Drugs for the treatment of Attention-Deficit Hyperactivity Disorder

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Drugs for the treatment of Attention-Deficit
Hyperactivity Disorder

• Julia Drabs

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What is ADHD?

• Psychological disorder characterized by three
  main traits
• Inattention
• Hyperactivity
• Impulsivity

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Characteristics

• Poor attention and concentration
• Easily distracted
• Shifting activities frequently
• Day dreaming
• Forgetfulness

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Long Term Effects

• Anxiety
• Depression
• Divorce
• Job loss
• Stress
• Antisocial behavior
• Lower educational achievement

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Causes?

• Relatively unknown
• Deficiencies in
• Seratonergic neurotransmitter systems
• Dopaminergic neurotransmitter systems
• Noradrenergic neurotransmitter systems

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DRUGS!

• Antidepressants
• Antihypertensive agents
• Amino acids
• Wake promoting agents
• Cholinergic agents
• Norepinephrine Reuptake inhibitors
• STIMULANTS!

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Antidepressants

• Bupropion
• Effective
• Tricyclic Antidepressants
• Ineffective
• Monoamine oxidase inhibitors
• Ineffective

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Why Bupropion?

• Bupropion is a dopamine and norepinephrine
  reuptake inhibitor.
• ADHD is a deficiency in the dopamine and
  norepinephrine reuptake inhibitor
• Selective serotonin reuptake inhibitors do not
  appear to be affective in ADHD

Bupropion
Norepinephrine
Dopamine
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Antihypertensive Agents

• ?-adrenoceptor agonists
• Clonidine
• Guanfacine
• Not very effective in treating ADHD

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Amino Acids

• One study
• Ineffective

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Wake Promoting agents

• Drugs used to treat narcolepsy
• Recently approved
• 2 studies
• 1st study, 48 responded positively
• 2nd study, no difference from placebo

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Cholinergic Agents

• Nicotine shown to reduce symptoms of ADHD

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Norepinephrine reuptake inhibitors

• Atomoxetine
• AKA Strattera

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Structure
P450 Enzyme
Strattera
4-hydroxyatomoxetine
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Discovery

• Eli Lilly and Company
• 2003

Norepinephrine
P450 Enzyme
Strattera 4-hydroxyatomoxetine
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Norepinephrine Binding Site
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Strattera Pathway


Pre synaptic site
Presynaptic site where atomoxetine is pushed
instead of dopamine




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Side Effects

• Abdominal Pain
• Vomiting
• Decreased Appetite
• Dizziness
• Headache
• Irritability
• Coughing

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Stimulants

• Methylphenidate
• AKA Ritalin
• Adderall

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Ritalin

• Discovered 1957, Novatris
• Leading stimulant to treat ADHD
• Lasts about 4 hours

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Structure

Dextroamphetamine Ritalin

• Ritalin was discovered as a piperidine derivative
  of dextroamphetamine.

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Enantiomers

d-threo enantiomer l-threo enantiomer

• Ritalin consists of a mixture of d-threo and
  l-threo enantiomers, but only the d-threo
  enantiomer is active

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Ritalin Pathway


Pre synaptic site
Presynaptic site where atomoxetine is pushed
instead of dopamine




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Side Effects

• Decreased appetite
• Insomnia
• Headaches
• Tics
• Stomach aches
• Jitteriness
• Irritability
• Proneness to crying (children)
• RARE
• Psychotic symptoms
• Sensitivity reactions
• Cognitive Toxicity

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Adderall

• Discovered in the 1960s as a treatment for
  obesity, known as Obetrol, Rexar Pharmacal
• 1994, Richwood Pharmaceutical Company purchaced
  Rexar Pharmacal, and changed Obetrol to Adderall.

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Structure
4 salts of equal parts (by weight)

Dextroamphetamine sulfate Dextroamphetamine
saccharate

Amphetamine sulfate Amphetamine asparate
All four salts come in a d-levo and l-levo
form, although the d-levo is the active form, and
comes in a ratio of 31
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Mechanism

• CNS Stimulant
• Mode of therapeutic activity is unknown
• Theory
• Blocks the reuptake norepinephrine, but also
  stimulates the release of these
  neurotransmitters, increasing the amount of each
  available presynaptically.

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Side Effects

• Dry mouth
• Difficulties sleeping
• Dizziness
• Headache
• Loss of appetite
• Nausea
• Rapid heart rate
• Weight loss

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Compare
Drugs Stimulant? Addictive/ easily abused? Side Effects Targeted audience Time frame
Strattera No No More prominent Adults 4 hours
Ritalin Yes Yes Some Children 4 hours
Adderall Yes Yes Some Both 8 hours
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Future

• Longer lasting Drugs
• Ritalin
• Ritalin-SR
• OROS (Concerta)
• Metadate CD
• Ritalin LA
• Transdermal Ritalin
• Adderall
• SLI-381 (Adderall XR)
• Cholinergic agents

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Referances

• A Comparison of Ritalin and Adderall Efficacy
  and Time-Course in Children with
  Attention-Deficit/Hyperactivity Disorder.
  Pediatrics, Apr99 part 1 of 2, Vol. 103 Issue 4,
  p 9805-806.
• Adderall The New Psychostimulant. Brown
  University Psychopharmacology Update, Nov94, Vol.
  5 Issue 11, p 1-2.
• Doffing, Melissa A., Wolraich, Mark L.
  Pharmacokinetic Considerations in the Treatment
  of Attention-Deficit Hyperactivity Disorder with
  Methylphenidate. CNS Drugs. 2004, 18(4),
  243-250.
• FDA Clears use of Adderall for
  Attention-Deficit Disorder. Brown University
  Child and Adolescent Behavior Letter. Mar96, Vol.
  12, Issue 3.
• Health and Medicine Week, September 6, 2004, 79.
• Markowitz, John S., Patrick, Kennerly S.
  Pharmacology of Methylphenidate, Amphetamine
  Enantiomers and Pemoline in Attention-Deficit
  Hyperactivity Disorder. Human Psychopharmacology.
  1997, 12, 527-546.
• McKeage, Kate, Scott, Lesley J. SLI-381
  (Adderall XR). CNS Drugs. 2003 17(9), 669-675.
• Plosker, Greg L., Dimpson, Dene Atomoxetine A
  Review of its Use in Adults with Attention
  Deficit Hyperactivity Disorder. Drugs. 2004,
  64(2), 205-222.
• Wilens, Timothy E. Drug Therapy for Adults with
  Attention-Deficit Hyperactivity Disorder. Drugs.
  2003, 63(22), 2395-2411.
• http//www.rx-counter.com/
• http//www.neurologyreviews.com/jan03/newsroundup.
  html
• http//faculty.washington.edu/chudler/amp.html
• http//www.cwu.edu/chem/courses/Chem564/Scott_Lau
  ra_ADHD.htm