines have a volume of distribution of approximately 3–5 l kg 1 with low protein binding. These agents are extensively metabolized through hepatic and renal pathways via cytochrome P450 enzymes. Cytochrome CYP2D6 may be responsible for some amphetamine-related drug toxicity. Substrate competition or inhibition at this metabolic site may increase the half-life of amphetamines. Many metabolites have amphetamine activity. Elimination can vary greatly. Some amphetamines have primary renal elimination with the rate of elimination depending upon the urine pH (e.g., amphetamine). With others, less than 1% of the parent compound is renally excreted (e.g., methylphenidate). Halflives vary as well with intravenous methylphenidate at 1–2 h and chlorphentermine at 5 days.
Mechanism of Toxicity Amphetamines are indirect acting sympathomimetics, producing their effects by inhibiting the transporters of dopamine, norepinephrine, and serotonin at the presynaptic nerve terminal (Figure 2). This increases the release of norepinephrine, dopamine, and serotonin and increased norepinephrine levels at central synapses, which further stimulates alpha and beta receptors. Some amphetamines also inhibit monoamine oxidase, preventing the breakdown of catecholamines. These mechanisms combine to produce the sympathomimetic and central nervous system (CNS) effects seen with amphetamine abuse.
Acute and Short-Term Toxicity (or Exposure) Animal Amphetamine toxicity in animals manifests itself in a similar way as humans. Expected signs and symptoms include hypertension, tachycardia, seizures, coma, and hyperthermia. Rhabdomyolysis may also result and leads to renal failure if not treated aggressively.
Human Toxicity in humans will follow the expected sympathomimetic toxidrome. CNS effects include hypervigilance, agitation,
214
Amphetamines
Figure 2 Mechanism of action of methamphetamine on dopamine neurotransmission. MA, methamphetamine; DA, dopamine; DAT, dopamine transporter; VMAT, vesicular monoamine transporter-2. Source: Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J.T., Haggerty, D.A. 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Disease-a-Month 58 (2), 33–92.
restlessness, decreased appetite, irritability, stereotyped repetitive behavior, and insomnia with low doses. Patients may develop psychosis due to dopaminergic effects. With larger exposures, confusion, panic reactions, aggressive behavior, hallucinations, seizures, delirium, coma, and death can occur. Intracranial bleeding can result from untreated hypertension. Trauma is common secondary to behavior changes and impaired judgment. Frequent use results in fatigue, paranoia, and depression. Cardiovascular effects include tachycardia, hypertension, chest pain, myocardial ischemia or infarction, dysrhythmias, cardiovascular collapse, and death. Other effects include rhabdomyolysis, increased respiratory rate, flushing, diaphoresis, and dilated pupils. Hyperthermia may lead to multisystem organ failure. Serotonin syndrome is also possible in overdose of certain amphetamines alone or in combination with other serotonergic agents. Symptoms include altered mental status, hyperthermia, rigidity, and autonomic instability.
has been no increased carcinogenic activity in rats and mice fed varying doses of amphetamine over studies as long as 2 years.
Chronic Toxicity (or Exposure)
Reproductive Toxicity
Animal Animal models describe changes in behavior with toxicity and withdrawal. Chronic dosing of animals leads to stereotypic, compulsive behaviors of searching and examining in higher animals, sniffing and biting movements in lower animals. There
Human Chronic use may result in paranoia, psychosis, bruxism, compulsive behavior, and cardiomyopathy. Acute withdrawal may lead to headache, anxiety, and depression.
In Vitro Toxicity Data Several amphetamines have been shown to have monaminergic neurotoxic properties. Recent studies of PC12 dopaminergic cells have shown increased activity of capsase-3 and mitochondrial cytochrome c release. These findings suggest that amphetamines (particularly substituted amphetamines) may induce apoptosis, possibly via a mitochondrial pathway.
Amphetamines do not appear to cause congenital abnormalities when taken during pregnancy; however, intrauterine growth retardation, premature delivery, and maternal and fetal morbidity is significantly increased when abuse of amphetamines occurs during pregnancy. A mild withdrawal syndrome has also
Amphetamines
been reported after delivery with amphetamine use during pregnancy. Most studies of long-term follow-up of children exposed to amphetamines during pregnancy have found no significant chronic behavioral changes. Adverse effects in utero to the vasoconstrictive effects of amphetamines have been reported including cerebral injury. Poor outcomes occurring during amphetamine exposure during pregnancy may also be due to factors other than the drug itself including multiple drug use, poor maternal health, socioeconomic factors, and other lifestyle variables.
215
Exposure Standards and Guidelines Amphetamine is a Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) hazardous substance and subjects to the release reporting requirement of CERCLA section 103, 40 CFR parts 302 and 355. It is an extremely hazardous substance and subjects to reporting requirements when stored in amounts of 1000 lbs or greater (the threshold planning quantity).
Miscellaneous Genotoxicity
Drug Screening
Amphetamines are not thought to be mutagenic.
Qualitative tests such as immunoassays may have false positive results for products containing ephedrine and pseudoephedrine. Other substances, such as labetalol and ranitidine, may cross-react with antiamphetamine antibodies, giving a false positive test result as well. Selegiline, a selective monoamine oxidase inhibitor type B, is partially metabolized to amphetamine and thus will give a positive result by most analytical methods. Additionally some newer designer drugs such as MDMA may not react with antiamphetamine antibodies and will result in a negative test. Limitations such as these may make clinical interpretations more difficult and imprecise. A confirmatory test, such as gas chromatography– mass spectrometry, offers greater specificity and sensitivity and may be the best choice in avoiding false positives and false negatives.
Carcinogenicity Amphetamines are not carcinogenic in humans. Some amphetamines have been shown to have beneficial effects in the treatment of certain cancers, in particular hematologic malignancies.
Clinical Management After assessment of airway, breathing, and circulation with necessary supportive care, decontamination of the gastrointestinal tract should be undertaken for substantial recent ingestions. If patients present within an hour of ingestion or have taken a modified release product, consider activated charcoal; a 10:1 ratio of activated charcoal per gram of ingested substance may be administered to patients who are awake and alert and can protect their airway. Gastric lavage may be recommended in potentially life-threatening ingestions that present within 60 min of ingestion. Determination of specific toxic doses is difficult in chronic users of amphetamines due to the development of tolerance. Oxygen and benzodiazepines should be administered as needed for agitation, shortness of breath, or chest pain. Increased blood pressure can be managed with benzodiazepines. Although vasodilators such as nitroprusside have been recommended, reflex tachycardia is a common result. Beta blockers are not recommended for use in overdose due to possible unopposed alpha adrenergic effects, which may lead to exacerbation of symptoms, i.e., worsening hypertension. Benzodiazepines may be necessary for agitated or combative patients. Benzodiazepines, cooling, and rehydration are standard treatments for patients with increased temperature and rhabdomyolysis. Hyperthermia is a poor prognostic sign and should be aggressively treated.
Clinical Management and Suggested Diagnostic Tests Electrolytes, urinalysis, complete blood count, urine toxicology screen, creatine kinase, and cardiac enzymes are helpful laboratory tests for evaluation. In patients with severe toxicity monitor arterial blood gas (ABG), liver function tests, coagulation studies and disseminated intravascular coagulation panel.
See also: Drugs of Abuse; Benzodiazepines; Methylenedioxymethamphetamine; Poisoning Emergencies in Humans.
Further Reading Baselt, R.C., 2002. Disposition of Toxic Drugs and Chemicals in Man, sixth ed. Biomedical Publications, Foster City, CA. 64–66. Biaggioni, I., Robertson, D., 2009. Adrenoceptor agonists & sympathomimetic drugs (Chapter 9). In: Katzung, B., Masters, S.B., Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, eleventh ed. McGraw-Hill (Access Medicine). Blanckaert, P., van Amsterdam, J., Brunt, T., van den Berg, J., Van Durme, F., Maudens, K., Van Bussel, J., 2013. 4-methyl-amphetamine: a health threat for recreational amphetamine users. J. Psychopharmacol. 27 (9), 817–822. Chiang, W., 2010. Amphetamines. In: Flomenbaum, et al. (Eds.), Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill, New York, NY, pp. 1078–1090. German, C.L., Fleckenstein, A.E., Hanson, G.R., 2013. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci.. S0024-3205(13) 00424–4. Kraemer, T., Maurer, H.H., 2002. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine and their N-alkyl derivatives. Ther. Drug Monit. 24 (2), 277–289. McCann, U.D., Ricaurte, G.A., 2004. Amphetamine neurotoxicity: accomplishments and remaining challenges. Neurosci. Biobehav. Rev. 27, 821–826. POISINDEX® System: Amphetamines. Klasco, R.K. (Ed.), POISINDEX® System. Thomson Reuters, Greenwood Village. Colorado Edition Expires (04/2012). Prosser, J.M., Nelson, L.S., 2012. The toxicology of bath salts: a review of synthetic cathinones. J. Med. Toxicol. 8 (1), 33–42. Vearrier, D., Greenberg, M.I., Ney Miller, S., Okaneku, J., Haggerty, D.A., 2012. Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Dis. Mon. 58 (2), 33–92.
216
Amphetamines
Relevant Websites http://emedicine.medscape.com/article/812518-overview – Amphetamine toxicity – Medscape reference an online resource on diagnosis, mechanism of toxicity, clinical management and treatment of amphetamine toxicity. http://health.utah.gov/meth/index.html – Utah Department of Health Methamphetamine. http://www.drugabuse.gov/sites/default/files/drugfacts_bath_salts_final_0_1.pdf – National Institute on Drug Abuse (NIDA) information on bath salts (cathinones).
http://www.aiha.org/aihce06/handouts/po118vandyke.pdf – National Jewish Medical Center power point resource on methamphetamine particle size and persistence after methamphetamine cook. http://www.dtsc.ca.gov/SiteCleanup/ERP/upload/OEHHA_Memo-Nov2007.pdf – Office of Environmental Health Hazard Assessment for children’s exposure to methamphetamine surface residue in use and clandestine laboratory environment. www.erowid.org/ – Online resource for intoxicating plants and drugs – information and resources including journal articles, timelines, media, prohibition sites, harm reduction, subjective user reports and chemical information.