Sedative-Hypnotic and Anxiolytic drugs Flashcards
Benzodiazepines
Alprazolam Chlordiazepoxide Diazepam Estazolam Flurazepam Triazolam Clonazepam Midazolam Lorazepam Oxazepam Temazepam
Benzodiazepines - MoA
They bind between the a and g subunit and increase the affinity of GABA for its binding site on the GABAa receptors-Cl ion channel complex –> Increase the frequency of the channel opening, and increase the influx of Cl at postsynaptic cell –> neuronal membrane hyperpolarization –> counteract the depolarizing effect of excitatory neurotransmitters.
They also inhibit neuronal reuptake of adenosine –> increases inhibitory effect of adenosine on neurons that release ACh from pedunculopontine nucleus of the reticular formation which mediates arousal.
Benzodiazepines - Clinical use
Anxiety disorders Insomnia Muscle spasm Seizure disorders Spasticity Alcohol withdrawal
Benzodiazepines - Advers effects
CNS depression Mild respiratory depression Drug dependence Sedation Anxiolytic effect Motor incoordination Dizziness Excessive drowsiness Impaired cognitive processing Affect concentration Judgment and planning Interfere with driving and other psychomotor skills Hypotension Arrhythmia
Long-term use:
Physical dependence
If the medication is abruptly discontinued after several months of continues use: withdrawal syndrome; rebound anxiety, insomnia, headache, irritability, muscle twitches, seizures (alprazolam)
Mild euphoria
Reduce behavioral inhibitors
All sedative-hypnotic agents indicated for sleep disorders: increased risk of hypersensitivity reactions (anaphylaxis, angioedema), + complex sleep-related behaviors
Benzodiazepines - Interactions
Increase Sedative effect after eating a high-fat meal: fatty meal causes the gallbladder to empty –> delivers bile containing diazepam to intestines for reabsorption into the circulation.
Antidote: Flumazenil;
b-carboline derivatives: inverse agonists (decreased response of an effector system below the basal level). Act to decrease chloride conductance by the GABAa receptor-Cl ion channel –> anxiety and seizures.
Chronic use not recommended during pregnancy
Alprazolam - MoA
Converted to short-acting a-hydroxyl metabolite before undergoing glucuronide formation.
Alprazolam - Clinical use
Anxiety (primarily)
Panic disorder
Alprazolam - Interactions
Alcohol and other CNS depressants potentiate effects
Fluoxetine and fucoxamine increase serum levels and effects
Chlordiazepoxide and Diazepam - MoA
Converted to long-acting metabolites: desmethyldiazepam (nordiazepam) –> converted to oxazepam –> excreted as a polar glucuronate conjugate
Chlordiazepoxide, Diazepam - Clinical use
Anxiety Alcohol detoxification (prevent seizures and other withdrawal symptoms)
Diazepam - Clinical use
Terminate acute recurrent seizures
Severe muscle spasm
Spasticity ass with degenerative and demyelinating neurologic disorders.
Chlordiazepoxide, Diazepam, Estazolam, and Flurazepam - Interactions
Alcohol and other CNS depressants potentiate effects
Cimetidine increases and rifampin decreases serum levels
Flurazepam - Adverse effects
Because it is longer acting: drowsiness and drug hangover the next day
Triazolam - Adverse effects
Rebound insomnia when it is discontinued
Amnesia, confusion, delirium; esp in old pat
Triazolam - Interactions
Alcohol and other CNS depressants potentiate effects
Cimetidine, erythromycin, ketoconazole and oral contraceptives increase serum levels
Midazolam - Clinical use
Anesthetic for endoscopy, other diagnostic procedures or minor surgery.
Lethal injection
Midazolam - Adverse effects
Respiratory depression
Midazolam - Interactions
Alcohol and other CNS depressants potentiate effects
Ca channel blockers, erythromycin and ketoconazole increase serum levels
Which benzodiazepines are not metabolized?
Lorazepam
Oxazepam
Temazepam
Lorazepam - Clinical use
Anxiety
Control seizures
Lorazepam and Oxazepam - Interactions
Alcohol and other CNS depressants potentiate effects
Rifampin decreases serum levels
Oxazepam - Clinical use
Anxiety
Temazepam - Clinical use
Primarily Insomnia
Temazepam - Interactions
Alcohol and other CNS depressants potentiate effects
Cimetidine increases and rifampin decreases serum levels
Barbiturates
Amobarbital
Pentobarbital
Phenobarbital
Thiopental
Barbiturates - MoA
Bind to GABAa receptor at the alpha or beta subunit. Barbiturates increase the affinity of the receptor for GABA and the duration of the time the chloride channel remains open. Decrease activity of excitatory neurotransmitter (Ach, glutamate).
It also directly increase Cl influx in the absence of GABA –> no ceiling effect.
Barbiturates increase chloride conductance independent of the presence of GABA –> greater SNS depression and toxicity
Barbiturates - Clinical use
Insomnia
Seizure disorders
Induction of general anesthesia
Barbiturates - Adverse effects
Higher dose; Respiratory depression, coma, death
CNS depression, drug dependence
Barbiturates - Interactions
Induce CytP450: accelerate their own metabolism + other drugs metabolized by these enzymes.
Potentiated effects of other CNS depressants
Induce a-aminolevulinate synthase –> exacerbate porphyria
Amobarbital and Pentobarbital - Clinical use
Insomnia
Phenobarbital - Clinical use
Seizures disorders
Jaundice
Thiopental - Clinical use
Induction to anesthesia
Estazolam, Flurazepam and Triazolam - Clinical use
Insomnia
Antihistamines
Diphenhydramine
Hydroxyzine
Doxepine
Antihistamines - MoA
Cross blood-brain barrier and produce varying degrees of sedation.
Sedative action due to their ability to bind to H1 receptors and reduce ACh released by neurons in the reticular nuclei. Drug that block ACh release induce drowsiness and sleep via their effects on the cholinergic projections of the reticular nuclei.
In contrast: caffeine and methylxanthines can increase arousal by blocking presynaptic adenosine receptors –> increase cholinergic activity in the reticular nuclei.
Antihistamines - Adverse effects
Anticholinergic effects: blurred vision, dry mouth, urinary retention, dizziness, drowsiness
Some tolerance can occur during the long-term use
Antihistamines - Interactions
Alcohol, barbiturates, CNS depressants potentiate CNS effects
Diphenhydramine and Doxepine - Clinical use
Insomina
Hydroxyzine - Clinical use
Anxiety, sometimes used as a sedative before surgery
Zolpidem, Zaleplon and Eszopiclone - MoA
Facilitate the activity of g-aminobutyric acid (GABA), GABAa receptor- Cl ion channels. They bind on the a subunit and increase the frequency which the channel open and cause hyperpolarization.
Zolpidem, Zaleplon and Eszopiclone - Clinical use
Insomnia
Zaleplon: midsleep awakenings
Zolpidem and Zaleplon - Adverse effects
Dizziness
Drowsiness
Headache
Eszopiclone - Adverse effects
Drowsiness
Dizziness
Difficulty with coordination
Zolpidem, Zaleplon and Eszopiclone - Interactions
Effects potentiated by alcohol and other CNS depressants
Flumazenil - MoA
Competitive benzodiazepine receptor antagonist. Block effects of agonists such as diazepam, but also inverse agonists
Flumazenil - Clinical use
Counteract the adverse effects of benzodiazepines, such as respiratory depression due to IV adm or in the case of accidental or intentional overdose.
Flumazenil - Adverse effects
Seizures Arrhythmia Blurred vision Emotional lability Dizziness
Melatonin - MoA
Interacts with specific receptors in the CNS and elsewhere, and is believed to be the principal mediator of the biologic clock that determines circadian, seasonal and reproductive rhythms in animal species.
In humans: released before the onset of sleep and produces drowsiness
Melatonin - Clinical use
Jet-lag Insomnia in shift-change workers Insomnia in elderly pt who do not secrete adequate melatonin. Delayed sleep-phase syndrome Non-24-hour sleep-wake disorder
Melatonin - Adverse effects
If taken at bedtime for a few nights –> accelerate the resetting of the biologic clock
Ramelteon - MoA
Act selectively at melatonin receptors
Ramelteon - Clinical use
Sleep-onset insomnia
Ramelteon - Interactions
Fluvoxamine (strong CYP1A2 inh): increase plasma conc.
Tasimelteon - MoA
Melatonin agonist
Tasimelteon - Clinical use
Insomnia: non-24 hour sleep-wake disorder
Chloral Hydrate - MoA
Prodrug that is converted to its active metabolite, trichloroethanol.
Chloral Hydrate - Clinical use
Preanesthetic sedation in pediatric patients
Chloral Hydrate - Interactions
Effect are potentiated by alcohol
Buspirone - MoA
Partial agonist at serotonin 5-HT1A receptors and activated feedback inhibition of serotonin release –> upregulation of postsynaptic serotonin receptors.
Buspirone - Clinical use
Chronic anxiety
Buspirone - Adverse effects
Headache
Dizziness
Nervousness
Propranolol - MoA
b-adrenoceptor antagonists
Propranolol - Clinical use
Prevent physiologic manifestations of stage fright or acute situational or performance anxiety –> prevent tachycardia and pther signs and symptoms of acute anxiety caused by symptomatic stimulation.
Propranolol - Adverse effects
Bradycardia Bronchoconstriction Depression Fatigue Hypersensitivity Hypotension Impaired glycogenolysis Vivid dreams.
Propranolol - Interactions
Cardiac depression increased by CCBs
