Transcript Drugs for the treatment of Attention

Drugs for the treatment of
Attention-Deficit Hyperactivity
Disorder
Julia Drabs
What is ADHD?
 Psychological disorder characterized by
three main traits
 Inattention
 Hyperactivity
 Impulsivity
Characteristics
Poor attention and concentration
 Easily distracted
 Shifting activities frequently
 Day dreaming
 Forgetfulness

Long Term Effects
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Anxiety
Depression
Divorce
Job loss
Stress
Antisocial behavior
Lower educational achievement
Causes?
• Relatively unknown
• Deficiencies in:
– Seratonergic neurotransmitter systems
– Dopaminergic neurotransmitter systems
– Noradrenergic neurotransmitter systems
DRUGS!
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Antidepressants
Antihypertensive agents
Amino acids
Wake promoting agents
Cholinergic agents
Norepinephrine Reuptake inhibitors
STIMULANTS!
Antidepressants

Bupropion


Tricyclic Antidepressants


Effective
Ineffective
Monoamine oxidase inhibitors

Ineffective
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
O
Cl
NHBu
Me
Bupropion
HO
OH
HO
NH2
Norepinephrine
HO
H
HO
NH2
Dopamine
Antihypertensive Agents
ά-adrenoceptor agonists
– Clonidine
– Guanfacine
– Not very effective in treating ADHD
Amino Acids
 One study
 Ineffective
Wake Promoting agents
• Drugs used to treat narcolepsy
– Recently approved
– 2 studies
•1st study, 48% responded positively
•2nd study, no difference from placebo
Cholinergic Agents
• Nicotine shown to reduce
symptoms of ADHD
Norepinephrine reuptake inhibitors

Atomoxetine

AKA Strattera®
CH3
O
CH3
NH
Structure
CH3
CH3
P450 Enzyme
O
O
CH3
NH
CH3
NH
OH
Strattera
4-hydroxyatomoxetine
Discovery
Eli Lilly and Company
2003
HO
HO
OH
NH2
H3C
Norepinephrine
H3C
O
HO
O
P450 Enzyme
HN CH
3
Strattera
HN CH
3
4-hydroxyatomoxetine
Norepinephrine Binding Site
H
O
O
H
CO2
Strattera Pathway
H
Pre synaptic
site
O
O
H
HO
H
HO
NH2
CO2
H3C
HO
Presynaptic site
where atomoxetine is
pushed instead of
dopamine
HO
O
HO
HN CH
3
H3C
H
HO
HO
O
NH2
HN CH
3
HO
H
NH2
Side Effects
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Abdominal Pain
Vomiting
Decreased Appetite
Dizziness
Headache
Irritability
Coughing
Stimulants

Methylphenidate
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
Adderall
AKA Ritalin®
Ritalin



Discovered: 1957, Novatris
Leading stimulant to treat ADHD
Lasts about 4 hours
Structure
HO
CO2CH3
HO
NH2
Dextroamphetamine
H
NH+
Ritalin
• Ritalin was discovered as a piperidine
derivative of dextroamphetamine.
Enantiomers
HO
HO
CO2CH3
HO
H
CO2CH3
HO
H
NH
+
d-threo enantiomer
NH+
l-threo enantiomer
• Ritalin consists of a mixture of d-threo
and l-threo enantiomers, but only the dthreo enantiomer is active
Ritalin Pathway
H
Pre synaptic
site
HO
O
O
H
HO
H
NH2
CO2
HO
CO2CH3
HO
Presynaptic site
where atomoxetine is
pushed instead of HO
dopamine
HO
H
NH+
HO
H
HO
CO2CH3
HO
NH2
H
NH+
HO
H
NH2
Side Effects
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Decreased appetite
Insomnia
Headaches
Tics
Stomach aches
Jitteriness
Irritability
Proneness to crying (children)
RARE:



Psychotic symptoms
Sensitivity reactions
Cognitive Toxicity
Adderall
• Discovered in the 1960’s as a treatment
for obesity, known as Obetrol, Rexar
Pharmacal
• 1994, Richwood Pharmaceutical Company
purchaced Rexar Pharmacal, and changed
Obetrol to Adderall.
Structure
4 salts of equal parts (by weight)
C6H8O8
O S O
NH2
NH2
Dextroamphetamine sulfate
HO
Dextroamphetamine saccharate
H
HO
H3N C CO2
HO
SO2
CH3
NH2
Amphetamine sulfate
*
Ch2
HO
CH3
NH2
O
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 3:1
O
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.
Side Effects
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Dry mouth
Difficulties sleeping
Dizziness
Headache
Loss of appetite
Nausea
Rapid heart rate
Weight loss
Compare
Drugs
Stimulant?
Addictive/
easily
abused?
Side
Effects
Targeted Time
audience frame
Strattera® No
No
More
Adults
prominent
4
hours
Ritalin®
Yes
Yes
Some
Children
4
hours
Adderall®
Yes
Yes
Some
Both
8
hours
Future
• Longer lasting Drugs
 Ritalin
•
•
•
•
•
Ritalin®-SR
OROS® (Concerta®)
Metadate® CD
Ritalin® LA
Transdermal Ritalin
 Adderall
• SLI-381 (Adderall XR®)
• Cholinergic agents
Referances
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“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_Laura_ADHD.htm