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 = <vote slug="inattention">Inattention</vote>, <vote slug="productivity">Productivity</vote> | | 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> | ||
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| 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 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. | | 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) | ||
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* <effect ref="seizure">Caution in epilepsy.</effect> | * <effect ref="seizure">Caution in epilepsy.</effect> | ||
* <effect ref="withdrawal">Fatigue, rebound hyperactivity, dysphoria on dose offset.</effect> | * <effect ref="withdrawal">Fatigue, rebound hyperactivity, dysphoria on dose offset.</effect> | ||
| interactions = * '''MAOIs''' | | interactions = * '''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. | Like racemic methylphenidate, '''few CYP-mediated interactions''' due to CES1-dominated metabolism. | ||
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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 = | ||
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}}<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 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> | '''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) | ||
| Line 149: | 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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*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> | ||