Medications for Attention-Deficit/Hyperactivity Disorder

Chapter 41


Medications for Attention-Deficit/Hyperactivity Disorder






INDICATIONS



Labeled Uses




• Attention-deficit/hyperactivity disorder (AD/HD); see Table 41-1



• Narcolepsy: dextroamphetamine, armodafinil, ephedrine, methylphenidate, modafinil, sodium oxybate


• Obesity: benzphetamine, dexfenfluramine, diethylpropion, fenfluramine, methamphetamine, orlistat, phendimetrazine, phentermine, phenylpropanolamine


• Sleep apnea: armodafinil, modafinil




This chapter discusses drugs used primarily in the treatment of AD/HD. The number of children and teens in the United States diagnosed with attention-deficit/hyperactivity disorder from 2000 to 2010 increased 66% to 10.4 million in 2010. Patients with this disorder have difficulty regulating their attention, inhibiting their attention to nonrelevant stimuli, and/or focusing too intensely on specific stimuli to the exclusion of what is relevant. Many persons with AD/HD or ADD pay too much attention to too many things, leading them to have little focus rather than having too little attention. Both amphetamines and amphetamine-like drugs act to alter levels of neurotransmitters in the brain, thereby modifying behaviors to improve and maintain function in patients with attention-deficit disorder with or without hyperactivity and narcolepsy.


Atomoxetine, which is indicated only for the treatment of AD/HD, increases extracellular concentrations of norepinephrine, although the precise mechanism for efficacy in AD/HD is unknown. Antidepressants are used occasionally in children who have failed to respond to other therapy. Modafinil, a CNS analeptic with a unique mechanism of action, is used to treat excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder in adults. It does not have FDA approval for use in AD/HD. Analeptics are not discussed here in detail. An analeptic is a drug that acts as a stimulant to the CNS. Caffeine is the most common analeptic seen in primary care. It is used on an OTC basis to help people stay awake and restore mental alertness and as an adjunct in analgesic formulations. It is a methylxanthine and is not discussed here in detail. An extended-release clonidine (Kapvay) was approved in late 2010 as adjunctive therapy to stimulants for AD/HD or as monotherapy. Chapter 16 provides a discussion of the theophyllines, which are related chemically to the methylxanthines.


Amphetamines, which have very high potential for abuse, are category II drugs. They are used primarily in long-acting formulations, which may make dosing easier for AD/HD in primary care. Methylphenidate, a commonly used drug, is similar to the amphetamines but has less abuse potential, although it is a Schedule II drug. New, longer-acting formulations provide dosing options.


Miscellaneous drugs with central α-agonist action, tricyclic antidepressant desipramine, and analeptics have also been approved for use in AD/HD.



Therapeutic Overview


Pathophysiology


AD/HD is a heterogeneous disorder of unknown cause. Structural and functional neuroimaging studies have not identified a unique origin. Although a positive family history is typical, no specific genetic marker has been identified, and studies that have found a familial association fail to distinguish between the actions of genes and family-specific environmental causes. The neurobiologic processes involved in attention and inhibition necessitate coordination of cortical and subcortical functioning; the most critical structure for maintaining alertness and attention is the reticular activating system, whereas the ability to inhibit distractions is cortically mediated at the prefrontal cortex. Circuits that connect these areas help to control how the brain both sustains and filters attention in response to stimuli. Executive functions are major tasks of the frontal lobes. MRI of the right mesial prefrontal cortex in persons with AD/HD strongly supports decreased activation (low arousal) during tasks that require inhibition of a planned motor response and timing of a motor response to a sensory cue. There is also evidence of weakened activity in the right inferior prefrontal cortex and left caudate during a task that involves timing of a motor response to a sensory cue. The catecholamines are the main neurotransmitters with frontal-lobe function. Catecholamine-controlled dopamine and norepinephrine appear to be important in linking subcortical areas to the frontal lobe. Stimulant drugs probably work by increasing “background” dopamine levels in the synapses. However, diagnostic trials of stimulant medications have failed to distinguish between children with and those without AD/HD.


The key features of AD/HD are inattention and hyperactivity/impulsivity. Although the disorder occurs in individuals of all races and socioeconomic strata, a 6:1 male:female ratio has been noted in childhood, and a positive family history is common. Environmental factors associated with AD/HD include poverty, maternal psychopathology, and family conflict, although none of these has been determined to be causally linked with AD/HD. Substance abuse, school failure, and, later, difficulty in maintaining a job may be associated with AD/HD; however, evidence suggests that patients who are treated properly with medication and who are given support do very well. It is estimated that up to 65% of children with AD/HD have at least one other comorbid condition such as depression, conduct disorder, oppositional defiant disorder, Tourette’s syndrome, or a learning disability.



Disease Process


The diagnosis of AD/HD in children is made after observation and history taking. It requires a documented history of inattention and impulsivity, with or without hyperactivity, causing impairment in at least two settings (usually home and school) before the age of 7. Symptoms must have been prominent for at least 6 months. AD/HD is common, affecting 4% to 12% of school-age children and 3% to 4% of adults. Childhood AD/HD is a prerequisite for the diagnosis of AD/HD in adults, but it is increasingly recognized that adults may have the disorder, along with symptoms that were present in childhood, without ever having received a formal diagnosis as a child.


The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV-TR), defines three subtypes of AD/HD: attentional, hyperactive/impulsive, and combined, which is usually a combination of attentional and hyperactive forms. In children with AD/HD, Predominantly Inattentive Type, inattention is the major problem. The child cannot focus on instructions or tasks, fails to finish schoolwork, often loses things, cannot organize, and is forgetful and easily distracted. Inattentive children may not be noticed in the school setting because they are not disruptive. Thus, their condition often is not diagnosed until they are attending middle or high school.


The second subtype of AD/HD defined by the DSM-IV-TR is AD/HD, Predominantly Hyperactive-Impulsive Type. These children receive more attention in the classroom—often negative attention—because they fidget, cannot wait their turn, interrupt others, act as if “driven by a motor,” talk incessantly, have difficulty enjoying quiet leisure activities, and act impulsively. These children often come to the attention of the health care provider because of concerns expressed by parents and teachers as early as preschool or kindergarten.


Finally, children with AD/HD, Combined Type, exhibit both behavior sets.


AD/HD is a dimensional, not a categorical, disorder with varying degrees of severity, some so mild that they may almost appear normal. In children, hyperactivity usually predominates. Although the hyperactive behavior may abate, or may be better controlled, with age, the attentional cluster of symptoms—inattention, lack of concentration, forgetfulness, shift in activities, executive operation dysfunction, and disorganization—tend to persist. Adolescents often display oppositional and restless behavior. Adults have increased problems with attention- and executive-level functioning and may underperform in their jobs.


The major neurologic functions that are disturbed by neurotransmitter imbalance of AD/HD are the executive function tasks. The six major execution function tasks that are most commonly distorted with this disorder are (1) shifting from one mindset or strategy to another (e.g., flexibility), (2) organization (e.g., anticipating both needs and problems), (3) planning (e.g., goal setting), (4) working memory (e.g., receiving, storing, and then retrieving information with short-term memory), (5) separating affect from cognition (i.e., detaching one’s emotions from one’s reason), and (6) inhibiting and regulating verbal and motoric action (e.g., jumping to conclusions too quickly, difficulty waiting in line in an appropriate fashion).


Before AD/HD is diagnosed, other causes of impaired concentration and memory should be ruled out through a comprehensive neurologic and behavioral examination. Laboratory studies typically are not necessary but may include comprehensive metabolic panel, thyroid studies, and heavy metal screening, with particular attention to lead and toxicology screens. Absence and simple partial seizures can present with staring spells; an electroencephalogram may be indicated to rule out seizures. Children with sleep disorders that interfere with REM sleep may present with inattention and poor school performance; a comprehensive sleep study may be needed to evaluate this possibility. Other psychiatric diagnoses that should be considered and ruled out include anxiety disorders, affective disorders, adjustment disorders, behavioral disorders, and developmental disorders, including speech and language delays, which may cause a child to appear inattentive as a result of an inability to understand classroom directions.


Even though AD/HD has been recognized in children, awareness is only now increasing about the fact that adolescents and adults may have AD/HD and may not have had treatment. In many of these individuals, the condition is diagnosed when they have problems with employment or when they seek treatment for depression or another type of medical problem. Much of the information generated by research about children with AD/HD appears to apply to adults also. Adults benefit from behavioral therapy and from the use of medication to keep them focused and functional.



Mechanism of Action


Amphetamine-like Drugs


Methylphenidate is a mild cortical stimulant with CNS actions similar to those of the amphetamines. It inhibits the reuptake of both norepinephrine and dopamine in the cerebral cortex. This results in an increase in neurotransmitter in the synaptic cleft and enhanced stimulation of the cerebral cortex and subcortical structures. In normal children, as well as in children with AD/HD, this effect enhances the child’s ability to selectively filter stimuli, leading to a decrease in motor activity and an increase in attention and cognition. Dexmethylphenidate contains the more pharmacologically active of the dextro and levo isomers.






Psychostimulants


Caffeine, a methylxanthine, competitively blocks adenosine receptors and is a potent stimulant of the CNS. It also produces cardiac stimulation, dilation of coronary and peripheral blood vessels, constriction of cerebral blood vessels, skeletal muscle stimulation, augmentation of gastric acid secretion, and diuretic activity. It may produce tachycardia or premature ventricular contractions as well. The CNS-stimulating effects and associated constriction of cerebral blood vessels are effective as analgesic adjuncts. It also increases absorption of ergot alkaloids. Tolerance to these effects may develop.


Modafinil is a pharmacologically distinct psychostimulant approved for use in shift work sleep disorders, sleep apnea, narcolepsy, and excessive daytime sleepiness in adults. Although the exact mechanism of action is unknown, studies have demonstrated that it inhibits the reuptake of dopamine and activates glutamatergic circuits while inhibiting GABA. It is thought to have less abuse potential because of the absence of euphoric effects. It is used off-label but recommended for AD/HD.



Treatment Principles


Standardized Guidelines



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Jul 22, 2016 | Posted by in PHARMACY | Comments Off on Medications for Attention-Deficit/Hyperactivity Disorder

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