Intro to sedative hypnotics Flashcards
Benzodiazepines drug list
Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) Midazolam (Versed) Oxazepam Quazepam Temazepam (Restoril) Triazolam
Benzodiazepine Antagonist drug list
Flumazenil
Barbiturates
drug list
Phenobarbital
Miscellaneous Sedative-Hypnotic Drugs
drug list
Buspirone (BuSpar) Eszopiclone (Lunesta) Ramelteon (Rozerem) Zaleplon (Sonata) Zolpidem (Ambien, Ambien-CR)
Sedative
Reduces anxiety, exerts calming effect
May be side effect of drugs which are not general CNS depressants (e.g., antidepressants, antihistamines, neuroleptics/antipsychotics
Hypnotic
Produces drowsiness, facilitates onset & maintenance of sleep
More pronounced CNS depression
Dose-Response Curves for Hypothetical Sedative-Hypnotics
Linear: barbiturates, alcohols, and older sedative-hypnotics
Plateau: benzodiazepines and newer sedative-hypnotics
what do Benzodiazepines
do?
Capable of: sedation, hypnosis, muscle relaxation, anxiolytic, and anticonvulsant effects
what do barbiturates do?
Capable of: mild sedation anesthesia, anxiolytic, hypnotic, and anticonvulsant effects
what do the new hypnotics do?
Useful for: sleep aid, delirium, anxiety, seizures
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
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
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
3 drugs that only require conjugation, useful for those with hepatic impairment
Lorazepam
Oxazepam
Torazepam
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
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
