Anxiolytic and Hypnotic Drugs Chapter 19 PDF

Anxiolytic and Hypnotic Drugs Chapter 19 by Susan Hartfield PA-C, PharmD Objectives Review common definitions. Discuss the mechanism of action, uses, monitoring parameters, basic side effects and withdraw syndromes associated with the following classes of medications...

Anxiolytic and Hypnotic Drugs Chapter 19 by Susan Hartfield PA-C, PharmD Objectives Review common definitions. Discuss the mechanism of action, uses, monitoring parameters, basic side effects and withdraw syndromes associated with the following classes of medications: Barbiturates Benzodiazepines “Z-drugs”- Zolpidem, zaleplon, eszopiclone Buspirone Discuss other agents used for insomnia Melatonin receptor agonist Orexin receptor antagonist First generation antihistamines Chemical Classification Benzodiazepines Barbiturates Zolpidem, zaleplon, eszopiclone (Z-drugs) Similar mechanism of action Melatonin receptor agonists Ramelteon, tasimelteon Orexin antagonist Suvorexant, Lemborexant Buspirone Other agents: antihistamines, antipsychotics and antidepressants.  Definitions Sedative (anxiolytic) Should reduce anxiety and cause a calming effect. CNS depression should be the minimum consistent with therapeutic efficacy Hypnotic Should produce drowsiness and encourage the onset and maintenance of a state of sleep. Involve more pronounced CNS depression. Typically, just a higher dose of a sedative.  Definitions Tolerance: Reduced drug effect with repeated use of the drug. It’s a physiological state. Higher doses are needed to produce the same effect. A state of reduced effectiveness. Cross tolerance: will be tolerant to other drugs in the same class. Dependence: Characterized by signs and symptoms of withdraw when drug levels fall. Can be physical or psychological.  Absorption and Distribution Pharmacokineti Oral absorption depends on lipophilicity- cs determines rate at which a particular sedative-hypnotic enters the CNS. i.e. benzo’s-triazolam, diazepam; most barbiturates and new agents (Z-drugs). All cross the placental barrier during pregnancy and are detectable in breast milk which may exert depressive effects in the nursing infant.  Pharmacokinetics Biotransformation-benzodiazepines Hepatic metabolism accounts for clearance of all benzodiazepines. Most undergo Phase 1 reactions (oxidation) Many metabolites are active - desmethyldiazepam. Alpha hydroxylation - alprazolam and triazolam have short lived pharmacological effects. And Phase II (glucuronides that are excreted in the urine). Biotransformation  Pharmacokinetics Biotransformation Barbiturates Oxidation and glucuronidation Phenobarbital t1/2 is 4-5 days Newer agents Zolpidem - rapidly metabolized to inactive metabolites. Elimination t1/2 greater in women. Zaleplon - metabolized to inactive metabolites Eszopiclone - metabolized by cyp3A4 to inactive and weakly active metabolite. CYP 3A4 substrate. Suvorexant is a substrate of 3a4.  Pharmacokinetics Excretion Water-soluble metabolites are formed via phase II conjugation of phase I metabolites, then excreted mainly via the kidney. Phenobarbital is excreted 20-30% unchanged in the urine. Can be significantly increased by alkalinization of the urine. Weak acid  Pharmacodynamics Molecular pharmacology of the GABAA receptor GABA is a major inhibitory NT in the CNS GABA binds to molecular components of the GABAA receptor in neuronal membranes in the CNS. Functions as a ligand gated Cl ion channel Results in membrane hyperpolarization Reducing the firing rate Sedative-hypnotics mediate effects through the GABAA but do not directly open the channel Alter the gating property Pentameric structure assembled from 5 subunits GABAA receptor-Cl ion channel macromolecular complex  Pharmacodynamics Benzodiazepines Bind to the GABAA channel at the interface of the alpha and gamma subunit Increases the frequency of channel-opening events “Z-drugs” are selective agonists at the benzodiazepine sites that contain an alpha-1 subunit.  Pharmacodynamics Barbiturates So-named because they are all derived from barbituric acid. Binds to the α & β-subunit of the GABAA channel. Increase the duration of GABA-gated chloride channel openings. At high concentrations may be GABA-mimetic. Less selective in their actions than benzo’s because they depress the excitatory NT glutamic acid via binding to the AMPA receptor.  Pharmacodynamics Organ Level Effects Sedation - calming effect with reduction in anxiety at lower doses Usually has some psychomotor and cognitive depressant effects. Dose dependent anterograde amnestic effects. Hypnosis - all induce sleep at high enough dose Decreases time to fall asleep REM sleep is decreased May cause anxiety, irritability and REM rebound when d/c Stage 4 NREM slow wave sleep is decrease Tolerance may develop after 1-2 weeks Stages of Sleep  Pharmacodynamics Hypnosis Zolpidem - decrease latency and decreases REM sleep. REM rebound at higher doses when d/c. Zaleplon - decreases latency with little effect on total sleep time, REM or NREM sleep. REM rebound at higher doses when d/c Eszopiclone - decreases latency, increases stage 2 stage sleep and NREM sleep. Decreases REM in high doses. Suvorexant - decreases sleep latency and increases total sleep time.  Pharmacodynamics Organ level effects Anesthesia Barbiturates: Thiopental and methohexital are very lipid soluble, penetrate the BBB to stage III general anesthesia. Benzo’s: Diazepam, lorazepam and midazolam Given in large doses as adjuncts to general anesthesia but may contribute to post anesthesia respiratory depression (long t1/2, active metabolites)  Pharmacodynamics Organ level effects Anticonvulsant effects Most are capable of inhibiting the development and spread of epileptiform electrical activity in the CNS (except “z- drugs”). Benzo’s: Clonazepam, lorazepam, and diazepam. Barbiturates: Phenobarbital is effective in generalized seizures. Muscle relaxation Useful for relaxing contracted voluntary muscles in spasm or essential tremor. Benzo’s and meprobamate  Pharmacodynamics Organ level effects Respiration and CV function At hypnotic doses-comparable to changes of respiration during natural sleep as in healthy people Significant respiratory depression can result in patients with pulmonary disease. Dose-related Can lead to death if depression of the medulla respiratory center CV: No significant effect in healthy patients. With impaired function may cause CV depression d/t action on medullary vasomotor center.  Tolerance/Dependence Tolerance is a common feature. ? Downregulation of receptors. Occurs in varying degrees to many of the pharmacological effects Not the same for all effects. Cross tolerance can happen. Unlikely for z-drugs used