1. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 36 Central Nervous System Stimulants and Attention-Deficit/Hyperactivity Disorder

2. 2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. CNS Stimulants  Increase the activity of CNS neurons  Enhance neuronal excitation; a few suppress neuronal inhibition  In sufficient doses, all can cause convulsions  Limited clinical applications

3. 3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. CNS Stimulants and Attention- Deficit/Hyperactivity Disorder  Amphetamines  Methylphenidate and dexmethylphenidate  Methylxanthines  Miscellaneous stimulants  Attention-deficit/hyperactivity disorder (ADHD)

4. 4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Chemistry  Dextroamphetamine and levamphetamine  Amphetamine  Lisdexamfetamine  Methamphetamine  Mechanism of action  Release norepinephrine (NE)  Release dopamine (DA)

5. 5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Pharmacologic effects  Central nervous system  Cardiovascular system  Tolerance  With regular use, develops to elevation of mood, suppression of appetite, and stimulation of the heart and blood vessels  Physical dependence  Abstinence syndrome with abrupt withdrawal  Abuse  High potential for abuse due to euphoria

6. 6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 36 – 1. Structural formulas of the amphetamines.

7. 7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Adverse effects  CNS stimulation  Weight loss  Cardiovascular effects  Psychosis

8. 8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Toxicity  Dysrhythmias  Hypertension  Dizziness  Confusion  Hallucinations  Convulsions  Paranoid delusions  Coma  Palpitations  Cerebral hemorrhage

9. 9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Treatment  Chlorpromazine: hallucinations  Alpha-adrenergic blocker: hypertension  Diazepam: seizures  Therapeutic uses  ADHD  Narcolepsy

10. 10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Amphetamines  Preparations, dosage, and administration  Dextroamphetamine sulfate  Short duration (Dexedrine, Dextrostat)  Long duration (Dexedrine Spansules)  Amphetamine/dextroamphetamine mixture  Short duration (Adderall)  Long duration (Adderall-XR)  Methamphetamine (Desoxyn)

11. 11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylphenidate and Dexmethylphenidate  Methylphenidate and dexmethylphenidate are nearly identical in structure and pharmacologic actions  The pharmacology of both drugs is nearly identical to that of amphetamines

12. 12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylphenidate  ADHD and narcolepsy  Trade names  Ritalin, Metadate, Methylin, Concerta, Daytrana  50:50 mixture of dextro and levo isomers  Preparations, dosage, and administration  Short duration Ritalin, Methylin Ritalin, Methylin  Intermediate duration Ritalin SR, Metadate ER, Methylin ER Ritalin SR, Metadate ER, Methylin ER  Long duration Concerta, Metadate CD, Ritalin LA Concerta, Metadate CD, Ritalin LA

13. 13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dexmethylphenidate (Focalin)  Drug for ADHD  Dextro isomer of methylphenidate  50:50 mixture of dextro and levo isomers  Schedule II drug

14. 14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylxanthines  Derivatives of xanthine  Caffeine Few clinical applications Few clinical applications Widespread ingestion for nonmedical purposes Widespread ingestion for nonmedical purposes  Dietary sources Chocolate Chocolate Desserts Desserts Soft drinks Soft drinks Cola nut Cola nut

15. 15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylxanthines  Mechanism of action  Reversible blockade of adenosine receptors  Calcium permeability  Accumulation of cyclic AMP  Low doses  Decrease drowsiness and fatigue and increase capacity for prolonged intellectual exertion  Increasing doses  Nervousness, insomnia, tremors  Seizures with very large amounts AMP = adenosine monophosphate.

16. 16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 36 – 2. Structural formulas of the methylxanthines.

17. 17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylxanthines  Pharmacologic effects  Central nervous system  Heart  Blood vessels  Bronchi  Kidney  Reproduction  Pharmacokinetics  Readily absorbed from the GI tract  Achieve peak plasma levels within 1 hour  Eliminated by hepatic metabolism

18. 18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylxanthines  Therapeutic uses  Neonatal apnea  Promoting wakefulness  Other applications  Acute toxicity  Stimulation of the CNS  Tachycardia  Respiratory stimulation  Sensory phenomena

19. 19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methylxanthines  Preparations, dosage, and administration  For promoting wakefulness  For neonatal apnea  Theophylline  Theobromine

20. 20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Miscellaneous CNS Stimulants  Pemoline  Actions, uses, and adverse effects Causes less cardiac stimulation and vasoconstriction Causes less cardiac stimulation and vasoconstriction Can cause liver failure Can cause liver failure  Preparations, dosage, and administration

21. 21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Miscellaneous CNS Stimulants  Modafinil (Provigil, Alertec)  Therapeutic use Promotes wakefulness Promotes wakefulness  Mechanism of action  Pharmacokinetics Rapidly absorbed in the GI tract Rapidly absorbed in the GI tract Elimination by hepatic metabolism Elimination by hepatic metabolism Half-life: about 15 hours Half-life: about 15 hours

22. 22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Miscellaneous CNS Stimulants  Modafinil (Provigil, Alertec) (cont’d)  Adverse effects Headache Headache Nausea Nausea Nervousness Nervousness Diarrhea Diarrhea Rhinitis Rhinitis  Drug interactions Oral contraceptives Oral contraceptives Cyclosporine Cyclosporine

23. 23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Miscellaneous CNS Stimulants  Modafinil (Provigil, Alertec) (cont’d)  Preparations, dosage, and administration  Blockade  Strychnine: not used as a medicine  Poisoning Causes: accidental ingestion, street drugs Causes: accidental ingestion, street drugs Symptoms: convulsions, depression Symptoms: convulsions, depression Treatment: intravenous diazepam, general anesthesia, or neuromuscular blocker Treatment: intravenous diazepam, general anesthesia, or neuromuscular blocker  Armodafinil  Doxapram  Cocaine

24. 24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Attention-Deficit/Hyperactivity Disorder (ADHD) in Children  Signs and symptoms  Inattention  Hyperactivity  Impulsivity  Fidgety  Unable to concentrate

25. 25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Signs and symptoms (cont’d)  Unable to wait his or her turn  Switches excessively from one activity to another  Calls out excessively in class  Present before age 7 years  Present for at least 6 months

26. 26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Etiology  Management overview  Cognitive therapy  Stimulant drugs  Drug therapy I: CNS stimulants  Methylphenidate (Ritalin, Concerta, others)  Dexmethylphenidate (Focalin)  Dextroamphetamine (Dexedrine, others)  Amphetamine mixture (Adderall)  Pemoline (Cylert)

27. 27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Drug therapy II: atomoxetine  Description and therapeutic effects Nonstimulant Nonstimulant No potential for abuse No potential for abuse Administered once a day Administered once a day

28. 28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Drug therapy II: atomoxetine (cont’d)  Mechanism of action Selective inhibitor of NE reuptake Selective inhibitor of NE reuptake  Pharmacokinetics Plasma levels peak in 1–3 hours Plasma levels peak in 1–3 hours Metabolized in the liver Metabolized in the liver

29. 29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Drug therapy II: atomoxetine (cont’d)  Adverse effects GI reactions GI reactions Reduced appetite Reduced appetite Dizziness Dizziness Somnolence Somnolence Mood swings Mood swings Trouble sleeping Trouble sleeping

30. 30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Drug therapy II: atomoxetine (cont’d)  Drug interactions MAO inhibitors (isocarboxazid, phenelzine) MAO inhibitors (isocarboxazid, phenelzine) CYP2D6 (paroxetine, fluoxetine, quinidine) CYP2D6 (paroxetine, fluoxetine, quinidine)  Role in ADHD therapy  Preparations, dosage, and administration Children who weigh less than 70 kg Children who weigh less than 70 kg Children who weigh 70 kg or more Children who weigh 70 kg or more

31. 31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Children  Drug therapy III: antidepressants  Tricyclic antidepressants Decrease hyperactivity Decrease hyperactivity Little effect on impulsivity and inattention Little effect on impulsivity and inattention Second-line drugs Second-line drugs  Bupropion (Wellbutrin) Can reduce behavioral symptoms Can reduce behavioral symptoms Less effective than stimulants Less effective than stimulants Poses risk of seizure Poses risk of seizure Second-line drug Second-line drug

32. 32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. ADHD in Adults  Drug therapy III: antidepressants  60% of ADHD cases persist into adulthood  Symptoms Poor concentration Poor concentration Stress intolerance Stress intolerance Antisocial behavior Antisocial behavior Outbursts of anger Outbursts of anger Inability to maintain a routine Inability to maintain a routine  Drug therapy Methylphenidate Methylphenidate

33. 33Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drugs Used for ADHD  Drug therapy  Methylphenidate (Ritalin, Concerta)  Dexmethylphenidate (Focalin)  Dextroamphetamine (DextroStat)  Amphetamine mixture (Adderall)  Nonstimulants  Atomoxetine (Strattera)  Guanfacine (Intuniv)  Clonidine (Kapvay)