Systematic (IUPAC) name
methyl phenyl(piperidin-2-yl)acetate
Identifiers
CAS number : 113-45-1
ATC code : N06BA04
PubChem : 4158
DrugBank : APRD00657
ChemSpider : 4015
Chemical data
Formula : C14H19NO2
Mol. mass : 233.31 g/mol
SMILES : eMolecules & PubChem
Pharmacokinetic data
Bioavailability 11–52%
Protein binding 30%
Metabolism Liver
Half life 2–4 hours
Excretion Urine
Therapeutic considerations
Pregnancy cat. C
Routes Oral, Transdermal, IV, Nasal
Methylphenidateis the most commonly prescribed psychostimulant and is indicated in the treatment of attention-deficit hyperactivity disorder, Postural Orthostatic Tachycardia Syndrome and narcolepsy, although off-label uses include treating lethargy, depression, neural insult, and obesity. In North America it is most commonly known as the brand name Ritalin, which is an instant-release racemic mixture, although a variety of brand names and formulations exist.Methylphenidate is a potent central nervous system stimulant derived from amphetamine, and is thought to exert its effect by increasing dopaminergic stimulation in the brain.
History
Methylphenidate was patented in 1954 by the CIBA pharmaceutical company (now Novartis) as a potential cure for Mohr's disease
Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Today methylphenidate is the most commonly prescribed medication to treat ADHD around the world.Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.
Attention deficit hyperactivity disorder Methylphenidate is approved by the FDA for the treatment of attention-deficit hyperactivity disorderThe addition of behavioural modification therapy (e.g. CBT) has additional benefits on treatment outcomeThere is a lack of evidence of the effectiveness in the long term of beneficial effects of methylphenidate with regard to learning and academic performance.A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature. There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD has also been noted.A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed.The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose therefore should be titrated to an optimal level which achieves therapeutic benefit and minimal side effectsTherapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.
Pregnancy Implications
There are no well-controlled studies establishing safety in pregnant women. Animal studies have shown teratogenic effects to the fetus. Do not use in women of childbearing age unless the potential benefit outweighs the possible risk.
Lactation
Excretion in breast milk unknown/use caution
Hypersensitivity to methylphenidate, any component of the formulation, or idiosyncrasy to sympathomimetic amines; marked anxiety, tension, and agitation; glaucoma; use during or within 14 days following MAO inhibitor therapy; Tourette's syndrome or tics
Warnings/Precautions:
Has demonstrated value as part of a comprehensive treatment program for ADHD. Safety and efficacy in children <6 years of age not established. Use with caution in patients with bipolar disorder, diabetes mellitus, cardiovascular disease, hyperthyroidism, seizure disorders, insomnia, porphyria, or hypertension. Use caution in patients with history of ethanol or drug abuse. May exacerbate symptoms of behavior and thought disorder in psychotic patients. Do not use to treat severe depression or fatigue states. Potential for drug dependency exists - avoid abrupt discontinuation in patients who have received for prolonged periods. Visual disturbances have been reported (rare). Stimulant use has been associated with growth suppression. Growth should be monitored during treatment. Stimulants may unmask tics in individuals with coexisting Tourette's syndrome. should not be used in patients with esophageal motility disorders or pre-existing severe gastrointestinal narrowing (small bowel disease, short gut syndrome, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, Meckel's diverticulum).
Stability
Immediate release tablet: Do not store above 30°C (86°F); protect from light Extended release capsule: Store in dose pack provided at 25°C (77°F) Sustained release tablet: Do not store above 30°C (86°F); protect from moisture Osmotic controlled release tablet Store at 25°C (77°F); protect from humidity
Mechanism of Action
Mild CNS stimulant; blocks the reuptake mechanism of dopaminergic neurons; appears to stimulate the cerebral cortex and subcortical structures similar to amphetamines
Methylphenidate is a medication prescribed for individuals (usually children)
who have attention-deficit hyperactivity disorder (ADHD), which consists of a
persistent pattern of abnormally high levels of activity, impulsivity, and/or
inattention that is more frequently displayed and more severe than is typically
observed in individuals with comparable levels of development. The pattern of
behavior usually arises between the ages of 3 and 5, and is diagnosed during
the elementary school years due to the child’s excessive locomotor activity, poor attention, and/or impulsive behavior.
Most symptoms improve during adolescence or adulthood, but the disorder can
persist or present in adults. It has been estimated that 3–7 percent of school-age children have ADHD. Methylphenidate also is occasionally prescribed for
treating narcolepsy.
Health Effects
Methylphenidate is a central nervous system (CNS) stimulant. It has effects
similar to, but more potent than, caffeine and less potent than amphetamines. It has a notably calming and “focusing” effect on those with ADHD, particularly
children.
Note /Government Notification: These chemicals are designated as those that are used in the manufacture of the controlled substances and are important to the manufacture of the substances. For any (Control Substance) products Import and Export *** subjected to your country government laws /control substance ACT.
Information: The information on this web page is provided to help you to work safely, but it is intended to be an overview of hazards, not a replacement for a full Material Safety Data Sheet (MSDS). MSDS forms can be downloaded from the web sites of many chemical suppliers. ,also that the information on the PTCL Safety web site, where this page was hosted, has been copied onto many other sites, often without permission. If you have any doubts about the veracity of the information that you are viewing, or have any queries, please check the URL that your web browser displays for this page. If the URL begins "www.tajapi.com/www/Denatonium Benzoate.htm/" the page is maintained by the Safety Officer in Physical Chemistry at Oxford University. If not, this page is a copy made by some other person and we have no responsibility for it.
The Controlled Substances Act (CSA) was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970.[1] The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated. The Act also served as the national implementing legislation for the Single Convention on Narcotic Drugs.
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[edit] Narcolepsy
Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden attacks of sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[29] Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test, but performance does not improve to levels comparable to healthy controls.[30]
[edit] Adjunctive
Use of stimulants such as methylphenidate in cases of refractory depression is controversial.[31] In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.[32] Methylphenidate may be used in addition to an antidepressant for treatment-refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, HIV-positive patients.[33] However, benefits tend to be only partial with stimulants being generally less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation. Stimulants may however, have fewer side effects than tricyclic antidepressants in the elderly and medically ill.[34] A review of the literature found that methylphenidate was ineffective for refractory cases of major depression.[35]
[edit] Substance dependence
Methylphenidate has shown some benefits as a replacement therapy for methamphetamine addicts.[36] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence[37][38][39] in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.[40]
Early research began in 2007-8 in some countries on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence. That it can satisfy cravings for cocaine in a way which is subjectively and pharmacologically equivalent but longer-lasting as well as easier on the body and somewhat safer and easier to manage has long been part of the 'street lore' associated with stimulants in many parts of the world. Methylenedioxymethcathinone (another closely related phenethylamine derived stimulant) shows particular potential for this application due to its closer similarity to the effect of cocaine than amphetamine.[citation needed] This is similar to the way that other substitution drugs such as methadone, buprenorphine, LAAM, butorphanol, extended-release oral morphine, dihydrocodeine, and clonidine were amongst opioid users in various times over the past century.
[edit] Pervasive developmental disorders
Given the high co-morbidity between ADHD and autism, a few studies have examined the efficacy and effectiveness of methylphenidate in the treatment of autism. However, most of these studies examined the effects of methylphenidate on attention and hyperactivity symptoms among kids with autism spectrum disorders. Aman and Langworthy (2000) attempted to examine the effects of methylphenidate on social-communication and self-regulation behaviors among kids with ASDs.[41]
The sample included 33 children with pervasive developmental disorder (29 boys) with a mean age of 6.93 years (range 5-13). This was a 4-week randomized, double-blind, cross-over placebo study, with treatment changing each week between 4 conditions: placebo, low dose, medium dose, and high dose. In this design, neither the experimenters nor the families know which of the 4 treatments the child is receiving at any given time. In addition, the treatment condition changes randomly each week, without anyone knowing the nature of the old or new condition. This allows the experimenters to assume that consistent changes in behaviors that occur during a particular treatment is truly due to the effect of that treatment and not to the expectation of the treatment (placebo effect).
The results indicate that children showed significantly more joint attention behaviors when receiving methylphenidate than when receiving the placebo (although the most effective dosage varied by individual). Furthermore, at a group level, the low dose of methylphenidate resulted in significantly improved joint attention behaviors when compared to the placebo, but no differences were noted between the low, medium, and high doses. Low and medium doses of methylphenidate also resulted in improved self-regulation behavior when compared to placebo.
The study presents compelling preliminary evidence suggesting that methylphenidate is effective in improving some social behaviors among children with autism spectrum disorders.[42]
[edit] Investigational
Animal studies using rats with ADHD like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of followup study whether this occurs in ADHD like animals and whether it occurs in humans.[43] However, long lasting benefits of stimulant drugs have not been found in humans.[44]
Methylphenidate may reduce the risk of falls in older adults by treating cognitive deficits associated with aging and disease.[45]
[edit] Delivery formulations
Ritalin 10 mg pill (Ciba/Novartis)
All media are in milligrams. Ritalin is mostly administered in the form of a tablet or capsule.
[edit] Tablets
* Ritalin: 5, 10 or 20 mg tablets.
* Ritalin SR: 20 mg controlled-release tablets.
* Attenta: 10 mg tablets.
* Methylin: 5, 10 or 20 mg tablets.
* Methylin ER: 5, 10 and 20 mg controlled-release tablets.
* Metadate ER: 10 and 20 mg controlled-release tablets.
* Equasym: 5, 10, 20 or 30 mg tablets.
* Rubifen: 5, 10 or 20 mg tablets.
* Motiron: 5, 10 or 20 mg tablets.
[edit] Capsules
* Concerta: 18, 27, 36, and 54 mg osmotic controlled release capsules. (goes off patent in 2018)[46]
Note: Some adults may take two 36 mg capsules for an effective dose of 72 mg.[47]
* Ritalin LA: 10, 20, 30 or 40 mg controlled-release capsules.
* Metadate CD: 10, 20, 30, 40, 50 or 60 mg controlled-release capsules.
* Biphentin: 10, 15, 30, 40, or 60 mg suspended release capsules.
[edit] Patches
* Daytrana 10, 15, 20 or 30 mg controlled-release patches (1.1, 1.6, 2.2 or 3.3 mg/hour for 9 hours).
Contents
* Pharmacology
* Indications
* Contraindications
* Warnings
* Precautions
* Adverse Effects
* Overdose
* Dosage
* Supplied
* Research
Methylphenidate is a mild CNS stimulant.
The mode of action in man is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the CNS.
Methylphenidate is rapidly and extensively absorbed from the tablets following oral administration; however, owing to extensive first-pass metabolism, bioavailability is low (approx. 30%) and large individual differences exist (11 to 52%).
In one study, the administration of methylphenidate with food accelerated absorption, but had no effect on the amount absorbed.
Peak plasma concentrations of 10.8 and 7.8 ng/mL were observed, on average, 2 hours after administration of 0.30 mg/kg in children and adults, respectively. However, peak plasma concentrations showed marked variability between subjects. Both the area under the plasma concentration curve (AUC), and the peak plasma concentrations (C(max)) showed dose-proportionality.
Methylphenidate is eliminated from the plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults. The apparent mean systemic clearance is 10.2 and 10.5 L/hr/kg in children and adults, respectively for a 0.3 mg/kg dose. These data indicate that the pharmacokinetic behavior of methylphenidate in hyperactive children is similar to that in normal adults. The apparent distribution volume of methylphenidate in children was approximately 20 L/kg, with substantial variability (11 to 33 L/kg).
Following oral administration of methylphenidate, 78 to 97% of the dose is excreted in the urine and 1 to 3% in the feces in the form of metabolites within 48 to 96 hours. The main urinary metabolite is ritalinic acid (alpha-phenyl-2-piperidine acetic acid, PPAA); unchanged methylphenidate is excreted in the urine in small quantities (<1%). Peak PPAA plasma concentrations occurred at approximately the same time as peak methylphenidate concentrations, however, levels were several-fold greater than those of the unchanged drug. The half-life of PPAA was approximately twice that of methylphenidate.
In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites exhibit low plasma protein binding (approx. 15%).
Methylphenidate in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the Ritalin SR tablet, compared to the Ritalin tablet, measured by the urinary excretion of the methylphenidate major metabolite (PPAA), was 105% (49 to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 4.7 hours (1.3 to 8.2 hours) for the extended-release tablets and 1.9 hours (0.3 to 4.4 hours) for the regular tablets. The elimination half-life and the cumulative urinary excretion of PPAA are not significantly different between the two dosage forms. An average of 67% of the extended-release tablet dose was excreted in children as compared to 86% in adults.
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Indications
Attention-Deficit Hyperactivity Disorder (ADHD), previously known as Attention-Deficit Disorder. Other terms being used to describe this behavioral syndrome include: minimal Brain Dysfunction in Children, Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Methylphenidate is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Non-localizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of CNS dysfunction may or may not be warranted.
Special Diagnostic Considerations:
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational and social resources.
Characteristics commonly reported include:
Chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.
Narcolepsy.
NIDA InfoFacts: Stimulant ADHD Medications - Methylphenidate and Amphetamines
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Stimulant medications (e.g., methylphenidate and amphetamines) are often prescribed to treat individuals diagnosed with attention-deficit hyperactivity disorder (ADHD). ADHD is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequently displayed and more severe than is typically observed in individuals at a comparable level of development. This pattern of behavior usually becomes evident in the preschool or early elementary years, and the median age of onset of ADHD symptoms is 7 years. For many individuals, ADHD symptoms improve during adolescence or as age increases, but the disorder can persist into adulthood. In the United States, ADHD is diagnosed in an estimated 8 percent of children ages 4–17 and in 2.9–4.4 percent of adults.1,2,3
How Do Prescription Stimulants Affect the Brain?
All stimulants work by increasing dopamine levels in the brain—dopamine is a brain chemical (or neurotransmitter) associated with pleasure, movement, and attention. The therapeutic effect of stimulants is achieved by slow and steady increases of dopamine, which are similar to the natural production of the chemical by the brain. The doses prescribed by physicians start low and increase gradually until a therapeutic effect is reached. However, when taken in doses and routes other than those prescribed, stimulants can increase brain dopamine in a rapid and highly amplified manner—as do most other drugs of abuse—disrupting normal communication between brain cells, producing euphoria, and increasing the risk of addiction.
What Is the Role of Stimulants in the Treatment of ADHD?
Treatment of ADHD with stimulants, often in conjunction with psychotherapy, helps to improve the symptoms of ADHD, as well as the self-esteem, cognition, and social and family interactions of the patient. The most commonly prescribed medications include amphetamines (e.g., Adderall®, a mix of amphetamine salts) and methylphenidate (e.g., Ritalin and Concerta—a formulation that releases medication in the body over a period of time). These medications have a paradoxically calming and “focusing” effect on individuals with ADHD. Researchers speculate that because methylphenidate amplifies the release of dopamine, it can improve attention and focus in individuals who have dopamine signals that are weak.4
One of the most controversial issues in child psychiatry is whether the use of stimulant medications to treat ADHD increases the risk of substance abuse in adulthood. Research thus far suggests that individuals with ADHD do not become addicted to their stimulant medications when taken in the form and dosage prescribed by their doctors. Furthermore, several studies report that stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life.5,6,7 More research is needed, however, particularly in adolescents treated with stimulant medications.
Why and How Are Prescription Stimulants Abused?
Stimulants have been abused for both “performance enhancement” and recreational purposes (i.e., to get high). For the former, they suppress appetite (to facilitate weight loss), increase wakefulness, and increase focus and attention. The euphoric effects of stimulants usually occur when they are crushed and then snorted or injected. Some abusers dissolve the tablets in water and inject the mixture. Complications from this method of use can arise because insoluble fillers in the tablets can block small blood vessels.
What Adverse Effects Does Prescription Stimulant Abuse Have on Health?
Stimulants can increase blood pressure, heart rate, body temperature, and decrease sleep and appetite, which can lead to malnutrition and its consequences. Repeated use of stimulants can lead to feelings of hostility and paranoia. At high doses, they can lead to serious cardiovascular complications, including stroke.
Addiction to stimulants is also a very real consideration for anyone taking them without medical supervision. This most likely occurs because stimulants, when taken in doses and routes other than those prescribed by a doctor, can induce a rapid rise in dopamine in the brain. Furthermore, if stimulants are used chronically, withdrawal symptoms—including fatigue, depression, and disturbed sleep patterns—can emerge when the drugs are discontinued.
How Widespread Is Prescription Stimulant Abuse?
Monitoring the Future Survey*
Each year, the Monitoring the Future (MTF) survey assesses the extent of drug use among 8th-, 10th-, and 12th-graders nationwide. For amphetamines and methylphenidate, the survey measures only past-year use, which refers to use at least once during the year preceding an individual’s response to the survey. Use outside of medical supervision was first measured in the study in 2001; nonmedical use of stimulants has been falling since then, with total declines between 25 percent and 42 percent at each grade level surveyed. MTF data for 2008 indicate past-year nonmedical use of Ritalin by 1.6 percent of 8th-graders, 2.9 percent of 10th-graders, and 3.4 percent of 12th-graders.
Since its peak in the mid-1990s, annual prevalence of amphetamine use fell by one-half among 8th-graders to 4.5 percent and by nearly one-half among 10th-graders to 6.4 percent in 2008. Amphetamine use peaked somewhat later among 12th-graders and has fallen by more than one-third to 6.8 percent by 2008. Although general nonmedical use of prescription stimulants is declining in this group, when asked, “What amphetamines have you taken during the last year without a doctor’s orders?” 2.8 percent of all 12th-graders surveyed in 2007 reported they had used Adderall. Amphetamines rank third among 12th-graders for past-year illicit drug use.
Other Information Sources
For more information on treating ADHD, visit the Web site for the National Institute of Mental Health, National Institutes of Health,
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein.
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