Central Nervous System Stimulants and Attention-Deficit/Hyperactivity Disorder

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

CNS Stimulants and Attention- Deficit/Hyperactivity Disorder  Amphetamines  Methylphenidate and dexmethylphenidate  Methylxanthines  Miscellaneous stimulants  Attention-deficit/hyperactivity disorder (ADHD)

Amphetamines  Chemistry  Dextroamphetamine and levamphetamine  Amphetamine  Lisdexamfetamine  Methamphetamine  Mechanism of action  Release norepinephrine (NE)  Release dopamine (DA)

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

Fig. 36 – 1. Structural formulas of the amphetamines.

Amphetamines  Adverse effects  CNS stimulation  Weight loss  Cardiovascular effects  Psychosis

Amphetamines  Toxicity  Dysrhythmias  Hypertension  Dizziness  Confusion  Hallucinations  Convulsions  Paranoid delusions  Coma  Palpitations  Cerebral hemorrhage

Amphetamines  Treatment  Chlorpromazine: hallucinations  Alpha-adrenergic blocker: hypertension  Diazepam: seizures  Therapeutic uses  ADHD  Narcolepsy

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)

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

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

Dexmethylphenidate (Focalin)  Drug for ADHD  Dextro isomer of methylphenidate  50:50 mixture of dextro and levo isomers  Schedule II drug

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

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.

Fig. 36 – 2. Structural formulas of the methylxanthines.

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

Methylxanthines  Therapeutic uses  Neonatal apnea  Promoting wakefulness  Other applications  Acute toxicity  Stimulation of the CNS  Tachycardia  Respiratory stimulation  Sensory phenomena

Methylxanthines  Preparations, dosage, and administration  For promoting wakefulness  For neonatal apnea  Theophylline  Theobromine

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

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

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

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

Attention-Deficit/Hyperactivity Disorder (ADHD) in Children  Signs and symptoms  Inattention  Hyperactivity  Impulsivity  Fidgety  Unable to concentrate

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

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)

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

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

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

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

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

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

Drugs Used for ADHD  Drug therapy  Methylphenidate (Ritalin, Concerta)  Dexmethylphenidate (Focalin)  Dextroamphetamine (DextroStat)  Amphetamine mixture (Adderall)  Nonstimulants  Atomoxetine (Strattera)  Guanfacine (Intuniv)  Clonidine (Kapvay)