Intro to sedative hypnotics Flashcards by Briana Tillman

Benzodiazepines drug list

Alprazolam (Xanax)
Clonazepam (Klonopin)
Diazepam (Valium)
Lorazepam (Ativan)
Midazolam (Versed)
Oxazepam 
Quazepam 
Temazepam (Restoril)
Triazolam

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Benzodiazepine Antagonist drug list

Flumazenil

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Barbiturates

drug list

Phenobarbital

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Miscellaneous Sedative-Hypnotic Drugs

drug list

Buspirone (BuSpar)
Eszopiclone (Lunesta)
Ramelteon (Rozerem)
Zaleplon (Sonata)
Zolpidem (Ambien, Ambien-CR)

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Sedative

Reduces anxiety, exerts calming effect
May be side effect of drugs which are not general CNS depressants (e.g., antidepressants, antihistamines, neuroleptics/antipsychotics

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Hypnotic

Produces drowsiness, facilitates onset & maintenance of sleep
More pronounced CNS depression

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Dose-Response Curves for Hypothetical Sedative-Hypnotics

Linear: barbiturates, alcohols, and older sedative-hypnotics

Plateau: benzodiazepines and newer sedative-hypnotics

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what do Benzodiazepines

do?

Capable of: sedation, hypnosis, muscle relaxation, anxiolytic, and anticonvulsant effects

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what do barbiturates do?

Capable of: mild sedation  anesthesia, anxiolytic, hypnotic, and anticonvulsant effects

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what do the new hypnotics do?

Useful for: sleep aid, delirium, anxiety, seizures

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Mechanisms of Action

Benzodiazepines
Promote binding of GABA to GABAA receptor
Enhance GABA-induced ion currents
Increase frequency of channel opening

Barbiturates
Potentiate GABA-induced Cl- currents
Increase duration of channel opening
May activate channel directly at high concentrations

Miscellaneous
Eszopiclone, zaleplon, zolpidem: GABAA receptor agonists
Ramelteon: activates MT1 and MT2 receptors

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Pharmacokinetics- Absorption & Distribution

Lipid solubility important determinant of rate of CNS entry
Most rapidly absorbed into blood following oral administration
Sedative-hypnotics cross CNS, placental barrier, and breast milk

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Pharmacokinetics- Biotransformation of benzodiazepines

Hepatic drug-metabolizing enzyme systems important mediators of drug inactivation and elimination

Benzodiazepines

Hepatic metabolism for clearance of all benzodiazepines
Most undergo phase I reactions (CYP3A4) followed by glucuronidation (phase II)
Cumulative toxicity

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3 drugs that only require conjugation, useful for those with hepatic impairment

Lorazepam
Oxazepam
Torazepam

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Pharmacokinetics: Biotransformation of barbiturates

Hepatic drug-metabolizing enzyme systems important mediators of drug inactivation and elimination

Barbiturates
Most undergo hepatic metabolism and excreted in urine as glucuronide conjugates (phenobarbital 20-30% excreted unchanged)
Long t1/2’s and cumulative toxicity

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Pharmacokinetics: Biotransformation of newer hypnotics

CYP3A4 plays a role in eszopiclone, zolpidem, and zaleplon metabolism
Relatively short t1/2’s

Fast metabolism (quick onset) with long half-lives

oxidation- ex. alprazolam, diazepam

Intermediate metabolism (intermediate onset after oral administration)

Estazolam
Oxazepam
Lorazepam
Temazepam

fast onset with shorter halflives

eszopiclone
zaleplon
Zolopidem

Tolerance

Decrease in responsiveness to a drug following repeated exposure (common feature of sedative-hypnotic use)
Cross-tolerance – repeated use of a drug produces tolerance to that drug but also drugs in same structural/mechanistic class

Mechanisms:

Down-regulation of GABAA receptors (benzodiazepines)
Enzyme induction (barbiturates)

(remembering phenobarbital induces its own metabolism)

Dependence

Sedative-Hypnotics: relief of anxiety, euphoria, disinhibition, and promotion of sleep

Physiologic – increased anxiety, insomnia, CNS excitability

Psychologic – cravings, irritability, insomnia, depression
When use becomes compulsive, physiologic dependence and tolerance likely to develop

Adverse Effects

Dose-related CNS depression
Low doses – drowsiness, impaired judgment, & diminished motor skills
Severe toxicity – respiratory depression
Increased sensitivity to sedative-hypnotics in the elderly and in patients with cardiovascular disease, respiratory disease, or hepatic impairment

Flumazenil

MOA: competitive antagonist at benzodiazepine site on GABAA receptor
Blocks actions of – benzodiazepines, zolpidem, zaleplon, and eszopiclone
Does not block – barbiturates, buspirone, ramelteon

**PK: short t1/2 0.7-1.3 hours (repeated doses necessary)

Use: reverse CNS depressant effects of benzodiazepine overdose and shorten recovery following anesthetic and diagnostic procedures

ADRs: agitation, confusion, dizziness, nausea

Ramelteon

MOA: agonist at MT1 and MT2 melatonin receptors
PK: extensive first-pass effect
Use: treatment of insomnia (difficulty with sleep onset)
ADRs: dizziness, somnolence, fatigue

no abuse potential

Buspirone

MOA: unknown; mediated through serotonergic or dopaminergic systems PK: extensive first-pass effect, extensive metabolism (CYP3A4) Use: generalized anxiety disorder (3-4 weeks to become established) ADRs: tachycardia, palpitations, nervousness, GI distress, paresthesias * no abuse potential

Clinical Pharmacology

Clinical uses: Relief of anxiety Insomnia Sedation and amnesia before and during medical surgical procedures Treatment of epilepsy and seizure states Component of balanced anesthesia (IV administration) Control of ethanol or other sedative-hypnotic withdrawal states Muscle relaxation in specific neuromuscular disorders Diagnostic aids or for treatment in psychiatry

Treatment of Anxiety

Benzodiazepines used for the management of acute anxiety states (situational anxiety) and rapid control of panic attacks Advantages - High therapeutic index - Antagonist available for overdose (flumazenil) - Low risk of drug-drug interactions - Minimal effect on CV and autonomic function Disadvantages - Risk of dependence - CNS depression - Amnesic effects

Sleep Disorders

Sleep aids should decrease sleep latency and provide sufficient sleep duration with minimal hangover effects Benzodiazepines used but daytime sedation a disadvantage - Patients may also develop anterograde amnesia and tolerance Zolpidem, zaleplon, and eszopiclone - Highly effective - Rapid onset with minimal hangover effects - Zolpidem in biphasic release formulation for sustained sleep maintenance - Zaleplon and zolpidem act rapidly - Eszopiclone has a longer half-life

A 30 y/o female presents to her PCP with complaints of constant worrying, muscular tension, poor concentration, and restlessness. She is diagnosed with generalized anxiety disorder. The physician writes a prescription for lorazepam. Which of the following mechanisms best describes the drug’s anxiolytic properties? Blocks beta-adrenergic receptors Increases the duration of GABAA channel opening Increases the frequency of GABAA channel opening Increases the release of norepinephrine within the CNS Inhibits serotonin reuptake

C. Increases the frequency of GABAA channel opening

A 25 y/o male presents to his physician’s office with complaints of excessive anxiety. He is always worried about his family, friends, and job performance. He has difficulty concentrating and is often tired. PMH: alcohol dependence SH: newly married (would like to avoid drugs which affect sexual performance) If long-term therapy is indicated, which agent is most appropriate? ``` Buspirone Fluoxetine Imipramine Lorazepam Propranolol ```

with alcohol dependence, avoid lorazepam SSRIs can cause sexual dysfunction and anti-cholinergic effects (eliminate Fluoxetine and Imipramine) Buspirone is the answer. Takes 3-4 weeks to take effect. (Propanolol is not good for generalized anxiety disorder)

A 37 y/o male presents for routine follow-up with complaints of difficulty falling asleep. He has had an increased workload and is only getting about 5-6 hours of sleep/night (usually needs 7 hours to feel rested). Which of the following agents, used to treat insomnia, has no appreciable affinity for the GABA receptor complex? ``` Eszopiclone Ramelteon Temazepam Zaleplon Zolpidem ```

Ramelteon binds melatonin receptor.

His physician would like to prescribe a benzodiazepine but the patient is concerned these drugs cause a hangover effect. Which of the following is not metabolized extensively via hepatic oxidation to longer acting metabolites? ``` Chlordiazepoxide Clorazepate Diazepam Flurazepam Lorazepam ```

Lorazepam

In the news… A 44 y/o female with a history of insomnia is prescribed a hypnotic sleep aid. One week later she wakes up in her pajamas in jail with no recollection of the previous night. The last thing she remembers is enjoying a glass of wine and then taking her medication before bed. Police inform her she was arrested after wrecking her car, appearing under the influence. What drug did the FDA require additional warnings on prescription labeling due to reports of sleep-driving?

Zolpidem (ambien)

A 32 y/o male is found unresponsive by his neighbor. Empty pill bottle at his side. BP: 115/74 mmHg; HR: 62 bpm; RR: 12 rpm PE: impaired cognition, slurred speech, muscle weakness Pupils normal size; normal bowel tones Which drug is most appropriate for this patient? Atropine Ethanol Flumazenil Naloxone

This is a benzodiazepine overdose (no hemodynamic compromise, etc.) Pupils would be pinpoint in an opioid overdose So flumazenil is good