University:
West Coast University
Course:
PHAR 835 | IPC Neurology/Psychiatry
Academic year:

2024
Views:

500

Pages:

20
Author:

Asal A.

GABA Pharmacology Sedative-Hypnotic Supplemental Guidance to Handout and Reading Assignment Parto Khansari Ph.D. 8/23/2024 (8:00-12:30 pm) Drug List chartthat knowthe fillout needto we Hypnotic-Sedative Pharmacology Glutamate excitatory GAIAandGlysire • Sedatives (anxiolytic) reduce anxiety, • Hypnotic drugs produce drowsiness and sleep, • Both are associate with CNS depression • Individual drugs have a different degree of CNS depression • γ-aminobutyric acid (GABA), major inhibitory neurotransmitters, Gainhibitory associated with hypnotic-sedative effect • Some agents produce CNS depression through other pathways such as melatonin or serotonin Graded Dose-Dependent Depression of CNS Function Eton soo Brainstem Breathing control gÉ at Bento metabolizedbyliner oftheding highconcentration knowifthay'retoligonotherensmed weshould GABA Synthesis GABA is synthesized from glutamate by the activity of glutamic acid decarboxylase (GAD) Arabcache glutamatesynthesize to Kgbcycle GABA Receptors  GABAA ion a • Ionotropic • Fast • Selectively permeable to Cl– • Requires binding to 2 molecules of GABA dona e  GABAB  Slow  Metabotropic  Either inhibit Ca2+ channels or activate K+ channels GABAA Receptors  Consists of five subunits  Multiple forms of α, β, and γ Subunits ji  Different arrangement result in GABAA receptors heterogeneity GABAB Receptors  linked to second messenger systems such as adenylyl cyclase (AC) or phospholipase C (PLC) Termination of GABA Action GABA fromcallsBa redontwant removeGABA gotake up GABA via specific GABA transporters In extracellular space,: neurons and glia (GATs), GAT-1 through GAT-4, with different distribution in the CNS. In neurons: GABA transaminase (GABA-T) catalyzes the conversion of GABA to succinic semialdehyde (SSA), which is oxidized to succinic acid by SSA dehydrogenase. Succinic acid enters the Krebs cycle to become α-ketoglutarate, and GABA-T regenerates glutamate from α-ketoglutarate Examples of Dose-Response Relationship Sedative-Hypnotic Drugs Drug A Linear Slope , typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. Drug B Require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action. Acnsetteattocoma as dose or the you sedation 4 from older t dog goes sheskipthis slide The γ-aminobutyric acid type A (GABAA) chloride (Cl–) channel. The figure demonstrates a typical configuration of the GABAACl– channel, which consists of two α, two β, and one γ isoforms. The benzodiazepine (BZD) receptor is located between an α and a γ subunit. Neurosteroid binding at the opposite side of the α isoform is a positive allosteric modulator. Source: Antidotes in Depth, Goldfrank's Toxicologic Emergencies, 10e Citation: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank's Toxicologic Emergencies, 10e; 2015 Available at: http://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=65087997 Accessed: March 23, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved Potential Drug Target Bindtoreceptor Benzodiazepines PGABA • Modulators of GABAA receptors that act at allosteric binding sites to enhance GABAergic neurotransmission • Have sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects rarely cause fatal CNS depression. bindtoreceptortheykeepthe whilethey so Barbiturates receptor • open Also facilitate the actions of GABA at multiple sites but in contrast to benzodiazepines increase the duration of the GABA-gated chloride channel openings. Clinical Use of Benzodiazepines BENZODIAZEPINE Clorazepate Midazolam Alprazolam Lorazepam Chlordiazepoxide Clobazam Clonazepam Diazepam Triazolam Estazolam Temazepam Flurazepam Quazepam CLINICAL USES Anxiety disorders, seizures Preanesthetic, IV general anesthetic Anxiety disorders, phobias Anxiety disorders, status epilepticus, IV general anesthetic Anxiety disorders, alcohol withdrawal Anxiety disorders, seizures Seizures Anxiety disorders, status epilepticus, muscle relaxant, IV general anesthetic, alcohol withdrawal Insomnia Insomnia Insomnia Insomnia Insomnia DURATION OF ACTION Short-acting (3–8 hours) Short-acting (3–8 hours) Intermediate-acting (11–20 hours) Intermediate-acting (11–20 hours) Long-acting (1–3 days) Long-acting (1–3 days) Long-acting (1–3 days) Long-acting (1–3 days) Short-acting (3–8 hours) Intermediate-acting (11–20 hours) Intermediate-acting (11–20 hours) Long-acting (1–3 days) Long-acting (1–3 days) Sedative (anxiolytic) Benzodiazepines: Inhibits synapses in the limbic system, a CNS region that controls emotional behavior and is characterized by a high density of GABAA receptors. The sedative benzodiazepines differ in their rates of onset, durations of effect, and tendencies to cause rebound insomnia when withdrawn. what Sedative Drugs Alprazolam Buspirone Chlordiazepoxide Clorazepate Diazepam Halazepam Lorazepam Oxazepam Phenobarbital Hypnotic Agents Benzodiazepines • Facilitate sleep onset and • increase the overall duration of sleep • Increase length of stage 2 non-rapid eye movement (NREM) sleep • Decrease the length of REM sleep Hypnotic Drugs Chloral hydrate Estazolam Eszopiclone Lorazepam Quazepam Secobarbital Suvorexant Tasimelteon Temazepam Triazolam Zaleplon Zolpidem PK Properties of Benzodiazepines Exert Drug Tmax (hours)1 t½ (hours)2 Comments Alprazolam Chlordiazepoxide 1–2 2–4 12–15 15–40 Clorazepate 50–100 Diazepam 1–2 (nordiazepam) 1–2 Eszopiclone Flurazepam 1 1–2 6 40–100 Active metabolites; erratic bioavailability from IM injection Minor active metabolites Active metabolites with long half-lives Lorazepam Oxazepam Temazepam Triazolam 1–6 2–4 2–3 1 10–20 10–20 10–40 2–3 No active metabolites No active metabolites Slow oral absorption Rapid onset; short duration of action Zaleplon <1 1–2 Metabolized via aldehyde dehydrogenase Zolpidem 1–3 1.5–3.5 No active metabolites 20–80 Rapid oral absorption Active metabolites; erratic bioavailability from IM injection Prodrug; hydrolyzed to active form in stomach AccessPharmacy > Basic & Clinical Pharmacology, 15e > Sedative-Hypnotic Drugs Bertram G. Katzung, Todd W. Vanderah Tolerance with GABA Modulators Tolerance: Psychological & Physiologic Dependence • Induced by chronic use of GABA modulators • Requires an increase in the dose to maintain Pharmacological effect • May results from down-regulation of brain benzodiazepine receptors. Buspirone- Ramelteon • Buspirone • Anxiolytic effects • No anticonvulsant or muscle relaxant properties get • Does not interact directly with GABAergic systems • Acts as a partial agonist at brain 5-HT1A receptors • also has affinity for brain dopamine D2 receptors. • Buspirone-treated patients show no rebound anxiety or withdrawal signs on abrupt discontinuance. Ramelteon  Hypnotic effect  Melatonin receptor agonists Benzodiazepines Benzodiazepines

GABA Pharmacology Sedative-Hypnotic

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