{"id":971,"date":"2020-02-18T11:12:27","date_gmt":"2020-02-18T05:42:27","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=971"},"modified":"2020-02-18T11:12:27","modified_gmt":"2020-02-18T05:42:27","slug":"nmda-receptors-and-drugs-acting-on-them","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/nmda-receptors-and-drugs-acting-on-them\/","title":{"rendered":"Nmda Receptors And Drugs Acting On Them"},"content":{"rendered":"\n<p><strong>Nmda Receptors And Drugs Acting On Them<\/strong><\/p>\n\n\n\n<p><strong>Glutamate:<\/strong><\/p>\n\n\n\n<ul><li>Principal excitatory neurotransmitter<\/li><li>Widely and uniformly distributed in CNS<\/li><li>Derived from:<ul><li>Glucose via Kreb\u2019s cycle<\/li><\/ul><ul><li>Glutamine by glial cells.<\/li><\/ul><\/li><li>Stored in synaptic vesicles<\/li><li>Released by Ca<sup>2+ <\/sup>dependent exocytosis<\/li><li>Taken up by Na<sup>+<\/sup>\/H<sup>+<\/sup>\/K<sup>+<\/sup> dependent transporters<\/li><li>Action terminated by carrier mediated reuptake into nerve terminals and neighboring astrocytes.<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"318\" height=\"316\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-424.png?w=318\" alt=\"\" class=\"wp-image-983\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-424.png 318w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-424-300x298.png 300w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-424-150x150.png 150w\" sizes=\"(max-width: 318px) 100vw, 318px\" \/><\/figure>\n\n\n\n<p>GABA- T\u00e0 GABA transaminase;<\/p>\n\n\n\n<p>GAD\u00e0 Glutamic acid Decarboxylase.<\/p>\n\n\n\n<p><strong>GLUTAMATE RECEPTOR SUBTYPES<\/strong><\/p>\n\n\n\n<ul><li>Metabotropic (G-protein coupled receptors)<\/li><li>Ionotropic (Ligand gated ion channels)<\/li><\/ul>\n\n\n\n<p><strong>METABOTROPIC RECEPTORS<\/strong><\/p>\n\n\n\n<ul><li>8 different receptor types (mGlu 1-8)<\/li><li>Functions as homodimers cross-linked by a disulfide bridge across extracellular domain of each protein.<\/li><li>Divided into 3 groups.<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"400\" height=\"266\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-425.png?w=400\" alt=\"\" class=\"wp-image-984\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-425.png 400w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-425-300x200.png 300w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><\/figure>\n\n\n\n<p>IONOTROPIC RECEPTORS<\/p>\n\n\n\n<ul><li>3 main subtypes:<ul><li>NMDA\u00e0 N-methyl D-aspartic acid<\/li><\/ul><ul><li>AMPA\u00e0 \u03b1- amino-3-hydroxy-5-methylisoxazole-4-propionic acid<\/li><\/ul><ul><li>Kainate<\/li><\/ul><\/li><li>International Union of Basic and Clinical Pharmacology (IUPHAR)<ul><li>NMDA receptors\u00e0 7 subunits\u00e0 GluN1; GluN2A; GluN2B; GluN2C; GluN2D; GluN3A; GluN3B<\/li><\/ul><ul><li>AMPA receptors\u00e0 GluA1-4<\/li><\/ul><ul><li>Kainate receptors\u00e0 GluK1-5<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>NMDA RECEPTOR<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"326\" height=\"307\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-426.png?w=326\" alt=\"\" class=\"wp-image-985\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-426.png 326w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-426-300x283.png 300w\" sizes=\"(max-width: 326px) 100vw, 326px\" \/><\/figure>\n\n\n\n<ul><li>Most important receptor<\/li><li>Involved in processes like-<ul><li>Memory acquisition<\/li><\/ul><ul><li>Development of synaptic plasticity<\/li><\/ul><ul><li>Epilepsy<\/li><\/ul><ul><li>Neuronal excitotoxicity due to cerebral ischemia.<\/li><\/ul><ul><li>Pentamer; High permeability to Ca<sup>2+<\/sup><\/li><\/ul><ul><li>Widely distributed in spinal cord, hippocampus, cerebral cortex, glial cells.<\/li><\/ul><\/li><\/ul>\n\n\n\n<ul><li>6 pharmacologically distinct binding sites\/modulatory sites:<ul><li>Glu (or NMDA) binding site<\/li><\/ul><ul><li>Modulatory site for glycine<\/li><\/ul><ul><li>Polyamines regulatory sites<\/li><\/ul><ul><li>Phencyclidine binding site<\/li><\/ul><ul><li>Voltage dependent Mg<sup>2+<\/sup> binding site<\/li><\/ul><ul><li>Voltage independent Zn<sup>2+<\/sup> binding site.<\/li><\/ul><\/li><\/ul>\n\n\n\n<ul><li><strong>Important role in:<\/strong><ul><li>Long term adaptive changes\u00e0 synaptic plasticity<\/li><\/ul><ul><li>Pathologic changes in brain\u00e0 excitotoxicity<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>SYNAPTIC PLASTICITY<\/strong><\/p>\n\n\n\n<ul><li>Long term changes in synaptic connectivity &amp; efficacy following:<ul><li>Physiological alterations in neuronal activity (memory &amp; learning)<\/li><\/ul><ul><li>Pathological disturbances (Epilepsy, pain, drug dependence)<\/li><\/ul><\/li><li>Mechanism\u00e0 Long Term Potentiation\u00e0 AMPA &amp; NMDA play central role.<\/li><\/ul>\n\n\n\n<p><strong>LONG TERM POTENTIATION<\/strong><\/p>\n\n\n\n<p>Long term potentiation\u00e0 a prolonged (hours in vitro; days\/weeks in vivo) enhancement of synaptic transmission occurring at various CNS synapses following short bursts of high frequency presynaptic stimulation.<\/p>\n\n\n\n<p>These phenomena are studied at various synapses in CNS esp hippocampus (learning and memory)<\/p>\n\n\n\n<ul><li>Long term depression\u00e0 produced at some synapses by longer train of stimuli and lower frequency.<\/li><li>Characteristic feature\u00e0 enhancement of synaptic strength following simultaneous activity in both pre &amp; postsynaptic neurons.<\/li><li>At normal membrane potentials, NMDA channels are blocked by Mg<sup>2+.<\/sup> A sustained post synaptic depolarization produced by glutmate acting on AMPA removes Mg<sup>2+<\/sup> block leading to NMDA receptor activation and calcium entry into the cell.<\/li><li>Rise in calcium in postsynaptic cell activates protein kinases, phospholipases and nitric oxide synthase which act jointly facilitating transmission via AMPA receptors.<\/li><\/ul>\n\n\n\n<p><strong>EXCITOTOXICITY<\/strong><\/p>\n\n\n\n<ul><li>Glutamate\u00e0 highly toxic to neurons\u00e0 excitotoxicity<\/li><li>\u201cChinese restaurant syndrome\u201d. -set of symptoms that some people have after eating Chinese food. A food additive called monosodium glutamate (MSG) has been blamed for the condition.<\/li><li>Symptoms\u00e0 Headache, Sweating, Skin flushing, Numbness in mouth &amp; throat, nausea, fatigue<\/li><li>Local injection of Glutamate agonist Kainic acid\u00e0 excitation of local glutamate releasing neurons\u00e0 release of glutamate acting on NMDA and metabotropic receptors\u00e0 neuronal death.<\/li><li>Calcium overload.<\/li><li>Increased calcium affects many processes relevant to neurotoxicity. They are:<ul><li>Increased glutamate release<\/li><\/ul><ul><li>Activation of proteases; Lipases\u00e0 membrane damage<\/li><\/ul><ul><li>Increased arachidonic acid\u00e0 increased free radical production\u00e0 inhibits glutamate uptake.<\/li><\/ul><\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"640\" height=\"297\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-427.png?w=640\" alt=\"\" class=\"wp-image-986\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-427.png 640w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-427-300x139.png 300w\" sizes=\"(max-width: 640px) 100vw, 640px\" \/><\/figure>\n\n\n\n<p>The potential therapeutic interest in ionotropic glutamate receptor antagonists lies mainly in the reduction of brain damage following strokes and head injury,<\/p>\n\n\n\n<p>as well as in the treatment of epilepsy and Alzheimer\u2019s disease. They have also been considered for indications such as drug dependence, schizophrenia and depression<\/p>\n\n\n\n<p><strong>KETAMINE AND PHENCYCLIDINE<\/strong><\/p>\n\n\n\n<ul><li>Together classified as \u201cClub Drugs\u201d<\/li><li>Sold under the names \u201cAngel dust\u201d, \u201cHog\u201d, \u201cSpecial K\u201d.<\/li><li>Non-competitive antagonists of NMDA receptors<\/li><li>Pure forms\u00e0 white crystalline powders.<\/li><li>Also available as liquids, capsules\/ pills.<\/li><li>Psychedelic effects\u00e0 1 hour.<\/li><li>Effects\u00e0 increased BP, Impaired memory function, visual alterations.<\/li><\/ul>\n\n\n\n<p><strong>KETAMINE<\/strong><\/p>\n\n\n\n<ul><li>Congener of phencyclidine.<\/li><li>Partially water soluble; Highly lipid soluble.<\/li><li>Dissociative anesthesia\u00e0profound analgesia, immobility, amnesia with light sleep. Patient appears to be conscious that is eyes open, swallowing present, muscles shift but he is unable to process sensory stimuli and does not react to them.<\/li><li>Primary site\u00e0 cortex, subcortical areas not in reticular activating system.<\/li><li>MOA\u00e0 Inhibition of NMDA receptor complex.<\/li><li>ACTIONS:<ul><li>Analgesia<\/li><\/ul><ul><li>Stimulation of sympathetic nervous system<\/li><\/ul><ul><li>Bronchodilation<\/li><\/ul><ul><li>Minimal respiratory depression<\/li><\/ul><\/li><li>Route of Administration\u00e0 IV, IM<\/li><li>Dose: 1-2 mg\/kg IV or 4-6mg\/kg IM<\/li><li>ADR: Psychomimetic effects.<\/li><\/ul>\n\n\n\n<p><strong>ACAMPROSATE<\/strong><\/p>\n\n\n\n<ul><li>Antagonist of NMDA glutamate receptor<\/li><li>Interferes with forms of synaptic plasticity that depend on NMDA receptors.<\/li><li>Use: R<sub>x <\/sub>alcoholism<\/li><li>To be started soon after withdrawing alcohol and then given continuously at a dose of 666 mg 2-3 times a day.<\/li><li>ADR: Allergic reactions; Arrhythmia; BP variations; Headache; Insomnia; Impotence; Hallucinations in elderly patients.<\/li><\/ul>\n\n\n\n<p><strong>MEMANTINE<\/strong><\/p>\n\n\n\n<ul><li>Excitotoxic activation of glutamate transmission via NMDA receptors\u00e0 Contributes to pathophysiology of Alzheimer\u2019s disease.<\/li><li>Memantine\u00e0 binds to NMDA receptor channels- produces a non-competitive blockade.<\/li><li>Less toxic and better tolerated than other cholinesterase inhibitors.<\/li><\/ul>\n\n\n\n<p><strong>AMANTADINE<\/strong><\/p>\n\n\n\n<ul><li>Antiviral agent -prophylaxis of influenza A2<\/li><li>Weak anti-parkinsonism properties.<\/li><li>An antagonist of NMDA receptor<\/li><li>Uses:<ul><li>Parkinson\u2019s Disease<\/li><\/ul><ul><li>Iatrogenic dyskinesia<\/li><\/ul><\/li><\/ul>\n\n\n\n<p>Overdose\u00e0 acute toxic psychosis<\/p>\n\n\n\n<p>\u201cLivedo reticularis\u2019\u00e0 headache, heart failure, postural hypotension, urinary retention, GI disturbances.<\/p>\n\n\n\n<p><strong>FELBAMATE<\/strong><\/p>\n\n\n\n<ul><li>Effective for partial seizures.<\/li><li>Causes aplastic anemia and severe hepatitis.<\/li><li>MOA:<ul><li>Produces use-dependent block of NMDA receptor with selectivity for NR1-2B subtype.<\/li><\/ul><ul><li>Produces barbiturate like potentiation of GABA<sub>A<\/sub> receptor responses.<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>FLUPIRTINE<\/strong><\/p>\n\n\n\n<ul><li>Neither an opioid analgesic or a NSAID<\/li><li>Not yet approved by US FDA<\/li><li>Acts indirectly as NMDA receptor antagonist by activation of K<sup>+<\/sup> channels\u00e0 hyperpolarization of neuronal membrane\u00e0 neuron becomes less excitable.<\/li><li>Causes a dose-dependent reduction of NMDA receptor mediated glutamate induced rise in intracellular Ca<sup>++<\/sup>&nbsp;concentration<\/li><li>Analgesic, Muscle relaxant, Antiparkinsonian<\/li><\/ul>\n\n\n\n<p><strong>Idrocilamide; Riluzole<\/strong>\u00e0 newer drugs for treatment of Amyotrophic Lateral Sclerosis (ALS).<\/p>\n\n\n\n<ul><li>Spasm reducing effects possibly through inhibition of glutamatergic transmission in CNS.<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Nmda Receptors And Drugs Acting On Them Glutamate: Principal excitatory neurotransmitter Widely and uniformly distributed in CNS Derived from: Glucose via Kreb\u2019s cycle Glutamine by glial cells. Stored in synaptic vesicles Released by Ca2+ dependent exocytosis Taken up by Na+\/H+\/K+ dependent transporters Action terminated by carrier mediated reuptake into nerve terminals and neighboring astrocytes. GABA-[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/971"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=971"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/971\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=971"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=971"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=971"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}