How Long Until It Works

• Some immediate effects can be seen with first dosing

• Can take several weeks to attain maximum therapeutic benefit

If It Works (for adhd)

• The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

• Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

• Reevaluate the need for treatment periodically

• Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

If It Doesn’t Work (for adhd)

• Consider adjusting dose or switching to another formulation of d-amphetamine or to another agent

• Consider behavioral therapy

• Consider the presence of noncompliance and counsel patient and parents

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

✽ Some ADHD patients and some depressed patients may experience lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require either augmenting with a mood stabilizer or switching to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

✽ Best to attempt other monotherapies prior to augmenting

• For the expert, can combine immediate-release formulation with a sustained-release formulation of d-amphetamine for ADHD

• For the expert, can combine with modafinil or atomoxetine for ADHD

• For the expert, can occasionally combine with atypical antipsychotics in highly treatment-resistant cases of bipolar disorder or ADHD

• For the expert, can combine with antidepressants to boost antidepressant efficacy in highly treatment-resistant cases of depression while carefully monitoring patient

Tests

• Before treatment, assess for presence of cardiac disease (history, family history, physical exam)

• Blood pressure should be monitored regularly

• In children, monitor weight and height

AMPHETAMINE (D): SIDE EFFECTS

How Drug Causes Side Effects

• Increases in norepinephrine peripherally can cause autonomic side effects, including tremor, tachycardia, hypertension, and cardiac arrhythmias

• Increases in norepinephrine and dopamine centrally can cause CNS side effects such as insomnia, agitation, psychosis, and substance abuse

Notable Side Effects

✽ Insomnia, headache, exacerbation of tics, nervousness, irritability, overstimulation, tremor, dizziness

• Anorexia, nausea, dry mouth, constipation, diarrhea, weight loss

• Can temporarily slow normal growth in children (controversial)

• Sexual dysfunction long-term (impotence, libido changes) but can also improve sexual dysfunction short-term

Life-Threatening or Dangerous Side Effects

• Psychotic episodes, especially with parenteral abuse

• Seizures

• Palpitations, tachycardia, hypertension

• Rare activation of hypomania, mania, or suicidal ideation (controversial)

• Cardiovascular adverse effects, sudden death in patients with preexisting cardiac structural abnormalities

Weight Gain

• Reported but not expected

• Some patients may experience weight loss

Sedation

• Reported but not expected

• Activation much more common than sedation

What to Do About Side Effects

• Wait

• Adjust dose

• Switch to a long-acting stimulant

• Switch to another agent

• For insomnia, avoid dosing in afternoon/evening

Best Augmenting Agents for Side Effects

• Beta blockers for peripheral autonomic side effects

• Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

AMPHETAMINE (D): DOSING AND USE

Usual Dosage Range

• Narcolepsy: 5–60 mg/day (divided doses for tablet, once daily morning dose for Spansule capsule)

• ADHD: 5–40 mg/day (divided doses for tablet, once daily morning dose for Spansule capsule)

Dosage Forms

• Spansule capsule 5 mg, 10 mg, 15 mg

• Tablet 5 mg scored, 10 mg

How to Dose

• Narcolepsy (ages 12 and older): initial 10 mg/day; increase by 10 mg each week; give first dose on waking

• ADHD (ages 6 and older): initial 5–10 mg/day in 1–2 doses; increase by 5 mg each week; give first dose on waking

• Can give once daily dosing with Spansule capsule or divided dosing with tablet (every 4–6 hours)

Dosing Tips

• Clinical duration of action often differs from pharmacokinetic half-life

✽ Immediate-release dextroamphetamine has 3–6 hour duration of clinical action

✽ Sustained-release dextroamphetamine (Dexedrine spansule) has up to 8-hour duration of clinical action

• Tablets contain tartrazine, which may cause allergic reactions, particularly in patients allergic to aspirin

• Dexedrine spansules are controlled-release and should therefore not be chewed but rather should only be swallowed whole

✽ Controlled-release delivery of dextroamphetamine may be sufficiently long in duration to allow elimination of lunchtime dosing in many but not all patients

✽ This innovation can be an important practical element in stimulant utilization, eliminating the hassle and pragmatic difficulties of lunchtime dosing at school, including storage problems, potential diversion, and the need for a medical professional to supervise dosing away from home

• Avoid dosing late in the day because of the risk of insomnia

✽ May be possible to dose only during the school week for some ADHD patients

• Off-label uses are dosed the same as for ADHD

✽ May be able to give drug holidays over the summer in order to reassess therapeutic utility and effects on growth and to allow catch-up from any growth suppression as well as to assess any other side effects and the need to reinstitute stimulant treatment for the next school term

• Side effects are generally dose-related

• Taking with food may delay peak actions for 2–3 hours

Overdose

• Rarely fatal; panic, hyperreflexia, rhabdomyolysis, rapid respiration, confusion, coma, hallucination, convulsion, arrhythmia, change in blood pressure, circulatory collapse

Long-Term Use

• Often used long-term for ADHD when ongoing monitoring documents continued efficacy

• Dependence and/or abuse may develop

• Tolerance to therapeutic effects may develop in some patients

• Long-term stimulant use may be associated with growth suppression in children (controversial)

• Periodic monitoring of weight, blood pressure, CBC, platelet counts, and liver function may be prudent

Habit Forming

• High abuse potential, Schedule II drug

• Patients may develop tolerance, psychological dependence

How to Stop

• Taper to avoid withdrawal effects

• Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder and may require follow-up and reinstitution of treatment

• Careful supervision is required during withdrawal from abusive use since severe depression may occur

Pharmacokinetics

• Half-life approximately 10–12 hours

Drug Interactions

• May affect blood pressure and should be used cautiously with agents used to control blood pressure

• Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid, ascorbic acid, fruit juices, etc.) and urinary acidifying agents (ammonium chloride, sodium phosphate, etc.) lower amphetamine plasma levels, so such agents can be useful to administer after an overdose but may also lower therapeutic efficacy of amphetamines

• Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) and urinary alkalinizing agents (acetazolamide, some thiazides) increase amphetamine plasma levels and potentiate amphetamine’s actions

• Desipramine and protryptiline can cause striking and sustained increases in brain concentrations of d-amphetamine and may also add to d-amphetamine’s cardiovascular effects

• Theoretically, other agents with norepinephrine reuptake blocking properties, such as venlafaxine, duloxetine, atomoxetine, milnacipran, and reboxetine, could also add to amphetamine’s CNS and cardiovascular effects

• Amphetamines may counteract the sedative effects of antihistamines

• Haloperidol, chlorpromazine, and lithium may inhibit stimulatory effects of amphetamines

• Theoretically, atypical antipsychotics should also inhibit stimulatory effects of amphetamines

• Theoretically, amphetamines could inhibit the antipsychotic actions of antipsychotics

• Theoretically, amphetamines could inhibit the mood-stabilizing actions of atypical antipsychotics in some patients

• Combinations of amphetamines with mood stabilizers (lithium, anticonvulsants, atypical antipsychotics) is generally something for experts only, when monitoring patients closely and when other options fail

• Absorption of phenobarbital, phenytoin, and ethosuximide is delayed by amphetamines

• Amphetamines inhibit adrenergic blockers and enhance adrenergic effects of norepinephrine

• Amphetamines may antagonize hypotensive effects of veratrum alkaloids and other antihypertensives

• Amphetamines increase the analgesic effects of meperidine

• Amphetamines contribute to excessive CNS stimulation if used with large doses of propoxyphene

• Amphetamines can raise plasma corticosteroid levels

• MAOIs slow absorption of amphetamines and thus potentiate their actions, which can cause headache, hypertension, and rarely hypertensive crisis and malignant hyperthermia, sometimes with fatal results

• Use with MAOIs, including within 14 days of MAOI use, is not advised, but this can sometimes be considered by experts who monitor depressed patients closely when other treatment options for depression fail