What is methylphenidate?

What is Methylphenidate?

Methylphenidate is a central nervous system (CNS) stimulant that functions primarily by blocking the reuptake of dopamine and norepinephrine into presynaptic neurons and increasing the release of these monoamines into the extraneuronal space. 1, 2

Chemical Structure and Classification

Methylphenidate hydrochloride is chemically described as (d,l racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. 2 It is a racemic mixture comprised of the d- and l-threo enantiomers, with the d-threo enantiomer being more pharmacologically active than the l-threo enantiomer. 2, 3

Mechanism of Action

Methylphenidate works by inhibiting dopamine and norepinephrine transporters, with additional effects including agonist activity at the serotonin type 1A receptor and redistribution of the vesicular monoamine transporter 2. 1 By enhancing the impact of dopamine and norepinephrine, methylphenidate increases the efficiency of prefrontal cortex activity and optimizes executive and attentional function. 1

The drug readily penetrates the CNS, particularly the striatum, in its d-isomer form. 4 While the precise mode of therapeutic action in ADHD is not fully known, the dopaminergic and noradrenergic enhancement appears central to its clinical effects. 2, 5

Clinical Indications

Primary FDA-Approved Uses

• Attention Deficit Hyperactivity Disorder (ADHD): Methylphenidate has been used since the 1950s for treating ADHD in children and is prescribed for over 90% of children in the US diagnosed with ADHD. 1, 3 It is a first-line pharmacotherapy for patients with ADHD in both children and adults. 1

• Narcolepsy: Methylphenidate is conditionally recommended for the treatment of narcolepsy in adults, demonstrating clinically significant improvements in disease severity. 1

Off-Label Uses

• Cancer-related fatigue: Used in medically ill patients with fatigue, including those with cancer, multiple sclerosis, Parkinson's disease, opioid-induced sedation, and HIV. 1

• Cognitive and motor deficits in Parkinson disease: MPH may ameliorate cognitive, affective, and motor deficits in PD patients by increasing dopaminergic stimulation at the postsynaptic receptor level. 5

Pharmacokinetics

Absorption and Distribution

• Rapid absorption with time to peak plasma concentration (Tmax) at 1 to 2 hours after dosing under fasted conditions. 2
• Peak plasma concentration occurs at about 2 hours with maximum behavioral effects occurring when plasma concentrations are increasing. 4, 3
• Plasma protein binding is 10% to 33%, with a volume of distribution of 2.65 ± 1.11 L/kg for d-methylphenidate. 2
• High-fat meals increase Cmax and AUC by approximately 13% and 25%, respectively, and delay Tmax by about 1 hour. 2

Metabolism and Elimination

• Mean terminal half-life of 2.7 hours, with a duration of action of 1 to 4 hours for immediate-release formulations. 2, 4, 3
• Metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. 2
• Approximately 90% of radioactivity is recovered in urine after oral dosing, with ritalinic acid accounting for approximately 80% of the dose. 2
• The drug undergoes stereoselective clearance with systemic clearance of 0.40 ± 0.12 L/h/kg for d-methylphenidate. 2

Available Formulations

Short-Acting Formulations

• Immediate-release tablets and oral solution: Typically administered twice daily (at breakfast and lunch) to minimize insomnia, with effects lasting approximately 4 hours. 1, 4
• Starting dose: 2.5–5 mg daily or twice daily; dose range: 5–30 mg/day, usually divided as twice daily. 1

Long-Acting Formulations

• Extended-release preparations with behavioral effects lasting 8-12 hours have been developed to alleviate difficulties with multiple daily dosing. 1, 4
• 8-hour preparations (Metadate CD and Ritalin LA) utilize microbead technology. 4
• 12-hour preparation (Concerta) utilizes an osmotic pump system. 4
• Serdexmethylphenidate: A prodrug of d-methylphenidate considered a new molecular entity by the FDA, combined with immediate-release d-MPH for earlier onset, longer duration, and potentially lower abuse potential. 1
• Novel delivery systems include chewable tablets, liquid formulations, and transdermal patches. 1

Long-acting formulations are associated with better medication adherence and probably a lower risk of rebound effects, while short-acting formulations allow for more flexibility with dosing frequency and titration. 1

Adverse Effects

Common Side Effects

• Decreased appetite, sleep disturbances (insomnia), increased blood pressure and pulse, headaches, irritability, and stomach pain are the most common adverse effects. 1
• Agitation and insomnia are the most common side effects, manageable with dose reduction and scheduling medication early in the day. 1
• Long-term treatment effects include dry mouth, sweating, headache, loss of appetite, and stomach discomfort. 1

Cardiovascular Effects

• Statistically significant increases in blood pressure and heart rate occur, which may be clinically relevant for patients with preexisting cardiovascular diseases. 1
• Methylphenidate should be avoided in patients with uncontrolled hypertension, underlying coronary artery disease, and tachyarrhythmias. 1
• Rare cardiovascular side effects include hypertension, palpitations, arrhythmias, and in overdose situations, vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. 1, 2

Growth Effects

• Treatment with methylphenidate is associated with statistically significant reduction in height and weight gain in children, though effects are usually minor. 1
• These effects are dose-related and require careful monitoring. 1

Psychiatric Effects

• Rare psychiatric side effects include confusion, psychosis, and tremor. 1
• Recent evidence suggests that psychostimulant medication decreases the risk of suicidal events in patients with ADHD rather than increasing it. 1

Withdrawal and Dependence

• Methylphenidate may produce physical dependence and tolerance. 2
• Withdrawal signs after abrupt discontinuation include dysphoric mood, depression, fatigue, vivid unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. 2

Abuse Potential and Regulatory Status

Methylphenidate is an FDA Schedule II federally controlled substance with a black box warning stating that it should be given cautiously to patients with a history of drug dependence or alcoholism. 1 It has a high potential for abuse, and prolonged administration may lead to dependence. 1

Misuse and abuse of CNS stimulants, including methylphenidate, can result in overdose and death, with this risk increased at higher doses or with unapproved methods of administration such as snorting or injection. 2 Available data suggest that methylphenidate has pharmacokinetic properties that reduce its abuse potential compared with stimulant drugs of abuse such as cocaine. 1

A growing number of young individuals misuse or abuse methylphenidate to sustain attention, enhance intellectual capacity, and increase memory, raising concerns about its use as a cognitive enhancement substance. 6 Intravenous administration is most common among individuals not diagnosed with ADHD or narcolepsy. 7

Dosing Considerations

There is marked individual variability in the dose-response relationship for methylphenidate, requiring dosage titration for optimal effect and avoidance of toxicity in each patient. 3 Treatment typically starts at a low dosage (10-15 mg/day) with increases of 10-15 mg at weekly intervals to a maximum dosage of 60 mg/day, irrespective of formulation. 4

Assessment of plasma concentrations is not clinically useful, nor does weight help in deciding an appropriate dosage due to the variability in behavioral responses. 4 Long-acting stimulant formulations differ in their pharmacokinetic profiles, particularly regarding the rate at which peak levels are attained and decline, and physicians should choose formulations appropriate for the symptom profile and individual needs of the patient. 1

Special Populations and Precautions

Based on animal data, methylphenidate may cause fetal harm, though human data are insufficient to determine risk. 1 The balance of risks and harms is likely different for pregnant and breastfeeding women. 1

Prescribers should exercise caution in adult methylphenidate users and should make a thorough co-medication assessment, as narcolepsy cases tend to be older and use co-medications more frequently than ADHD cases. 7 Clinical guidelines recommend monitoring of pulse and blood pressure when prescribing psychostimulant medication. 1