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

Antidepressants Bupropion Tricyclic Antidepressants Effective Tricyclic Antidepressants Ineffective Monoamine oxidase inhibitors

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

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®

Structure P450 Enzyme Strattera 4-hydroxyatomoxetine

Discovery Eli Lilly and Company 2003 Strattera 4-hydroxyatomoxetine Norepinephrine P450 Enzyme Strattera 4-hydroxyatomoxetine

Norepinephrine Binding Site

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

Side Effects Abdominal Pain Vomiting Decreased Appetite Dizziness Headache Irritability Coughing

Stimulants Methylphenidate AKA Ritalin® Adderall

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

Structure Dextroamphetamine Ritalin Ritalin was discovered as a piperidine derivative of dextroamphetamine.

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

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

Side Effects 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) 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 3:1

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

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

Future Longer lasting Drugs Cholinergic agents Ritalin Adderall 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