Sedative-Hypnotic and Anxiolytic drugs Flashcards by David Sisa Gangai

Benzodiazepines

Alprazolam
Chlordiazepoxide
Diazepam
Estazolam
Flurazepam
Triazolam
Clonazepam
Midazolam
Lorazepam
Oxazepam
Temazepam

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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.

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Benzodiazepines - Clinical use

Anxiety disorders
Insomnia
Muscle spasm
Seizure disorders
Spasticity
Alcohol withdrawal

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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

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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

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Alprazolam - MoA

Converted to short-acting a-hydroxyl metabolite before undergoing glucuronide formation.

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Alprazolam - Clinical use

Anxiety (primarily)

Panic disorder

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Alprazolam - Interactions

Alcohol and other CNS depressants potentiate effects

Fluoxetine and fucoxamine increase serum levels and effects

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Chlordiazepoxide and Diazepam - MoA

Converted to long-acting metabolites: desmethyldiazepam (nordiazepam) –> converted to oxazepam –> excreted as a polar glucuronate conjugate

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Chlordiazepoxide, Diazepam - Clinical use

Anxiety
Alcohol detoxification (prevent seizures and other withdrawal symptoms)

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Diazepam - Clinical use

Terminate acute recurrent seizures
Severe muscle spasm
Spasticity ass with degenerative and demyelinating neurologic disorders.

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Chlordiazepoxide, Diazepam, Estazolam, and Flurazepam - Interactions

Alcohol and other CNS depressants potentiate effects

Cimetidine increases and rifampin decreases serum levels

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Flurazepam - Adverse effects

Because it is longer acting: drowsiness and drug hangover the next day

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Triazolam - Adverse effects

Rebound insomnia when it is discontinued

Amnesia, confusion, delirium; esp in old pat

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Triazolam - Interactions

Alcohol and other CNS depressants potentiate effects

Cimetidine, erythromycin, ketoconazole and oral contraceptives increase serum levels

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Midazolam - Clinical use

Anesthetic for endoscopy, other diagnostic procedures or minor surgery.
Lethal injection

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Midazolam - Adverse effects

Respiratory depression

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Midazolam - Interactions

Alcohol and other CNS depressants potentiate effects

Ca channel blockers, erythromycin and ketoconazole increase serum levels

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Which benzodiazepines are not metabolized?

Lorazepam
Oxazepam
Temazepam

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Lorazepam - Clinical use

Anxiety

Control seizures

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Lorazepam and Oxazepam - Interactions

Alcohol and other CNS depressants potentiate effects

Rifampin decreases serum levels

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Oxazepam - Clinical use

Anxiety

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Temazepam - Clinical use

Primarily Insomnia

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Temazepam - Interactions

Alcohol and other CNS depressants potentiate effects

Cimetidine increases and rifampin decreases serum levels

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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