Amphetamine (contracted from a lpha- m ethyl ph en et hyl amine ) is a potent central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamines correctly refers to certain chemicals, racemic free bases, which are equal parts of two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine form. The term is often used informally to refer to a combination of enantiomers, or only from themselves. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an enhancer of athletic performance and cognitive enhancers, and recreation as an aphrodisiac and euphoria. It is a prescription drug in many countries, and unauthorized ownership and distribution of amphetamines are often tightly controlled because of significant health risks associated with recreational use.
The first amphetamine drug is Benzedrine, a brand used to treat various conditions. Currently, pharmaceutical amphetamines are prescribed as rasemic amphetamines, Adderall, dextroamphetamine, or inactivated lisdexamfetamine prodrug. Amphetamines increase monoamine and excitatory neurotransmission in the brain, with the most prominent effects that target the norepinephrine and dopamine neurotransmitter systems.
In therapeutic doses, amphetamines cause emotional and cognitive effects such as euphoria, changes in sexual desire, increased awareness, and increased cognitive control. It induces physical effects such as better reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and cause rapid muscle damage. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. Very high doses can cause psychosis (eg, delusions and paranoia) that are rare in therapeutic doses even during long-term use. The recreational dose is generally much greater than the prescribed therapeutic dose and carries a much greater risk of serious side effects.
Amphetamine belongs to the phenethylamine class. It is also a parent compound of its own structural class, substituted amphetamine, which includes important substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically associated with a naturally occurring trace amine neuromodulator, specifically phenethylamine and N -methylphenethylamine , both of which are produced in humans. body. Phenethylamine is the parent compound of amphetamines, while N -methylphenethylamine is the position isomer of amphetamine which differs only in the placement of the methyl group.
Video Amphetamine
Usage
Medical
Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (sleep disorder), and obesity, and is sometimes prescribed off-label for previous medical indications, especially for chronic depression and pain. Long-term exposure to high doses of amphetamines in some animal species is known to result in the development of abnormal dopamine systems or nerve damage, but in humans with ADHD, pharmaceutical amphetamines appear to promote brain development and neuronal growth. Magnetic resonance imaging research (MRI) reviews indicate that long-term treatment with amphetamines reduces abnormalities in brain structures and function found in subjects with ADHD, and improves function in some parts of the brain, such as the right caudate nucleus of the basal ganglia.
Research reviews of clinical stimulants have established the safety and effectiveness of long-term sustained use of amphetamines for the treatment of ADHD. Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD covering 2 years have demonstrated the effectiveness and safety of treatment. Two reviews have shown that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (ie, hyperactivity, poor attention, and impulsivity), improving quality of life and academic achievement, and resulting in improvements in a large number of functional outcomes in 9 outcome categories related to academics, antisocial behavior, driving, non-drug use, obesity, employment, self-esteem, use of services (ie, academic, occupational, health, financial, and legal services), and social functions. One review highlights nine months of randomized controlled trials of amphetamine treatment for ADHD in children who found an average increase in IQ points of 4.5, a continuous increase in attention, and a steady decline in disruptive and hyperactive behaviors. Other reviews indicate that, based on the longest follow-up study conducted to date, lifelong stimulation therapy initiated during childhood continues to be effective in controlling the symptoms of ADHD and reducing the risk of developing substance use disorders as adults.
Current ADHD models suggest that this is associated with functional impairment in some brain neurotransmitter systems; this functional impairment involves the interruption of dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projection of the coeruleus locus to the prefrontal cortex. Psychostimulants such as methylphenidate and amphetamine are effective in treating ADHD because they increase the activity of neurotransmitters in this system. About 80% of those using this stimulant see improvement in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better at school, are less distracted and impulsive, and have longer attention spans. The Cochrane Collaboration review on ADHD treatment in children, adolescents, and adults with pharmaceutical amphetamines states that while these drugs improve short-term symptoms, they have higher rates of discontinuation than non-stimulant drugs because of adverse side effects. A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome suggests that generalized stimulants do not make tics worse, but high doses of dextroamphetamine may exacerbate tics in some individuals.
Improved performance
Cognitive performance
In 2015, a systematic review and high quality meta-analysis of clinical trials found that, when used at low doses (therapeutic), amphetamines resulted in simple but unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and several aspects attention, in normal healthy adults; this cognitive enhancement effect of amphetamines is known to be partially mediated through the indirect activation of both dopamine receptors D 1 and adrenoceptors? 2 in the prefrontal cortex. A systematic review of 2014 found that low doses of amphetamines also increased memory consolidation, which in turn led to increased memory of information. Therapeutic doses of amphetamine also increase the efficiency of cortical tissue, an effect that mediates improvement in working memory in all individuals. Amphetamine and other ADHD stimulants also enhance the meaning of the task (motivation to perform the task) and increase the passion (wake), in turn promoting the behavior directed towards the goal. Stimulants such as amphetamines can improve performance on difficult and tedious tasks and are used by some students as a study and test aid. Based on a self-reported study of self-reported stimulants, 5-35% students use a transferable ADHD stimulant, primarily used for performance improvement rather than recreational drugs. However, high doses of amphetamines above the therapeutic range may interfere with memory work and other aspects of cognitive control.
Physical performance
Amphetamines are used by some athletes for the effect of improving psychological and athletic performance, such as increased endurance and alertness; however, the use of non-medical amphetamines is prohibited at sporting events organized by college, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance under anaerobic conditions, and endurance (ie, delay onset of fatigue), while increasing reaction time. Amphetamine increases endurance and reaction time primarily through reuptake inhibition and smoothing of dopamine in the central nervous system. Amphetamines and other dopaminergic drugs also increase the power output at a steady level of perceived power by ignoring the "safety switch" which allows the increased core temperature limit to access the normally forbidden reserve capacity. In therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamines can cause devastating effects on performance, such as rapid muscle breakdown and increased body temperature.
Maps Amphetamine
Contraindications
According to the International Program on Chemical Security (IPCS) and the US Food and Drug Administration (USFDA), amphetamines are contraindicated in people with a history of drug abuse, cardiovascular disease, severe agitation, or severe anxiety. It is also contraindicated in people who currently have advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormones), or moderate to severe hypertension. These institutions show that people who have had an allergic reaction to other stimulants or who use monoamine oxidase inhibitors (MAOIs) should not take amphetamines, although the safe concurrent use of amphetamines and monoamine oxidase inhibitors has been documented. These bodies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics or Tourette syndrome should monitor their symptoms while taking amphetamines. Evidence from human studies suggests that the use of therapeutic amphetamines does not cause developmental abnormalities in fetuses or newborns (ie, these are not human teratogens), but amphetamine abuse poses a risk to the fetus. Amphetamine has also been shown to pass to breast milk, so IPCS and USFDA advise mothers to avoid breastfeeding when using it. Because of the potential for reversible growth disorders, the USFDA recommends high monitoring and weight loss of children and adolescents who are prescribed amphetamine pharmaceuticals.
Side effects
Side effects of amphetamine are numerous and varied, and the amount of amphetamine used is a major factor in determining the likelihood and severity of side effects. Amphetamine products such as Adderall, Dexedrine, and its generic equivalents are currently approved by USFDA for long-term therapeutic use. The use of recreational amphetamines generally involves a much larger dose, which has a greater risk of serious side effects than the dose used for therapeutic reasons.
Physical
At normal therapeutic doses, the physical side effects of amphetamines vary greatly by age and from person to person. Cardiovascular side effects may include hypertension or hypotension of the vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate). Sexual side effects in men may include erectile dysfunction, frequent erections, or prolonged erections. Abdominal side effects may include abdominal pain, loss of appetite, nausea, and weight loss. Other potential side effects include blurred vision, dry mouth, excessive teeth grinding, nosebleeds, sweating, medicamentous rhinitis (drug-induced nasal congestion), reduced seizure threshold, and tics (a movement disorder). Hazardous physical side effects are rare in certain pharmaceutical doses.
Amphetamine stimulates the medullary respiratory center, producing faster and deeper breathing. In normal people with therapeutic doses, these effects are usually not seen, but when respiration is compromised, it may be proven. Amphetamine also induces contractions in the bladder sphincter, the muscle that controls the urine, which can cause difficulty urinating. This effect can be useful in treating bedwetting and loss of bladder control. The effects of amphetamines on the gastrointestinal tract are unpredictable. If intestinal activity, amphetamines can reduce gastrointestinal motility (the rate at which the content moves through the digestive system); However, amphetamines can increase motility when smooth muscle of the channel is relaxed. Amphetamine also has little analgesic effect and can increase the opioid pain-relieving effect.
USFDA-assigned studies from 2011 show that in children, young adults, and adults there is no association between serious serious cardiovascular events (sudden death, heart attack, and stroke) and medical use of amphetamines or other ADHD stimulants. However, amphetamine drugs are contraindicated in individuals with cardiovascular disease.
Psychological
In normal therapeutic doses, the most common psychological side effects of amphetamines include increased alertness, fear, concentration, initiative, self-confidence, and socialization, mood swings (joyful mood followed by a slightly depressed mood), insomnia or awake, and decreased fatigue. Less common side effects include anxiety, libido changes, grandiosity, irritability, repetitive or obsessive behavior, and anxiety; this effect depends on the user's personality and current mental state. Amphetamine psychosis (eg, delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur in therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive or hostile behavior.
Amphetamine has also been shown to result in conditioned place preference in humans using therapeutic doses, which means that individuals get a preference for spending time in places where they have previously used amphetamine.
Overdose
Overdose amphetamine can cause many different symptoms, but is rarely fatal with proper care. The severity of overdose symptoms increases with the dose and decreases with drug tolerance to amphetamines. Individuals who are tolerant have been known to consume as much as 5 grams of amphetamine in a day, which is about 100 times greater than daily therapeutic doses. The symptoms of moderate and very large overdoses are listed below; Fatal amphibamin poisoning usually also involves seizures and coma. In 2013, overdose in amphetamines, methamphetamines, and other compounds involved in "amphetamine use disorders" resulted in about 3,788 deaths worldwide ( 3,425-4,145 deaths, 95% confidence).
Pathological overactivation of the mesolimbic pathway, the dopamine pathway connecting the ventral ventral region to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who frequently overdose on amphetamines during recreational use have a high risk of developing amphetamine addiction, since recurrent overdose gradually increases the accumbal rate? FosB, a "molecular switch" and "master master protein" for addiction. After the nucleus accumbens? FosB is quite expressed, it begins to increase the severity of addictive behavior (ie, looking for compulsive drugs) with a further increase in its expression. While there is currently no effective cure for treating amphetamine addiction, regularly engaging in sustainable aerobic exercise seems to reduce the risk of developing such addiction. Regular aerobic exercise regularly also appears to be an effective treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and can be used as a combination therapy with cognitive behavioral therapy, which is currently the best available clinical care.
Dependency
Addiction is a serious risk with the use of severe recreational amphetamines but may not arise from typical long-term medical use at therapeutic doses. Drug tolerance is growing rapidly in the misuse of amphetamine (ie, recreational amphetamine overdoses), so extended periods of use require larger doses of the drug to achieve the same effect.
Biomolecular mechanism
The use of chronic amphetamine in excessive doses leads to alteration of gene expression in the mesocorticolimbic projection, which appears through transcriptional and epigenetic mechanisms. The most important transcription factor that produces this change is? FosB, cAMP element binding protein (CREB), and nuclear factor kappa B (NF-? B). Fosb is the most important biomolecular mechanism in addiction because Fosb's overexpression in middle-spaced neurons of type D1 in the nucleus accumbens is necessary and sufficient for many nerve adaptations and behavioral effects (eg, increased expression dependent on self-administration and reward sensitization drugs) seen in drug addiction. Once? FosB is sufficiently expressed, it induces an addictive state that gets progressively worse with a further increase in the FosB expression. It has been implicated in alcoholism, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and amphetamine substitutions, among others.
? JunD, transcription factors, and G9a, the histone methyltransferase enzyme, both opposed to Fosb's function and inhibited the increase in expression. Simply over-expressed? JunD in nucleus accumbens with viral vectors can actually block many of the nerve changes and behaviors seen in chronic drug abuse (ie, changes mediated by? FosB). Fosb also plays an important role in regulating behavioral responses to natural rewards, such as good food, sex, and exercise. Because both natural rewards and addictive drugs induce expression? FosB (that is, they cause the brain to produce more), this chronic appreciation can result in the same pathological state of addiction. Consequently, Fosb is the most significant factor involved in amphetamine-induced and amphetamine-induced sex addiction, which is compulsive sexual behavior resulting from excessive sexual activity and amphetamine use. This sex addiction is associated with dopamine dysregulation syndrome that occurs in some patients taking dopaminergic drugs.
The effects of amphetamine on gene regulation are both dose-dependent and route-dependent. Most studies of gene regulation and addiction are based on animal studies with intravenous administration of amphetamines at very high doses. Several studies that have used the equivalent dose of human therapy (adjusted weight) and oral administration suggest that these changes, if they occur, are relatively small. This suggests that the medical use of amphetamines does not significantly affect gene regulation.
Pharmacological treatments
In 2015, there is no effective pharmacotherapy for amphetamine addiction. Reviews from 2015 and 2016 show that TAAR1 selective agonists have significant therapeutic potential as a treatment for psychostimulary addiction; however, in February 2016, the only compound known to function as a TAAR1 selective agonist was an experimental drug. Amphetamine addiction is largely mediated through increased activation of dopamine receptors and NMDA co-localization receptors NMDA in nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the calcium channel of the receptor. One review suggested that, based on animal testing, the use of pathological psychostimulants (which trigger addiction) significantly reduces the level of intracellular magnesium throughout the brain. Additional magnesium treatment has been shown to reduce amphetamine self-administration (ie, self-administered dose) in humans, but it is not an effective monotherapy for amphetamine addiction.
Treatment behavior
Current cognitive behavioral therapy is the most effective clinical treatment for psychostimulary addiction. In addition, research on the neurobiological effects of physical exercise shows that daily aerobic exercise, especially endurance exercises (eg, marathon run), prevents the development of drug addiction and is an effective additional therapy (ie, additional treatment) for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, especially for psychostimulant addiction. Specifically, aerobic exercise decreases the administration of psychostimulant self-administration, reduces recovery (ie, relapsing) of drug-seeking, and induces increased dopamine receptor D 2 (DRD2) density in the striatum. This is the opposite of the use of pathological stimulation, which induces decreased striatal DRD2 density. One review noted that exercise can also prevent the development of drug addiction by altering the immunoreactivity of FosB or c-Fos in the striatum or other parts of the reward system.
Dependence and tethering
According to other Cochrane Collaboration reviews about withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users suddenly discontinue amphetamine use, many reports of limited-time withdrawal syndrome occur within 24 hours of their last dose." This review notes that withdrawal symptoms in chronic high-dose users is common, occurs in about 88% of cases, and persists for 3-4 weeks with the "stuck" phase marked during the first week. Symptoms of withdrawal of amphetamines may include anxiety, drug cravings, depression, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or drowsiness, and lucid dreams. This review shows that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. Symptoms of mild withdrawal from cessation of amphetamine treatment at therapeutic doses can be avoided by reducing the dose.
Toxicity
In rodents and primates, high doses of amphetamines cause dopaminergic neurotoxicity, or damage to dopamine neurons, characterized by terminal dopamine degeneration and reduced transporter and receptor function. There is no evidence that amphetamines are directly neurotoxic in humans. However, large doses of amphetamines indirectly can cause dopaminergic neurotoxicity as a result of hyperpyrexia, excessive reactive oxygen species formation, and increased dopamine autoxidation. Animal models of neurotoxicity from high doses of amphetamine exposure suggest that the occurrence of hyperpyrexia (ie, core body temperature> = Ã, 40Ã,  ° C) is required for the development of amphetamine-induced neurotoxicity. A rise in brain temperature over 40Ã, ° C probably promotes the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting the function of cellular proteins, and temporarily increasing the permeability of blood brain barrier.
Psychosis
Severe amphetamine overdose can cause stimulatory psychosis that may involve multiple symptoms, such as delusions and paranoia. A Cochrane Collaboration review on treatment for amphetamines, dextroamphetamine, and methamphetamine psychosis states that about 5-15% users fail to recover completely. According to the same review, there is at least one trial that suggests an effective antipsychotic drug resolves the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
Interactions
Many types of substances are known to interact with amphetamines, resulting in altered drug action or amphetamine metabolism, interacting substances, or both. An enzyme inhibitor that metabolizes amphetamines (eg, CYP2D6 and FMO3) will lengthen the elimination half-life, which means that the effect will last longer. Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, because MAOI and amphetamines increase plasma catecholamines (ie, norepinephrine and dopamine); Therefore, concurrent use is dangerous. Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamines can decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants. Amphetamine may also decrease the antihypertensive and antipsychotic effects due to their effect on blood pressure and dopamine. Zinc supplements can reduce the minimum effective dose of amphetamine when used for the treatment of ADHD.
In general, there is no significant interaction when consuming amphetamine with food, but the pH of the gastrointestinal and urine contents affects absorption and excretion of amphetamines, respectively. Acid substances reduce amphetamine absorption and increase urinary excretion, and alkaline substances do the opposite. Because of the effect of pH on absorption, amphetamine also interacts with gastric acid reductions such as proton pump inhibitors and antihistamines H 2 , which increases the gastrointestinal pH (ie, makes it less acidic).
Pharmacology
Pharmacodynamics
Amphetamines provide behavioral effects by altering the use of monoamines as nerve signals in the brain, particularly in catecholamine neurons in the reward and executive brain function pathways. The major neurotransmitter concentrations involved in the reward circuit and executive function, dopamine and norepinephrine, increase dramatically by dose-dependent amphetamine because of their effect on the monoamine transporter. The effects of strengthening and advancing the motivation of amphetamines are largely due to increased dopaminergic activity in the mesolimbic pathway. The euphoric and locomotor stimulating effects of amphetamine depend on the magnitude and velocity that increases the synaptic dopamine and norepinephrine concentration in the striatum.
Amphetamine has been identified as a potent agonist of receptors associated with amines 1 (TAAR1), a G s -coupled and G q -coupled G protein-coupled receptor (GPCR) was discovered in 2001, which is important for the regulation of brain monoamines. Activation of TAAR1 increases cAMP production by cyclase adenylyl activation and inhibits the function of the monoamine transporter. The autoreceptor monoamines (eg, D 2 short, presinaptic 2 , and presynaptic 5-HT 1A ) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. In particular, amphetamines and amine amines have a high binding affinity for TAAR1, but not for monoamine autoreceptors. The imaging studies show that inhibition of monoamine reuptake by amphetamines and amine amines is site-specific and depends on the presence of TAAR1 co-localization in related monoamine neurons. In 2010, the co-localization of TAAR1 and dopamine transporters (DAT) was visualized in rhesus monkeys, but co-localization from TAAR1 with norepinephrine (NET) transporters and serotonin transporters ( SERT) is only evidenced by the expression of messenger RNA (mRNA).
In addition to neuronal monoamine transport, amphetamines also inhibit vesicular monoamine transporters, VMAT1 and VMAT2, and SLC1A1, SLC22A3, and SLC22A5. SLC1A1 is an excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in a neuron, SLC22A3 is an extraneuronal monoamine transporter present in astrocytes, and SLC22A5 is a high affinity carnitine transporter. Amphetamines are known to strongly induce expression of cocaine and amphetamine-regulated transcript (CART) genes, a neuropeptide involved in eating, stress, and reward behaviors, which induce observable improvements in neurodevelopment and vitality in vitro . CART receptors have not been identified, but there is significant evidence that CART binds to G i /G o -coupled GPCR . Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less monoamine and amine metabolism and a higher concentration of synaptic monoamines. In humans, the only post-synaptic receptor in which amphetamine is known to bind is the 5-HT1A receptor , where it acts as an agonist with micromolar affinity.
The full profile of the amphetamine short-term drug effect in humans is largely obtained through enhanced cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epinephrine, histamine, CART peptide, endogenous opioids, adrenocorticotropic hormones, corticosteroids, and glutamate, which are transmitted through interactions with CART , 5-HT1A , EAAT3 , TAAR1 , VMAT1 , VMAT2 , and possibly other biological targets.
Dextroamphetamine is a stronger agonist than TAAR1 than levoamphetamine. As a result, dextroamphetamine produces greater CNS stimulation than levoamphetamine, about three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.
Dopamine
In certain areas of the brain, amphetamine increases the concentration of dopamine in the synaptic cleft. Amphetamine can enter either presinaptic neurons via DAT or by spreading across the neuronal membrane directly. As a consequence of taking DAT, amphetamine results in competitive reuptake inhibition in the transporter. Upon entering the presinaptic neuron, amphetamine activates
Amphetamine is also a substrate for presynaptic vesicular monoamine transport, VMAT2 . After amphetamine uptake in VMAT2, amphetamine induces the fall of the vesicular pH gradient, which results in the release of dopamine molecules from the synaptic vesicles to the cytosol through depletion of dopamine via VMAT2. Subsequently, the dopamine cytopathic molecule is released from the presinaptic neuron into the synaptic cleft by return transport on DAT .
Norepinephrine
Similar to dopamine, amphetamine-dependent doses increase the level of synaptic norepinephrine, a direct precursor of epinephrine. Based on the abnormal neuronal < Serotonin
Amphetamines provide analogous, but less prominent, effects on serotonin as in dopamine and norepinephrine. Amphetamine affects serotonin through VMAT2 and, like norepinephrine, is considered phosphorylated SERT via TAAR1 . Like dopamine, amphetamine has a low micromolar affinity in human 5-HT1A receptors.
Other neurotransmitters, peptides, and hormones
The administration of acute amphetamines in humans increases the release of endogenous opioids in some brain structures in the reward system. Extracellular glutamate levels, the main stimulating neurotransmitter in the brain, have been shown to increase striatum after exposure to amphetamine. This increase in extracellular glutamate may occur through amphetamine-induced internalization of EAAT3, glutamate reuptake transporter, in dopamine neurons. Amphetamine also induces the selective release of histamine from mast cells and depletion of histaminergic neurons via VMAT2 . Acute amphetamine administration may also increase the hormone adrenocorticotropic and corticosteroid levels in the blood plasma by stimulating the hypothalamus-pituitary-adrenal axis.
Pharmacokinetics
Oral amphetamine oral bioavailability varies with gastrointestinal pH; it is well absorbed from the intestine, and bioavailability is usually over 75% for dextroamphetamine. Amphetamine is a weak base with p K a 9.9; consequently, when the pH is basic, more drugs are in the lipid-soluble base form, and are more absorbed through the lipid-rich cell membrane of the intestinal epithelium. In contrast, acidic pH means the drug is mainly in the form of cationic (salt) that is soluble in water, and less absorbed. About 15-40% of amphetamines circulating in the bloodstream are bound by plasma proteins. After absorption, amphetamines are readily distributed to most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.
The half-life of amphetamine enantiomers is different and varies with urinary pH. At normal urinary pH, half of dextroamphetamine and levoamphetamine life respectively 9-11 and clock 11-14 . Extremely acidic urine will reduce the half-life of the enantiomers up to 7 hours; Highly alkaline urine will increase the half-life to 34 hours. The release of direct and extended releases of salts from both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Amphetamines are removed through the kidney, with <30% -40% of the excreted drug unchanged at normal urine pH. When the basic urine pH, amphetamine is in its free base form, so less is excreted. When the urine pH is abnormal, urinary recovery of amphetamines can range from a low of 1% to a high of 75%, depending on whether the urine is too basic or acidic, respectively. After oral administration, amphetamines appear in the urine within 3 hours. About 90% of the digestible amphetamines are removed 3 days after the last oral dose
The prodrug lisdexamfetamine is not sensitive to pH as amphetamine when it is absorbed in the gastrointestinal tract; after absorption into the bloodstream, it is altered by enzymes associated with red blood cells to dextroamphetamine through hydrolysis. The elimination half-life of lisdexamfetamine is generally less than 1 hour.
CYP2D6, dopamine? -hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butat-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are enzymes known to metabolize their amphetamines or metabolites in humans. Amphetamines have a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hypuratic acid and norephedrine. , and phenylacetone. Among these metabolites, active sympathomimetics are 4-hydroxyamphetamine , 4-hydroxynorephedrine , and norephedrine. The main metabolic pathway involves aromatic hydroxylation, aliphatic alpha and beta hydroxylation, N-oxidation, N-dealkylation, and deamination. Known metabolic pathways, detectable metabolites, and human metabolic enzymes include the following:
Related endogenous compounds
Amphetamines have structures and functions that are very similar to endogenous trace amines, naturally occurring neurotransmitter molecules produced in the human body and brain. Among these groups, the most closely related compounds are phenethylamine, the parent compound of amphetamines, and N -methylphenethylamine , an isomer of amphetamine (ie, it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the amino acid decarboxylase enzyme (AADC), which converts L-DOPA to dopamine as well. In turn, N -methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine to epinephrine. Like amphetamines, both phenethylamine and N -methylphenethylamine regulate monoamine neurotransmission through TAAR1 ; unlike amphetamines, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.
Chemistry
Amphetamine is methyl homologous from the phenotylamine neurotransmitter mammal with the chemical formula C 9 H 13 N. The carbon atoms adjacent to the primary amine are the stereogenic centers, and amphetamines comprise a racemic mixture of 1: 1 of two enantiomeric mirror images. This racemic mixture can be separated into its optical isomers: levoamphetamine and dextroamphetamine. At room temperature, a pure-free base of amphetamines is a fluid that moves, is colorless and volatile with a strong amine odor, and a sharp burning sensation. Commonly prepared amphetamine solids include amphetamine aspartate, hydrochloride, phosphate, saccharate and sulfate, the latter being the most common amphetamine salt. Amphetamine is also a parent compound of its own structural class, which includes a number of psychoactive derivatives. In organic chemistry, amphetamines are excellent chiral ligands for stereoselective synthesis of 1,1'-bi-2-naphthol .
Derivable substitute
Substituted derivatives of amphetamine, or "amphetamine substitution", are various chemicals containing amphetamines as "backbones"; specifically, this class of chemistry includes derived compounds formed by replacing one or more hydrogen atoms in the amphetamine core structure with a substituent. Classes include amphetamines themselves, stimulants such as methamphetamine, serotonergic empathy such as MDMA, and decongestants such as ephedrine, among other subgroups.
Synthesis
Since the first preparation was reported in 1887, many synthetic routes for amphetamines have been developed. The most common routes of both legal and forbidden amphetamine synthesis employ a non-metallic reduction known as Leuckart's reaction (method 1). In the first step, the reaction between phenylacetone and formamide, either using an additional formic acid or formamide itself as a reducing agent, produces N -formylamphetamine . The intermediate material is then hydrolyzed using hydrochloric acid, and then preheated, extracted with an organic solvent, concentrated, and distilled to produce a free base. The free base is then dissolved in an organic solvent, sulfuric acid is added, and amphetamines settle out as sulfate salts.
A number of chiral resolutions have been developed to separate the two enantiomers from amphetamines. For example, rasemic amphetamine can be treated with d-tartaric acid to form a fractionally crystallized diastereoisomeric salt to produce dextroamphetamine. Chiral resolutions remain the most economical method of obtaining pure amphetamine on a large scale. In addition, several amphetamine enantioselective syntheses have been developed. In one example, pure optical ( R ) - 1-phenyl-ethanamine is condensed with phenylacetone to produce a chiral Schiff base. In a key step, this intermediate is reduced by catalytic hydrogenation by chiral transfer to an alpha carbon atom to the amino group. Termination of amine benzylic bond by hydrogenation yields pure pure dextroamphetamine.
A large number of alternative synthetic routes for amphetamines have been developed based on classical organic reactions. One example is the alkylation of Friedel-Crafts from benzene by allyl chloride to produce beta chloropropylbenzene which is then reacted with ammonia to produce rasemic amphetamine (method 2). Another example uses the Ritter reaction (method 3). In this route, allyl benzene is reacted acetonitrile in sulfuric acid to produce organosulfates which in turn are treated with sodium hydroxide to provide amphetamine through the intermediates of the acetamide. The third route starts with ethyl 3-oxobutanoate which through double alkylation with methyl iodide followed by benzyl chloride can be converted to 2-methyl-3-phenyl-propanoic acid . This synthetic intermediate material can be converted to amphetamine by using a Hofmann or Curtius rearrangement (method 4).
A large number of amphetamine synthesis has a reduction of nitro, imine, oxime, or other nitrogen-containing functional groups. In one example, the Knoevenagel condensation of benzaldehid with the result of nitroethane phenyl-2-nitropropene . The double bond and the intermediate nitro group are reduced by catalytic hydrogenation or by treatment with lithium aluminum hydride (method 5). Another method is the reaction of phenylacetone with ammonia, resulting in imine intermediates being reduced to a primary amine using hydrogen through a palladium or lithium aluminum hydride catalyst (method 6).
Detection in body fluids
Amphetamines are often measured in urine or blood as part of a drug test for exercise, occupation, toxic diagnostics, and forensics. Techniques such as immunoassay, which is the most common form of amphetamine assays, can react with a number of sympathomimetic drugs. Special chromatographic methods for amphetamines are used to prevent false-positive results. Chiral separation techniques can be used to help differentiate the source of the drug, whether it is an amphetamine recipe, an amphetamine-producing recipe, (eg, selegiline), a drug-free product containing levomethamphetamine, or an illegally obtained substitutionary amphetamine. Some prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. This compound can produce positive results for amphetamine on the drug test. Amphetamines are generally only detected by standard drug tests for about 24 hours, although high doses can be detected during 2-4 days.
For the test, a study notes that enzymes multiplied by immunoassay (EMIT) techniques for amphetamines and methamphetamine can produce more false positives than liquid-tandem liquid chromatography spectrometry. Gas chromatography-mass spectrometry (GC-MS) of amphetamine and methamphetamine with a derivatization agent ( S ) - (-) - trifluoroacetylprolyl chloride makes it possible to detect methamphetamine in urine. GC-MS amphetamine and methamphetamine with chiral derivative materials Mosher chloride acid allows to detect dextroamphetamine and dextromethamphetamine in urine. Therefore, the latter method can be used in positive tested samples using other methods to help differentiate between various drug sources.
History, society and culture
Amphetamine was first synthesized in 1887 in Germany by the Romanian chemist Lazard Edeleanu who called it phenylisopropylamine ; the stimulant effect remained unknown until 1927, when it was independently re-synthesized by Gordon Alles and reported to have sympathomimetic properties. Amphetamine had no medical use until the end of 1933, when Smith, Kline and France began selling it as an inhaler with the Benzedrine brand as a decongestant. Benzedrine sulfate was introduced 3 years later and was used to treat various medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others. During World War II, amphetamines and methamphetamine were used extensively by Allied forces and Poros for their stimulant effects and improved performance. When the addictive nature of the drug is known, the government began putting strict controls on the sale of amphetamines. For example, during the early 1970s in the United States, amphetamines became controlled substance II under the Controlled Substance Act. Regardless of strict government control, amphetamine has been used legally or illegally by people from diverse backgrounds, including writers, musicians, mathematicians, and athletes.
Amphetamine is still illegally synthesized today in secret labs and sold on the black market, especially in European countries. Among EU Member States, 1.2 million young adults use prohibited amphetamines or methamphetamine by 2013. During 2012, about 5.9 metric tons of prohibited amphetamine are seized in EU Member States; "road prices" of prohibited amphetamines within the EU range from EUR6-38 per gram over the same period. Outside Europe, the black market for amphetamines is much smaller than the market for methamphetamine and MDMA.
Legal status
As a result of the 1971 United Nations Convention on Psychotropic Substances, amphetamines become Schedule II controlled substances, as defined in the treaty, in all 183 States Parties. As a result, it is highly regulated in most countries. Some countries, such as South Korea and Japan, have banned amphetamine replacements for medical purposes. In other countries, such as Canada (Schedule I Drugs), Netherlands (List I Drugs), United States (Schedule II Drugs), Australia (Schedule 8), Thailand (Narcotics category 1), and English (Class B) amphetamines are in a limited national drug schedule that allows it to be used as a medical treatment.
Pharmaceutical products
Some of the amphetamine formulations currently prescribed contain enantiomers, including Adderall, Adderall XR, Mydayis, Adzenys XR-ODT , DyanavelÃ, XR, and Evekeo, the latter containing rasemic amphetamine sulfate. Amphetamines are also prescribed in the form of enantiopure and prodrug as dextroamphetamine and lisdexamfetamine. Lisdexamfetamine is structurally different from amphetamine, and is inactivated until the metabolism becomes dextroamphetamine. The free base of amphetamine rasemic was previously available as Benzedrine, Psychedrine, and Sympatedrine. Levoamphetamine was previously available as Cydril. Many amphetamine drugs today are salt because of the relatively high volatility of the free base. However, oral suspensions and oral disintegrating tablet form (ODT) consisting of free bases were introduced in 2015 and 2016, respectively. Some of the current and generic brands are listed below.
Note
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Reference notes
References
External links
- CID 3007 from PubChemÃ, - Amphetamine
- CID 5826 from PubChemÃ, - Dextroamphetamine
- CID 32893 from PubChemÃ, - Levoamphetamine
- Comparative Toxicogenomics Data entry: Amphetamine
- Comparative Toxicogenomics Database entry: CARTPT
Source of the article : Wikipedia
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