Amphetamine methylphenidate and

The development of psychosis is the most striking clinical characteristic of high-dose stimulant abuse. The amphetamines, methylphenidate, and phen-metrazine all produce psychosis (Ellinwood et al. 1973 Harris and Batki 2000 Iversen et al. 1978 Lucas and Weiss 1971 McCormick and McNeil 1962). 

In rats, cocaine (6 mg/kg, i.p. or p.o.) has been shown to induce a significant increase in sleep latency and a reduction in total sleep time, including a decrease in both non-REM sleep and REM sleep (Schwartz 2004). In humans, cocaine, amphetamines, and methylphenidate also produce decreases in sleepiness, an increased latency to sleep, and a marked decrease in REM sleep associated with an increased latency to the onset of this state. Amphetamine, methylphenidate, and cocaine are known to act by enhancing the amount of the monoamines available within the synaptic cleft of synapses in the CNS. 

Lin J. S., Hou Y., Jouvet M. (1996). Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc. Natl. Acad. Sci. USA 93, 14128-33. 

Other possible pharmacological causes of sleep disturbance in the medically ill should also be considered, including high-potency diuretics or drugs with CNS stimulant activity (e.g.., caffeine, amphetamines, methylphenidate, and newer stimulants)... 

However, clinical results with compounds enhancing cholinergic function have not been overly convincing (272). In the case of tacriae, however, the beneficial therapeutic iadex was sufficient to justify regulatory approval ia several countries. Psychostimulants such as pemoline, amphetamine, procaine, and methylphenidate have failed to show cognitive enhancing effects ia patients with dementia, except possibly as iadirect consequences of mood elevation. 

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

Mild increases in tonic dopamine release - as a consequence of the administration of both methylphenidate and amphetamine - could have important impact on subsequent phasic release by feedback mechanisms (lowering the concentration). 

Psychostimulants. Table 2 Influence of the psychostimulants amphetamine, cocaine, and methylphenidate on the different biogene amines... 

Dextromethorphan, meperidine, and pentazocine ° Amphetamine, fenfluoramine, dexfenfluoramine, methylphenidate, and cocaine ° Sibutramine, St. John s wort, ondansetron, granisetron, dolasetron, and palonosetron... 

The proposed mechanism of ADHD pharmacotherapy is to modulate neurotransmitters in order to improve academic and social functioning. Pharmacologic therapy can be divided into two categories stimulants and non-stimulants. Stimulant medications include methylphenidate, dexmethylphenidate, amphetamine salts, and dextroamphetamine, whereas non-stimulant medications include atomoxetine, tricyclic antidepressants (e.g., imipramine), clonidine, guanfacine, and bupropion. 

Psychostimulants (e.g., methylphenidate and dextroamphetamine with or without amphetamine) are the most effective agents in treating ADHD. Once the diagnosis of ADHD has been made, a stimulant medication should be used first line in treating ADHD (Fig. 39-1). Stimulants are safe and effective, with a response rate of 70% to 90% in patients with ADHD.3,13,14 Generally, a trial of at least 3 months on a stimulant is appropriate, and this includes dose titration to response... 

Sellings LHL, Clarke PBS (2003) Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial medial shell and core, J Neurosci 23 6295-6303 Sellings EH, McQuade EE, Clarke PB (2006) Characterization of dopamine-dependent rewarding and locomotor stimulant effects of intravenously-administered methylphenidate in rats. Neuroscience 141 1457-1468... 

Dextroamphetamine (Dexedrine). Dextroamphetamine is the second most widely used stimulant and the most commonly used amphetamine in the United States. It is about twice as potent as methylphenidate and should be initiated in the treatment of ADHD at 2.5 mg taken twice daily with breakfast and lunch. Like other stimulants, the benefits of dextroamphetamine can be seen almost immediately. With weekly visits while starting treatment, the dose can be increased in 2.5-5 mg increments until the effective dose is found. Because dextroamphetamine is also slightly longer acting than methylphenidate, patients may be less likely to need an evening dose. If an after-school dose is used, then like methylphenidate it should be 25-50% of the daytime dose. 

Methylphenidate and amphetamines have been used for ADHD management for many years but due to abuse potentials, these drugs are controlled substances." " Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule. It was developed for the intention of creating a longer-lasting and more-difficult-to-abuse version of dextroamphetamine, as the requirement... 

CNS stimulants can be classified as Psychomotor stimulants compounds that display a stimulatory effect primarily on brain functions and which activate mental and physical activity of the organism. They are made up of methylxanthines (caffeine, theophylline, pentoxifyllin), amphetamines (dextroamphetamine, methamphetamine), and also methylphenidate and pemoline. Respiratory stimulants or analeptics compounds, which cause certain activations of mental and physical activity of the organism, and primarily excite the vasomotor and respiratory centers of the medulla (doxapram, almitrine).Drwgi that suppress appetite or anorectics drags that activate mental and physical activity of the organism, but primarily accentuate the excitatory center of satiation in the hypothalamus (phentermine, diethylpropion).In order to increase mental capability, nootropics — drugs that increase the functional state of the brain — are sometimes used, the effect of which is associated with blood flow and metabolism of the brain. 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

The most common treatments for ADHD are the stimulant medications methylphenidate and amphetamines. Secondary medications include dopaminergic or noradrenergic reuptake blockers (e.g., a tamoxetine) and ttj-adrenergic agonists. These treatments are reviewed in this volume (see Chapters 20, 21, 24, and 35). Thus, only brief reference will be made here to the possible effects these compounds may have vis-a-vis modulation of attentional circuits. These ideas are summarized in Figure 8.2. 

Methylphenidate and D-amphetamine are both short-acting compounds, with an onset of action within 30 to 60 minutes and a peak clinical effect seen usually between 1 and 2 hours after administration, lasting 2 to 5 hours. Therefore, multiple daily administrations are required for a consistent daytime response. The amphetamine compound Adderall, the sustained-release preparations of methylphenidate and dextroamphetamine, and pemoline are all intermediate-acting compounds with an onset of action within 60 minutes and a peak clinical effect seen usually between 1 and 3 hours after administration and maintained for up to 8 hours (8 hours with metadate C.D. and Ritalin LA 12 hours with Concerta), allowing for a single dose for the entire school day. Adderall XR is a 12 hour preparation. 

Dextroamphetamine, the d-isomer of amphetamine, is available in immediate-release and extended-release formulations. It is functionally more potent than methylphenidate and may be associated with a greater risk of growth retardation and abuse. 

Amphetamine/dextroamphetamine (Adderall) is also more potent than methylphenidate, and it has a longer half-life. It is a mixture... 

Cocaine, amphetamine, dextroamphetamine, methylphenidate, and pemoline are classified as psychomotor stimulants, producing an acute euphoria in control subjects, as well as a wide variety of responses in psychiatric patients. These stimulants are also effective in postponing the deterioration in psychomotor performance that often accompanies extreme fatigue, a property that may be useful in some carefully selected cases. 

Rush, C.R. et al., Reinforcing and subject-rated effects of methylphenidate and D-amphetamine in non-drug-abusing humans, J. Clin. Psychopharmacol., 21, 273, 2001. 

FIGURE 7—53- Heroic combo 9 Mirtazapine plus stimulant. Here, 5HT, NE, and DA are all single-boosted. The stimulants could include ( -amphetamine, methylphenidate, phentermine, or di-ethylpropion. It could also include direct-acting dopamine agonists such as pramipexole. 

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and ( -amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and ( -amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12— 2 and 12—3). These agents not only block the dopamine transporter but may actually... 

In this chapter, we have looked at two topics in cognitive enhancement attention and memory. We have first reviewed the role of dopamine and norepinephrine/ noradrenaline in the neuropharmacology of attention, and then the syndrome of attention deficit disorder as a common problem associated with a disorder of attention. We then discussed the use of stimulants for improving attention, primarily in attention deficit disorder, and reviewed the pharmacological mechanisms of action of methylphenidate, d and 1 amphetamine, pemoline, and secondary therapies such as clonidine and guanfacine. 

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