Pathways

Methylnaltrexone, also known as Relistor, is a μ-opioid antagonist. This drug is used in the treatment of opioid-induced constipation in palliative patients that are not responding to laxative therapy. This drug acts on the gastrointestinal tract to decrease opioid-induced constipation without producing analgesic effects or withdrawal symptoms as it does not cross the blood-brain barrier. Methylnaltrexone is given as a subcutaneous injection or as an oral tablet. Methylnaltrexone is a quaternary derivative of naltrexone. The most common (>5%) adverse reactions reported with methylnaltrexone bromide are abdominal pain, flatulence, nausea, dizziness, diarrhea, and hyperhidrosis. Methylnaltrexone inhibits the mu-opioid receptor located on neurons in the intestine. This inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. cAMP increases the excitability in spinal cord pain transmission neurons which allows the patient to feel pain rather than the analgesic effects of opioids. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Methylnaltrexone also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. The inhibition of mu-opioid receptors prevents hyperpolarization in the neuron, allowing it to fire at a normal rate. The neuron is able to depolarize and the high concentration of calcium releases acetylcholine and nitric acid into the neuromuscular junction. Acetylcholine binds to nicotinic acetylcholine receptors on the smooth muscles of the intestines, causing muscle contraction. The nitric oxide diffuses into the myocyte and causes muscle relaxation. The rythmic action of the neurotransmitters creates the peristalsis and the good GI transit.

Methylphenidate, known commonly as Ritalin, is a central nervous system stimulant used mainly for ADHD, but also for narcolepsy. ADHD is caused by an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene. It has also been found to affect the alpha-2A adrenergic receptor in the prefrontal cortex. This abnormality makes it harder for dopamine and norepinephrine to bind to the receptors. These receptors regulate attention, movement, and impulsivity so a defeciency in the regulation of those systems causes ADHD. Methylphenidate blocks the reuptake transporters of both dopamine and norepinephrine which prolongs their duration in the synapse so that they can bind more readily to the receptors. Since it works in the brain Methylphenidate crosses the blood brain barrier through diffusion. Dopamine is synthized in the ventral tegmental area of the brain from tyrosine being synthesized into L-dopa by the enzyme Tyrosine 3-monooxygenase . L-Dopa is then syntheized into dopamine with the enzyme aromatic-L-amino-acid decarboxylase. Dopamine then travels to the prefrontal cortex where it is released into the synapse when the neuron is stimulated and fires. Methylphenidate binds to the sodium-dependent dopamine transporter which prevents dopamine from re-entering the presynaptic neuron. The dopamine then binds to Dopamine D4 receptors on the postsynaptic membrane. The dopamine D4 receptor activates the Gi protein cascade which inhibits adenylate cyclase. This prevents adenylate cyclase from catalyzing ATP into cAMP. The low concentration of cAMP is unable to activate protein kinase A which prevents or lowers neuronal excitability. It is unknown how exactly this helps with ADHD, but it is speculated to help by regulating attention, movement, and impulsivity to a greater degree. Other dopamine and norepinephrine receptors are likely also involved, but the main receptors complicit in ADHD are the dopamine D4 receptor and the alpha-2A adrenergic receptor. This helps people with ADHD to sustain attention and working memory.

Methylphenidate is taken orally as any of the brand names Adhansia, Aptensio, Biphentin, Concerta, Cotempla, Daytrana, Foquest, Jornay, Metadate, Methylin, Quillichew, Quillivant, Relexxii, or Ritalin. Methylphenidate is rapidly absorbed from the small intestine into the blood stream via the transporter P-glycoprotein or through diffusion. Methylphenidate can diffuse through many membranes, but P-glycoprotein has been found to help transport the drug some of the time. From there it travels to the liver where it is likely transported in by P-glycoprotein. In the liver Methylphenidate is metabolized by Carboxylesterase 1A1 into Ritalinic acid. While other Carboxylesterase are well understood, this one is less well understood and studied so it is unknown where exactly in the liver this metabolism takes place. 60%-86% is metabolized into ritalinic acid. This is transported out of the liver likely again by P-glycoprotein back into the blood vessel where it travels to the kidney and is excreted renally. A very small portion is excreted as Methylphenidate. 78%-97% is excreted as Ritalinc acid. Some is excreted as minor other metatbolites.

Methylphenidate, known commonly as Ritalin, is a central nervous system stimulant used mainly for ADHD, but also for narcolepsy. ADHD is caused by an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene. It has also been found to affect the alpha-2A adrenergic receptor in the prefrontal cortex. This abnormality makes it harder for dopamine and norepinephrine to bind to the receptors. These receptors regulate attention, movement, and impulsivity so a defeciency in the regulation of those systems causes ADHD. Methylphenidate blocks the reuptake transporters of both dopamine and norepinephrine which prolongs their duration in the synapse so that they can bind more readily to the receptors. Since it works in the brain Methylphenidate crosses the blood brain barrier through diffusion. Norepinephrine similarly works but it is synthesized in the locus coeruleus where it is synthesized from dopamine by the enzyme dopamine beta-hydroxylase. Norepinephrine is then transported to the prefrontal cortex and released into the synapse when the neuron is stimulated and fires. Methylphenidate binds and blocks the sodium-dependent noradrenaline transporter which prevents the synaptic norepinephrine from re-entering the presynaptic neuron. Norepinephrine then binds to the Alpha-2A adrenergic receptor on the postsynaptic membrane. Alpha-2A adrenergic receptor activates the Gi coupled protein cascade which inhibits adenylate cyclace. This means adenylate cyclase cannot catalyze ATP into cAMP. The reduced cAMP isn't able to activate protein kinase A as much which causes a reduction neuronal excitability. Alpha-2A adrenergic receptor is associated with regulating and improving working memory. It is unknown how exactly this helps with ADHD, but it is speculated to help by regulating attention, movement, and impulsivity to a greater degree. Other dopamine and norepinephrine receptors are likely also involved, but the main receptors complicit in ADHD are the dopamine D4 receptor and the alpha-2A adrenergic receptor. This helps people with ADHD to sustain attention and working memory.

Mephobarbital, a barbiturate, undergoes metabolism into phenobarbital and has been employed for similar purposes, particularly in managing epilepsy; however, there exists no evidence supporting its superiority over phenobarbital. It serves to alleviate anxiety, tension, and apprehension, also functioning as an anticonvulsant for epilepsy treatment. In combination with acetaminophen or aspirin and caffeine, methylphenobarbital, a barbiturate variant, is utilized to induce sedation and relaxation in addressing tension headaches, migraines, and pain. Barbiturates exhibit nonselective depressive effects on the central nervous system, yielding a spectrum of mood alterations from stimulation to mild sedation, hypnotic states, and even profound comas under sufficiently high therapeutic dosages, including anesthesia induction. Methylphenobarbital's binding to a specific site connected to a Cl- ionopore at the GABAA receptor prolongs the opening duration of the ionopore, consequently extending GABA's inhibitory impact in the thalamus. Around 50% of an orally administered mephobarbital dose is absorbed through the gastrointestinal tract and is metabolized primarily in the liver via the hepatic microsomal enzyme system. Notably, approximately 75% of a solitary oral mephobarbital dose is transformed into phenobarbital within a 24-hour span.

Metabolites of Methylphenobarbital are predicted with biotransformer.

Methylphosphinic acid is an experimental drug being tested to be a possible cholinesterase inhibitor, as it appears to inhibit the breakdown of acetylcholine. Further research needs to be conducted in order to confirm results, safety and confirm the mechanism of action.