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Queen's University
Pharmacology and Toxicology
PHAR 100
Hisham Elbatarny

Sedative-Hypnotic agents Introduction • drugs that are used to sedate and aid in sleep ◦ insomnia: inability to fall asleep or stay asleep ▪ short-term due to day-to-day stresses ▪ long-term due to psychiatric disorder, chronic pain • sedative-hypnotic agents are drugs that produce a dose-dependent depression of the CNS Low Dose ------------------------------------------→ High Dose Anti-anxiety Sedation Hypnosis Anesthesia → coma and fatalities refer to sleep • produce a graded depression of the ReticularActivating System (regulates arousal and the sleep/wake cycle) Therapeutic Indications • anxiety disorders (panic attacks, phobias) • sedation (reduce sensory-motor function reduce tension) • hypnosis (sleep) • seizure disorders: muscle relaxing characteristics • skeletal muscle spasm • alcohol withdrawal syndrome: relieve symptomes Types Sedative-Hypnotics • benzodiazepines (e.g., diazepam (valium), flurazepam) • barbiturates (e.g., phenobarbital, secobarbital) • other agents (e.g., ethanol, chloral hydrate) • over-the-counter agents (e.g., antihistamines – sometimes has sedatives properties as well) History • nineteenth century few drugs were available to calm people down or aid sleep ◦ alcohol, bromides, chloral hydrate and opium ◦ marginally effective, but unwanted side effects • barbiturates (BAR) were first synthesized in 1864 ◦ widely used for over 100 years – gold standard for treating anxiety and insomnia ◦ high dependence liability (illicit drug use as “downers”) ◦ narrow margin of safety: overdose quite readily ◦ adverse side effects: depressing all parts of the brain ▪ sedative activities have onANS → adverse effects • first synthesis of benzodiazepines (BDZ) in 1930 • all benzodiazepines share similar effects, but differ in potency ◦ some are more sedative, others more hypnotic; speed of action also differs (based on prep) • of particular interest: Flunitrazepam (Rohypnol aka date rape drug) ◦ 1995: highest illicit use according to the WHO ◦ used as a party drug in conjunction with alcohol (used together: additive effect) • cause anterograde amnesia: reduces ability to create new memories • have no memory of while on drug Routes of Administration & Absorption • produces CNS depression • readily absorbed from the digestive tract ◦ depends on required effect (i.e., rapid effects require IV injection, but for long-term use, oral administration is appropriate) • different preparations are available with different lipid solubilities ◦ highly lipid soluble agents enter the cell more readily and have greater therapeutic effect • variability in the rate of absorption and peak blood levels ◦ alcohol increases absorption of drug (additive effect) GABARefresher • Gamma-aminobutyric acid (GABA): major inhibitory neurotransmitter in the nervous system • GABAhas two receptors: ◦ GABA : ioAotropic BAR ◦ GABA : seBond messenger w/ metabotropic receptor GABA • barbiturates and benzodiazepines bind to GABA recAptors ◦ makes GABAbind more readily BDZ ◦ bind to specific sites that are different from the GABAbind sites GABA ReAeptors • GABAinteraction with the GABAAreceptor leads to opening of the chloride channel ◦ increase in chloride ions (Cl-) flowing into the neuron ◦ inside of neuron becomes more negative thus preventing an action potential ◦ hence GABA’s inhibitory activity • barbiturates and benzodiazepines also bind to specific sites on the GABA rAceptors Mechanism of Action • neuronal depression throughout the brain ◦ increased depression with increased dosage ◦ cessation of respiration, deep coma, death • older BDZ have active metabolites (when metabolized, products are active) ◦ they can have longer half-lives and different effects ◦ newer BDZ try to eliminate the possibility of active metabolites • benzodiazepines and barbiturates freely pass via the placenta and are found in breast milk ◦ what does the mean for the fetus? And baby? ◦ mothers can go into withdrawal • alcohol inhibits BDZ metabolism ◦ increased BDZ half-life ◦ in the body it takes longer to produce effects Mechanism of Action • BAR & BDZ increase GABA’s tendency to bind to its receptor and open chloride channels ◦ positive GABAAmodulators (increase affinity for GABA) • each type of drug (BAR & BDZ) has its own unique binding site on the GABA receptor A • positive allosteric modulators • BAR: Increase the duration of channel opening • BDZ: Increase the frequency of channel-opening events BAR & BDZ • barbiturates
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