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The addictive properties of amphetamine were recognized and its use is now restricted as a prescription medication for disorders such as attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Because of its high addiction potential and relatively easy access, amphetamines are one of the most commonly abused drugs. These results are complemented by those of Ermer et al. (2011), who reported that the PK profiles were identical when lisdexamfetamine was administered intranasally or orally, indicating that attempts to increase its potential for recreational abuse by ‘snorting’ would similarly be futile. Although the findings do not demonstrate that lisdexamfetamine lacks any potential for recreational abuse, they do indicate that its attractiveness to abusers will be reduced compared with IR d-amphetamine. Based on these data, the likelihood that lisdexamfetamine will be widely abused by the intravenous or nasal route is very low.
When ingested, a dose may vary from several tens to several hundreds of milligrams depending on the purity. These two forms were previously called the –- or l-stereoisomer and the +- or d-stereoisomer, but in modern usage are defined as the R- and S-stereoisomers. Amphetamines in their pure form exist as white crystalline powder and are odorless and bitter.
Recreational
In contrast, l-amphetamine was either as potent, or more so, than d-amphetamine as a releaser of 3Hnoradrenaline (Easton et al., 2007; Heikkila et al., 1975). The monoamine transporters are not particularly selective in terms of which monoamines they transport, and this lack of selectivity is explained by the close structural similarity between them (Figure 1). Furthermore, this structural similarity between the monoamine neurotransmitters and amphetamine explains why the latter has promiscuous actions to release the important CNS monoamines (noradrenaline, dopamine and 5-HT). Amphetamine also releases adrenaline from the peripheral sympathetic nervous system, an action linked to its cardiovascular side effects. Although most of these experiments have looked at the effects of amphetamine isomers on basal 3Hmonoamine release from synaptosomes or slices, amphetamine also augments electrically stimulated efflux (Easton et al., 2007). This action indicates that its retro-transport mechanism can act both co-operatively with, and independently of, neuronal firing.
The pharmacology of amphetamine
- It is believed that amphetamine was first manufactured in the 1880s by the German chemist Leuckart, although evidence for this is lacking.
- Amphetamine enters the presynaptic axon terminal through diffusion or uptake by the monoamine transporters DAT, NET, and SERT.
- Methylphenidate is sold under the brand names of Ritalin and Concerta, and is another commonly used stimulant for the treatment of ADHD.
- These observations are entirely consistent with the postulated rate-limited enzymatic conversion of lisdexamfetamine to d-amphetamine.
- Amphetamines (pronounced “am-FET-uh-meens”) make your body release extra dopamine and norepinephrine.
This difference in PK characteristics had a profound impact on the pharmacological effects of these two compounds in rats (Figure 5). Lisdexamfetamine produced a gradual and sustained increase in striatal dopamine efflux, whereas the increase produced by IR d-amphetamine was faster in onset, reaching a peak at 30 min, and it subsequently declined more rapidly (Figure 5). Consistent with the findings in microdialysis experiments, d-amphetamine has greater potency than l-amphetamine to evoke stimulant-like subjective effects in rats (Schechter, 1978) and behavioural activation in primates (Scraggs and Ridley, 1978).
- The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
- Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals.
- The time required by the body to remove a drug or metabolite is measured in terms of the elimination half-life, which is the time required to remove half of the total substance from the body.
- Compared with placebo, 50 mg lisdexamfetamine significantly increased the peak systolic blood pressure when administered both orally and intravenously and diastolic blood pressure when given orally (Figure 6).
Other neurotransmitters, peptides, hormones, and enzymes
Following oral use, the effects usually start within 30 minutes and last for hours. Later, users may feel irritable, restless, anxious, depressed and lethargic. At this time, there is no medicine that can help reduce the use of amphetamines by blocking their effects. Although not all of these side effects may occur, if they do occur they may Amphetamine Drug Profile need medical attention. The amount of medicine that you take depends on the strength of the medicine.
Another way to produce a more gentle increase of brain dopamine is to bind d-amphetamine to a support. MES-amphetamine XR employs a bead technology to deliver two bolus doses of amphetamine, the first immediately and the second approximately 4 h later, giving a Cmax for amphetamine’s d- and l-isomers 6–8 h (Adderall XR®, US Product Label). Therefore, the maximum therapeutic effect of MES-amphetamine XR (Biederman et al., 2007a) coincided almost exactly with the tmax for plasma d-amphetamine (Adderall XR®, US Product Label). These findings are also consistent with the preclinical PK/PD relationship for IR d-amphetamine that found a lack of hysteresis between plasma d-amphetamine concentration and the functional response, that is, locomotor activity. The choice of agent for initial therapy is based on cost, patient preference, and concern for abuse.
Detection in body fluids
Although d-amphetamine is a competitive substrate for DAT rather than a classical reuptake inhibitor, these same principles apply to its pharmacological action. Thus, the rate and magnitude of neuronal dopamine release produced by amphetamine is absolutely dependent on the rate and concentration of drug that reaches DAT sites in the brain (Heal et al., 2008, 2009). There has been little research conducted in humans on this kinetic course using brain imaging, but it seems likely that the same rules apply. In that period amphetamine has transformed from a drug that was widely available without prescription for the treatment of a broad range of disorders to being highly restricted Controlled Drugs that, in Europe at least, have all but disappeared from the formularies in many countries. The very clear links between molecular structure and pharmacological mode of action and, in turn, efficacy and safety in humans, makes amphetamine a textbook example of translational validity. The primary pharmacology of these drugs is not only responsible for providing efficacy in disorders such as ADHD and narcolepsy, but also for their spectrum of adverse events and liability for recreational abuse, making the balance of benefit/risk the key challenge in their clinical use.
Binge eating disorder
Use with medications that increase stomach or urine alkalinity, including sodium bicarbonate, acetazolamide, and some thiazide diuretics (water pill) should be avoided. Check with your doctor right away if you or your child have anxiety, restlessness, a fast heartbeat, fever, sweating, muscle spasms, twitching, nausea, vomiting, diarrhea, or see or hear things that are not there. Your risk may be higher if you also take certain other medicines that affect serotonin levels in your body.
High doses of amphetamines can lead to cardiotoxicities including arrhythmias and infarctions that can be fatal. The pharmacokinetic/pharmacodynamic (PK/PD) relationships of lisdexamfetamine and immediate-release (IR) d-amphetamine sulphate have been explored in rats, where automated blood sampling was combined with striatal microdialysate sampling. After administration of equivalent doses of lisdexamfetamine and IR d-amphetamine (1.5 mg/kg ip as d-amphetamine base), the observed plasma PK profiles for the pharmacologically active moiety, d-amphetamine, were very different. The AUC0-480 min values were identical, but the maximum concentration reached in plasma (the Cmax) was 50% lower after administration of lisdexamfetamine and the time to Cmax (the tmax) was doubled (Jackson et al., 2011). These observations are entirely consistent with the postulated rate-limited enzymatic conversion of lisdexamfetamine to d-amphetamine.
In spite of considerable coverage in the medical literature and the popular press describing the powerful central effects of these new drugs, the addictive potential of amphetamine was largely dismissed (see Bett, 1946; Guttmann and Sargent, 1937; Tidy, 1938). The doses of amphetamines used for the treatment of ADHD are not considered to be addictive, but amphetamines have a high addiction potential at higher doses. Prescription amphetamines should be taken in the prescribed fashion and at the prescribed doses. However, prescription amphetamines are often used by college students in an attempt to improve academic or athletic performance.
Lisdexamfetamine dimesylate
Amphetamines that are illicitly sold may take the form of powder, capsules, tablets or crystals. The appearance of amphetamines sold illicitly varies depending on the presence of impurities and the color may vary from white to brown with traces of green and pink. A comparison of the pharmacodynamics and pharmacokinetics of orally versus intravenously administered 50 mg lisdexamfetamine. Displacement was determined in vitro at a lisdexamfetamine concentration of 10μM. If you are using the extended-release oral disintegrating tablet, make sure your hands are dry before you handle the tablet.
Kuczenski et al. (1995) determined the effects of both amphetamine enantiomers on caudate 5-HT release. The effect was considerably smaller than found for dopamine and there was a smaller potency separation between the two isomers. Consistent with the mechanism described above, in vitro experiments have unequivocally demonstrated that amphetamine’s d- and l-isomers non-selectively release 3Hmonoamines from preloaded slices or synaptosomes prepared from rat brain. There are experimental reports stating that d-amphetamine releases 3H noradrenaline, dopamine and 5-HT from synaptosomes (Holmes and Rutledge, 1976; Rothman et al., 2001) and brain slices (Heal et al., 1998). L-Amphetamine releases noradrenaline, dopamine and 5-HT from synaptosomes (Heikkila et al., 1975; Holmes and Rutledge, 1976) and noradrenaline and dopamine from rat brain slices (Easton et al., 2007). Comparing the relative potencies of d- and l-amphetamine, Heikkila et al. (1975) and Easton et al. (2007) reported that the d-isomer was approximately fourfold more potent than the l-isomer as a releaser of 3Hdopamine.
Different mechanisms leading to a 50% reduction in monoamine reuptake produced by a classical reuptake inhibitor versus a competitive substrate (releasing agent). Based on data from 24 sentinel hospitals in 18 countries (17 EU countries and Norway), forming part of the Euro-DEN Plus network, there were acute drug-toxicity presentations at emergency services in 2021 (see Figure Proportion of the acute drug-toxicity presentations with amphetamine involved). Amphetamine was involved in the presentations at 22 of the 24 hospitals and was the fifth most common substance reported by Euro-DEN Plus hospitals in 2021, found in 11% (596) of cases. Out of the 20 centres that reported data on the number of presentations involving amphetamine in both 2020 and 2021, 15 reported a decrease, 3 an increase and 2 a stable number.
Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much of this medicine is taken, it may become habit-forming (causing mental or physical dependence). If you feel that the medicine is not working properly after using it for several weeks, check with your doctor first and do not increase the dose. Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur.