Methylphenidate

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of methylphenidate
Simplified structural formula without stereochemistry
General
Non-proprietary name Methylphenidate
other names
  • (±) -2-Phenyl-2- (2-piperidyl) acetic acid methyl ester ( IUPAC )
Molecular formula C 14 H 19 NO 2
External identifiers / databases
CAS number
  • 113-45-1 (methylphenidate)
  • 298-59-9 [(2 RS , 2 ′ RS ) -methylphenidate · hydrochloride ]
PubChem 4158
DrugBank DB00422
Wikidata Q422112
Drug information
ATC code

N06 BA04

Drug class

Sympathomimetic , stimulant

Mechanism of action

Dopamine / norepinephrine reuptake inhibitors

properties
Molar mass 233.31 g · mol -1
Melting point
  • 224–226 ° C (hydrochloride)
  • 74-75 ° C (base)
boiling point

135-137 ° C (79.98 Pa, methylphenidate)

solubility

good in water, ethanol and chloroform (hydrochloride)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning 08 - Dangerous to health

danger

H and P phrases H: 302-334
P: 261-342 + 311
Toxicological data

350 mg kg −1 ( LD 50 ,  rat ,  oral , hydrochloride)

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Methylphenidate ( MPH for short ; trade names including Ritalin , Medikinet , Concerta ) is a drug from the group of phenylethylamines . It has a stimulating effect and is now mainly used to treat attention deficit / hyperactivity disorder (ADHD) and, less often, for narcolepsy .

Although MPH is structurally similar to amphetamines , it is counted among the derivatives of piperidine . It has a similar effect to pemoline and is chemically closely related to deoxypipradrol . In Germany, methylphenidate is classified as a marketable and prescription drug .

history

Methylphenidate was first synthesized in 1944 by Leandro Panizzon, an employee of the Swiss company Ciba (now Novartis ). At that time it was also common practice to conduct self- tests with newly developed substances - therefore Leandro Panizzon and his wife Marguerite ("Rita") tried methylphenidate. Marguerite was particularly impressed that her tennis performance improved after taking methylphenidate. The well-known trade name Ritalin for methylphenidate is derived from her nickname Rita .

Ritalin was launched on October 6, 1954 by Ciba on the German-speaking market. The drug was initially dispensed without a prescription in Germany, but in 1971 it was made subject to the Narcotics Act .

pharmacology

Methylphenidate has a stimulating and exciting effect (psychoanaleptic). It suppresses tiredness and increases physical performance in the short term. Warning signals that normally occur during physical overload, such as pain and a feeling of exhaustion, are reduced. It also inhibits appetite.

Mode of action

The signal transmission from the axon of one neuron (above) to the dendrite of another neuron (below) is normally quickly terminated after a stimulus. To do this, transporters transport the released neurotransmitter back into the presynapse . Methylphenidate now blocks these transporters and thus the reuptake of the neurotransmitters. As a result, these accumulate in the gap between the cells and can act longer on the receptors. As a consequence, the signal transmission from cell to cell is increased and amplified.

Methylphenidate inhibits the re-uptake of the neurotransmitters dopamine and norepinephrine by blocking the function of their transporters . These transporters are located in the cell membrane of the presynaptic nerve cells and are used to quickly take up the neurotransmitters from the synaptic cleft . As a result of the reuptake inhibition , the concentration of the messenger substances increases and their effect lasts longer.

This leads to increased signal generation at the receptor and, among other things, to an increase in sympathetic tone . To a small extent, methylphenidate ensures the release of catecholamines , but the large increase in dopamine concentration is achieved primarily through inhibition of reuptake. Orally ingested MPH works primarily in the striatum (part of the basal ganglia), which has the greatest density of dopamine transporters in the brain.

Methylphenidate shows an affinity for the serotonin receptor 5-HT 1A and 5-HT 2B . An effect as an agonist could not be proven. With regard to the blockade of the dopamine transporter (DAT), MPH is similar in its effects to cocaine . However, both substances differ greatly in their influx rate (depending on the form of administration ) and thus also their addictive potential .

Metabolism

Methylphenidate is rapidly and almost completely absorbed after oral administration. Simultaneous consumption of food has no relevant effect on absorption. In the liver, it is mainly broken down into ritalic acid by carboxylesterase 1A1 (CES1). Since MPH is hardly metabolized by CYP enzymes, the risk of drug interactions is rather low.

The bioavailability is 22 ± 8% for the d-enantiomer and 5 ± 3% for the l-enantiomer po in un- retarded form.

An effect sets in after approx. 30 minutes and the maximum plasma concentration is reached after approx. 2 hours. Methylphenidate is eliminated from plasma with a mean half-life of 2 to 3 hours and the systemic clearance is 0.40 ± 0.12 l / h / kg for D- methylphenidate and 0.73 ± 0.28 l / h / kg for L -methylphenidate. The absolute duration of action is approx. 4 hours.

chemistry

Methylphenidate does not belong to the classic phenethylamines , but is an indirect sympathomimetic with a central effect. The chemical structure is partly similar to the ethanolamine skeleton of the catecholamines .

Stereoisomers of methylphenidate

Isomerism

Methylphenidate has two stereogenic centers. So there are four configurational isomers: (2 R , 2 ′ R ) form, (2 S , 2 ′ S ) form, (2 R , 2 ′ S ) form and the (2 S , 2 ′ R ) form . In the non-stereoselective synthesis , the (2 R , 2 ' R ) form and the (2 S , 2' S ) form are formed as a racemate in the same amount, as is the racemate from the (2 R , 2 ' S ) form and the (2 S , 2 ′ R ) form. Both the racemate of the threo form, the [(2 RS , 2 ′ RS ) methylphenidate], and the pure D - threo form are used medicinally . Dexmethylphenidate, which is mainly responsible for the pharmacological effect . Erythro- methylphenidate [(2 RS , 2 ′ SR ) -methylphenidate] is classified in Germany as a marketable, but not a prescription drug.

synthesis

Classic synthesis route of methylphenidate
Selective synthesis of threo methylphenidate

Various synthetic routes are known for the production of methylphenidate. As early as 1944, Pannizon presented a synthetic route that leads to a diastereomeric mixture of methylphenidate. Newer synthetic routes enable the selective production of threo -methylphenidate or dexmethylphenidate.

Synthesis according to Pannizon

The synthesis route described by Pannizon and the numerous known modifications of this synthesis route represent the classic route for the production of methylphenidate. In the first step of this synthesis, benzyl cyanide is arylated with 2-chloropyridine in a basic medium . The phenyl- (2-pyridyl) -acetonitrile obtained is hydrolyzed in acid and esterified with methanol to give the corresponding methyl ester . The final reduction of the pyridine ring with hydrogen under platinum - catalysis in aqueous acetic acid leads to a diastereomeric mixture of methylphenidate. The energetically favored threo isomers can be obtained from the erythro isomers of the diastereomer mixture by epimerization.

Synthesis of threo-methylphenidate

One possibility for the selective preparation of threo- methylphenidate consists in a condensation of phenylglyoxylic acid esters with piperidine and a subsequent lactam cleavage.

Synthesis of dexmethylphenidate

The synthesis of the eutomer dexmethylphenidate is considered to be more demanding . Enantiomeric enrichment by recrystallization allows the isolation of dexmethylphenidate with loss of substance. The separation of enantiomers also succeeds during the synthesis, for example with the aid of ( S ) - (-) - α-methylbenzylamine at the level of the intermediate (±) - threo- ritalic acid or using dibenzoyl D -tartrate at the level of the amide. Separation of enantiomers from (±) - threo -methylphenidate is possible with ( R ) - (-) - binaphthyl-2,2'-diyl hydrogen phosphate, (-) - methoxyacetic acid, O , O ' -di- p -toluoyl- D - tartaric acid or O , O ' -dibenzoyl- D -tartaric acid possible.

Starting from L - erythro -2-phenyl-2- (2-piperidyl) acetamide, a stereoselective synthesis was described for the first time in 1958. Further stereoselective synthesis routes for dexmethylphenidate start from ( R ) - pipecolic acid and phenyllithium or phenyldiazoacetic acid methyl ester and N -BOC-piperidine under Rh 2 (5 R -MEPY) 4 catalysis .

Structure-activity relationships

Numerous MPD analogs were synthesized to investigate structure-activity relationships (SAR). The introduction of a single bromine atom in the aromatic compound increases the inhibition of certain monoamine transporters ( dopamine transporter (DAT), norepinephrine transporter (NET), affinity increase about 20-fold each) most strongly in the meta position . As shown elsewhere, the electrostatic property of the amino nitrogen is of little concern to the monoamine transporter (MAT) bond; The fact that the spatial profile has a decisive influence, on the other hand, is shown by the replacement by building blocks of similar spatial shape (isosteres). By ring contraction to the pyrrolidinyl can for serotonin transporter affinity (SERT affinity) compounds are produced. The ester group can be exchanged for alkyls or carbonyls according to a tried and tested pattern .

Analytics

The reliable qualitative and quantitative analytical detection of methylphenidate is possible in the various test materials such as blood , blood serum , blood plasma , hair , urine , saliva , sewage or blowfly larvae after suitable sample preparation by coupling chromatographic methods such as gas chromatography or HPLC with mass spectrometry . Also enzyme immunoassays are as screening tests available, but should for forensic be supplemented purposes by the aforementioned specific methods.

application areas

ADHD in children and adolescents

Methylphenidate is indicated as part of an overall therapeutic strategy for the treatment of attention deficit / hyperactivity disorder (ADHD) in children from the age of 6 years and adolescents when other therapeutic measures alone have proven inadequate. The diagnosis must not be based solely on the presence of symptoms, but must be based on a complete medical history and examination of the patient using the criteria in the DSM-5 or ICD-10 . A behavioral disorder specialist must oversee treatment.

The area of ​​application was restricted across Europe in June 2006 as a result of a decision by the EU Commission following a European risk assessment procedure. In the case of ADHD in need of therapy , a multimodal form of therapy is regularly indicated; The exclusive drug treatment with methylphenidate is usually insufficient and should be considered improper. In Germany, the Federal Joint Committee followed up on this in September 2010 and stipulated in the Drugs Directive that methylphenidate may only be prescribed for the intended, authorized use at the expense of the statutory health insurance companies .

It used to be recommended that methylphenidate only be used on school days. Nowadays, continuous medication (i.e. also on school-free days) is often practicable if the extra-curricular social behavior is also the aim of the therapy.

Since June 2006, a transdermal patch (Daytrana from Shire Pharmaceuticals ) for the application of methylphenidate over the skin has been available in the USA as a further dosage form . The patch is worn for up to nine hours a day, with a duration of action of up to twelve hours. The effects and side effects of transdermally applied methylphenidate are comparable to those of the prolonged-release capsules. In addition, skin irritation and allergic reactions can occur at the application site, which can lead to a general hypersensitivity to methylphenidate.

ADHD in adults

In April 2011, the approved area of ​​application for a drug containing methylphenidate (Medikinet adult) was expanded to include the treatment of ADHD in adults ; In May 2014, Ritalin adult was added as another treatment option.

Up until then, their therapy was only possible off-label and therefore not reimbursable. The approval includes both further treatment beyond childhood or adolescence as well as recruitment with methylphenidate in adulthood if ADHD has persisted since childhood and other therapeutic measures alone have proven to be inadequate. In order to increase drug safety, it was necessary to make different preparations available for children, adolescents and adults. The package inserts and technical information differ significantly due to different application details, such as the recommended maximum dose and times of intake.

Narcolepsy

In addition, methylphenidate is used in the therapy of narcolepsy , where it is supposed to reduce excessive daytime sleepiness .

dosage

The dosage is carried out individually after a careful diagnosis , as the optimal effect is achieved with different doses. The individually optimal effect can neither be attributed to body weight nor to the plasma concentration alone.

Methylphenidate hydrochloride (MPH-HCl) is used medicinally. For therapy, tablets or capsules are available in various strengths and with either rapid, slowed ( retarded ) or combined (initially faster, then slower) release of active ingredients. This results in a different duration of action, which can range from one to four hours (non-retarded forms) to twelve hours (retarded forms). After the end of the duration of action, the symptoms of ADHD may become more pronounced (a so-called rebound ).

Drug therapy is started with a low single dose (e.g. 2.5 or 5 mg in children) and increased weekly by 5–10 mg per day (so-called titration method) until the optimal dose is reached. The average dose for children is 10–20 mg / day and for adults 20–30 mg / day. In many cases a new setting to a higher dose is necessary after a few months. The maximum dose is 1 mg per kg of body weight, but not more than 60 mg for children and 80 mg for adults per day. At the start of therapy, methylphenidate is given in a quick-release, short-acting form because it is easier to control. Later you can switch to a sustained-release preparation. It is not possible to make a fundamental statement about the correct dose: in some cases a daily dose of 5–10 mg is sufficient, while in other cases up to 60 mg (MPH-HCl) is required. The daily dose is usually divided into two to three individual doses of a short-acting drug form or one to two doses of a retarded form. For the treatment of ADHD in adulthood , a single dose of 10 mg is usually given initially. An increase to doses higher than the upper limit of 60 mg / day recommended for children is not uncommon. According to BtMVV, prescriptions of more than 92.5 mg / day (MPH-HCl, corresponding to 80 mg / day MPH) are only permitted in justified individual cases and while maintaining the necessary safety of narcotics traffic.

Overdose

A moderate overdose (for example, by accidentally taking a double dose) of methylphenidate can lead to dizziness, palpitations, sleep disorders, increased vigilance ("alertness") or excessive sedation. Due to the short duration of action of a few hours, no treatment is usually required.

A strong overdose can cause hyperarousal the central nervous system, convulsions and delirium up to comatose lead. High blood pressure and cardiac arrhythmias can occur. Medical treatment is urgently needed in such cases. Delirium can only occur if the drug is abruptly discontinued for several weeks.

Interactions

Methylphenidate must not be added to non-selective, irreversible monoamine oxidase inhibitors (MAOIs) (up to 14 days after the last dose), as there may be a risk of a hypertensive crisis .

When used at the same time, methylphenidate can reduce the effect of antihypertensive agents, especially guanethidine . On the other hand, the initial sympathomimetic effects of guanethidine and amantadine can be enhanced.

Since methylphenidate inhibits the breakdown of anticoagulants of the coumarin type, antiepileptics ( e.g. phenobarbital , phenytoin , primidone ), neuroleptics and tricyclic antidepressants (e.g. imipramine, desipramine) and phenylbutazone in the organism, their dose must be reduced when administered together.

If alcohol is taken together with methylphenidate, the metabolism of the active substance may change.

Some retarded formulations of methylphenidate should not be taken together with antacids or H₂ receptor antagonists , as this can lead to a more rapid release.

Side effects

During treatment with methylphenidate, children and adolescents experience a rate of 556 per 1000 non-serious adverse events, compared to a rate of 406 per 1000 in control groups. The most common are problems with sleeping and decreased appetite.

According to the patient information, the very common side effects (in more than 1 in 10 cases) include decreased appetite, insomnia, headache, dry mouth, nervousness and nausea at the start of treatment. They can usually be controlled by reducing the dose or by skipping the afternoon or evening dose.

General complaints

Common (1 in 100 to 1 in 10): loss of appetite, anxiety, initial insomnia, depression, nervousness, anxiety, agitation , aggression, teeth grinding, depression, decreased libido, confusion, excitement, dizziness, trembling, tingling (tingling), damping (Sedation) , tension headache, blurred vision, vertigo, pain in the nose and throat, belching (dyspepsia), vomiting, constipation, excessive sweating, muscle tension, irritability, weight loss, muscle twitching (tic), emotional lability.

The following symptoms may also occur in children and adolescents: inflammation of the nasopharynx, dizziness, cough, upper abdominal pain and fever.

Very rarely (less than 1 in 10,000 cases) disorientation, acoustic and visual hallucinations, manias and the onset of psychoses, anger, agitation, mood swings, depressive moods, sadness, lethargy or sleepiness occur.

appetite

Decrease in appetite and fluid intake is a common side effect. This can be alleviated by giving the methylphenidate after a meal or by moving the main meal to the evening after the effects have wore off. Usually this side effect disappears within a few months.

sleep

Review articles ( meta-analyzes ), which summarize a large number of studies that have already been carried out, determine with regard to the administration of stimulants in children and adolescents with ADHD that sleep disorders increase, the time to fall asleep is delayed, sleep efficiency deteriorates and sleep becomes shorter. A possible dose-response relationship emerged, i. H. The more often the drug was taken during a day, the stronger the effect.

Gastrointestinal disorders

Since methylphenidate is usually in the form of a hydrochloride, it reacts slightly acidic when it dissolves. If methylphenidate tablets are taken without liquids, nausea or burning sensation in the esophagus may occur. Abdominal pain or vomiting is common at the start of treatment.

Skin, subcutaneous tissue

Increased sweating, dermatitis (inflammatory reaction of the skin), itching , Quincke's edema can occur during the treatment of children, and hair loss can also occur. In addition, scaly skin diseases and hives can occur.

Suicidality

In addition to suicide, suicide attempts and suicidal ideation have been observed in some patients treated with methylphenidate. However, a 2017 study based on data from 25,629 patients treated with methylphenidate showed no evidence of a possible causal relationship between this treatment and suicide attempts.

Cardiovascular system

Frequently (1: 100 to 1:10) tachycardia (rapid heartbeat), palpitations (heart palpitations), arrhythmias (cardiac arrhythmias) and changes (usually increases) in blood pressure and heart rate occur. Angina pectoris occurs rarely (1: 10000 to 1: 1000) .

Due to reports of sometimes severe adverse cardiovascular effects, a step-by-step plan procedure was initiated for drugs containing methylphenidate to avert drug risks, as a result of which the product information texts were revised with regard to the corresponding safety instructions.

A study by the German Society for Pediatric Cardiology comes to the conclusion that the administration of Ritalin can lead to an increase in blood pressure in individual cases.

Driving ability

Drowsiness and dizziness may occur during treatment with methylphenidate. This can lead to impairments when using machines and driving a car. In Germany, driving vehicles under the influence of methylphenidate is generally permitted. Some studies have shown that taking methylphenidate significantly improves the driving ability of people with ADHD in a dose-dependent manner.

pregnancy

No clinical studies have been performed to determine whether methylphenidate is safe to use during pregnancy. For this reason, methylphenidate should only be taken by pregnant women if absolutely necessary.

Dependency development

Cases of addiction have not been reported with appropriate drug therapy for ADHD using methylphenidate. Accordingly, the risk of developing addiction is not included in the list of undesirable effects in the patient information ("package insert"). The sudden (unauthorized) discontinuation of methylphenidate should, however, be avoided, as this may lead to so-called withdrawal symptoms such as increased hyperactivity, irritability or depressive mood.

In general, the group of people with ADHD is assumed to have an increased tendency to use addictive substances (e.g. nicotine, alcohol or cannabis). Studies show that treating ADHD with stimulants such as methylphenidate reduces the risk of addiction in those affected.

growth

In children, the long-term use of methylphenidate could lead to growth retardation and reduced weight gain, although in most cases the growth process of the children should return to normal after stopping the medication. To date, however, there is a lack of reliable data from long-term studies.

Non-medical use

When used in high doses, especially when consumed nasally or intravenously , methylphenidate has a strong drive-increasing effect and can lead to exuberant euphoria . With intravenous consumption there is a risk of embolism due to the pharmaceutical excipients and other side effects. In the drug scene , drugs containing methylphenidate are sometimes traded as a substitute for amphetamine (speed) .

According to media reports, methylphenidate is used improperly for brain doping in order to improve performance at university and at work and to avoid the normal dips in concentration in everyday life . This seems to be mostly limited to students. A 2013 study examined the use of methylphenidate by medical students based on English, Spanish and Portuguese publications from 1990 to 2012. The proportion of medical students who had consumed methylphenidate within the last year was estimated at 3% to 16%, depending on the publication. There were no differences between the sexes. The reasons cited by the students can be subsumed under an increase in their academic performance. The research concluded that there was no evidence of increased learning or memory performance. The use simply increases the general wakefulness and alertness and shortens the duration of sleep. Thus the expectations of positive effects exceeded the actual benefit of the substance (see also neuroethics ).

Law

In Germany, methylphenidate is subject to narcotic drug regulations and therefore a separate prescription requirement . Corresponding to the maximum dose of 80 mg per day for adults, a doctor may in principle not prescribe more than 2400 mg within 30 days.

Prescription and consumption statistics

In Germany, the consumption of methylphenidate increased in terms of quantity over a number of years; Consumption statistics from the Federal Institute for Drugs and Medical Devices (BfArM) show a particularly large increase for the year 2000 with an increase of 91% compared to the previous year to 463 kg. Although the number of prescriptions and the number of patients treated with methylphenidate are not recorded by the BfArM, the changes in the amount of purchase that result from the reports from pharmacies about BtM drugs dispensed may also reflect changes in medical prescriptions. In 2009, the conditions for treating ADHD in children and adolescents were redefined as part of a European risk assessment process. In 2014, the BfArM reported that there had been no increase in methylphenidate consumption for the first time in 20 years: after the high of 1839 kg in 2012, the quantities fell by almost 2% in 2013. In 2014, the amount consumed fell again.

The prescription statistics of the drug prescription report show a comparable picture: after an increase in the number of prescriptions from 26 million daily doses (DDD) of methylphenidate in 2004 to a high of 58 million DDD in 2012, the number of prescriptions declined slightly. The decrease is countered by an increase in the prescriptions for the psychostimulant lisdexamfetamine introduced in 2013 . From 2016, there was also an increase in methylphenidate; in 2018, 53 million DDDs were prescribed by German doctors.

The number of prescriptions is also different depending on the region and age and gender.

Trade names

Concerta (D, A, CH, USA), Daytrana (USA), Equasym (D, A, CH), Medikinet (D, A, CH), Medikinet retard (D, A, CH), Medikinet adult (D), Metadate (USA), Ritalin / Ritalin-LA / Adult (D, A, CH, USA) and various generics.

literature

Web links

Commons : Methylphenidate  - Collection of pictures, videos, and audio files

Individual evidence

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  72. ↑ INCB Report 2014 , (English) International Narcotics Control Board, p. 37 ff. ( PDF )
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