Sedative Hypnotics

Compare the safety margin of benzodiazepines versus barbiturates.

Benzodiazepines have a wide safety margin, whereas barbiturates have a lower safety margin and higher toxicity risk.

How do barbiturates affect REM sleep compared to benzodiazepines?

Barbiturates suppress REM sleep leading to rebound increases and hangovers, while benzodiazepines have a lesser effect on normal sleep architecture.

Why are barbiturates considered to have higher abuse liability than benzodiazepines?

Barbiturates are potent enzyme inducers, lead to metabolic tolerance, and cause physical/psychic dependence more readily than benzodiazepines.

What type of sedative hypnotic can be used as daytime anxiolytics?

benzodiazepines

What type of sedative hypnotic has higher rates of overdose and poisoning?

Barbiturates because of its amnesia with automatism

What is the site of action for low dose sedative hypnotics?

depress the limbic system without depressing reticular activating system (RAS). Hence, reduce anxiety with no sleep induction.

What is the site of action for high dose sedative hypnotics?

suppress RAS and induces sleep.

What is the GABA(A) receptor and how is it activated?

Ligand gated Cl- ion channel activated by hyperpolarization and decreased membrane excitability

What is the agonist for GABA(B) receptors?

spasmolytic Baclofen

What are the types of anti-anxiety benzodiazepines?

Diazepam

Lorazepam

Alprazolam

Oxazepam

Chlordiazepoxide

What are the ultra short acting benzodiazepines?

Thiopental Na and Methohexital

What are the types of anti-convulsant benzodiazepines?

Diazepam

Lorazepam

Clonazepam

Clobazam

What is the mechanism of action of benzodiazepines?

Enhance GABA mediated synaptic inhibition by increasing the frequency of GABA gated chloride channel opening

What acts on the modulatory site of benzodiazepines and non-benzodiazepines?

BZ antagonist Flumazenil and inverse agonist β carbolines.

What is Flumazenil?

A benzodiazepine antagonist blocking the action of Z drugs used to revert anesthesia or treat overdose

What types of benzodiazepines have long half lives?

diazepam (50h) and chlordiazepoxide (40h)

What types of benzodiazepines skip hepatic metabolism?

lorazepam, oxazepam and temazepam (LOT) and therefore can be safely administered in liver dysfunction

What are the pharmacodynamics of benzodiazepines?

Sedation, Hypnosis, Anesthesia, Anticonvulsant effects, and Skeletal muscle relaxation

What pharmacodynamics of benzodiazepines are dose dependant?

depression of vasomotor, respiratory and CV function

What are the primary clinical uses of benzodiazepines?

Anxiety neuroses, preanesthetic/ anesthesia, muscle spasm, seizures, alcohol withdrawal, insomnia

Which benzodiazepines are preferred for alcohol withdrawal?

Diazepam and chlordiazepoxide.

What benzodiazepine is misused in sexual assults?

Flunitrazepam (AKA Rohpynol or Roofie) due to its sedative and amnestic property

What are the common adverse effects of benzodiazepines?

Drowsiness, fatigue, disorientation, lethargy, anterograde amnesia, and impairment of psychomotor skills.

What are the risk factors for dependence of benzodiazepines?

continuous use, high doses, use of BZs with short t1/2 and use in patients with drug dependent personality traits

What are the symptoms of benzodiazepines withdrawal?

headache, tremors, impaired concentration, vivid dreams & others

What are the types of Non-benzodiazepine Hypnotics (Z- Drugs)?

Zopiclone

Eszopiclone

Zolpidem

Zaleplon

What is the mechanism of action of Non-Benzodiazepine Hypnotics?

They act selectively on BZ1 receptors, resulting in no muscle relaxant, amnestic, or anticonvulsant effects.

What are the clinical advantages of Z drugs over traditional benzodiazepines?

minimal residual daytime sedation, and have no risk of tolerance, dependence, or rebound insomnia.

What is the use of Zolpidem (Ambien) and Zaleplon?

transient insomnia

What is the use of Zopiclone and Eszopiclone?

short term insomnia

What are the types of melatonin agonists?

-Melatonin

-Ramelteon

-Tasimelteon

What is Melatonin?

A hormone produced in the pineal gland from tryptophan stimulated by darkness and inhibited by light

What is the mechanism of action of melatonin agonists?

Stimulates MT1/2 receptors in suprachiasmatic nucleus to induce sleep and maintain circadian rhythm

What are the pharmacokinetics of melatonin agonists?

Rapidly absorbed orally, food enhances bioavailability, undergoes first pass metabolism

What are the primary clinical uses of melatonin agonists like ramelteon?

To alleviate symptoms of jet lag and to treat insomnia in elderly patients who are hypnotic-dependent.

What are the types of sedating (1st gen) antihistamine?

-Hydroxyzine

-Promethazine

-Diphenhydramine

-Doxylamine

What are the uses of hydroxyzine and promethazine?

older antihistamines used as sleeping aids alongside doxylamine and diphenhydramine sold OTC

What endocrine side effects are associated with the use of melatonin agonists?

Decreased serum LH and increased prolactin levels (hyperprolactinemia).

What is the mechanism of action of Buspirone?

It is a partial agonist at 5HT1A and D2 receptors in the brain that is a selective anxiolytic

Why is Buspirone not suitable for the management of acute anxiety?

Its anxiolytic effects take 3-4 weeks to appear and therefor only used for generalized anxiety

What is the adverse effect of Buspirone?

rise in BP in patients using MAO-I

What is the mechanism of action of Suvorexant?

It is an orexin receptor antagonist, blocking peptides responsible for wakefulness.

What is Orexin A and B?

peptides responsible for wakefulness control leading to narcolepsy

What is the clinical use of Suvorexant?

Used for insomnia

What are the DDI's of Suvorexant?

Additive effect when sedative hypnotics combined with other CNS depressants including alcohol  

Which stimulant medications are used to treat narcolepsy?

Methylphenidate, Amphetamine, and Modafinil.

What is a long acting barbiturate?

Phenobarbitone

What are the short acting barbiturates?

Butobarbitone and Pentobarbitone

What is the mechanism of action of Barbiturates?

Potentiate GABA mediated inhibitory effects by increasing the duration of Cl- channel opening.

What is the pharmacokinetic effects from prolonged use of barbiturates?

metabolic enzyme induction, alkalinization of urine with NaHCO3, and enhanced elimination with NH4Cl

What are the pharmacokinetics of Thiopental and methohexital?

undergoes redistribution due very high lipid solubility

What are the pharmadynamics of barbiturates?

sedation, hypnosis, anesthesia, coma, and death

What are the clinical uses of barbiturates?

General anesthesia (ultra short acting via IV) and Anticonvulsants (phenobarbital)

What are the adverse effects of barbiturates?

Hepatic microsomal enzyme induction, abuse liability, dependence, withdrawal, hangover amnesia, automatism, respiratory depression, drug allergy

Why are barbiturates contraindicated in patients with porphyria?

They induce the hepatic ALA synthase enzyme, which worsens the condition.

What is the treatment for acute toxicity of barbiturates?

Forced alkaline diuresis with mannitol and NaHCO3.