PTSD develops in 4% of men at some time in their lives and in 10% to 14% of women. Traumatic events that involve interpersonal violence (e.g., assault, rape, torture) are more likely to cause PTSD than are traumatic events that do not (e.g., car accidents, natural disasters). For example, among rape victims, the incidence of PTSD is 45.9% for women and 65% for men. In contrast, among natural disaster survivors, the incidence is 5.4% for women and 3.7% for men. Combat carries a high risk of PTSD; the disorder develops in up to 40% of soldiers who go to war.
Treatment
PTSD can be treated with psychotherapy and with drugs, as described in an evidence-based guideline—VA/DoD Clinical Practice Guideline for the Management of Post-Traumatic Stress—released by the Department of Veterans Affairs and Department of Defense in 2010. Two basic types of psycho- therapy are recommended: trauma-focused therapy and stress inoculation training. Trauma-focused therapy uses a variety of cognitive behavioral techniques, including a very effective one known as exposure therapy, in which patients repeatedly reimagine traumatic events as a way to make those events lose their power. Stress inoculation training helps patients identify cues that can trigger fear and anxiety, and then teaches them techniques to cope with those disturbing reactions.
Regarding drugs, evidence of efficacy is strongest for three SSRIs (fluoxetine, paroxetine, and sertraline) and one SNRI (venlafaxine). Of these four drugs, only two—paroxetine [Paxil]
and sertraline [Zoloft]—are FDA approved for PTSD. If none of the first-line drugs is effective, the guidelines suggest several alternatives: mirtazapine, a TCA (amitriptyline or imipramine), or an MAOI (phenelzine). Current evidence does not support the use of monotherapy with bupropion, buspirone, trazodone, or a benzodiazepine.
Benzodiazepines (e.g., clonazepam [Klonopin, Rivotril ], alprazolam [Xanax]) are an option for some patients. These drugs are well tolerated and their benefits are immediate, unlike those of the SSRIs. As a result, benzodiazepines can provide rapid relief and can be used PRN. Accordingly, these drugs are well suited for people whose fear is limited to performance situations and who must face those situations only occasionally.
The usual dosage is 1 to 3 mg/day for clonazepam, and 1 to 6 mg/day for alprazolam.
Propranolol [Inderal] and other beta blockers can benefit patients with performance anxiety. When taken 1 to 2 hours before a scheduled performance, beta blockers can reduce symptoms caused by autonomic hyperactivity (e.g., tremors, sweating, tachycardia, palpitations). Doses are relatively small—only 10 to 80 mg for propranolol.
POST-TRAUMATIC STRESS DISORDER Characteristics
Post-traumatic stress disorder (PTSD) develops following a traumatic event that elicited an immediate reaction of fear, helplessness, or horror. PTSD has three core symptoms: re- experiencing the event, avoiding reminders of the event (coupled with generalized emotional numbing), and a persistent state of hyperarousal. A traumatic event is one that involves a threat of injury or death, or a threat to one’s physical integrity. Many events meet this criterion. Among these are physical or sexual assault, rape, torture, combat, industrial explosions, serious accidents, natural disasters, being taken hostage, displacement as a refugee, and terrorist attacks. It should be noted that PTSD can affect persons who were only witnesses to a traumatic event—not just those who were directly involved.
The epidemiology of PTSD is revealing. In the United States, more than 8 million Americans have PTSD in any given year, making PTSD the fourth most common psychiatric disorder.
KEY POINTS
■ Anxiety is an uncomfortable state that has psychologic manifestations (fear, apprehension, dread, uneasiness) and physical manifestations (tachycardia, palpitations, trembling, dry mouth, sweating, weakness, fatigue, shortness of breath).
■ When anxiety is persistent and disabling, intervention is indicated.
■ As a rule, optimal therapy of anxiety disorders consists of psychotherapy combined with drug therapy.
■ The drugs used most often for anxiety disorders are serotonergic reuptake inhibitors and benzodiazepines.
■ Benzodiazepines are used primarily for panic disorder (PD) and generalized anxiety disorder (GAD), whereas SRIs are used for all anxiety disorders.
■ GAD is a chronic condition characterized by uncontrollable worrying.
■ First-line drugs for GAD are SRIs, buspirone, and benzodiazepines.
■ SRIs (venlafaxine, paroxetine, escitalopram, and duloxetine) are especially well suited for treating patients who have depression in addition to GAD. However, they are also effective even when depression is absent.
■ With buspirone, venlafaxine, paroxetine, escitalopram, and duloxetine, anxiolytic effects are delayed. Accordingly, these drugs are best suited for long-term management—not rapid relief.
■ Buspirone has three advantages over benzodiazepines: It does not cause CNS depression, has no abuse potential, and does not intensify the effects of CNS depressants.
■ Buspirone levels can be increased by erythromycin, ketoconazole, and grapefruit juice.
■ Benzodiazepines suppress symptoms of GAD immediately.
Accordingly, these drugs are preferred agents for rapid stabilization, especially when anxiety is severe.
■ Benzodiazepines are CNS depressants and hence can cause sedation and psychomotor slowing. In addition, they can intensify CNS depression caused by other drugs.
■ Benzodiazepines have some potential for abuse, and hence should be used with caution in patients known to abuse alcohol or other psychoactive drugs.
■ When taken long term, benzodiazepines can cause physical dependence. To minimize withdrawal symptoms, dosage
should be tapered gradually—over a period of several months.
■ Patients with panic disorder experience recurrent panic attacks, characterized by palpitations, pounding heart, chest pain, derealization or depersonalization, and fear of dying or going crazy.
■ Many patients with panic disorder also experience agora- phobia, a condition characterized by anxiety about being in places or situations from which escape might be difficult or embarrassing, or in which help might be unavailable if a panic attack should occur.
■ SSRIs are first-line drugs for panic disorder.
■ SSRIs decrease the frequency and intensity of panic attacks, anticipatory anxiety, and avoidance behavior, and they work regardless of whether the patient has depression.
■ Obsessive-compulsive disorder (OCD) is characterized by persistent obsessions and compulsions that cause marked distress, consume at least 1 hour a day, and significantly interfere with daily living.
■ SSRIs are first-line drugs for OCD.
■ Social anxiety disorder, formerly known as social phobia, is characterized by an intense, irrational fear of being scrutinized by others or of doing something that could be embarrassing or humiliating.
■ The SSRIs are first-line drugs for most patients with social anxiety disorder.
■ When social anxiety disorder is limited to fear of speaking or performing in public and when these situations arise infrequently, PRN treatment with a benzodiazepine may be preferred to long-term treatment with an SSRI.
■ Post-traumatic stress disorder (PTSD) develops following a traumatic event that elicited an immediate reaction of fear, helplessness, or horror.
■ PTSD has three core symptoms: re-experiencing, avoidance/
emotional numbing, and hyperarousal.
■ Events that can lead to PTSD include physical or sexual assault, rape, torture, combat, industrial explosions, serious accidents, natural disasters, being taken hostage, displace- ment as a refugee, and terrorist attacks.
■ According to a VA/DoD guideline, PTSD can be treated with psychotherapy and with drugs.
■ Two SSRIs—paroxetine and sertraline—are approved by the FDA for first-line drug treatment of PTSD. Additional drugs used for treatment of PTSD include venlafaxine (an SNRI), TCAs, and MAOIs.
Please visit http://evolve.elsevier.com/Lehne for chapter- specific NCLEX® examination review questions.
36 Central Nervous System Stimulants and Attention-Deficit/Hyperactivity Disorder
CENTRAL NERVOUS SYSTEM STIMULANTS, p. 406 Amphetamines, p. 406
Methylphenidate and Dexmethylphenidate, p. 408
Methylphenidate, p. 408 Dexmethylphenidate, p. 409 Methylxanthines, p. 409
Caffeine, p. 409
Miscellaneous CNS Stimulants, p. 411 Modafinil, p. 411
Armodafinil, p. 411 Doxapram, p. 411
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, p. 411
Basic Considerations, p. 411 ADHD in Children, p. 411 ADHD in Adults, p. 412 Drugs Used for ADHD, p. 412
CNS Stimulants, p. 412 Nonstimulants, p. 412 Key Points, p. 415
Summary of Major Nursing Implications, p. 415
AMPHETAMINES
The amphetamine family consists of amphetamine, dextroam- phetamine, methamphetamine, and lisdexamfetamine. All are powerful CNS stimulants. In addition to their CNS actions, amphetamines have significant peripheral actions—actions that can cause cardiac stimulation and vasoconstriction. The amphetamines have a high potential for abuse.
Chemistry
Dextroamphetamine and Levamphetamine. Amphet- amines are molecules with an asymmetric carbon atom. As a result, amphetamines can exist as mirror images of each other.
Such compounds are termed optical isomers or enantiomers.
Dextroamphetamine and levamphetamine both contain the same atomic components, but those components are arranged differently around the asymmetric carbon. Because of this structural difference, these compounds have somewhat different properties. For example, dextroamphetamine is more selective than levamphetamine for causing stimulation of the CNS, and hence produces fewer peripheral side effects.
CENTRAL NERVOUS SYSTEM STIMULANTS
Central nervous system (CNS) stimulants increase the activity of CNS neurons. Most stimulants act by enhancing neuronal excitation. A few act by suppressing neuronal inhibition. In sufficient doses, all stimulants can cause convulsions.
Clinical applications of the CNS stimulants are limited.
Currently these drugs have two principal indications: attention- deficit/hyperactivity disorder (ADHD) and narcolepsy.
Please note that CNS stimulants are not the same as anti- depressants. The antidepressants act selectively to elevate mood, and hence can relieve depression without affecting other CNS functions. In contrast, CNS stimulants cannot elevate mood without producing generalized excitation. Accordingly, the role of stimulants in treating depression is minor.
Our principal focus is on amphetamines, methylphenidate [Ritalin, others], and methylxanthines (e.g., caffeine). These are by far the most widely used stimulant drugs.
Prototype Drugs
Central Nervous System Stimulants Amphetamines
Amphetamine sulfate Amphetamine-like Drugs Methylphenidate
Methylxanthines Caffeine
Drugs for Attention-Deficit/Hyperactivity Disorder CNS Stimulants
Methylphenidate Nonstimulants Atomoxetine
Amphetamine. The term amphetamine refers not to a single compound but rather to a 50 : 50 mixture of dextroam- phetamine and levamphetamine. (In chemistry, we refer to such equimolar mixtures of enantiomers as racemic.)
to those of cocaine.) Because of their abuse potential, all amphetamines, including lisdexamfetamine, are classified under Schedule II of the Controlled Substances Act and must be dispensed accordingly. Whenever amphetamines are used therapeutically, their potential for abuse must be weighed against their potential benefits.
Adverse Effects
CNS Stimulation. Stimulation of the CNS can cause insomnia, restlessness, and extreme loquaciousness. These effects can occur at therapeutic doses.
Weight Loss. By suppressing appetite, amphetamines can cause weight loss.
Cardiovascular Effects. At recommended doses, stimulants produce a small increase in heart rate and blood pressure.
For most patients, these increases lack clinical significance.
However, for patients with pre-existing cardiovascular disease, stimulants may cause dysrhythmias, anginal pain, or hyper- tension. Accordingly, amphetamines must be employed with extreme caution in these people. Any patient who develops cardiovascular symptoms (e.g., chest pain, shortness of breath, fainting) while using a stimulant should be evaluated immediately.
Do amphetamines increase the risk of sudden death? Prob- ably not. Sudden death in children on these medications is very rare, and evidence is conflicting regarding the risk of sudden death. Should children routinely receive an electrocardiogram (ECG) before using these drugs? Probably not—despite a 2008 statement from the American Heart Association (AHA) saying it would be reasonable to consider obtaining an ECG in children being evaluated for stimulant therapy of ADHD.
Why is the AHA concerned? Because 14 children, 5 with heart defects, died suddenly while using Adderall, a mixture of amphetamine and dextroamphetamine. However, given that millions of children have used the drug, the death rate is no greater than would be expected for a group this size, whether or not Adderall was being used. The bottom line?
First, there are conflicting data showing that stimulants increase the risk of sudden death, even in children with heart disease.
Second, there are no data showing that limiting the use of stimulants in children with heart defects will protect them from sudden death. And third, there are no data showing that screening for heart disease with an ECG before start- ing stimulants will be of benefit. Therefore, it would seem that routine ECGs are unnecessary before starting a child on stimulant therapy, especially if there is no evidence of heart disease. However, if there is evidence of heart disease, or evidence of hereditary cardiovascular defects, an ECG might be appropriate.
Psychosis. Excessive amphetamine use produces a state of paranoid psychosis, characterized by hallucinations and paranoid delusions (suspiciousness, feelings of being watched). Amphetamine-induced psychosis looks very much like schizophrenia. Symptoms are thought to result from the release of DA. Consistent with this hypothesis is the obser- vation that symptoms can be alleviated with a DA receptor blocking agent (e.g., haloperidol). Following amphetamine withdrawal, psychosis usually resolves spontaneously within a week.
In some individuals, amphetamines can unmask latent schizophrenia. For these people, symptoms of psychosis do not clear spontaneously, and hence psychiatric care is indicated.
Lisdexamfetamine. Lisdexamfetamine [Vyvanse] is a prodrug composed of dextroamphetamine covalently linked to L-lysine. Following oral dosing, the drug undergoes rapid hydrolysis by enzymes in the intestine and liver to yield lysine and free dextroamphetamine, the active form of the drug. If lisdexamfetamine is inhaled or injected, hydrolysis will not take place, and hence the drug is not effective by these routes.
Accordingly, it may have a lower abuse potential than other forms of amphetamine.
Methamphetamine. Methamphetamine is simply dextro- amphetamine with an additional methyl group.
Mechanism of Action
The amphetamines act primarily by causing release of norepi- nephrine (NE) and dopamine (DA), and partly by inhibiting reuptake of both transmitters. These actions take place in the CNS and in peripheral nerves. Most pharmacologic effects result from release of NE.
Pharmacologic Effects
Central Nervous System. The amphetamines have prominent effects on mood and arousal. At usual doses, they increase wakefulness and alertness, reduce fatigue, elevate mood, and augment self-confidence and initiative. Euphoria, talkativeness, and increased motor activity are likely. Task performance that had been reduced by fatigue or boredom improves.
Amphetamines can stimulate respiration and suppress appetite and the perception of pain. Stimulation of the medullary respiratory center increases respiration. Effects on the hypo- thalamic feeding center depress appetite. By a mechanism that is not understood, amphetamines can enhance the analgesic effects of morphine and other opioids.
Cardiovascular System. Cardiovascular effects occur secondary to release of NE from sympathetic neurons. Nor- epinephrine acts in the heart to increase heart rate, atrioven- tricular conduction, and force of contraction. Excessive cardiac stimulation can cause dysrhythmias. In blood vessels, NE promotes constriction. Excessive vasoconstriction can cause hypertension.
Tolerance
With regular amphetamine use, tolerance develops to elevation of mood, suppression of appetite, and stimulation of the heart and blood vessels. In highly tolerant users, doses up to 1000 mg (IV) every few hours may be required to maintain euphoric effects. This compares with daily doses of 5 to 30 mg for nontolerant individuals.
Physical Dependence
Chronic amphetamine use produces physical dependence. If amphetamines are abruptly withdrawn from a dependent person, an abstinence syndrome will ensue. Symptoms include exhaus- tion, depression, prolonged sleep, excessive eating, and a craving for more amphetamine. Sleep patterns may take months to normalize.
Abuse
Because amphetamines can produce euphoria (extreme mood elevation), they have a high potential for abuse. Psychologic dependence can occur. (Users familiar with CNS stimulants find the psychologic effects of amphetamines nearly identical
METHYLPHENIDATE AND DEXMETHYLPHENIDATE
Methylphenidate and dexmethylphenidate are nearly identical in structure and pharmacologic actions. Furthermore, the pharmacology of both drugs is nearly identical to that of the amphetamines.
Methylphenidate
Although methylphenidate [Ritalin, Metadate, Methylin, Concerta, Daytrana, Biphentin ] is structurally dissimilar from the amphetamines, the pharmacologic actions of these drugs are essentially the same. Consequently, methylphenidate can be considered an amphetamine in all but structure and name. Methylphenidate and amphetamine share the same mechanism of action (promotion of NE and DA release, and inhibition of NE and DA reuptake), adverse effects (insomnia, reduced appetite, emotional lability), and abuse liability (Schedule II). Like amphetamine, methylphenidate is not a single compound, but rather a 50 : 50 mixture of dextro and levo isomers. The dextro isomer is highly active; the levo isomer is not. Methylphenidate has two indications: ADHD and narcolepsy.
Preparations, Dosage, and Administration
Methylphenidate is available in three types of formulations:
IR, sustained-release (SR), and once-daily doses. All three are indicated for ADHD. As a rule, the SR and IR formulations must be taken 2 or 3 times a day.
Immediate Release. Ritalin and Methylin are available in standard tablets (5, 10, and 20 mg), chewable tablets (2.5, 5, and 10 mg), and an oral solution (5 and 10 mg/5 mL). Effects begin rapidly and last 3 to 5 hours.
Because effects are brief, dosing must be done 2 or 3 times a day. The usual maintenance dosage for ADHD is 5 mg twice daily, with a maximum dose of 60 mg daily in two or three divided doses.
Sustained Release. Ritalin-SR and Metadate ER are available in 20-mg tablets, and Quillivant XR is available in a 25-mg/5 mL oral suspension or as Quillichew ER in 20-, 30-, and 40-mg chewable tablets. Effects are delayed and last 6 to 8 hours. Dosing is done once or twice daily. For children with ADHD, the usual maintenance dosage is 20 to 40 mg in the morning, supple- mented with 20 mg in the early afternoon if needed.
Once-Daily Dosing. Five products are available. Their brand names are Concerta, Metadate CD, Aptensio XR, Ritalin LA, and Daytrana. With all five, dosing is done once daily in the morning; no afternoon dose is needed.
Concerta. Concerta tablets—formulated as an osmotic-release oral system (OROS)—consist of an outer coating of IR methylphenidate and a special inner core that releases the remainder of each dose gradually. As a result, effects begin rapidly and last 10 to 12 hours. Because of their special archi- tecture, Concerta tablets must be swallowed whole, not crushed or chewed.
The tablet shell may not dissolve fully in the GI tract. Accordingly, patients should be informed that they may see tablet “ghosts” in the stool. Concerta tablets are available in four strengths: 18, 27, 36, and 54 mg.
Dosage depends on whether the patient is already taking methylphenidate (IR or SR). For children not already taking methylphenidate, the initial dosage is 18 mg once daily in the morning. Dosage can be increased to a maximum of 72 mg once daily. For children who are taking methylphenidate (IR or SR), the initial dosage of Concerta is as follows:
• For those taking 5 mg (2 or 3 times a day) of IR methylphenidate or 20 mg once daily of SR methylphenidate, start with 18 mg of Concerta.
• For those taking 10 mg (2 or 3 times a day) of IR or 40 mg once daily of SR, start with 36 mg of Concerta.
• For those taking 15 mg (2 or 3 times a day) of IR or 60 mg once daily of SR, start with 54 mg of Concerta.
Metadate CD. Metadate CD is available in 10-, 20-, 30-, 40-, 50-, and 60-mg capsules that contain IR and delayed-release beads. The beads release Acute Toxicity
Symptoms. Overdose produces dizziness, confusion, hallucinations, paranoid delusions, palpitations, dysrhythmias, and hypertension. Death is rare. Fatal overdose is associated with convulsions, coma, and cerebral hemorrhage.
Treatment. Hallucinations can be controlled with atypical antipsychotic drugs (e.g., olanzapine). An alpha-adrenergic blocker (e.g., phentolamine) can reduce hypertension (by promoting vasodilation). Owing to its ability to block alpha receptors, chlorpromazine helps lower blood pressure. Seizures can be managed with diazepam.
Therapeutic Uses
Attention-Deficit/Hyperactivity Disorder. The role of amphetamines in ADHD is discussed later in this chapter.
Narcolepsy. Narcolepsy is a disorder characterized by daytime somnolence and uncontrollable attacks of sleep. By stimulating the CNS, amphetamines can promote arousal and thereby alleviate symptoms.
Safety Alert
AMPHETAMINES
Amphetamines have a high potential for abuse and dependence.
In patients who use amphetamines chronically, withdrawal may occur if use of these medications is suddenly stopped.
Preparations, Dosage, and Administration
Four members of the amphetamine family are used clinically: dextroamphet- amine sulfate, an amphetamine/dextroamphetamine mixture, lisdexamfetamine, and methamphetamine. In clinical practice, amphetamines are given orally.
(These drugs are not approved for IV administration. Amphetamines for IV use are available only through illegal sources.) All amphetamines are regulated under Schedule II of the Controlled Substances Act and must be dispensed accordingly.
Dextroamphetamine Sulfate. Dextroamphetamine is available in immediate-release (IR) and extended-release (ER) formulations. Both are indicated for ADHD.
Immediate Release. IR dextroamphetamine is available in 2.5-, 5-, 7.5-, 10-, 15-, 20-, and 30-mg tablets sold as Zenzedi and as a 5-mg/mL solution sold as Procentra. Effects begin rapidly and last 4 to 6 hours. The usual maintenance dosage for ADHD is 5 to 10 mg once or twice daily, up to 40 mg/day.
Extended Release. ER dextroamphetamine [Dexedrine] is available in 5-, 10-, and 15-mg capsules. Effects begin rapidly and last 6 to 10 hours. The usual maintenance dosage for ADHD is 5 mg once or twice daily.
Amphetamine/Dextroamphetamine Mixture. Amphetamine/
dextroamphetamine mixture is available in IR [Adderall] and ER [Adderall XR] formulations. Both are used for ADHD.
Immediate Release. Adderall is available in IR tablets (5, 7.5, 10, 12.5, 15, 20, and 30 mg). Effects begin rapidly and last 4 to 6 hours. The usual maintenance dosage for ADHD is 5 mg twice daily, taken in the morning and 4 to 6 hours later.
Extended Release. Adderall XR is available in 5-, 10-, 15-, 20-, 25-, and 30-mg ER capsules. Half the dose is released immediately, and the remainder is released 4 hours later. As a result, effects begin rapidly and last 10 to 12 hours. The usual maintenance dosage for ADHD is 20 mg once daily in the morning. This is equivalent to taking 10 mg of IR Adderall at 8:00 AM and again around noon.
Lisdexamfetamine. Lisdexamfetamine [Vyvanse] is available in capsules (10, 20, 30, 40, 50, 60, and 70 mg) and chewable tablets (10, 20, 30, 40, 50, and 60 mg). Effects begin rapidly and persist about 13 hours. Dosing is done once daily in the morning without regard to meals. The capsules may be swallowed intact, or their contents may be dissolved in water and swallowed immediately. The usual daily maintenance dosage for ADHD is 30 mg.
Methamphetamine. Methamphetamine [Desoxyn] is indicated for ADHD, although it is not a preferred treatment for this condition. The drug is available in 5-mg IR tablets. The usual regimen for ADHD is 20 to 25 mg/
day, administered in two divided doses.
METHYLXANTHINES
The methylxanthines are methylated derivatives of xanthine, hence the family name. These compounds consist of a xanthine nucleus with one or more methyl groups attached. Caffeine, the most familiar member of the family, will serve as our prototype.
30% of the dose rapidly and the remaining 70% 4 hours later. As a result, plasma levels peak twice—at 1.5 and 4.5 hours. This is the same pattern produced by taking IR methylphenidate twice daily. For ADHD patients not already taking methylphenidate, the initial dosage is 20 mg once daily in the morning. This can be gradually increased to a maximum of 60 mg once daily.
For patients who are already taking methylphenidate, start with 20 mg of Metadate CD once daily (for those taking 10 mg of IR methylphenidate twice daily) or with 40 mg of Metadate CD once daily (for those taking 20 mg of IR methylphenidate twice daily). If needed, Metadate CD capsules can be opened and sprinkled on a small amount of soft food (e.g., applesauce) right before ingestion.
Aptensio XR. Aptensio XR is formulated in capsules (10, 15, 20, 30, 40, 50, and 60 mg) that contain delayed-release beads. Therapeutic effects begin rapidly and persist for 12 hours. The capsules may be swallowed intact or opened to permit sprinkling the beads onto applesauce or some other soft food. Aptensio XR capsules are approved for treating ADHD in children, adolescents, and adults.
Ritalin LA. Ritalin LA is formulated as ER capsules (10, 20, 30, 40, and 60 mg). The product is much like Metadate CD in that some of the dose is released immediately and the rest 4 hours later. Dosing is done once daily in the morning. As with Metadate CD and Concerta, dosage depends on whether the patient is already taking methylphenidate (IR or SR). For children not already taking methylphenidate, the initial dosage is 20 mg. Dosage can be gradually increased to a maximum of 60 mg. For children who are taking methylphenidate (IR or SR), the initial dosage is as follows:
• For those taking 10 mg twice daily of IR methylphenidate or 20 mg once daily of SR methylphenidate, start with 20 mg of Ritalin
• For those taking 15 mg twice daily of IR, start with 30 mg of Ritalin LA.
• For those taking 20 mg twice daily of IR or 40 mg once daily of SR, LA.
start with 40 mg of Ritalin LA.
• For those taking 30 mg twice daily of IR or 60 mg once daily of SR, start with 60 mg of Ritalin LA.
Daytrana. Daytrana—a transdermal methylphenidate patch—is the first nonoral treatment for ADHD. Following patch application, blood levels of methylphenidate rise slowly and peak in about 9 hours, after which the patch should be removed. Because of the slow rise, effects are delayed about 2 hours. Furthermore, effects will persist for about 3 hours after patch removal. Daytrana patches are available in four sizes—12.5, 18.75, 25, and 37.5 cm2—that deliver 10, 15, 20, and 30 mg/9 hr, respectively. Treatment should begin with the smallest patch, even in patients already taking meth- ylphenidate PO. If needed, larger patches can be tried at weekly intervals.
Patients should apply the patch to the hip in the morning—alternating hips each day—and remove it no more than 9 hours later. (They can remove it sooner to terminate effects early.) Application to inflamed skin or application of heat will accelerate drug absorption, and hence should be avoided. Patients should be informed that bathing, showering, and swimming will not dislodge the patch.
Side effects of the patch are like those of oral methylphenidate, with two exceptions. First, users may experience erythema and pruritus at the application site. Second, exposing the skin to methylphenidate can cause a hypersensitivity reaction. If hypersensitivity develops, the patient may be unable to use any methylphenidate formulation—transdermal or oral—ever again.
Dexmethylphenidate
Dexmethylphenidate [Focalin, Focalin XR], a drug for ADHD, is simply the dextro isomer of methylphenidate. As noted, the dextro isomer accounts for most of the pharmacologic activity of methylphenidate, a 50 : 50 mixture of dextro and levo isomers. Accordingly, the pharmacology of dexmethylphenidate is nearly identical to that of methylphenidate. The only difference is that the dosage of dexmethylphenidate is one-half the dosage of methylphenidate.
Dexmethylphenidate is available in IR tablets (2.5, 5, and 10 mg) marketed as Focalin, and in ER capsules (5, 10, 15, 20, 25, 30, 35, and 40 mg) marketed as Focalin XR. Both formulations may be administered with or without food. For children currently treated with methylphenidate, the initial dosage of dexmethylphenidate is one-half the methylphenidate dosage. For children who are not currently being treated, the initial dosage is 2.5 mg twice daily using Focalin or 10 mg once daily using Focalin XR. The maximum dosage is 10 mg twice daily for Focalin and 40 mg once daily for Focalin XR. Dexmethylphenidate is a Schedule II drug and must be dispensed accordingly.
Stimulants
Life Stage Patient Care Concerns
Infants Caffeine citrate [Cafcit] is used for neonatal apnea. Other CNS stimulants should be avoided in this population.
Children The stimulant class of drugs for treatment of ADHD has been proven safe and effective for this population. Atomoxetine, a nonstimulant for ADHD, may cause suicidal thinking in children and adolescents.
Pregnant
women Caffeine may pose a small risk of birth defects, although human data are lacking.
Methylphenidate and atomoxetine are classified as FDA Pregnancy Risk Category C,a as adverse fetal effects have been demonstrated in animal studies.
Breast- feeding women
Stimulants, such as methylphenidate, do not have any reported side effects in the breast-feeding infant. There are limited to no data on nonstimulants and the effects on breast-feeding infants.
Older adults Most studies focus on patients older than 65 years, since stimulants are often used for the treatment of apathy, depression, and fatigue in the older adult population. Stimulants should be avoided in patients with cardiac disease or glaucoma. Consider a lower starting dose, and monitor heart rate, blood pressure, and weight.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
Caffeine
Caffeine is consumed worldwide for its stimulant effects. In the United States, per capita consumption is about 200 mg/
day, mostly in the form of coffee. Although clinical applications of caffeine are few, caffeine remains of interest because of its widespread ingestion for nonmedical purposes.
Dietary Sources
Caffeine can be found in chocolates, desserts, soft drinks, and beverages prepared from various natural products. Common dietary sources are coffee, tea, and cola drinks. The caffeine in cola drinks derives partly from the cola nut and partly from caffeine added by the manufacturer. Caffeine is also present in many noncola soft drinks. The caffeine content of some common foods and beverages is shown in Table 36.1.
vessels is thought to underlie the drug’s ability to relieve headache.
Bronchi. Caffeine and other methylxanthines cause relaxation of bronchial smooth muscle and thereby promote bronchodilation. Theophylline is an especially effective bronchodilator, and hence can be used to treat asthma (see Chapter 76).
Kidney. Caffeine is a diuretic. The mechanism underlying increased urine formation is likely related to suppression of antidiuretic hormone in the posterior pituitary.
Reproduction. Caffeine readily crosses the placenta and may pose a risk of birth defects, although that risk appears low. When applied to cells in culture, caffeine can cause chro- mosomal damage and mutations. However, the concentrations required are much greater than can be achieved by drinking caffeinated beverages. Also, although there is clear proof that caffeine can cause birth defects in animals, studies have failed to document birth defects in humans. Although caffeine-induced birth defects seem unlikely, caffeine has been associated with low birth weight.
According to a meta-analysis reported in 2010, consuming less than 300 mg of caffeine daily does not increase the risk of preterm birth. An additional review in 2013 revealed that restricting caffeine consumption during the second and third trimesters of pregnancy did not affect birth weight or length of gestation. Whether higher doses might increase risk is unclear.
Pharmacokinetics
Caffeine is readily absorbed from the GI tract and achieves peak plasma levels within 1 hour. Plasma half-life ranges from 3 to 7 hours. Elimination is by hepatic metabolism.
Therapeutic Uses
Neonatal Apnea. Premature infants may experience prolonged apnea (lasting 15 seconds or more) along with bradycardia. Hypoxemia and neurologic damage may result.
Caffeine and other methylxanthines can reduce the number and duration of apnea episodes and can promote a more regular pattern of breathing.
Promoting Wakefulness. Caffeine is used commonly to aid in staying awake. The drug is marketed in various over- the-counter preparations [Maximum Strength NoDoz, Vivarin, others] for this purpose. Of course, individuals desiring increased alertness can get just as much caffeine by drinking coffee or some other caffeine-containing beverage.
Other Applications. Intravenous caffeine can help relieve headache induced by spinal puncture. The drug is used orally to enhance analgesia induced by opioids and by nonopioid analgesics (e.g., aspirin).
Acute Toxicity
Caffeine toxicity is characterized by intensification of the responses seen at low doses. Stimulation of the CNS results in excitement, restlessness, and insomnia; if the dosage is very high, convulsions may occur. Tachycardia and respiratory stimulation are likely. Sensory phenomena (ringing in the ears, flashing lights) are common. Death from caffeine overdose is rare. When fatalities have occurred, between 5 and 10 gm have been ingested.
Preparations, Dosage, and Administration
For Promoting Wakefulness. Caffeine is available in three formulations for promoting wakefulness: 200-mg tablets, 200-mg capsules, and 75-mg lozenges. The usual dosage is 100 to 200 mg every 3 to 4 hours as needed.
For Neonatal Apnea. Caffeine citrate [Cafcit] is used for neonatal apnea. The drug is available in oral and IV solutions. Both have the same concentration: 20 mg/mL. Treatment consists of an IV loading dose (20 mg/
Mechanism of Action
Several mechanisms of action have been proposed. These include (1) reversible blockade of adenosine receptors, (2) enhancement of calcium permeability in the sarcoplasmic reticulum, and (3) inhibition of cyclic nucleotide phosphodi- esterase, resulting in accumulation of cyclic adenosine monophosphate (cyclic AMP). Blockade of adenosine receptors appears responsible for most effects.
Pharmacologic Effects
Central Nervous System. In low doses, caffeine decreases drowsiness and fatigue and increases the capacity for prolonged intellectual exertion. With increasing dosage, caffeine produces nervousness, insomnia, and tremors. When administered in very large doses, caffeine can cause convulsions. Despite popular belief, there is little evidence that caffeine can restore mental function during intoxication with alcohol, although it might delay passing out.
Heart. High doses of caffeine stimulate the heart. When caffeinated beverages are consumed in excessive amounts, dysrhythmias may result.
Blood Vessels. Caffeine affects blood vessels in the periphery differently from those in the CNS. In the periphery, caffeine promotes vasodilation, whereas in the CNS, caffeine promotes vasoconstriction. Constriction of cerebral blood
Product Amount Caffeine (mg)
COFFEE
Brewed (typical) 8 oz 60–180
Instant 8 oz 30–120
Espresso 1.5 oz 77
Decaffeinated 8 oz 1–5
TEA
Brewed 8 oz 35–40
Herbal tea 8 oz 0
Iced tea mix, decaffeinated 8 oz <5
SODA AND ENERGY DRINKS
Energy drink 12 oz 71
Diet cola 12 oz 47
Cola 12 oz 45
Orange soda 12 oz 40
Concentrated energy drink 2 oz 200
Caffeinated water 16 oz 100
ICE CREAM AND YOGURT
Coffee ice cream 12 cup 20–30
Coffee yogurt 4 oz 22
MISCELLANEOUS
Cocoa 8 oz 2–50
Chocolate milk 1.5 oz 3–11
Milk chocolate bar 1.5 oz 10
Dark chocolate bar 1.5 oz 31
TABLE 36.1 ■ Dietary Caffeine
of modafinil. Otherwise, the two drugs are essentially identical, although armodafinil costs more. Armodafinil has the same indications as modafinil—
improving wakefulness in people with narcolepsy, SWSD, and OSAHS—and has similar adverse effects, including the potential for rare but severe skin reactions. Like modafinil, armodafinil is classified as a Schedule IV substance.
Armodafinil is available in 50-, 150-, and 250-mg tablets. The recommended dosage for narcolepsy and OSAHS is 150 or 250 mg, taken in the morning. The recommended dosage for SWSD is 150 mg, taken 1 hour before the work shift.
Doxapram
Doxapram [Dopram] stimulates the CNS at all levels. The drug is employed clinically to stimulate respiration. However, since the doses required are close to those that can produce generalized CNS stimulation and convulsions, doxapram must be used with great care. Furthermore, although doxapram is labeled for the treatment of general CNS depressant overdose, its use for this purpose should be discontinued: Experience has shown that respiratory depression from CNS depressant overdose can be managed more safely and effectively with mechanical support of ventilation than with pharmacologic stimulation of respiration.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
Our discussion of ADHD has two parts. We begin by addressing basic concepts in ADHD—specifically, signs and symptoms, etiology, and treatment strategy. After that, we discuss the pharmacology of the drugs used for treatment.
BASIC CONSIDERATIONS ADHD in Children
ADHD is the most common neuropsychiatric disorder of child- hood, affecting 5% to 11% of school-age children. The incidence in boys is two to three times the incidence in girls. Symptoms begin between ages 3 and 7, usually persist into the teens, and often persist into adulthood. The majority (60% to 70%) of children respond well to stimulant drugs. Methylphenidate [Ritalin, Concerta, others] is the agent employed most.
Signs and Symptoms
ADHD is characterized by inattention, hyperactivity, and impulsivity. Affected children are fidgety, unable to concentrate on schoolwork, and unable to wait their turn; switch excessively from one activity to another; call out excessively in class; and never complete tasks. To make a diagnosis, symptoms must appear before age 12 years and be present for at least 6 months.
Since other disorders—especially anxiety and depression—may cause similar symptoms, diagnosis must be done carefully.
ADHD can be subclassified as predominantly inattentive type, predominantly hyperactive-impulsive type, or combined type, depending on the symptom profile. Former names for ADHD—hyperkinetic syndrome and minimal brain dysfunction—
are misleading and have been abandoned.
Etiology
Although various theories have been proposed, the underlying pathophysiology of ADHD is only partly understood. Neuro- imaging studies indicate structural and functional abnormalities in multiple brain areas, including the frontal cortex, basal ganglia, brainstem, and cerebellum—regions involved with regulating attention, impulsive behavior, and motor activity.
Several theories implicate dysregulation in neuronal pathways that employ NE, DA, and serotonin as transmitters. These
kg) followed every 24 hours by an oral or IV maintenance dose (5 mg/kg).
Note: The amount of caffeine base in a 20-mg dose of caffeine citrate is only 10 mg (i.e., one-half of the total dose on a milligram basis).
MISCELLANEOUS CNS STIMULANTS Modafinil
Therapeutic Use
Modafinil [Provigil, Alertec ], a unique nonamphetamine stimulant, is approved for promoting wakefulness in patients with excessive sleepi- ness associated with three disorders: narcolepsy, shift-work sleep disorder (SWSD), and obstructive sleep apnea/hypopnea syndrome (OSAHS). However, although the drug has only three approved uses, most prescriptions (95%) are written for off-label uses, including fatigue, depression, ADHD, jet lag, and sleepiness caused by medications. Investigational uses include ADHD and fatigue associated with multiple sclerosis. The military studied the drug for use in sustaining alertness in helicopter pilots and found it superior to placebo.
In clinical trials, modafinil has been moderately effective. In patients with narcolepsy, modafinil increased wakefulness, but only to about 50% of the level seen in normal people. In contrast, methylphenidate and dextroamphet- amine increase wakefulness to about 70% of normal. In patients with SWSD and OSAHS, benefits are about the same as those seen in narcolepsy.
Mechanism of Action
How modafinil works remains unclear. The drug does seem to influence hypothalamic areas involved in maintaining the normal sleep-wakefulness cycle. Also, there is evidence that modafinil inhibits the activity of sleep- promoting neurons (in the ventrolateral preoptic nucleus) by blocking reuptake of norepinephrine.
Pharmacokinetics
Modafinil is rapidly absorbed from the GI tract. Plasma levels peak in 2 to 4 hours. Food decreases the rate of absorption but not the extent. Elimination is by hepatic metabolism followed by renal excretion. The half-life is about 15 hours.
Adverse Effects
Modafinil is generally well tolerated. The most common adverse effects are headache, nausea, nervousness, diarrhea, and rhinitis. Modafinil does not disrupt nighttime sleep. In clinical trials, only 5% of patients dropped out because of undesired effects. Initially, the drug was believed devoid of car- diovascular effects. However, we now know it can increase heart rate and blood pressure, apparently by altering autonomic function. Subjective effects—euphoria; altered perception, thinking, and feeling—are like those of other CNS stimulants. However, modafinil has less abuse potential, and hence is regulated as a Schedule IV substance. Physical dependence and withdrawal have not been reported. Modafinil is embryotoxic in laboratory animals, and hence should be avoided during pregnancy.
Postmarketing reports link modafinil to rare cases of serious skin reactions, including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis. Patients should be informed about signs of these reactions—swelling or rash, especially in the presence of fever or changes in the oral mucosa—and instructed to discontinue the drug if they develop.
Drug Interactions
Modafinil inhibits some forms of cytochrome P450 (CYP) and induces others.
Induction of CYP3A4 (the 3A4 isoenzyme of P450) may accelerate the metabolism of oral contraceptives, cyclosporine, and certain other drugs, thereby causing their levels to decline. Caution is advised.
Preparations, Dosage, and Administration
Modafinil is available in 100- and 200-mg tablets. For patients with narcolepsy or OSAHS, the usual dosage is 200 mg/day, taken as a single dose in the morning. For patients with SWSD, the usual dosage is 200 mg/day, taken as a single dose 1 hour before the shift starts. For patients with severe hepatic impairment, doses should be decreased by 50%. Dosage reduction may also be needed in older adults.
Armodafinil
Armodafinil [Nuvigil] is simply the R-enantiomer of modafinil, a mixture of R- and S-enantiomers. Armodafinil differs from modafinil in that the R-enantiomer (armodafinil) has a somewhat longer half-life than the S-enantiomer component
Although reduction of impulsiveness and hyperactivity with a stimulant may seem paradoxical, it isn’t. Stimulants don’t suppress rowdy behavior directly. Rather, they improve attention and focus. Impulsiveness and hyperactivity decline because the child is now able to concentrate on the task at hand. It should be noted that stimulants do not create positive behavior;
they only reduce negative behavior. Accordingly, stimulants cannot give a child good study skills and other appropriate behaviors. Rather, these must be learned once the disruptive behavior is no longer an impediment.
The dosing schedule employed is important and is determined by the time course of the formulation selected. As discussed previously and shown in Table 36.2, CNS stimulants are available in IR, SR, and 24-hour formulations. With the IR and SR formulations, the child usually takes two or three doses a day. In contrast, the 24-hour formulations are taken just once a day (in the morning). Not only is once-daily dosing more convenient, it spares the child any embarrassment or stigma associated with taking medicine at school. Accordingly, 24-hour formulations (e.g., Adderall XR, Concerta, Daytrana) are generally preferred. With all formulations, dosage should be low initially and then gradually increased. Maintenance dosage is determined by monitoring for improvement in symptoms and the appearance of side effects.
Principal adverse effects of the stimulants are insomnia and growth suppression. Insomnia results from CNS stimulation and can be minimized by reducing the size of the afternoon dose and taking it no later than 4:00 PM. Growth suppression occurs secondary to appetite suppression. Growth reduction can be minimized by administering stimulants during or after meals (which reduces the impact of appetite suppression). In addition, some clinicians recommend taking “drug holidays”
on weekends and in the summer (which creates an opportunity for growth to catch up). However, other clinicians argue against this strategy because depriving children of medication during these unstructured times can be hard on them. When stimulants are discontinued, a rebound increase in growth will take place;
as a result, adult height may not be affected. Other adverse effects include headache and abdominal pain, which have an incidence of 10%, and lethargy and listlessness, which can occur when dosage is excessive.
Nonstimulants
Several nonstimulants are used for ADHD, although only three of them—atomoxetine, guanfacine, and clonidine—are approved by the U.S. Food and Drug Administration (FDA) for this use.
The nonstimulants are less effective than the stimulants, and hence are considered second-choice drugs. For treatment of ADHD, the nonstimulants may be employed as monotherapy or as add-on therapy with a stimulant. Unlike the stimulants, the nonstimulants are not regulated as controlled substances.
Atomoxetine, a Norepinephrine Uptake Inhibitor Description and Therapeutic Effects. Atomoxetine [Strattera] is a unique drug approved for ADHD in children and adults. It was the first nonstimulant approved for ADHD,a and one of only three drugs approved for ADHD in adults (the theories would be consistent with the effects of atomoxetine
(which blocks NE reuptake), imipramine (which blocks NE and serotonin uptake), and stimulant drugs (which promote the release of NE and DA and to some degree block their uptake). Genetic factors play a significant role.
Management Overview
Multiple strategies may be employed to manage ADHD. In addition to drugs, which are considered first-line treatment, the management program can include family therapy, parent training, and cognitive therapy for the child. Guidelines issued by the American Academy of Pediatrics emphasize the impor- tance of a comprehensive treatment program involving col- laboration among clinicians, families, and educators. For long-term gains, a combination of cognitive therapy and stimulant drugs appears most effective. Of the drugs employed for ADHD, stimulants are most effective, and so are considered agents of choice. The nonstimulants (e.g., atomoxetine, guanfacine, clonidine) are less effective than stimulants, and hence are considered second-choice drugs.
ADHD in Adults
In about 30% to 60% of cases, childhood ADHD persists into adulthood. In the United States, about 8 million adults are afflicted, although an estimated 90% are undiagnosed and untreated. Symptoms include poor concentration, stress intoler- ance, antisocial behavior, outbursts of anger, and inability to maintain a routine. Also, adults with ADHD experience more job loss, divorce, and driving accidents. As in childhood ADHD, therapy with a stimulant drug is the foundation of treatment.
Methylphenidate is prescribed most often. About 33% of adults fail to respond to stimulants or cannot tolerate their side effects.
For these patients, a trial with a nonstimulant may help.
Combining behavioral therapy with drug therapy may be more effective than drug therapy alone.
DRUGS USED FOR ADHD CNS Stimulants
Stimulant drugs are the mainstay of ADHD therapy. Drugs with proven efficacy include methylphenidate [Ritalin, Concerta, others], dexmethylphenidate [Focalin], dextroamphetamine/
amphetamine mixture [Adderall], and lisdexamfetamine [Vyvanse]. There are no data to support the use of one stimulant over another. If one stimulant is ineffective, another should be tried before considering a second-line agent.
The response to stimulants can be dramatic. These drugs can increase attention span and goal-oriented behavior while decreasing impulsiveness, distractibility, hyperactivity, and restlessness. Tests of cognitive function (memory, reading, arithmetic) often improve significantly. Unfortunately, although benefits can be dramatic initially, in children they diminish after 2 to 3 years. This finding was initially reported in a 2009 paper: MTA at 8 Years: Prospective Follow-up of Children Treated for Combined-Type ADHD in a Multisite Study. The findings were corroborated in a systematic review of long-term outcomes in ADHD in 2012. Nonetheless, stimulant therapy can still buy time to teach children behavioral strategies to help them combat inattention and hyperactivity over the long term.
aSome older nonstimulants, such as imipramine and bupropion, although used for ADHD, are not actually approved for ADHD.
which a stimulant—methylphenidate [Concerta]—was again clearly superior to atomoxetine.
Mechanism of Action. Atomoxetine is a selective inhibitor of NE reuptake, and hence causes NE to accumulate at synapses.
Although the precise relationship between this neurochemical action and symptom relief is unknown, it would appear that adaptive changes that occur following uptake blockade underlie benefits. Uptake blockade occurs immediately, whereas full therapeutic effects are not seen for at least a week—suggesting that, after uptake blockade occurs, additional processes must take place before benefits can be seen.
Pharmacokinetics. Atomoxetine is rapidly and completely absorbed following oral administration. Plasma levels peak in 1 to 3 hours, depending on whether the drug was taken without or with food. Atomoxetine is metabolized in the liver, primarily by CYP2D6 (the 2D6 isoenzyme of cytochrome P450). For most patients, the half-life is 5 hours. However, for 5% to 10% of patients, the half-life is much longer: 24 hours. These patients have an atypical form of CYP2D6, which metabolizes atomoxetine slowly. Dosage should be reduced in these people.
Adverse Effects. Like the CNS stimulants, atomoxetine is generally well tolerated. In clinical trials, the most common others are amphetamine/dextroamphetamine mixture [Adderall
XR] and lisdexamfetamine [Vyvanse]). In contrast to the CNS stimulants, atomoxetine has no potential for abuse, and hence is not regulated as a controlled substance. As a result, prescrip- tions can be refilled over the phone, making atomoxetine more convenient than the stimulants. Like the long-acting stimulants, atomoxetine can be administered just once a day.
In clinical trials comparing atomoxetine with placebo in children or adults with ADHD, atomoxetine was clearly superior at reducing symptoms. Benefits were similar whether the drug was given once a day or in two divided doses. It should be noted that responses develop slowly: The initial response takes a few days to develop, and the maximal response is seen in 1 to 3 weeks. This contrasts with the CNS stimulants, whose effects are near maximal with the first dose.
How does atomoxetine compare with stimulants for treating children with ADHD? In two older 3-week randomized trials, comparing atomoxetine with either methylphenidate [Concerta]
or an amphetamine [Adderall XR], the stimulants were superior:
More children responded to the stimulants, symptom reduction was greater, and benefits developed more quickly. These results were reinforced in a large 6-week placebo-controlled trial, in
Drug Brand Name Duration (hr) Dosing Schedule Usual Pediatric Maintenance Dosage STIMULANTS
Methylphenidate
Immediate Release Ritalin, Methylin 3–5 2 or 3 times daily 10 mg at 8:00 AM and noon, and 5 mg at 4:00 PM
Sustained Release Ritalin-SR, Metadate ER, Quillivant XR, Quillichew ER
6–8 Once or twice daily 20 or 40 mg in AM plus 20 mg in the early PM if needed
24-Hour Concerta 10–12 Once daily 36 mg in the AM
Aptensio XR 12 Once daily 10 mg in the AM
Metadate CD 8–12 Once daily 30 mg in the AM
Ritalin LA 8–12 Once daily 30 mg in the AM
Daytrana 10–12 Once daily One 15- or 20-mg patch, applied in the
AM and removed 9 hr later Dexmethylphenidate
Immediate Release Focalin 4–5 Twice daily 10 mg in the AM plus 10 mg in the
early PM
Sustained Release Focalin XR 12 Once daily 10 mg in the AM
Dextroamphetamine
Immediate Release Zenzedi, Procentra 4–6 Once or twice daily 5 mg in the AM
Sustained Release Dexedrine 6–10 Once or twice daily 10 mg at 8:00 AM
Amphetamine Mixture
Immediate Release Adderall 4–6 Twice daily 5 mg in the AM and 4–6 hr later
Sustained Release Adderall XR 10–12 Once daily 20 mg in the AM
Lisdexamfetamine
Sustained Release Vyvanse 13 Once daily 30 mg in the AM
NONSTIMULANTS
Atomoxetine Strattera 24 Once or twice daily 80 mg in the AM or 40 mg in the AM
and early PM
Guanfacine Intuniv 24 Once daily 1–4 mg in the AM
Clonidine Kapvay 24 Twice daily 0.1–0.2 mg in the AM and PM
TABLE 36.2 ■ Major Drugs for Attention-Deficit/Hyperactivity Disorder