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Flashcards in Axiolytics and Sedatives Deck (40):

The first class of anxiolytic drugs to be discovered were the ---------------- and all drugs in this class are notable for having potent sedative effects.




is a sudden-onset drug tolerance which is not dose dependant and is difficult to reverse.


Receptor sites for both barbiturates and benzodiazepines

are adjacent to but are not the same location as the GABA (gamma-aminobutyric acid) sites on the cell membrane of neurons in the CNS.


What happens to GABA receptors when barbiturate or benzodiazepine binds to it’s specific receptor site?

the GABA receptor site changes in configuration and the affinity of that site for holding on to the GABA neurotransmitter is increased.


GABAa receptors

are ligand-gated ion channels.


GABAb receptors

are G protein-coupled receptors


what is the effect of increased GABA binding affinity?

The increased affinity for GABA at its receptor sites results in more frequent and prolonged opening of the chloride ion channels on the neuron.


how are seizures affected by blocking or promoting GABA binding?

blocking GABA function can result in seizures and augmenting GABA function can afford protection against seizures



first introduced for medical use in the early 1900s.
Barbiturates have also been used as anticonvulsants and as anesthetic agents.


Barbiturates general MOA

CNS depressants, Barbiturates produce a wide spectrum of central nervous system depression that ranges from mild sedation to coma depending on dose

• Barbiturates do not raise the pain threshold and have no analgesic properties.

They are generally classified as being ultra-short acting, short acting, intermediate acting or long-acting.


Ultra-short acting barbiturates

• The ultra-short acting barbiturates produce anesthesia within about one minute after intravenous administration.
• Ultra-short acting barbiturates in current medical use include:
• Methohexital/ Brevital
• Thiamyl/ Surital
• Thiopental/ Pentothal (induction phase of general anesthesia.)--truth serum!


Short acting barbiturates

• The short acting barbiturates are either taken orally or administered by IV. Oral doses may produce effects within approximately 15 to 30 minutes with a duration of 6 to 8 hours or longer. Short acting barbiturates include:
• Amobarbital/ Amytal
• Pentobarbital/ Nembutal (physician assisted suicide)
• Secobarbital/ Seconal
• Tuinal (Amobarbital/Secobarbital combination)

orally or administered by IV
all Schedule II drugs.


Intermediate-acting barbiturates

• After oral administration, the onset of action is from 20 to 40 minutes and the effects last up to six hours. Intermediate- acting barbiturates include:
• Butalbital/ Fiorinal (migraine med)
• Butabarbital/ Butisol
• Talbutal/ Lotusate
• Probarbital/ Alurate

used for insomnia and pre-operative sedation as well as being added to aspirin or acetaminophen as headache medications.


Long-acting barbiturates

• The full effects of these long-acting barbiturates are generally realized in ~1 hour and may last for ~ 12 hours.
• The long acting barbiturates are now used primarily in the treatment of seizure disorders.
• The long-acting barbiturates include:
• Phenobarbital/ Luminal
• Mephobarbital/ Mebaral


Phenobarbital / Luminal uses

• Phenobarbital is the most widely used anticonvulsant worldwide and the oldest medication for seizure control still commonly used.

• Phenobarbital also has sedative and hypnotic properties but as with other barbiturates, it has been superseded by the benzodiazepines for these indications.


issues with Barbiturates

As anxiolytics and sedatives, barbiturates have largely been replaced because of multiple potential problems which include:

• Drug tolerance
• Psychological and physical dependence
• Severe withdrawal symptoms (which can sometimes be fatal)
• Potential for coma and respiratory failure, particularly when alcohol is consumed.


Benzodiazepines MOA

1. • The binding of benzodiazepines to benzodiazepine receptor sites enhances the affinity of GABA receptors for circulating endogenous GABA.

2. • Binding of the GABA receptor site triggers the opening of chloride channels.

3. • The influx of chloride ions into the nerve causes hyper-polarization of the neuronal membrane, making it more difficult for excitatory neurotransmitters to subsequently depolarize the nerve cell.

4. • This has proven helpful in the treatment of seizures and severe muscle spasm.


other uses of Benzodiazepines

Sedative and hypnotic actions
Anticonvulsant activity
Muscle relaxation


Short-acting benzodiazepines

are generally used for patients with sleep onset insomnia (difficulty falling asleep).

• Alprazolam/ Xanax
• Estazolam/ ProSom
• Flurazepam/ Dalmane
• Temazepam/ Restoril
• Triazolam/ Halcion
•Midazolam (Versed) is utilized for sedation and anxiety prior to such procedures as upper and lower G.I. endoscopy as well as prior to general anesthesia and in critical care settings.


Midazolam/ Versed

• Versed has potent sedative, hypnotic, anxiolytic, anticonvulsant, skeletal muscle relaxant, and amnestic properties.
• Midazolam is also indicated for the acute management of aggressive, violent or delirious patients.

• Long-term use of Versed for the management of seizure disorders is not recommended, due to the development of tolerance to the drug as well the notable side effect of marked sedation.


Benzodiazepines with a longer duration of action

are also utilized to treat insomnia as well as the treatment of anxiety. These benzodiazepines include:
• Chlordiazepoxide/ Librium
• Clonazepam/ Klonopin
• Diazepam/ Valium
• Lorazepate/ Tranxene
• Lorazepam/Ativan


Examples of the long acting benzodiazepines include used to treat seizures are :

• Clonazepam/Klonopin
• Diazepam/ Valium
• Clorazepate/ Tranxene


Diazepam/ Valium

• Class: Benzodiazepine
• Indication: Anxiolytic, sedative, muscle
relaxant and seizure control
• MOA: Binds to benzodiazepine receptors
in the C.N.S. to enhance GABA activity • Char: P.O., I.V. Rapidly absorbed P.O.,
metabolized in liver to active metabolites which prolong clinical duration of action.


Diazepam/ Valium SE

• Side effects: Drowsiness, impaired mentation, tolerance and addiction. Rebound insomnia may occur after drug discontinuation. Withdrawal can be severe, similar to that of barbiturates, especially when patient has been on chronic therapy.
• Valium as a treatment option for insomnia has largely been replaced by shorter acting benzodiazepines such as Alprazolam (Xanax) and Triazolam (Halcion).


Benzodiazepine-like sedatives

• Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)

are drugs used for the treatment of insomnia that are categorized as benzodiazepine-like or non-benzodiazepine drugs.

• These medications also act to increase GABA receptor affinity for endogenous GABA by interaction with receptors that are neither the benzodiazepine receptor site nor the barbiturate receptor site.


Zolpidem/ Ambien

• Zolpidem is a short-acting non- benzodiazepine hypnotic that potentiates GABA by binding to GABAA receptors at the same location as benzodiazepines.

• It works quickly (usually within 15 minutes) and has a short half-life ( approximately 2 to 3 hours).

• Zolpidem has not adequately demonstrated effectiveness in maintaining sleep however it is effective in initiating sleep.


Eszopiclone/ Lunesta

• Class: Benzodiazepine-like hypnotic
• Indication: Treatment of insomnia
• MOA: Potentiation of GABA effect on chloride ion channels by binding to a specific receptor site not involved with the binding of benzodiazepines.
• Char: PO. Rapid onset of action, reported in the 15 to 30 minute range. Appears to have no evidence for the development of drug tolerance.


Eszopiclone/ Lunesta SE

• Side effects: Impaired mentation prior to sedation. Eszopiclone is reported as having minimal drowsiness upon awakening and minimal change in mentation relative to all other benzodizepines. As with almost every medication, the full side effect profile may not be fully appreciated until that drug has been in use for at least five years or more.


Melatonin agonists
• Ramelteon (Rozerem)

• Ramelteon (Rozerem) belongs to the newest class of sedative hypnotics.

• Ramelteon is a melatonin receptor agonist, with high binding affinity at the melatonin MT1 and MT2 receptors.

• By binding selectively at these receptors, the drug mimics and enhances the action of endogenous melatonin, which has been associated with maintenance of circadian sleep rhythm through the inhibitory activity of MT1 and MT2 systems.


Ramelteon/ Rozerem

• Ramelteon has showed no measurable affinity for a number of other systems, including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters, and no effect on the activity of various enzymes.

• No published studies have indicated whether Ramelteon is more or less safe or more or less effective than melatonin, widely available in the United States without a prescription.


Benzodiazepine withdrawal

• Benzodiazepine withdrawal syndrome, often referred to as “benzo withdrawal”, refers to the cluster of symptoms which can appear when a person who has taken benzodiazepines and has developed benzodiazepine dependence stops taking the drug.

• Benzodiazepine withdrawal syndrome can also occur as a result of an abrupt, marked reduction in drug dosage.


Benzodiazepine withdrawal syndrome

can provoke life threatening symptoms i.e. seizures.
• Generally the higher the dose and the longer a benzodiazepine has been used and/or the more rapidly a benzodiazepine is discontinued, the more likely that severe withdrawal symptoms may occur.


Benzodiazepine overdose

• Death as a result of benzodiazepine overdose is relatively uncommon, however the combination of high doses of benzodiazepines with alcohol, barbiturates, or opioids is particularly dangerous and can lead to severe complications such as coma or death.

• The most common symptoms of overdose include CNS depression and signs of intoxication with impaired balance, ataxia and slurred speech. coa and death may result


Benzodiazepine overdose TX

Can be adsorbed by activated charcoal, gastric lavage with activated charcoal is not beneficial in a pure benzodiazepine overdose as the risk of adverse effects outweigh the potential benefits from the procedure

It is only recommended if benzodiazepines have been taken in combination with other drugs that may benefit from gastric “decontamination”.

usually treated with supportive care!


Flumazenil/ Romazicon

• Flumazenil is a benzodiazepine receptor antagonist that can rapidly reverse the effects of benzodiazepines.
• I.V. administration only.
• Rapid onset of action (1 to 2 minutes) but a
half-life of only approximately one hour. Therefore, multiple doses must be given to maintain reversal of the benzodiazepine particularly with patients who have over- dosed on longer acting benzodiazepines.


Flumazenil/ Romazicon

• Flumazenil is very effective at reversing the CNS depression associated with benzodiazepines but is less effective at reversing respiratory depression.

• Administration of Flumazenil can abruptly precipitate withdrawal syndrome in patients who are benzodiazepine dependent or may cause seizures, particularly if the patient is on a benzodiazepine to control seizures.


Flumazenil/ Romazicon SE

Flumazenil is contraindicated in patients who have a history seizures, patients who have ingested additional substances that may lower the seizure threshold, or in patients who have tachycardia, patients with a widened QRS complex on ECG, anti-cholinergic signs or a history of long-term benzodiazepine use.

In the majority of cases there is no indication for the use of Flumazenil in the management of benzodiazepine overdose due to the list of contraindications and the possibility of inducing potentially severe and even life threatening reactions including seizures, cardiac arrythmias and death.

Dizziness, nausea and agitation are common side effects


Zolpidem (Ambien) RX

Zolpidem/Ambien 5 mg tabs
Sig: Take 1 tab po qhs prn
Dist: #30 (thirty)
Refills: 0 (zero)


Eszopiclone (Lunesta) RX

Eszopiclone /Lunesta 2 mg tabs
Sig: Take 1 tab po qhs prn
Dist: #30 (thirty)
Refills: 0 (zero)


Citalopram (Celexa) RX
panic disroders

Citalopram/Celexa 10 mg tabs
Sig: Take 1 tab po qhs prn
Dist: #30 (thirty)
Refills: 0 (zero)