Download Chapter 16 Cholinesterase Inhibitors

Central Nervous System Stimulants
and Attention-Deficit/Hyperactivity
Disorder
CNS Stimulants
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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 AttentionDeficit/Hyperactivity Disorder
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Amphetamines
Methylphenidate and dexmethylphenidate
Methylxanthines
Miscellaneous stimulants
Attention-deficit/hyperactivity disorder
(ADHD)
Amphetamines
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Chemistry
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Dextroamphetamine and levamphetamine
Amphetamine
Lisdexamfetamine
Methamphetamine
Mechanism of action
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Release norepinephrine (NE)
Release dopamine (DA)
Amphetamines
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Pharmacologic effects
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Tolerance
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With regular use, develops to elevation of mood,
suppression of appetite, and stimulation of the
heart and blood vessels
Physical dependence
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Central nervous system
Cardiovascular system
Abstinence syndrome with abrupt withdrawal
Abuse
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High potential for abuse due to euphoria
Fig. 36–1. Structural formulas of the amphetamines.
Amphetamines
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Adverse effects
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CNS stimulation
Weight loss
Cardiovascular effects
Psychosis
Amphetamines
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Toxicity
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Dysrhythmias
Hypertension
Dizziness
Confusion
 Hallucinations
 Convulsions
 Paranoid delusions
 Coma
 Palpitations
 Cerebral hemorrhage
Amphetamines
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Treatment
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Chlorpromazine: hallucinations
Alpha-adrenergic blocker: hypertension
Diazepam: seizures
Therapeutic uses
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ADHD
Narcolepsy
Amphetamines
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Preparations, dosage, and administration
Dextroamphetamine sulfate
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Amphetamine/dextroamphetamine mixture
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Short duration (Dexedrine, Dextrostat)
Long duration (Dexedrine Spansules)
Short duration (Adderall)
Long duration (Adderall-XR)
Methamphetamine (Desoxyn)
Methylphenidate and
Dexmethylphenidate
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Methylphenidate and dexmethylphenidate are
nearly identical in structure and
pharmacologic actions
The pharmacology of both drugs is nearly
identical to that of amphetamines
Methylphenidate
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ADHD and narcolepsy
Trade names
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Ritalin, Metadate, Methylin, Concerta, Daytrana
50:50 mixture of dextro and levo isomers
Preparations, dosage, and administration
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Short duration
• Ritalin, Methylin
Intermediate duration
• Ritalin SR, Metadate ER, Methylin ER
Long duration
• Concerta, Metadate CD, Ritalin LA
Dexmethylphenidate (Focalin)
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Drug for ADHD
Dextro isomer of methylphenidate
50:50 mixture of dextro and levo isomers
Schedule II drug
Methylxanthines
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Derivatives of xanthine
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Caffeine
• Few clinical applications
• Widespread ingestion for nonmedical purposes
Dietary sources
• Chocolate
• Desserts
• Soft drinks
• Cola nut
Methylxanthines
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Mechanism of action
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Low doses
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Decrease drowsiness and fatigue and increase
capacity for prolonged intellectual exertion
Increasing doses
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Reversible blockade of adenosine receptors
Calcium permeability
Accumulation of cyclic AMP
Nervousness, insomnia, tremors
Seizures with very large amounts
AMP = adenosine monophosphate.
Fig. 36–2. Structural formulas of the methylxanthines.
Methylxanthines
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Pharmacologic effects
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Central nervous system
Heart
Blood vessels
Bronchi
Kidney
Reproduction
Pharmacokinetics
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Readily absorbed from the GI tract
Achieve peak plasma levels within 1 hour
Eliminated by hepatic metabolism
Methylxanthines
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Therapeutic uses
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Neonatal apnea
Promoting wakefulness
Other applications
Acute toxicity
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Stimulation of the CNS
Tachycardia
Respiratory stimulation
Sensory phenomena
Methylxanthines
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Preparations, dosage, and administration
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For promoting wakefulness
For neonatal apnea
Theophylline
Theobromine
Miscellaneous CNS Stimulants
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Pemoline
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Actions, uses, and adverse effects
• Causes less cardiac stimulation and vasoconstriction
• Can cause liver failure
Preparations, dosage, and administration
Miscellaneous CNS Stimulants
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Modafinil (Provigil, Alertec)
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Therapeutic use
• Promotes wakefulness
Mechanism of action
Pharmacokinetics
• Rapidly absorbed in the GI tract
• Elimination by hepatic metabolism
• Half-life: about 15 hours
Miscellaneous CNS Stimulants
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Modafinil (Provigil, Alertec) (cont’d)
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Adverse effects
• Headache
• Nausea
• Nervousness
• Diarrhea
• Rhinitis
Drug interactions
• Oral contraceptives
• Cyclosporine
Miscellaneous CNS Stimulants
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Modafinil (Provigil, Alertec) (cont’d)
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Preparations, dosage, and administration
Blockade
Strychnine: not used as a medicine
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Poisoning
• Causes: accidental ingestion, street drugs
• Symptoms: convulsions, depression
• Treatment: intravenous diazepam, general anesthesia, or
neuromuscular blocker
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Armodafinil
Doxapram
Cocaine
Attention-Deficit/Hyperactivity
Disorder (ADHD) in Children
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Signs and symptoms
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Inattention
Hyperactivity
Impulsivity
Fidgety
Unable to concentrate
ADHD in Children
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Signs and symptoms (cont’d)
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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
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Etiology
Management overview
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Cognitive therapy
Stimulant drugs
Drug therapy I: CNS stimulants
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Methylphenidate (Ritalin, Concerta, others)
Dexmethylphenidate (Focalin)
Dextroamphetamine (Dexedrine, others)
Amphetamine mixture (Adderall)
Pemoline (Cylert)
ADHD in Children
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Drug therapy II: atomoxetine
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Description and therapeutic effects
• Nonstimulant
• No potential for abuse
• Administered once a day
ADHD in Children
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Drug therapy II: atomoxetine (cont’d)
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Mechanism of action
• Selective inhibitor of NE reuptake
Pharmacokinetics
• Plasma levels peak in 1–3 hours
• Metabolized in the liver
ADHD in Children
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Drug therapy II: atomoxetine (cont’d)
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Adverse effects
• GI reactions
• Reduced appetite
• Dizziness
• Somnolence
• Mood swings
• Trouble sleeping
ADHD in Children
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Drug therapy II: atomoxetine (cont’d)
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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
ADHD in Children
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Drug therapy III: antidepressants
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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
ADHD in Adults
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Drug therapy III: antidepressants
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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
Drugs Used for ADHD
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Drug therapy
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Methylphenidate (Ritalin, Concerta)
Dexmethylphenidate (Focalin)
Dextroamphetamine (DextroStat)
Amphetamine mixture (Adderall)
Nonstimulants
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Atomoxetine (Strattera)
Guanfacine (Intuniv)
Clonidine (Kapvay)