Methylphenidate (Ritalin | Concerta)- Mechanism of Action, Side Effects and Dosing

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Methylphenidate (DAT and NAT Inhibitor): Ritalin | Concerta

Mechanism of action:

Methylphenidate (MPH) non-competitively blocks the reuptake of dopamine and noradrenaline into the terminal by blocking the dopamine transporter (DAT) and noradrenaline transporter (NAT), increasing levels of dopamine and noradrenaline in the synaptic cleft.
MPH inhibits DAT to a greater extent than Amphetamine and thus indirectly increases dopaminergic and noradrenergic transmission.
MPH also protects the dopaminergic system against the ongoing ‘wearing off’ (by securing a substantial reserve pool of the neurotransmitter, stored in the presynaptic vesicles), translating into a relatively low risk of neurotoxic side effects in patients treated with MPH. [Jaeschke, 2021]
MPH leads to a 3 to 4-fold increase of DA and NA in the striatum and the prefrontal cortex. [Jaeschke, 2021]

3. Action on NAT and increase in extracellular noradrenaline with effects on β and ⍺ receptors.

MPH binds to several subtypes of α-adrenergic receptors: ⍺2A, ⍺2B and ⍺2C receptors linked to procognitive effects. [Jaeschke, 2021]
The ⍺1 receptor activation is linked to increased peripheral vascular resistance.

Note: Methylphenidate does not increase extracellular serotonin (c.f amphetamine which increases 5-HT)

MPH has almost 1300 times greater affinity for NAT, and about 2200 times greater affinity for DAT, in comparison to SERT. [Jaeschke, 2021]
MPH has agonist activity at the 5-HT_1A receptor. [Faraone, 2018].

Side Effects:

Common: Insomnia, decreased appetite, dysphoria, irritability, tics

Rare: anxiety, depression, psychosis, mania

Growth retardation (decreased height, weight, and bone marrow density) is observed when taken long-term in children. [Poulton et al, 2016].

Neurological: dizziness, headache, tics, restlessness/akathisia.

Gastrointestinal: nausea/vomiting, dry mouth, decreased appetite, weight loss, abdominal pain

Cardiovascular systems : Tachycardia, and palpitations.

Dermatological: Excessive sweating and ulceration of their digits. Raynaud’s syndrome.

Rare: Priapism, blurred vision.

Metabolism and Half-life:

Methylphenidate is metabolised primarily by de-esterification to α-phenyl-piperidine acetic acid (PPAA) which has little or no pharmacologic activity.
Carboxylesterase-1A1 (CES-1), located in the stomach and liver, is the primary enzyme involved with first-pass MPH metabolism.
Elimination half-life that is independent of the preparation of MPH (2.5 to 3.5 hours after oral administration)

Methylphenidate Immediate Release (Ritalin)

Ritalin is a racemate consisting of a 1:1 mixture of d-threo methylphenidate (d-MPH) and l-threo methylphenidate (l-MPH).
The pharmacological specificity of MPH resides entirely on the d-threo isomer.
Thus, more recently, high-purity formulations containing d-threo-MPH only (the most potent form of the drug) are developed. The drug-containing only this isomer is sometimes called d-TMP, although other names, dexmethylphenidate, D-MPH, or D-threomethylphenidate, are used. [New Pharmacological Treatments for Attention Deficit Hyperactivity Disorder (ADHD) – Viloxazine | Azstarys | Mazindol | Centanafadine
Available as a tablet
Onset – 20 to 60 minutes
Duration of action – 2 to 4 hours.
Dosing – Dose is initially 5 mg to 10 mg, titrated up in weekly increments by 5 mg to 10 mg to a maximum of 2.1 mg/kg/day, maximum dose 60 mg daily in children and 80 mg/day in adults. [PI]
Recommended monitoring blood pressure, pulse, appetite
Monitor for insomnia, mood changes and development of tics.
Product information from TGA.

Methylphenidate is also available in the extended-release version.

Ritalin LA (Long-acting)

Ritalin LA is available in capsule form.
One Ritalin LA capsule contains 10 mg, 20mg, 30mg, 40mg or 60 mg of methylphenidate hydrochloride.
Maximum doses of 60 mg /day in children and adolescents; 80 mg/day in adults.
Each modified-release, hard-gelatin capsule contains half the dose as immediate-release beads and the remaining half of the dose as enteric-coated, delayed-release beads. This provides an immediate release of methylphenidate followed by a delayed release of methylphenidate.
Duration of action – 6-8 hours
Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The two peak concentrations are observed at approximately 2 and approximately 6 h post-dose. [Wang et al, 2004]
In some children with ADHD, sleeplessness may occur as the effect of the drug wears off. On rare occasions, an additional dose at about 8.00 p.m. may help; a trial dose may help to clarify the issue in an individual case if the symptom warrants treatment. [PI]
These beaded preparations are useful for children who cannot take or dislike taking pills, as parents can open the capsules and sprinkle the medicine on their child’s food.
The capsules may be administered with or without food. A high-fat breakfast may slow the rate of absorption and, therefore, the onset of action.
Product information from TGA.

The recommended dose of Ritalin LA should be equal to the total daily dose of the immediate-release formulation, not exceeding a total dose of 60 mg in children and 80 mg in adults.

Concerta:

Methylphenidate XR (Concerta) uses an osmotic release oral system (OROS) which has an osmotic pump mechanism that creates an ascending profile of MPH in the blood, providing effective treatment for up to 10 to 12 hours.
Approximately 25% of the methylphenidate is delivered immediately, with the remaining 75% released gradually for sustained symptomatic relief.
The immediate-release component leads to the first peak plasma concentration about 1–2 h following the ingestion.
The slow-release component leads to a second peak plasma concentration about 7 h following the ingestion.
Available in doses of 18 mg, 27 mg, 36 mg, and 54 mg.
Dosing: 54 mg once a day in children and adolescents; 72 mg once a day in adults.
Product information from TGA.

Ritalin LA vs Concerta Pharmacokinetics: [Markowitz et al., 2003].

The Ritalin LA formulation shows more rapid initial absorption and reaches significantly higher peak plasma concentrations compared with Concerta without any differences in bioavailability.
The Ritalin LA capsule demonstrates a distinctly bimodal plasma concentration-time profile with peaks at approx 2 and 6 hrs post-dose.
MPH plasma concentrations resulting from Concerta reached a peak at 6 hours.
Thus the recommended starting dose of the Ritalin LA 20 mg capsule formulation provides more rapid absorption and higher peak plasma concentrations than the recommended 18 mg starting dose of the Concerta formulation.

While the above dosing regimes have been recommended in PI and guidelines, there is a general consensus amongst experts to consider flexible dosing. [Mattingly et al., 2021]

The general consensus among experts is that the strategic goal of treatment with MPH is to ensure the medication works all day long (to make the patient less likely to experience rebound symptoms of ADHD, once MPH wears off).

In line with the above, some recommendations include using long-acting MPH twice daily (around 8 a.m. and 15 p.m.) as the ‘cornerstone’ of pharmacotherapy for adults with ADHD, with shorter-acting formulations being considered as add-on treatments. This is postulated to make it less likely for a patient to develop rebound symptoms at bedtime. Some patients may find it beneficial to take low doses of short-acting MPH in the evening to become more peaceful and, hence, more likely to fall asleep. [Mattingly et al., 2021]

From a practical perspective, there is significant variability in doses of MPH for optimal efficacy. The rule of thumb has it that patients should not be prescribed MPH at doses exceeding 150 mg/day. [Jaeschke, 2021]

The position paper by members of the International Multicentre Persistent ADHD Collaboration, it was implied that ‘doses around 1 mg/kg [per body mass] of methylphenidate are correlated with better efficacy, yet are rarely achieved in studies of adult patients’. [Franke et al., 2018]

Drug Interactions: [PI]

Methylphenidate can inhibit the metabolism of warfarin, phenytoin, tricyclic antidepressants, or SSRIs and can increase plasma concentration.
Carbamazepine may reduce concentrations.
Concurrent use of MAOI is contraindicated.
Caution in patients with hypertension.
The metabolism of MPH may be also inhibited by alcohol.
Contraindicated in patients with severe cardiovascular disease. [Stimulant products, including methylphenidate, generally should not be used in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may increase the risk of sudden death due to the sympathomimetic effects of a stimulant drug].