Dexmethylphenidate
Encyclopedia
Dexmethylphenidate, otherwise known as d-threo-methylphenidate (D-TMP), is the dextrorotatory enantiomer of methylphenidate
. It is a norepinephrine-dopamine reuptake inhibitor
(NDRI) and releasing agent
and thus a psychostimulant, which affects the CNS
. Dexmethylphenidate is sold as Focalin by Novartis
, as Attenade by Celgene
and as a generic drug
by Teva
.
reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter
(DAT) and norepinephrine transporter
(NET), which are responsible for clearing catecholamines from the synapse
, particularly in the striatum
and meso-limbic system
.
Moreover, it is thought to act as a releasing agent
by increasing the release of dopamine and norepinephrine.
Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio
between the SS and RR enantiomers of MPH. "Dexmethylphenidate" is a preparation of the RR enantiomer
of MPH. In theory, d-TMP can be anticipated to be twice the strength of the racemic product. However, certain authors recommend that the ratio is ~70% increase in potency upon enantiopurification of the racemate.
and in certain cases of major depression.
Importantly, the propensity for "abuse" with d-TMP is much less than for the corresponding racemic product.
Dexmethylphenidate has a chemical structure similar to a family of key brain neurotransmitters called monoamines, which include norepinephrine and dopamine. The increase in dopamine which occurs with the use of this medication can create a sense of euphoria, and therefore may make the user subject to abuse of the drug.
Typical daily doses of dexmethylphenidate are around 10–20 mg for children and 20–40 mg for adults. As with all psychostimulant compounds, certain individuals may respond to a small dose and certain individuals may require a larger than average dose, hence, dosing is usually initiated at a typical range and then titrated to suit the patient.
There is a possibility of withdrawal symptoms if dexmethylphenidate use is discontinued suddenly. As with other stimulants, withdrawal symptoms may include emotional or behavioral depression. Tapering off is recommended, under the supervision of a doctor. Addiction
, which involves compulsive or harmful drug-seeking behavior, is rare but not impossible.
XR (another stimulant used to treat Attention-Deficit Hyperactivity Disorder
) for a period in 2005, however it was returned to the market in that same year after it was demonstrated that cardiac risk is low in patients free of congenital heart defect
s. Heart problems have been reported, predominantly in young people taking ADD stimulants, though the FDA has not concluded that psychostimulants increase risk of cardiac problems for a person without a heart condition. Suicidal thinking
has been reported in young people who are taking antidepressant
s at the same time they are taking an ADHD stimulant and many antidepressants carry a "black box warning
" label concerning a possible increase in suicidal ideation in patients under 18 years of age.
, dizziness, nausea
, stomach pain, euphoria
, headache
, anxiety
, anorexia
, and weight loss are common side effects.
Rare but much more serious side effects include uncontrolled muscle movements (e.g., stiffness, twitching, shaking), hyperthermia
, tics, edema
of the feet/hands, blurred vision, mental/mood/behavior changes (e.g., agitation
, aggression
, mood swings, depression
, hallucinations, abnormal thoughts/behavior), extreme tiredness, and severe sweating
, easy bleeding/bruising, shortness of breath, fainting
, chest/jaw/left arm pain, sudden vision changes, signs of infection (fever, persistent sore throat), tachycardia
, weakness
, seizures, confusion
, slurred speech, and severe headaches and in some very rare cases death.
Also, there is a potential for a severe allergic reaction, but it is extremely rare. Trouble breathing, itching, a rash, swelling, or dizziness are all signs/symptoms of this allergic reaction.
such as isocarboxazid
(Marplan), phenelzine
(Nardil), rasagiline
(Azilect), selegiline
(Eldepryl, Emsam), or tranylcypromine
(Parnate) that has been used in the past 14 days. Serious, life-threatening side effects can occur if dexmethylphenidate is taken with an MAOI.
in the United States
.
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
. It is a norepinephrine-dopamine reuptake inhibitor
Norepinephrine-dopamine reuptake inhibitor
A norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(NDRI) and releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
and thus a psychostimulant, which affects the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Dexmethylphenidate is sold as Focalin by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
, as Attenade by Celgene
Celgene
Celgene Corporation is a manufacturer of drug therapies for cancer and inflammatory disorders. It is incorporated in Delaware and headquartered in Summit, New Jersey...
and as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
by Teva
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
.
Mode of activity
Methylphenidate is a catecholamineCatecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT) and norepinephrine transporter
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET), which are responsible for clearing catecholamines from the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, particularly in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
and meso-limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
.
Moreover, it is thought to act as a releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
by increasing the release of dopamine and norepinephrine.
Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio
Eudysmic ratio
The Eudysmic ratio is a common term in pharmacology, chemistry, and molecular biology. The eudysmic ratio describes the difference in pharmacologic activity between the two enantiomers of a drug....
between the SS and RR enantiomers of MPH. "Dexmethylphenidate" is a preparation of the RR enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
of MPH. In theory, d-TMP can be anticipated to be twice the strength of the racemic product. However, certain authors recommend that the ratio is ~70% increase in potency upon enantiopurification of the racemate.
| Compd | DAT (Ki) | DA (IC50) | NET (Ki) | NE (IC50) |
|---|---|---|---|---|
| D-TMP | 161 | 23 | 206 | 39 |
| L-TMP | 2250 | 1600 | >10K | 980 |
| DL-TMP | 121 | 20 | 51 | 788 |
Therapeutic use
Dexmethylphenidate is used as a treatment for ADHD, ideally in conjunction with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Dexmethylphenidate may also improve listening skills and organization of tasks, and may help prevent tic disorders. Because it is a psychostimulant, dexmethylphenidate may also help with narcolepsyNarcolepsy
Narcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
and in certain cases of major depression.
Importantly, the propensity for "abuse" with d-TMP is much less than for the corresponding racemic product.
Pharmacology
Dexmethylphenidate has a 4-6 hour duration of effect (a long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL-TMP XR (Concerta, Ritalin LA), with flexible dosing and good tolerability.) It has also been demonstrated to reduce the symptoms of childhood ADHD, as well as ADHD in adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.Dexmethylphenidate has a chemical structure similar to a family of key brain neurotransmitters called monoamines, which include norepinephrine and dopamine. The increase in dopamine which occurs with the use of this medication can create a sense of euphoria, and therefore may make the user subject to abuse of the drug.
Typical daily doses of dexmethylphenidate are around 10–20 mg for children and 20–40 mg for adults. As with all psychostimulant compounds, certain individuals may respond to a small dose and certain individuals may require a larger than average dose, hence, dosing is usually initiated at a typical range and then titrated to suit the patient.
There is a possibility of withdrawal symptoms if dexmethylphenidate use is discontinued suddenly. As with other stimulants, withdrawal symptoms may include emotional or behavioral depression. Tapering off is recommended, under the supervision of a doctor. Addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
, which involves compulsive or harmful drug-seeking behavior, is rare but not impossible.
Efficacy
Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated. Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. It also showed greater efficacy than osmotic release oral system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.Concerns
The same concerns that apply to other stimulant drugs should be considered: Reports of sudden heart death in children caused Canada to stop marketing AdderallAdderall
Adderall is a brand name of amphetamine salts–based medication used for attention-deficit hyperactivity disorder and narcolepsy. It is a brand-name psychostimulant medication composed of racemic amphetamine aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine saccharide, and...
XR (another stimulant used to treat Attention-Deficit Hyperactivity Disorder
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
) for a period in 2005, however it was returned to the market in that same year after it was demonstrated that cardiac risk is low in patients free of congenital heart defect
Congenital heart defect
A congenital heart defect is a defect in the structure of the heart and great vessels which is present at birth. Many types of heart defects exist, most of which either obstruct blood flow in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern. Other...
s. Heart problems have been reported, predominantly in young people taking ADD stimulants, though the FDA has not concluded that psychostimulants increase risk of cardiac problems for a person without a heart condition. Suicidal thinking
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
has been reported in young people who are taking antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s at the same time they are taking an ADHD stimulant and many antidepressants carry a "black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
" label concerning a possible increase in suicidal ideation in patients under 18 years of age.
Side effects
InsomniaInsomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, dizziness, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, stomach pain, euphoria
Euphoria
Euphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, and weight loss are common side effects.
Rare but much more serious side effects include uncontrolled muscle movements (e.g., stiffness, twitching, shaking), hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
, tics, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
of the feet/hands, blurred vision, mental/mood/behavior changes (e.g., agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
, mood swings, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, hallucinations, abnormal thoughts/behavior), extreme tiredness, and severe sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, easy bleeding/bruising, shortness of breath, fainting
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
, chest/jaw/left arm pain, sudden vision changes, signs of infection (fever, persistent sore throat), tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, weakness
Weakness
Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a...
, seizures, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, slurred speech, and severe headaches and in some very rare cases death.
Also, there is a potential for a severe allergic reaction, but it is extremely rare. Trouble breathing, itching, a rash, swelling, or dizziness are all signs/symptoms of this allergic reaction.
Interactions
Dexmethylphenidate should not be used in combination with a monoamine oxidase inhibitor (MAOI)Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
such as isocarboxazid
Isocarboxazid
Isocarboxazid is an irreversible and nonselective monoamine oxidase inhibitor of the hydrazine chemical class used as an antidepressant and anxiolytic...
(Marplan), phenelzine
Phenelzine
Phenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
(Nardil), rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
(Azilect), selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
(Eldepryl, Emsam), or tranylcypromine
Tranylcypromine
Tranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
(Parnate) that has been used in the past 14 days. Serious, life-threatening side effects can occur if dexmethylphenidate is taken with an MAOI.
Usage
The Focalin XR capsules are sometimes prescribed over other extended release stimulants because the capsules can be opened and their contents mixed with applesauce or pudding to help children who cannot, or will not, swallow large capsules. This is possible due to the SODAS (Spheroidal Oral Drug Absorption System) delivery system, also used in Ritalin LA. Focalin XR comes in five, ten, fifteen, twenty, thirty, and forty milligram capsules. To determine appropriate dosage doctors first prescribe one to four 5 mg capsules. An appropriate treatment plan is then based on the patient's reaction to the initial dose. From there, doctors usually increase dose by 5 mg to 10 mg until finding the right dosage.Legal status
Dexmethylphenidate, due to its abuse potential is classed as a Schedule II controlled drugControlled Drug
The United Kingdom Misuse of Drugs Act 1971 aimed to control the possession and supply of numerous listed drugs and drug-like substances as a controlled substance. The act allowed and regulated the use of some Controlled Drugs by various classes of persons The United Kingdom Misuse of Drugs Act...
in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
.