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11/19/2014 Sedative‐Hypnotic and Anxiolytic Medications Indications Anxiety Panic disorders Sleep disturbances S i Seizure disorders di d Alcohol withdrawal syndrome Sedatives for medical procedures, blocking patient’s memory of event Sedative‐Hypnotic and Anxiolytic Medications Historical Use Historical Use Mid‐1800s Chloral hydrate, bromide for sleep induction Early 1900s Introduction of barbituates (e.g. phenobarbital) Early 1950s Alternative sedatives introduced – meprobamate, carisoprodol 1960s Benzodiazepines first marketed p Benzodiazepines most commonly prescribed today for anxiety disorders 1 11/19/2014 Mechanism of Action of Benzodiazepines and Barbiturates Positive allosteric modulators of GABA receptors Bi di Binding at sites adjacent to the GABA binding site results in a 3D conformational change in the t it dj t t th GABA bi di it lt i 3D f ti l h i th receptor, increasing affinity of GABA for receptor. Gamma‐Aminobutyric Acid (GABA) – Major Inhibitory Neurotransmitter Binds to GABAA (and sub‐subtypes) and GABAB receptors (ionotropic, fast‐acting) GABA receptor are chloride ion (Cl‐) channels. When open, Cl‐ can diffuse into neurons with its concentration gradient (against the electrical gradient) hyperpolarizing membranes, reducing propensity for action potentials. 2 11/19/2014 Membrane Potential Across Neurons Cells polarized: Outside cell Outside cell higher [Na+] higher [Cl‐] Inside cell higher [K+] higher [A‐] (charged proteins) Resting potential ‐70 mV Ion gradient maintained by active transport (requires energy) Depolarization of Neuron Can Lead to Action Potential if Threshold Reached Resting potential ‐70 70 mV mV Hyperpolarization Inside of cell becomes more negative e.g. ‐70 mV to ‐80 mV Cl‐ flows into cell – “inhibitory” Depolarization Inside of cell becomes more positive e.g. ‐70 mV to ‐55 mV Na+ flows into cell – “excitatory” Neurotransmitter binding to receptor can cause ion channels to open, leading to depolarization or hyperpolarization. 3 11/19/2014 Actions of Benzodiazepines and Barbiturates Anxiolytic properties Activation of GABA neurons at limbic centers – amygdala, orbitofrontal cortex, insula Sedation, cognitive impairment, amnesia, muscle relaxation, other side effects Activation of GABA neurons in other regions of CNS, including brain stem and cerebral cortex Barbiturates, Benzodiazepines, Ethanol and Other Sedatives Can Cause Anterograde Amnesia “Blackout” or “Brain syndrome” – Depressed nerve cell function leads to loss of memory for new events or actions while person is awake and performing such behavioral activities. Sedative‐hypnotics and anxiolytics have been used as “date rape” drugs • chloral hydrate • gamma‐hydroxybutyric acid (GHB) • flunitrazepam (Rohypnol®) 4 11/19/2014 Barbiturates – Limited Use in Medicine, Largely Replaced by Benzodiazepines Similar chemical structures, classified according to pharmacokinetics (long acting short acting) pharmacokinetics (long‐acting, short‐acting) Phenobarbital Treatment of seizures Occasionally used in alcohol, benzodiazepine detoxification (sedative, anticonvulsant) Pentobarbital Veterinary anesthetic and used in euthanasia in combination with phenytoin Used in combination with other drugs for executions in US High doses cause death by respiratory arrest Barbiturates – Limited Use in Medicine, Largely Replaced by Benzodiazepines 1. Lethal in over‐dose 2. Narrow therapeutic indexes 3. High potential for tolerance, dependence, abuse 4. Drug‐drug interactions 5 11/19/2014 Non‐Barbiturate, Non‐Benzodiazepine Based Sedative‐Hypnotic GHB gamma‐hydroxybutyrate GABA gamma‐aminobutyric acid Endogenous neurotransmitter Precursor for endogenous synthesis of GHB Marketed as sodium oxybate Marketed as sodium oxybate for narcolepsy for narcolepsy (Schedule III – other uses Schedule I) GHB Precursors Converted In Vivo to Active Drug Gamma‐butyrolactone (GBL) and 1,4‐butanediol accessed for illicit use 6 11/19/2014 Benzodiazepines Widely prescribed – estimated 2.5% of adult population has a benzodiazepine Rx Indicated only for short‐term use – up to one month, though often used long‐term 12 benzodiazepine derivatives marketed in US Administration routes and pharmacokinetics differ Benzodiazepines 7 11/19/2014 Benzodiazepine Pharmacokinetics Most are orally bioavailable, with good absorption Several generate active metabolites in vivo – Valium®, Librium® and thus have longer activities Half‐lives range from 2 hours to 80 hours Elderly patients metabolize more slowly – half‐lives may reach 7‐10 days for diazepam (Valium®) Benzodiazepine Side Effects and Toxicities – Amplified at High Doses or in Combination with Other Depressants, e.g. Alcohol • Sedation • Drowsiness • Mental confusion • Motor impairment • Cognitive impairment • Amnesia Flumazenil (Romazicon®) – benzodiazepine receptor antagonist for overdose Limited use ‐ may precipitate seizures 8 11/19/2014 Benzodiazepine Tolerance and Withdrawal Rebound and withdrawal symptoms Tolerance • Anxiety Builds more rapidly to the sedative, hypnotic, • Insomnia anticonvulsant, and muscle relaxant effects. • Agitation • Muscle spasms Anxiolytic effects can decrease within 4‐6 • Unpleasant dreams months of use. • Seizures can occur Benzodiazepines Versus Alternate Medications Benzodiazepines indicated for acute use • Short‐term treatment of debilitating anxiety Short term treatment of debilitating anxiety • Medical procedures where anterograde amnesia benefits patient Injectable lorazepam (Ativan®), midazolam (Versed®) Antidepressants or atypical antispsychotics preferred for long‐term treatment of: • Insomnia • Generalized anxiety disorder • Phobia • Panic disorder 9