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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 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 NH OH Strattera 4-hydroxyatomoxetine CH3 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 Abdominal Pain Vomiting Decreased Appetite Dizziness Headache Irritability Coughing Stimulants Methylphenidate 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 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 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 • • • • • • • • • • • • • “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