Drugs That Sedate: GABA-A Receptors vs NMDA Receptors PDF

Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Drugs that Produce Sedation, Hypnosis, and Anesthesia ! Glutamate is the primary excitatory neurotransmitter in the body and binds to several receptors including the NMDA receptor. ! g-Aminobutyric acid (GABA) is the primary in...

Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Drugs that Produce Sedation, Hypnosis, and Anesthesia ! Glutamate is the primary excitatory neurotransmitter in the body and binds to several receptors including the NMDA receptor. ! g-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the body and binds to several receptors including the GABA-A receptor. ! There are two basic mechanisms for producing sedation and/or anesthesia You can antagonize the excitatory glutamate-NMDA receptor pathway. Or you can stimulate the inhibitory GABA-GABAA receptor pathway. NMDA-R Antagonism Nitrous Oxide Ketamine Phencyclidine Positive Allosteric GABA-A Receptor Stimulation Barbiturates Benzodiazepines Fluranes (halothane) neurosteroids (alphaxolone) Z-Drugs (zolpidem) other (etomidate, propofol, alcohol) Never Ending Circles 3:16 CHVRCHES live Reading 2016 1 1 Drugs that Produce Sedation, Hypnosis, and Anesthesia NMDA-R Antagonism Nitrous Oxide Ketamine Phencyclidine Positive Allosteric GABA-A Receptor Stimulation Barbiturates Benzodiazepines Fluranes (halothane) neurosteroids (alphaxolone) Z-Drugs (zolpidem) other (etomidate, propofol, alcohol) 2 2 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Glutamate Receptors-Ionotropic and Metabotropic (GPCR) ! Glutamate is the primary excitatory neurotransmitter in the body. ! There are 11 basic subtypes of glutamate receptors, which are divided into two major groups: the “metabotropic” or G-protein coupled receptors. 3 3 Glutamate Receptors-Ionotropic and Metabotropic (GPCR) ! Glutamate is the primary excitatory neurotransmitter in the body. ! There are 11 basic subtypes of glutamate receptors, which are divided into two major groups: the “metabotropic” or G-protein coupled receptors. the “ionotropic” or ligand-gated ion channel receptors. ! NMDA receptors are selectively activated by N-methyl D-aspartic acid. ! NMDA receptors are the primary target for nitrous oxide, which antagonizes the binding of glutamate. ! And for the dissociative anesthetics, ketamine and phencyclidine, which block the ion channel. 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 GABA Receptors-Ionotropic and Metabotropic (GPCR) ! g-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the body. ! GABA receptors are divided into two major subtypes: GABA-A which are “ionotropic” or ligand-gated ion channel receptors. GABA-B which are “metabotropic” or G-protein coupled receptors. ! GABA-A receptors are a very important target for many “depressant” drugs, including ethanol, the benzodiazepines, barbiturates, and general anesthetics. ! GABA-B receptors are the target for baclofen, a muscle relaxant, and for g-hydroxybutyric acid (GHB), a drug of abuse. , GHB GABA-B GABA-A 5 5 Biosynthesis of GABA and Glutamate glutaminase glutamine synthetase glutamate decarboxylase + CO 2 6 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Biosynthesis of GABA and Glutamate EAAT = Excitatory Amino Acid Transporter GAT = GABA Transporter 7 7 Drugs that Produce Sedation, Hypnosis, and Anesthesia Differ in their Maximum CNS Depressant Effect 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Benzodiazepines (BZD) ! MOA: positive allosteric modulator (PAM) of GABA-A receptors. Binds to a BZD specific site that is also recognized by “Z-drugs”, which are nonbenzodiazepines. Enhances the actions of GABA by increasing the frequency of neuronal firing, thereby increasing chloride conductance and hyperpolarizing the neuron (making it resistant to depolarization). diazepine ring benzene ring zolpidem (nonbenzodiazepine) 9 9 Benzodiazepines (BZD) ! Major Properties: sedation (reducing excitement, anti-anxiety), anticonvulsant, muscle relaxing, hypnotic (sleep-inducing), amnesic (anterograde). Generally not used as a “stand alone” drug for anesthesia, although commonly used as a pre-anesthetic for its anti-anxiety and amnesic effects. Good therapeutic index and much safer than barbiturates, except when combined with other CNS depressants, esp. alcohol and opiates. benzodiazepines plus opiates benzodiazepines alone 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Benzodiazepines (BZD) ! Numerous BZDs have been marketed. Generally classified by half-life and onset of action. Longer half-life generally better for treatment of anxiety. Faster onset and shorter half-life better for treatment of insomnia. Flumazenil is a specific and competitive antagonist. ! Chronic use is associated with the development of tolerance and dependence. BZDs should generally not be used for more than 2-4 weeks. Withdrawal symptoms are frequently observed following chronic use. 11 11 Benzodiazepines (BZD)-Dependence and Withdrawal 12 12 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Barbiturates ! MOA: positive allosteric modulator (PAM) of GABA-A receptors. Binds to a barbiturate specific site, distinct from the BDZ site. Enhances the actions of GABA by increasing the duration of channel opening, thereby increasing chloride conductance and hyperpolarizing the neuron (making it resistant to depolarization). Barbituric acid BZD phenobarbital 13 13 Barbiturates ! Major Properties: sedation (reducing excitement, anti-anxiety), anticonvulsant, hypnotic (sleep-inducing), anesthetic. In contrast to BZDs, barbiturates have a much greater depressant effect and are used routinely for anesthesia. They are also used to cause death by lethal injection, whether it is capital punishment or euthanasia. The barbiturates have largely been replaced by the BZDs/Z-drugs for the treatment of anxiety and insomnia. 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Fluranes, Propofol, Neurosteroids ! MOA: positive allosteric modulator (PAM) of GABA-A receptors. All these agents, including ethanol, bind to sites, distinct from both the BDZ and barbiturate binding sites. They also have actions at other sites. Enhances the actions of GABA, thereby increasing chloride conductance and hyperpolarizing the neuron (making it resistant to depolarization). BZD Sevoflurane Propofol Alphaxolone 15 15 Fluranes, Propofol, Neurosteroids ! Fluranes (e.g., sevoflurane) are volatile liquids administered by inhalation. ! Propofol is given by intravenous infusion; widely used. ! Neurosteroids (e.g., alfaxalone) is given by intravenous infusion (veterinary). ! These agents produce anesthesia and are not analgesic (pain relieving). ! Have replaced agents like chloroform and ether. 16 16 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Ketamine and Phencyclidine ! MOA: channel blockade of NMDA receptors. Activation of NMDA receptors by glutamate/glycine increases cation conductance (importantly Ca2+) which is excitatory to neuronal activity. Channel blockade prevents the influx of Ca2+ resulting in an inhibition neuronal activity. ! Dissociative anesthetic and analgesic with little respiratory or cardiovascular depression. Administered by i.v. infusion. ! Anti-depressant activity at sub-anesthetic doses. glycine ketamine phencyclidine 17 17 Nitrous Oxide (laughing gas) ! MOA: antagonist of glutamate binding to NMDA receptors. Activation of NMDA receptors by glutamate/glycine increases cation conductance (importantly Ca2+) which is excitatory to neuronal activity. Interfering with the binding of glutamate inhibits neuronal activity. ! Weak dissociative anesthetic and analgesic administered by inhalation. ! Also known as “laughing gas” with abuse potential. Nitrous oxide glycine 18 18 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 Other Drug Targets that can Produce with Sedative, Hypnotic, and/or Analgesic Effects ! Central a2-adrenergic receptors (GPCR). Agonist stimulation increases the activity of inhibitory GABA neurons and produces sedative, hypnotic and analgesic effects as well as analgesia without significant respiratory depression. Dexmedetomidine is a very potent a2-adrenergic agonist that is approved for human and animal use, mostly for sedation. ! Central histamine H1 receptors (GPCR). Drugs with histamine H1 blocking activity are well known for their sedative effects and include classic antihistamines (Benadryl®) and antidepressants that are H1 receptor antagonists (e.g., doxepin, trazodone, mirtazepine). trazodone dexmedetomidine diphenhydramine 19 19 Other Drug Targets that can Produce with Sedative, Hypnotic, and/or Analgesic Effects ! Central melatonin M1 and M2 receptors (GPCR). Melatonin receptors are involved with activity of biological clocks and their stimulation can induce sleep. Ramelteon (Rozerem®) is a melatonin receptor agonist with this indication. ! Central orexin OX1 and OX2 receptors (GPCR). Oxrein receptors are part of a general “activating” system in the brain and blocking these receptors can induce sleep Suvorexant (Belsomra®) is an antagonist of the orexin receptors with such an indication. ramelteon melatonin suvorexant 20 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 20 10 Drugs that Sedate: GABA-A Receptors vs NMDA Receptors PCOL825B/Fall 2024 The End " 21 21 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 11