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Slow release Immediate release

abuse than MPH. Generics exist

The third line of therapy for ADHD, antidepressants and antihypertensive therapies, is used less frequently than stimulants, but can be effective. These drugs are sometimes used in combination with stimulants in patients with comorbid symptoms. Commonly used agents are tricyclic antidepressants (TCAs), bupropion, or alpha-adrenoceptor agonists (clonidine, guanfacine, etc.). The therapeutic limitations of these diverse compounds include weight loss, sleep disturbances, abuse liability, and social stigma of stimulants, and the cardiovascular side effects and less well-defined efficacy of atomoxetine, TCAs, or alpha-adrenergic agents.

6.05.6.1 Stimulants

The primary pharmacological treatment for ADHD continues to be the use of stimulants, particularly methylphenidate (Ritalin, Ritalin LA, Ritalin SR, Concerta, Focalin, Methylin, Methylin ER, Metadate ER, and Metadate CD) and amphetamines (Adderall, Adderall XR, Dexedrine, Dexedrine Spansule, and DesxtroStat).1' ' Stimulants are estimated to be effective in 70% of adolescents and appear to improve both cognitive deficits and general behavior.8,46 The beneficial effects of stimulants are similar for male and female adolescents, and for younger children. With lower doses of therapies, adult response rates are in the range of 50%. When higher doses were used, adults responded as well to treatment as do children.80

6.05.6.1.1 Sites and mechanism of action

Stimulant medications increase the synaptic availability of dopamine, and this mechanism is hypothesized to underlie the therapeutic effect. However, it is important to recognize that these compounds also have direct or indirect effects on other neurotransmitters, e.g., acetylcholine, norepinephrine, and 5HT. Based on preclinical data, for example, it has been suggested that the stimulant-induced decreases in hyperactivity may be due to increased 5HT81,82 (but see the discussion of SSRIs below); both norepinephrine and acetylcholine play important roles in attentional processing. Stimulant activity per se is not the critical determinant of efficacy in ADHD, however, since caffeine, a stimulant with a different mechanism of action, appears to be ineffective.83

While the stimulants act to increase the availability of neurotransmitters such as dopamine and norepinephrine, they do so via different mechanisms. Methylphenidate blocks reuptake transporters of dopamine, norepinephrine, and 5HT. Methylphenidate acts to block the reuptake of these monoaminergic neurotransmitters via action on the external surface of the neuron, but does not act as a substrate at these receptor sites. Methylphenidate binds to a site that has high affinity for cocaine. In contrast, amphetamine acts with the transporter substrate recognition site on DAT, but also crosses the cell membrane through transport and diffusion. In this way, amphetamine is able to displace dopamine and activate the release of newly synthesized (nonvesicular) dopamine by reverse transport, ultimately resulting in more synaptic dopamine. The increased abuse liability observed following amphetamine (compared to methylphenidate) may be due to these differences in mechanism of action.

6.05.6.1.2 Structure-activity relationship

Methylphenidate (methyl 2-phenyl-2-(2'-piperidyl)-acetate) can exist as four possible stereoisomers, although Ritalin is a racemic mixture of threo diastereomers.84 The erythoro isomers have little efficacy in the treatment of ADHD symptomology, but contribute to the hypertensive effects of Ritalin. In an attempt to decrease side effects while maintaining efficacy, a single isomer entity dexmethylphenidate (Focalin) was introduced. Figure 3 shows the chemical structures for both Ritalin and Focalin. Focalin is a chirally pure oral dexmethylphenidate (d-MPH); the single stereoisomer version of methylphenidate (dl-MPH). In studies comparing d-MPH to dl-MPH, the treatment effects of d-MPH were obtained at half the dose of dl-MPH. While both agents showed a reduction of ADHD on primary and secondary endpoints, patients treated with d-MPH showed significant improvements in math test scores at 6 h postdosing. In phase III studies, d-MPH was superior to the racemic dl-MPH in all parameter measures, with a longer duration of action and a low incidence of side effects (Figure 3).

6.05.6.1.3 Comparison within drug class

While methylphenidate has long been the leading treatment for ADHD, the compound has a short duration of action and a midday dose is required. In schoolchildren, this necessitates dosing during the school day and contributes to poor compliance and social stigma. Extended-release formulations of methylphenidate (Concerta), a novel formulation of methylphenidate designed to provide both rapid and sustained release, and amphetamine (Adderall XR), a formulation of mixed amphetamine salts, provide durations of action up to 12 h. The longer-acting compounds not only result in

Ritalin

Atomoxetine

Understanding And Treating ADHD

Understanding And Treating ADHD

Attention Deficit Disorder or ADD is a very complicated, and time and again misinterpreted, disorder. Its beginning is physiological, but it can have a multitude of consequences that come alongside with it. That apart, what is the differentiation between ADHD and ADD ADHD is the abbreviated form of Attention Deficit Hyperactive Disorder, its major indications being noticeable hyperactivity and impulsivity.

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