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Treatment of ADHD with Methylphenidate


(unlabelled use includes depression in the elderly, cancer and post stroke patients) ... with structural and pharmacologic properties similar to those of amphetamine ... – PowerPoint PPT presentation

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Title: Treatment of ADHD with Methylphenidate

Treatment of ADHD with Methylphenidate
Historical Context
  • Methylphenidate (MPH) was first synthesized in
  • Marketed by Ciba-Geiggy Pharmaceutical Company as
  • Initially used for chronic fatigue, lethargy,
    depressive states, disturbed and senile
    behaviour, psychosis associated with depression
    and narcolepsy
  • Today use restricted to ADHD
  • (unlabelled use includes depression in the
    elderly, cancer and post stroke patients)

MPH as a stimulant
  • Methylphenidate (MPH) is a CNS stimulant with
    structural and pharmacologic properties similar
    to those of amphetamine
  • prescription of stimulants is the most common
    treatment for attention deficit hyperactivity
    disorder (ADHD)
  • MPH is the most prescribed stimulant
  • Amphetamines are a common alternative
  • Brand names for drugs containing MPH include
    Ritalin SR, Ritalin LA, Metadate ER, Metadate CD,
    Methylin ER, Concerta.

Current Statistics
  • Most studies on MPH have been done on school-age
    children, and investigated short term effects.
    But there have also been studies with pre-school
    children, adolescents, and adults. As well as
    longer term longitudinal designs.
  • 2 - 2.5 of school aged children in North
    America receive pharmacological treatment for
    ADHD. 90 of them are treated with MPH
    (Greenhill Ford, 2002)
  • Nearly 10 of 10 year old boys in the United
    States take stimulants. Boys are 4 times more
    likely to be taking them than grils (Shader
    Oesterheld, 2006)

Therapeutic effects
  • In children with ADHD, MPH reduces disruptive
    behaviour, increases attention and task related
    behaviour as well as enhancing cognitive
  • MPH mainly exerts its effects on behaviour by
    enhancing dopaminergic neurotransmission in the

  • Action MPH acts as a reuptake inhibitor to
    increase the extracellular concentrations of
    norepinephrine and dopamine.
  • Increases concentration of DA at the synapse by
    binding to the DA transporter and blocking it.
  • Also affects other neurotransmitters
    (norepinephrine, acetylcholine, serotonin)
  • MPHs influence on the release of acetylcholine
    produces effects that simulate mania.
  • This is presumed to be achieved indirectly by
    stimulation of cortical D1 receptors.

Neurology possible mechanisms of action
  • Stimulant-induced DA increases in the striatum
    are believed to decrease background firing rates
    and increase signal-to-noise ratio of striatal
  • This could be a mechanism for improving attention
    by enhancement of task-related neuronal cell
  • DA increases in the nucleus accumbens would
    enhance the saliency of a task by increasing the
    interest that it elicits, thus improving
    attention and performance. (since DA also
    modulates incentive salience and motivation)

Possible mechanisms of action (contd)
  • MPH increases metabolism in cerebellum, decreases
    it in the basal ganglia
  • metabolismin cerebellum frontal temporal
    cortices is correlated with D2 density.
    Metabolism increases in people with higher D2
    density, but it decreases in people with low D2
  • the cerebellum plays an important role in higher
    cognitive functions, including memory, learning
    attention. So MPH could exert its beneficial
    effects partially by activation of the
    cerebello-thalamo-frontal circuits.
  • MPH enhances cognitive performance on tasks that
    are sensitive to frontal lobe damage including
    aspects of spacial and working memory.

  • The optimal dose varies considerably across
  • Differences in weight and metabolism rates are
    not sufficient to account for this variation.
  • Dose-response relship Up to a point, higher
    doses produce larger clinical responses
    (reductions in ADHD symptoms) but also result in
    increased side effects
  • For children, the modal dose is 10 mg, 2-3 times
    a day (for immediate-release MPH), but dosage can
    range from 5 to 20mg per administration
  • In a typical 30-kg child, the maximum serum
    concentration occurs about 1.5 to 2 hours
    afterward, dropping by 50 2 hours later
  • The therapeutic effects mimic this, with a
    maximal reduction of ADHD symptoms about 2 hours
    after taking a pill, followed by decline which
    requires another dose about 4 hours after the
  • Duration since ADHD is a chronic condition, the
    duration of treatment is unlimited and as
    necessary (symptoms may gradually disappear, but
    sometimes persist into adulthood).

Side effects
  • Main sleep problems, decreased appetite,
    stomachache, headache
  • Other nervousness, nausea and vomiting,
    dizziness, palpitations, changes in heart rate
    and blood pressure, skin rashes and itching,
    weight loss, and digestive problems, toxic
    psychosis, psychotic episodes, drug dependence
    syndrome, and severe depression upon withdrawal.
  • MPH was said to suppress growth, but more recent
    studies have found such effects to be clinically
  • MPH has also been linked to sudden death, but
    this evidence was found to be anecdotal, as the
    rate of sudden death linked to MPH was found to
    be no different than sudden death in the general

Abuse potential
  • The increase of DA in the brain is associated
    with reinforcing as well as therapeutic effects.
    Thus, there is a potential for abuse. (Schedule
    II drug)
  • MPH increases DA in the nucleus accumbens, which
    is thought to underlie the reinforcing effects of
    drug abuse.
  • MPH is self-administered by animals used
    recreationally by humans
  • Abuse in clinical context is said to be limited,
    and abuse by oral administration of is rare.
  • When abused, MPH is usually administered
    intranasally or injected intravenously, so as to
    produce large increases in DA quickly. This can
    overactivate the DA system, making the experience
    of the drug itself very salient
  • Reinforcing effects of stimulant drugs vary
    widely across individuals. Abusers have been
    found to have low levels of striatal D2 receptors

Abuse - Context of administration
  • Context differs greatly in abuse and clinical
  • Clinical controlled, school setting, expectancy
    doesnt play a prominent role.
  • Abuse response is affected by the context and
  • within the context of the classroom,
    methylphenidate appears to make schoolwork more
    salient but does not elicit drug craving or
    drug-seeking behavior to recreate this effect,
    but when it is procured illegally and taken with
    the expectation of getting high, powerful
    conditioning factors appear to operate that do
    elicit drug craving and drug seeking. (Volkow
    Swanson, 2003)

  • MPH is effective in decreasing ADHD symptoms in a
    majority of individuals
  • Non-response to MPH occurs in 15 to 30 of
    children with ADHD
  • 20 respond but require very high doses
  • Amphetamines may be an alternative for those who
    do not respond to MPH (non-response to both MPH
    amphetamines is rare)
  • There are potential decreases in long-term
    efficiency, which may be due to habituation and
    tolerance effects

  • Overall, I believe that if each case is looked at
    individually, and individual variables and side
    effects are taken into consideration and
    addressed, MPH can be an effective treatment,
    especially in the short term, with a good
    risk-benefit ratio.

Chemical structures
  • methylphenidate amphetamine
  • cocaine