Dexmethylphenidate: Difference between revisions
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| structure = Methylphenidate.svg | | structure = Methylphenidate.svg | ||
| classes = Psychostimulant, CNS stimulant, NDRI | | classes = Psychostimulant, CNS stimulant, NDRI | ||
| mechanism = Norepinephrine–dopamine reuptake inhibition (DAT, NET) | | mechanism = Norepinephrine–dopamine reuptake inhibition (DAT, NET), d-threo enantiomer of methylphenidate | ||
| uses = Inattention, Productivity | | uses = <vote slug="inattention">Inattention</vote>, <vote slug="productivity">Productivity</vote> | ||
| formula = C<sub>14</sub>H<sub>19</sub>NO<sub>2</sub> | | formula = C<sub>14</sub>H<sub>19</sub>NO<sub>2</sub> | ||
| routes = Oral | | routes = Oral | ||
| Line 14: | Line 14: | ||
| pregnancy = Category C | | pregnancy = Category C | ||
| legal = Schedule II | | legal = Schedule II | ||
| intro = '''Dexmethylphenidate''' | | intro = '''Dexmethylphenidate''', marketed as '''Focalin''' and '''Focalin XR''', is the isolated d-threo enantiomer of [[Methylphenidate|methylphenidate]]. Racemic methylphenidate contains both d- and l-threo enantiomers in equal amounts, but essentially all pharmacologic activity resides in the d-isomer; the l-isomer is rapidly cleared on first-pass and contributes little beyond a possible minor role in peripheral side effects. By delivering only the active enantiomer, Focalin achieves equivalent therapeutic effect at approximately half the milligram dose of racemic methylphenidate, with some patients reporting a cleaner subjective profile (less jitteriness, more focused effect). Its clinical problems, mechanism, contraindications, and adverse-effect profile are otherwise nearly identical to racemic methylphenidate. | ||
| pharmacokinetics = '''Absorption:''' Rapid oral absorption; peak plasma in ~1–1.5 h (IR) or ~6.5 h (XR, which has a biphasic release profile with an initial peak around 1.5 h and a second peak ~6.5 h). Bioavailability ~22–25% due to extensive first-pass metabolism. '''Distribution:''' Volume of distribution similar to racemic methylphenidate (~13 L/kg); plasma protein binding ~15%. '''Metabolism:''' Like the racemate, dexmethylphenidate is metabolized primarily by '''carboxylesterase 1 (CES1)''' to ritalinic acid (inactive). This non-CYP metabolic pathway means dexmethylphenidate, like its racemate, has '''few clinically significant CYP-mediated | | pharmacokinetics = '''Absorption:''' Rapid oral absorption; peak plasma in ~1–1.5 h (IR) or ~6.5 h (XR, which has a biphasic release profile with an initial peak around 1.5 h and a second peak ~6.5 h). Bioavailability ~22–25% due to extensive first-pass metabolism. '''Distribution:''' Volume of distribution similar to racemic methylphenidate (~13 L/kg); plasma protein binding ~15%. '''Metabolism:''' Like the racemate, dexmethylphenidate is metabolized primarily by '''carboxylesterase 1 (CES1)''' to ritalinic acid (inactive). This non-CYP metabolic pathway means dexmethylphenidate, like its racemate, has '''few clinically significant CYP-mediated med interactions'''. '''Elimination:''' Predominantly renal as ritalinic acid; parent half-life 2.2 h (IR) and ~3 h (XR parent). Multi-dose-daily IR dosing or once-daily XR is required for sustained therapeutic effect. | ||
| pharmacodynamics = Mechanistically identical to racemic methylphenidate at the molecular level | | pharmacodynamics = Mechanistically identical to racemic methylphenidate at the molecular level, competitive inhibition of the dopamine and norepinephrine transporters (DAT, NET), increasing synaptic catecholamine concentrations without acting as a transporter substrate (i.e., no reverse transport or vesicular displacement; '''reuptake inhibition only'''). The functional difference is purely stereochemical: dexmethylphenidate provides the same effective amount of pharmacologically active material at half the milligram dose. Minimal effect on serotonin; no MAO inhibition; no significant binding at 5-HT, histamine, or muscarinic receptors. | ||
| indications = * Attention-deficit hyperactivity disorder (children ≥6 y, adolescents, and adults) | | indications = * Attention-deficit hyperactivity disorder (children ≥6 y, adolescents, and adults) | ||
* Off-label: same off-label uses as racemic methylphenidate (treatment-resistant depression augmentation, cancer/HIV/MS fatigue) | * Off-label: same off-label uses as racemic methylphenidate (treatment-resistant depression augmentation, cancer/HIV/MS fatigue) | ||
* Not FDA-approved for narcolepsy (use racemic methylphenidate or an amphetamine for that | * Not FDA-approved for narcolepsy (use racemic methylphenidate or an amphetamine for that problem) | ||
| dosing = '''Focalin IR:''' Start 2.5 mg PO twice daily (separate doses by at least 4 h). Titrate by 2.5–5 mg/week. Max 20 mg/day (adults and children). | | dosing = '''Focalin IR:''' Start 2.5 mg PO twice daily (separate doses by at least 4 h). Titrate by 2.5–5 mg/week. Max 20 mg/day (adults and children). | ||
'''Focalin XR:''' Start 5 mg PO once daily AM (children), 10 mg PO once daily AM (adults). Titrate weekly. Max 30 mg/day (children); 40 mg/day (adults). | '''Focalin XR:''' Start 5 mg PO once daily AM (children), 10 mg PO once daily AM (adults). Titrate weekly. Max 30 mg/day (children); 40 mg/day (adults). | ||
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==== Therapeutic ==== | ==== Therapeutic ==== | ||
* <effect | * <effect ref="attention">Improved attention, executive function, and working memory. Many patients report a cleaner subjective effect than racemic methylphenidate at equivalent therapeutic doses.</effect> | ||
* <effect | * <effect ref="reduced-impulsivity"/> | ||
* <effect | * <effect ref="wakefulness"/> | ||
==== Common ==== | ==== Common ==== | ||
* <effect | * <effect ref="decreased-appetite">Often dose-limiting; may produce weight loss over time.</effect> | ||
* <effect | * <effect ref="insomnia">Especially with late-afternoon dosing.</effect> | ||
* <effect | * <effect ref="headache"/> | ||
* <effect | * <effect ref="abdominal-pain"/> | ||
* <effect | * <effect ref="irritability"/> | ||
* <effect | * <effect ref="dry-mouth"/> | ||
* <effect | * <effect ref="hr-bp-elevation">Usually mild but dose-dependent.</effect> | ||
* <effect | * <effect ref="weight-loss"/> | ||
==== Cardiovascular ==== | ==== Cardiovascular ==== | ||
* <effect | * <effect ref="palpitations"/> | ||
* <effect | * <effect ref="cardiac-event">Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).</effect> | ||
==== Psychiatric ==== | ==== Psychiatric ==== | ||
* <effect | * <effect ref="anxiety"/> | ||
* <effect | * <effect ref="agitation"/> | ||
* <effect | * <effect ref="psychosis">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
* <effect | * <effect ref="mania">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
* <effect | * <effect ref="hallucinations">Visual or tactile; rare, more common at higher doses or in predisposed patients.</effect> | ||
==== Other adverse ==== | ==== Other adverse ==== | ||
* <effect | * <effect ref="tics">May emerge or worsen; comorbid Tourette syndrome is a traditional relative contraindication.</effect> | ||
* <effect | * <effect ref="dependence">Schedule II controlled substance; abuse liability similar to racemic methylphenidate per milligram of active material. Crushed/insufflated/IV misuse is the major risk pattern.</effect> | ||
* <effect | * <effect ref="tolerance">To therapeutic effects, with chronic high-dose use.</effect> | ||
* <effect | * <effect ref="growth-suppression">Modest reduction in growth velocity in chronically-treated children.</effect> | ||
* <effect | * <effect ref="priapism">Rare but documented; FDA warning, especially in adolescents.</effect> | ||
* <effect | * <effect ref="vasculopathy">Raynaud-like phenomenon, rare digital ischemia.</effect> | ||
* <effect | * <effect ref="seizure">Caution in epilepsy.</effect> | ||
* <effect | * <effect ref="withdrawal">Fatigue, rebound hyperactivity, dysphoria on dose offset.</effect> | ||
| interactions = * '''MAOIs''', hypertensive crisis risk; contraindicated within 14 days | |||
* '''Tricyclic antidepressants''', possible elevation of TCA levels; additive cardiovascular effects | |||
* '''Warfarin''', possible elevation of INR | |||
* '''Phenytoin, phenobarbital, primidone''', possible elevation of anticonvulsant levels | |||
* '''Antihypertensives''', pressor effect of dexmethylphenidate may partially antagonize | |||
* '''Other sympathomimetics''' (pseudoephedrine, phenylephrine, decongestants), additive cardiovascular effects | |||
* '''Antipsychotics''', mutual pharmacologic antagonism | |||
* '''Alcohol''', may mask effects; possible increased exposure via altered metabolism | |||
| interactions = * '''MAOIs''' | * '''Caffeine''', additive stimulant and anxiogenic effects | ||
* '''Tricyclic antidepressants''' | |||
* '''Warfarin''' | |||
* '''Phenytoin, phenobarbital, primidone''' | |||
* '''Antihypertensives''' | |||
* '''Other sympathomimetics''' (pseudoephedrine, phenylephrine, decongestants) | |||
* '''Antipsychotics''' | |||
* '''Alcohol''' | |||
* '''Caffeine''' | |||
Like racemic methylphenidate, '''few CYP-mediated interactions''' due to CES1-dominated metabolism. | Like racemic methylphenidate, '''few CYP-mediated interactions''' due to CES1-dominated metabolism. | ||
<pharmaInteractions/> | |||
| pregnancy_details = Category C. Crosses the placenta. Reproductive data limited and largely extrapolated from racemic methylphenidate; overall not clearly teratogenic but cohort studies suggest a small increase in cardiac malformations. Third-trimester exposure can produce transient neonatal withdrawal. Risk-benefit decision; many patients defer ADHD treatment during pregnancy. Excreted in breast milk in low amounts; breastfeeding generally compatible at therapeutic doses with infant monitoring. | | pregnancy_details = Category C. Crosses the placenta. Reproductive data limited and largely extrapolated from racemic methylphenidate; overall not clearly teratogenic but cohort studies suggest a small increase in cardiac malformations. Third-trimester exposure can produce transient neonatal withdrawal. Risk-benefit decision; many patients defer ADHD treatment during pregnancy. Excreted in breast milk in low amounts; breastfeeding generally compatible at therapeutic doses with infant monitoring. | ||
| monitoring = * Baseline: cardiovascular history (including family history of sudden cardiac death), blood pressure, heart rate, weight/height, mental health history, history of tics or substance use | | monitoring = * Baseline: cardiovascular history (including family history of sudden cardiac death), blood pressure, heart rate, weight/height, mental health history, history of tics or substance use | ||
| Line 85: | Line 78: | ||
* At each visit: blood pressure, heart rate, weight (and height in children), efficacy, side effects, signs of misuse/diversion, tic emergence | * At each visit: blood pressure, heart rate, weight (and height in children), efficacy, side effects, signs of misuse/diversion, tic emergence | ||
* Sleep quality and timing of last dose | * Sleep quality and timing of last dose | ||
* Periodically reassess continued need; consider | * Periodically reassess continued need; consider med holidays in children | ||
| counseling = * Take in the morning (XR) or twice daily 4+ hours apart (IR); avoid late-afternoon dosing to minimize insomnia. | | counseling = * Take in the morning (XR) or twice daily 4+ hours apart (IR); avoid late-afternoon dosing to minimize insomnia. | ||
* '''Focalin XR capsules:''' may be swallowed whole or opened and sprinkled on applesauce; '''do not crush or chew the beads inside.''' | * '''Focalin XR capsules:''' may be swallowed whole or opened and sprinkled on applesauce; '''do not crush or chew the beads inside.''' | ||
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* Stay well-hydrated. | * Stay well-hydrated. | ||
* Do not combine with significant alcohol or other stimulants. | * Do not combine with significant alcohol or other stimulants. | ||
* Do not share or sell | * Do not share or sell, Schedule II controlled substance. | ||
* Report chest pain, palpitations, severe agitation, hallucinations, prolonged erection, or new/worsening tics. | * Report chest pain, palpitations, severe agitation, hallucinations, prolonged erection, or new/worsening tics. | ||
* If switching from racemic methylphenidate, dose conversion is roughly half | * If switching from racemic methylphenidate, dose conversion is roughly half, confirm with prescriber. | ||
* Plan for the "crash" when the dose wears off, especially with IR. | * Plan for the "crash" when the dose wears off, especially with IR. | ||
| anecdotes = | | anecdotes = | ||
| Line 99: | Line 92: | ||
| references = | | references = | ||
}}<h2 id="Pharmacokinetics">Pharmacokinetics</h2><span></span> | }}<h2 id="Pharmacokinetics">Pharmacokinetics</h2><span></span> | ||
'''Absorption:''' Rapid oral absorption; peak plasma in ~1–1.5 h (IR) or ~6.5 h (XR, which has a biphasic release profile with an initial peak around 1.5 h and a second peak ~6.5 h). Bioavailability ~22–25% due to extensive first-pass metabolism. '''Distribution:''' Volume of distribution similar to racemic methylphenidate (~13 L/kg); plasma protein binding ~15%. '''Metabolism:''' Like the racemate, dexmethylphenidate is metabolized primarily by '''carboxylesterase 1 (CES1)''' to ritalinic acid (inactive). This non-CYP metabolic pathway means dexmethylphenidate, like its racemate, has '''few clinically significant CYP-mediated | '''Absorption:''' Rapid oral absorption; peak plasma in ~1–1.5 h (IR) or ~6.5 h (XR, which has a biphasic release profile with an initial peak around 1.5 h and a second peak ~6.5 h). Bioavailability ~22–25% due to extensive first-pass metabolism. '''Distribution:''' Volume of distribution similar to racemic methylphenidate (~13 L/kg); plasma protein binding ~15%. '''Metabolism:''' Like the racemate, dexmethylphenidate is metabolized primarily by '''carboxylesterase 1 (CES1)''' to ritalinic acid (inactive). This non-CYP metabolic pathway means dexmethylphenidate, like its racemate, has '''few clinically significant CYP-mediated med interactions'''. '''Elimination:''' Predominantly renal as ritalinic acid; parent half-life 2.2 h (IR) and ~3 h (XR parent). Multi-dose-daily IR dosing or once-daily XR is required for sustained therapeutic effect.<h2 id="Pharmacodynamics">Pharmacodynamics</h2> | ||
Mechanistically identical to racemic methylphenidate at the molecular level | Mechanistically identical to racemic methylphenidate at the molecular level, competitive inhibition of the dopamine and norepinephrine transporters (DAT, NET), increasing synaptic catecholamine concentrations without acting as a transporter substrate (i.e., no reverse transport or vesicular displacement; '''reuptake inhibition only'''). The functional difference is purely stereochemical: dexmethylphenidate provides the same effective amount of pharmacologically active material at half the milligram dose. Minimal effect on serotonin; no MAO inhibition; no significant binding at 5-HT, histamine, or muscarinic receptors.<h2 id="Problems">Problems</h2> | ||
*Attention-deficit hyperactivity disorder (children ≥6 y, adolescents, and adults) | *Attention-deficit hyperactivity disorder (children ≥6 y, adolescents, and adults) | ||
*Off-label: same off-label uses as racemic methylphenidate (treatment-resistant depression augmentation, cancer/HIV/MS fatigue) | *Off-label: same off-label uses as racemic methylphenidate (treatment-resistant depression augmentation, cancer/HIV/MS fatigue) | ||
*Not FDA-approved for narcolepsy (use racemic methylphenidate or an amphetamine for that | *Not FDA-approved for narcolepsy (use racemic methylphenidate or an amphetamine for that problem)<h2 id="Dosing">Dosing and titration</h2> | ||
<span></span> | <span></span> | ||
| Line 114: | Line 107: | ||
'''Renal/hepatic impairment:''' caution; reduce dose and monitor.<h2 id="Effects">Effects</h2><span></span> | '''Renal/hepatic impairment:''' caution; reduce dose and monitor.<h2 id="Effects">Effects</h2><span></span> | ||
====Therapeutic==== | ====Therapeutic==== | ||
*<effect | *<effect ref="attention">Improved attention, executive function, and working memory. Many patients report a cleaner subjective effect than racemic methylphenidate at equivalent therapeutic doses.</effect> | ||
*<effect | *<effect ref="reduced-impulsivity"/> | ||
*<effect | *<effect ref="wakefulness"/> | ||
<span></span> | <span></span> | ||
====Common==== | ====Common==== | ||
*<effect | *<effect ref="decreased-appetite">Often dose-limiting; may produce weight loss over time.</effect> | ||
*<effect | *<effect ref="insomnia">Especially with late-afternoon dosing.</effect> | ||
*<effect | *<effect ref="headache"/> | ||
*<effect | *<effect ref="abdominal-pain"/> | ||
*<effect | *<effect ref="irritability"/> | ||
*<effect | *<effect ref="dry-mouth"/> | ||
*<effect | *<effect ref="hr-bp-elevation">Usually mild but dose-dependent.</effect> | ||
*<effect | *<effect ref="weight-loss"/> | ||
<span></span> | <span></span> | ||
====Cardiovascular==== | ====Cardiovascular==== | ||
*<effect | *<effect ref="palpitations"/> | ||
*<effect | *<effect ref="cardiac-event">Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).</effect> | ||
<span></span> | <span></span> | ||
====Psychiatric==== | ====Psychiatric==== | ||
*<effect | *<effect ref="anxiety"/> | ||
*<effect | *<effect ref="agitation"/> | ||
*<effect | *<effect ref="psychosis">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
*<effect | *<effect ref="mania">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
*<effect | *<effect ref="hallucinations">Visual or tactile; rare, more common at higher doses or in predisposed patients.</effect> | ||
<span></span> | <span></span> | ||
====Other adverse==== | ====Other adverse==== | ||
*<effect | *<effect ref="tics">May emerge or worsen; comorbid Tourette syndrome is a traditional relative contraindication.</effect> | ||
*<effect | *<effect ref="dependence">Schedule II controlled substance; abuse liability similar to racemic methylphenidate per milligram of active material. Crushed/insufflated/IV misuse is the major risk pattern.</effect> | ||
*<effect | *<effect ref="tolerance">To therapeutic effects, with chronic high-dose use.</effect> | ||
*<effect | *<effect ref="growth-suppression">Modest reduction in growth velocity in chronically-treated children.</effect> | ||
*<effect | *<effect ref="priapism">Rare but documented; FDA warning, especially in adolescents.</effect> | ||
*<effect | *<effect ref="vasculopathy">Raynaud-like phenomenon, rare digital ischemia.</effect> | ||
*<effect | *<effect ref="seizure">Caution in epilepsy.</effect> | ||
*<effect | *<effect ref="withdrawal">Fatigue, rebound hyperactivity, dysphoria on dose offset.</effect><h2 id="Contraindications">Contraindications</h2> | ||
*Hypersensitivity to dexmethylphenidate or methylphenidate | *Hypersensitivity to dexmethylphenidate or methylphenidate | ||
*Concurrent MAOI use, or within 14 days of MAOI discontinuation | *Concurrent MAOI use, or within 14 days of MAOI discontinuation | ||
| Line 156: | Line 149: | ||
*Severe anxiety, tension, or agitation | *Severe anxiety, tension, or agitation | ||
*'''Relative:''' Tourette syndrome / tic disorders, history of substance use disorder, bipolar disorder, psychotic disorders, structural cardiac abnormalities<h2 id="Interactions">Interactions</h2> | *'''Relative:''' Tourette syndrome / tic disorders, history of substance use disorder, bipolar disorder, psychotic disorders, structural cardiac abnormalities<h2 id="Interactions">Interactions</h2> | ||
*'''MAOIs''' | *'''MAOIs''', hypertensive crisis risk; contraindicated within 14 days | ||
*'''Tricyclic antidepressants''' | *'''Tricyclic antidepressants''', possible elevation of TCA levels; additive cardiovascular effects | ||
*'''Warfarin''' | *'''Warfarin''', possible elevation of INR | ||
*'''Phenytoin, phenobarbital, primidone''' | *'''Phenytoin, phenobarbital, primidone''', possible elevation of anticonvulsant levels | ||
*'''Antihypertensives''' | *'''Antihypertensives''', pressor effect of dexmethylphenidate may partially antagonize | ||
*'''Other sympathomimetics''' (pseudoephedrine, phenylephrine, decongestants) | *'''Other sympathomimetics''' (pseudoephedrine, phenylephrine, decongestants), additive cardiovascular effects | ||
*'''Antipsychotics''' | *'''Antipsychotics''', mutual pharmacologic antagonism | ||
*'''Alcohol''' | *'''Alcohol''', may mask effects; possible increased exposure via altered metabolism | ||
*'''Caffeine''' | *'''Caffeine''', additive stimulant and anxiogenic effects | ||
Like racemic methylphenidate, '''few CYP-mediated interactions''' due to CES1-dominated metabolism.<h2 id="Pregnancy">Pregnancy and lactation</h2> | Like racemic methylphenidate, '''few CYP-mediated interactions''' due to CES1-dominated metabolism.<h2 id="Pregnancy">Pregnancy and lactation</h2> | ||
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*At each visit: blood pressure, heart rate, weight (and height in children), efficacy, side effects, signs of misuse/diversion, tic emergence | *At each visit: blood pressure, heart rate, weight (and height in children), efficacy, side effects, signs of misuse/diversion, tic emergence | ||
*Sleep quality and timing of last dose | *Sleep quality and timing of last dose | ||
*Periodically reassess continued need; consider | *Periodically reassess continued need; consider med holidays in children<h2 id="Counseling">Patient counseling</h2> | ||
*Take in the morning (XR) or twice daily 4+ hours apart (IR); avoid late-afternoon dosing to minimize insomnia. | *Take in the morning (XR) or twice daily 4+ hours apart (IR); avoid late-afternoon dosing to minimize insomnia. | ||
*'''Focalin XR capsules:''' may be swallowed whole or opened and sprinkled on applesauce; '''do not crush or chew the beads inside.''' | *'''Focalin XR capsules:''' may be swallowed whole or opened and sprinkled on applesauce; '''do not crush or chew the beads inside.''' | ||
| Line 178: | Line 171: | ||
*Stay well-hydrated. | *Stay well-hydrated. | ||
*Do not combine with significant alcohol or other stimulants. | *Do not combine with significant alcohol or other stimulants. | ||
*Do not share or sell | *Do not share or sell, Schedule II controlled substance. | ||
*Report chest pain, palpitations, severe agitation, hallucinations, prolonged erection, or new/worsening tics. | *Report chest pain, palpitations, severe agitation, hallucinations, prolonged erection, or new/worsening tics. | ||
*If switching from racemic methylphenidate, dose conversion is roughly half | *If switching from racemic methylphenidate, dose conversion is roughly half, confirm with prescriber. | ||
*<nowiki>Plan for the "crash" when the dose wears off, especially with IR.{{#if:</nowiki><h2 id="Anecdotes">Personal experience</h2> | *<nowiki>Plan for the "crash" when the dose wears off, especially with IR.{{#if:</nowiki><h2 id="Anecdotes">Personal experience</h2> | ||
<span></span> | <span></span> | ||
| Line 186: | Line 179: | ||
''The following are personal accounts and not medical advice.'' | ''The following are personal accounts and not medical advice.'' | ||
<span></span><discuss slug="personal-experience" /> | <span></span><discuss slug="personal-experience" /> | ||
[[Category:Psychostimulants]] | |||
[[Category:Methylphenidates (Phenidates)]] | |||