Anxiolytics & Hypnotics

Anxiety

unpleasant state of tension, apprehension, or uneasiness

GABA

• major inhibitory neurotransmitter in the CNS

• target of benzodiazepines

• MOA: Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore. Influx of chloride ions decreases neurotransmission by inhibiting the formation of action potentials

• reduce anxiety

• sedative/hypnotic

• anterograde amnesia

• anticonvulsant

4 effects of benzodiazepines

baclofen

muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord

Benzodiazepines

• class of drug effective for the treatment of the anxiety symptoms secondary to panic disorder, GAD, social anxiety disorder, performance anxiety, posttraumatic stress disorder, OCD, and extreme anxiety associated with phobias

• useful in treating anxiety related to depression and schizophrenia reserved for severe anxiety only and not used to manage the stress of everyday life

• only used for short periods of time

• not recommended during pregnancy

• clonazepam

• lorazepam

• diazepam

BZDs preferred in those patients with anxiety that may require prolonged treatment.

tolerance

• decreased responsiveness to repeated doses of the drug

• associated with a decrease in GABA receptor density

alprazolam

BZD effective for short- and long-term treatment, although it may cause withdrawal reactions in about 30% of patients

hypnotic agents

• agents decrease the latency to sleep onset

• increase stage II of non–rapid eye movement (REM) sleep

• triazolam (short-acting)

• temazepam (intermediate)

• estazolam (intermediate)

• flurazepam (long-acting)

• quazepam (long-acting)

5 commonly prescribed benzodiazepines for sleep disorders

flurazepam

rarely used long-acting BZD, due to its extended half-life, which may result in excessive daytime sedation and accumulation

temazepam

• intermediate-acting BZD useful in patients who experience frequent wakening

• useful for insomnia caused by the inability to stay asleep

• 1-2

• bedtime

peak sedative effect of temazepam occurs 1-3 hrs after an oral dose and should be given _____ hours before _____

triazolam

• short-acting BZD effective in treating individuals who have difficulty in going to sleep

• not a preferred agent due to rebound insomnia

• best used intermittently

• often shows a rapid development of tolerance, early morning insomnia, daytime anxiety, amnesia and confusion

short-acting BZDs

• often employed as premedication for anxiety-provoking and unpleasant procedures

• cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures

midazolam

benzodiazepine used to facilitate amnesia while causing sedation

prior to anesthesia

Clonazepam

BZD occasionally used as an adjunctive therapy for certain types of seizures

• lorazepam

• diazepam

2 drugs of choice in terminating status epilepticus

• chlordiazepoxide

• clorazepate

• diazepam

• lorazepam

• oxazepam

5 BDzs useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures

diazepam

BZD useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders

• hepatic microsomal system

• glucuronides or oxidized metabolites

most BZDs are metabolized by _____ and are excreted in the urine as _____ or _____

• drowsiness

• confusion

2 most common side effects of the benzodiazepines

Cognitive impairment

• decreased long-term recall and retention of new knowledge

• can occur with use of benzodiazepines

• liver disease

• acute angle-closure

Benzodiazepines should be used cautiously in patients with _____ and avoided in px with ______

• Alcohol

• CNS depressants

______ and other ______ enhance the sedative–hypnotic effects of the benzodiazepines

flumazenil

• GABA receptor antagonist that can rapidly reverse the effects of benzodiazepines

• available for intravenous (IV) administration only

• may precipitate withdrawal in dependent patients or cause seizures if a benzodiazepine is used to control seizure activity

• tricyclic antidepressants

• antipsychotics

Seizures may also result if the patient has a mixed ingestion of flumazenil with _____ or _____

Antidepressants

effective in the treatment of chronic anxiety disorders and should be considered as first-line agents (esp. px with addiction)

SSRI / SNRI

• may be used alone or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment

• have a lower potential for physical dependence than the benzodiazepines and have become first-line treatment for GAD

Buspirone

• useful for the chronic treatment of GAD and has an efficacy comparable to that of the benzodiazepines

• slow onset of action

• not effective for short-term or “as-needed” treatment of acute anxiety states

• MOA: mediated by serotonin (5-HT1A) receptors

• lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines

barbiturates

• formerly the mainstay of treatment to sedate patients or to induce and maintain sleep

• induce tolerance and physical dependence and are associated with very severe withdrawal symptoms

• MOA: sedative–hypnotic action due to their interaction with GABA_A receptors; potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings

thiopental

• ultra-short-acting barbiturate used to induce anesthesia IV but infrequently used today

• acts within seconds; lasts 30 minutes

pentobarbital

Anesthetic concentrations of ____ also block high-frequency sodium channels

phenobarbital

• long-acting barbiturate that has a duration of action more than a day

• specific anticonvulsant activity

• used in long-term management of tonic–clonic seizures
  used for the treatment of refractory status epilepticus

• can depress cognitive development in children and decrease cognitive performance in adults

• used only if other therapies have failed

• pentobarbital

• secobarbital

• amobarbital

• butalbital

3 short-acting barbiturates

butalbital

barbiturate commonly used in combination products as a sedative to assist in the management of tension-type or migraine headaches

hangover

Hypnotic doses of barbiturates produce a drug “_____” that may lead to impaired ability to function normally for many hours after waking

acute intermittent porphy

Barbiturates are contraindicated in patients with _____

zolpidem

• provides a hypnotic effect for approximately 5 hours

• has no anticonvulsant or muscle-relaxing properties

• undergoes hepatic oxidation by the CYP450 system to inactive products

• rifampin

• CYP3A4

drugs such as _____, which induce CYP450 system, shorten the half-life of zolpidem, and drugs that inhibit the _____ isoenzyme may increase the half-life

zaleplon

• oral nonbenzodiazepine hypnotic similar to zolpidem

• causes fewer residual effects on psychomotor and cognitive function compared to zolpidem or the benzodiazepines

Eszopiclone

• oral nonbenzodiazepine hypnotic that also acts on the BZ1 receptor

• effective for insomnia for up to 6 months

Ramelteon

• selective agonist at the MT1 and MT2 subtypes of melatonin receptors

• indicated for the treatment of insomnia characterized by difficulty falling asleep (increased sleep latency)

• can be administered long term

melatonin

hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle

• diphenhydramine

• hydroxyzine

• doxylamine

3 antihistamine with sedating properties effective in treating mild types of situational insomnia

doxepin

• older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action

• approved at low doses for the management of insomnia

• trazodone

• mirtazapine

2 used off-label for the treatment of insomnia

D. All benzodiazepines have some sedative effects

Which one of the following statements is correct regarding benzodiazepines?

A. Benzodiazepines directly open chloride channels

B. Benzodiazepines show analgesic actions

C. Clinical improvement of anxiety requires 2 to 4 weeks of treatment with benzodiazepines

D. All benzodiazepines have some sedative effects

E. Benzodiazepines, like other CNS depressants, readily produce general anesthesia

D. Triazolam

Which one of the following is a short-acting hypnotic?

A. Phenobarbital

B. Diazepam

C. Chlordiazepoxide

D. Triazolam

E. Flurazepam

D. Phenobarbital induces respiratory depression, which is enhanced by the consumption of ethanol

Which one of the following statements is correct regarding the anxiolytic and hypnotic agents?

A. Phenobarbital shows analgesic properties

B. Diazepam and phenobarbital induce the cytochrome P450 enzyme system

C. Phenobarbital is useful in the treatment of acute intermittent porphyria

D. Phenobarbital induces respiratory depression, which is enhanced by the consumption of ethanol

E. Buspirone has actions similar to those of the benzodiazepines

B. Lorazepam

A 45-year-old man who has been injured in a car accident is brought into the emergency room. His blood alcohol level on admission is 275 mg/dL. Hospital records show a prior hospitalization for alcohol-related seizures. His wife confirms that he has been drinking heavily for 3 weeks. What treatment should be provided to the patient if he goes into withdrawal?

A. None

B. Lorazepam

C. Pentobarbital

D. Phenytoin

E. Buspirone

C. Zaleplon

Which one of the following is a short-acting hypnotic and better for sleep induction compared to sleep maintenance?

A. Temazepam

B. Flurazepam

C. Zaleplon

D. Buspirone

E. Escitalopram

C. Lorazepam

Which of the following agents has a rapid anxiolytic effect and would be best for the acute management of anxiety?

A. Buspirone

B. Venlafaxine

C. Lorazepam

D. Escitalopram

E. Duloxetine.

D. Ramelteon

Which of the following sedative–hypnotic agents utilizes melatonin receptor agonism as the mechanism of action to induce sleep?

A. Zolpidem

B. Eszopiclone

C. Estazolam

D. Ramelteon

E. Diphenhydramine

C. Doxepin

All of the following agents for the management of insomnia are controlled substances and may have a risk for addiction or dependence except:

A. Zaleplon

B. Flurazepam

C. Doxepin

D. Zolpidem

E. Triazolam

E. Ramelteon

All of the following agents may cause cognitive impairment, including memory problems when used at recommended doses except:

A. Diphenhydramine

B. Zolpidem

C. Alprazolam

D. Phenobarbital

E. Ramelteon

C. Flumazenil

Which agent is best used in the Emergency Room setting for patients who are believed to have received too much of a benzodiazepine drug or taken an overdose of benzodiazepines?

A. Diazepam

B. Ramelteon

C. Flumazenil

D. Doxepin

E. Naloxone