Chapter 36
Central Nervous System Stimulants
and Attention-Deficit/Hyperactivity
Disorder
Copyright © 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
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CNS Stimulants and AttentionDeficit/Hyperactivity Disorder





Amphetamines
Methylphenidate and dexmethylphenidate
Methylxanthines
Miscellaneous stimulants
Attention-deficit/hyperactivity disorder
(ADHD)
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Amphetamines

Chemistry





Dextroamphetamine and levamphetamine
Amphetamine
Lisdexamfetamine
Methamphetamine
Mechanism of action


Release norepinephrine (NE)
Release dopamine (DA)
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Amphetamines

Pharmacologic effects



Tolerance


With regular use, develops to elevation of mood,
suppression of appetite, and stimulation of the
heart and blood vessels
Physical dependence


Central nervous system
Cardiovascular system
Abstinence syndrome with abrupt withdrawal
Abuse

High potential for abuse due to euphoria
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Fig. 36–1. Structural formulas of the amphetamines.
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Amphetamines

Adverse effects




CNS stimulation
Weight loss
Cardiovascular effects
Psychosis
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Amphetamines

Toxicity




Dysrhythmias
Hypertension
Dizziness
Confusion
 Hallucinations
 Convulsions
 Paranoid delusions
 Coma
 Palpitations
 Cerebral hemorrhage
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Amphetamines

Treatment




Chlorpromazine: hallucinations
Alpha-adrenergic blocker: hypertension
Diazepam: seizures
Therapeutic uses


ADHD
Narcolepsy
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Amphetamines


Preparations, dosage, and administration
Dextroamphetamine sulfate



Amphetamine/dextroamphetamine mixture



Short duration (Dexedrine, Dextrostat)
Long duration (Dexedrine Spansules)
Short duration (Adderall)
Long duration (Adderall-XR)
Methamphetamine (Desoxyn)
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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
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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
Intermediate duration
• Ritalin SR, Metadate ER, Methylin ER
Long duration
• Concerta, Metadate CD, Ritalin LA
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Dexmethylphenidate (Focalin)




Drug for ADHD
Dextro isomer of methylphenidate
50:50 mixture of dextro and levo isomers
Schedule II drug
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Methylxanthines

Derivatives of xanthine


Caffeine
• Few clinical applications
• Widespread ingestion for nonmedical purposes
Dietary sources
• Chocolate
• Desserts
• Soft drinks
• Cola nut
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Methylxanthines

Mechanism of action




Low doses


Decrease drowsiness and fatigue and increase
capacity for prolonged intellectual exertion
Increasing doses


Reversible blockade of adenosine receptors
Calcium permeability
Accumulation of cyclic AMP
Nervousness, insomnia, tremors
Seizures with very large amounts
AMP = adenosine monophosphate.
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Fig. 36–2. Structural formulas of the methylxanthines.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
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Methylxanthines

Therapeutic uses




Neonatal apnea
Promoting wakefulness
Other applications
Acute toxicity




Stimulation of the CNS
Tachycardia
Respiratory stimulation
Sensory phenomena
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Methylxanthines

Preparations, dosage, and administration




For promoting wakefulness
For neonatal apnea
Theophylline
Theobromine
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Miscellaneous CNS Stimulants

Pemoline


Actions, uses, and adverse effects
• Causes less cardiac stimulation and vasoconstriction
• Can cause liver failure
Preparations, dosage, and administration
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Miscellaneous CNS Stimulants

Modafinil (Provigil, Alertec)



Therapeutic use
• Promotes wakefulness
Mechanism of action
Pharmacokinetics
• Rapidly absorbed in the GI tract
• Elimination by hepatic metabolism
• Half-life: about 15 hours
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Miscellaneous CNS Stimulants

Modafinil (Provigil, Alertec) (cont’d)


Adverse effects
• Headache
• Nausea
• Nervousness
• Diarrhea
• Rhinitis
Drug interactions
• Oral contraceptives
• Cyclosporine
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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
• Symptoms: convulsions, depression
• Treatment: intravenous diazepam, general anesthesia, or
neuromuscular blocker



Armodafinil
Doxapram
Cocaine
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Attention-Deficit/Hyperactivity
Disorder (ADHD) in Children

Signs and symptoms





Inattention
Hyperactivity
Impulsivity
Fidgety
Unable to concentrate
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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
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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)
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ADHD in Children

Drug therapy II: atomoxetine

Description and therapeutic effects
• Nonstimulant
• No potential for abuse
• Administered once a day
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ADHD in Children

Drug therapy II: atomoxetine (cont’d)


Mechanism of action
• Selective inhibitor of NE reuptake
Pharmacokinetics
• Plasma levels peak in 1–3 hours
• Metabolized in the liver
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ADHD in Children

Drug therapy II: atomoxetine (cont’d)

Adverse effects
• GI reactions
• Reduced appetite
• Dizziness
• Somnolence
• Mood swings
• Trouble sleeping
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ADHD in Children

Drug therapy II: atomoxetine (cont’d)

Drug interactions
• MAO inhibitors (isocarboxazid, phenelzine)
• CYP2D6 (paroxetine, fluoxetine, quinidine)
 Role in ADHD therapy
 Preparations, dosage, and administration
• Children who weigh less than 70 kg
• Children who weigh 70 kg or more
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ADHD in Children

Drug therapy III: antidepressants

Tricyclic antidepressants
• Decrease hyperactivity
• Little effect on impulsivity and inattention
• Second-line drugs
 Bupropion (Wellbutrin)
• Can reduce behavioral symptoms
• Less effective than stimulants
• Poses risk of seizure
• Second-line drug
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ADHD in Adults

Drug therapy III: antidepressants



60% of ADHD cases persist into adulthood
Symptoms
• Poor concentration
• Stress intolerance
• Antisocial behavior
• Outbursts of anger
• Inability to maintain a routine
Drug therapy
• Methylphenidate
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Drugs Used for ADHD

Drug therapy





Methylphenidate (Ritalin, Concerta)
Dexmethylphenidate (Focalin)
Dextroamphetamine (DextroStat)
Amphetamine mixture (Adderall)
Nonstimulants



Atomoxetine (Strattera)
Guanfacine (Intuniv)
Clonidine (Kapvay)
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