Drugs for the treatment of Drugs for the treatment of Attention-Deficit Attention-Deficit

Hyperactivity DisorderHyperactivity Disorder

Julia DrabsJulia Drabs

What is ADHD?What is ADHD?

Psychological disorder characterized by Psychological disorder characterized by three main traitsthree main traits InattentionInattention HyperactivityHyperactivity ImpulsivityImpulsivity

CharacteristicsCharacteristics

Poor attention and concentrationPoor attention and concentration Easily distractedEasily distracted Shifting activities frequentlyShifting activities frequently Day dreamingDay dreaming ForgetfulnessForgetfulness

Long Term EffectsLong Term Effects AnxietyAnxiety DepressionDepression DivorceDivorce Job lossJob loss StressStress Antisocial behaviorAntisocial behavior Lower educational achievementLower educational achievement

Causes?

• Relatively unknown

• Deficiencies in:

– Seratonergic neurotransmitter systems

– Dopaminergic neurotransmitter systems

– Noradrenergic neurotransmitter systems

DRUGS!

• Antidepressants• Antihypertensive agents• Amino acids• Wake promoting agents• Cholinergic agents• Norepinephrine Reuptake

inhibitors• STIMULANTS!

AntidepressantsAntidepressants

BupropionBupropion EffectiveEffective

Tricyclic AntidepressantsTricyclic Antidepressants IneffectiveIneffective

Monoamine oxidase inhibitorsMonoamine oxidase inhibitors IneffectiveIneffective

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

HO

HO OH

NH2

NHBu

O

Cl

Me

HO

HO H

NH2

Bupropion

Norepinephrine

Dopamine

Antihypertensive AgentsAntihypertensive Agents

άά-adrenoceptor agonists -adrenoceptor agonists – ClonidineClonidine– GuanfacineGuanfacine– Not very effective in treating ADHDNot very effective in treating ADHD

Amino AcidsAmino Acids

One studyOne study IneffectiveIneffective

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 Norepinephrine reuptake inhibitorsinhibitors

AtomoxetineAtomoxetine AKA Strattera®AKA Strattera®

CH3

O

NHCH3

StructureStructure

CH3

O

NHCH3

CH3

O

NHCH3

OH

Strattera 4-hydroxyatomoxetine

P450 Enzyme

DiscoveryEli Lilly and Company

2003HO

HO OH

NH2

NorepinephrineH3C

O

HN CH3

H3C

O

HN CH3

HO

Strattera 4-hydroxyatomoxetine

P450 Enzyme

Norepinephrine Binding Site

O

H

H

OCO2

Strattera Pathway

H

NH2

CO2

O

H

H

O

HO

HO

HO

HO H

NH2

HO

HO H

NH2

Presynaptic site where atomoxetine is pushed instead of dopamine

Pre synapticsite

H3C

O

HN CH3

HO

H3C

O

HN CH3

HO

Side EffectsSide Effects

Abdominal PainAbdominal Pain VomitingVomiting Decreased AppetiteDecreased Appetite DizzinessDizziness HeadacheHeadache IrritabilityIrritability CoughingCoughing

StimulantsStimulants

Methylphenidate Methylphenidate AKA Ritalin®AKA Ritalin®

AdderallAdderall

RitalinRitalin

Discovered: 1957, NovatrisDiscovered: 1957, Novatris Leading stimulant to treat ADHDLeading stimulant to treat ADHD Lasts about 4 hoursLasts about 4 hours

Structure

NH2

HO

HO

H

CO2CH3

NH+

Dextroamphetamine Ritalin

• Ritalin was discovered as a piperidine derivative of dextroamphetamine.

Enantiomers

HO

HO

H

CO2CH3

NH+

HO

HO

H

CO2CH3

NH+

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

Ritalin Pathway

H

NH2

CO2

O

H

H

O

HO

HO

HO

HO H

NH2

HO

HO H

NH2

Presynaptic site where atomoxetine is pushed instead of dopamine

Pre synapticsite

HO

HO

H

CO2CH3

NH+

HO

HO

H

CO2CH3

NH+

Side EffectsSide Effects Decreased appetiteDecreased appetite InsomniaInsomnia HeadachesHeadaches TicsTics Stomach achesStomach aches JitterinessJitteriness IrritabilityIrritability Proneness to crying (children)Proneness to crying (children) RARE: RARE:

Psychotic symptomsPsychotic symptoms Sensitivity reactionsSensitivity reactions

Cognitive ToxicityCognitive Toxicity

AdderallAdderall

• Discovered in the 1960’s as a Discovered in the 1960’s as a treatment for obesity, known as treatment for obesity, known as Obetrol, Rexar PharmacalObetrol, Rexar Pharmacal

• 1994, Richwood Pharmaceutical 1994, Richwood Pharmaceutical Company purchaced Rexar Company purchaced Rexar Pharmacal, and changed Obetrol to Pharmacal, and changed Obetrol to Adderall.Adderall.

Structure

NH2

O S O

NH2

C6H8O8

HO

HO

NH2CH3

SO2

HO

HO

NH2CH3OO

H3N CO2

H

Ch2

C

Dextroamphetamine sulfate Dextroamphetamine saccharate

Amphetamine sulfate Amphetamine asparate

4 salts of equal parts (by weight)

* 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

MechanismMechanism

CNS StimulantCNS Stimulant Mode of therapeutic activity is Mode of therapeutic activity is

unknownunknown Theory:Theory:

– Blocks the reuptake norepinephrine, but Blocks the reuptake norepinephrine, but also stimulates the release of these also stimulates the release of these neurotransmitters, increasing the neurotransmitters, increasing the amount of each available amount of each available presynaptically.presynaptically.

Side EffectsSide Effects

Dry mouthDry mouth Difficulties sleepingDifficulties sleeping DizzinessDizziness HeadacheHeadache Loss of appetiteLoss of appetite NauseaNausea Rapid heart rateRapid heart rate Weight lossWeight loss

CompareCompareDrugsDrugs StimulantStimulant

??Addictive/ Addictive/ easily easily abused?abused?

Side Side EffectsEffects

TargeteTargeted d audiencaudiencee

Time Time frameframe

StratteraStrattera®®

NoNo NoNo More More prominenprominentt

AdultsAdults 4 4 hourshours

Ritalin®Ritalin® YesYes YesYes SomeSome ChildreChildrenn

4 4 hourshours

AdderallAdderall®®

YesYes YesYes SomeSome BothBoth 8 8 hourshours

Future• Longer lasting Drugs Ritalin

• Ritalin®-SR• OROS® (Concerta®)• Metadate® CD• Ritalin® LA

• Transdermal Ritalin Adderall

• SLI-381 (Adderall XR®)

• Cholinergic agents

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_Laura_ADHD.htm