L4 Hypnotic, Sedative and Anxiolytic Drugs

Objectives

1. Define sedatives and Hypnotics

2. Discuss GABAergic neurotransmission

3. Discuss the pharmacological agents used to treat anxiety and insomnia

What neurotransmitters are involved in:

• Stimulating (wakefulness)

• Inhibitory (sleep)

Stimulating - Serotonin, Dopamine, Norepinephrine, Acetylcholine, Histamine

Inhibitory - GABA

Define anxiety

• Overactivity of adrenergic system

• Dysregulation of serotonergic system

Define Generalized Anxiety Disorder (GAD)

Persistent and excessive worry about various aspects of life (e.g., health, work, relationships)

Define panic disorder

Recurrent, unexpected panic attacks involving intense fear and physical symptoms like chest pain, rapid heartbeat, dizziness, and shortness of breath.

Define Social Anxiety Disorder (SAD)

Intense fear of being judged or embarrassed in social situations.

Define Specific Phobias

Irrational and intense fear of a specific object or situation (e.g., spiders, heights, flying).

Anxiolytic drugs often function as

• Anxiolytic

• Hypnotic (sleep-inducing) agents

• Some have anticonvulsant activity

Define Sedative-hypnotics

General depressants of the central nervous system

Define Sedatives

Reduce daytime anxiety, decrease excitement and promote calm state

Define Hypnotics

Produce drowsiness, help sleep onset and maintenance of sleep

GABA receptors affect:

Affect arousal and attention, memory formation, anxiety, sleep, and muscle tone

Modulation of GABA signaling is involved in the treatment of:

Focal or widespread neuronal hyperactivity in epilepsy

Ionotropic GABA receptors (GABA_A and GABA_C) → opens what ion channel?

Open an intrinsic chloride ion channel in the presence of GABA

Allosteric binding → GABA has to bind first and then benzos can activate receptor

Metabotropic GABA receptors (GABA_B) → opens what ion channel?

Also activate Heterodimeric G protein-coupled receptors

• Activate neuronal potassium channels through second messenger

• Hyperpolarization

What are the effects of inhibitory neurotransmission?

Gamma-aminobutyric acid (GABA) → Hyperpolarization

Direct effect: Cl- channel open

Indirect effect: K+ channels open + Ca²⁺ channels close

What are the effects of excitatory neurotransmission?

Glutamate → Depolarization

Direct effect: Na+ and Ca2+ channel open

Indirect effect: K+ channel closed

What are the effects of increased GABA_B receptor?

Decreased adenylyl cyclase and cAMP → minor effects on cellular excitability

Which of the following effects at the postsynaptic membrane is caused by inhibitory neurons?

A. Depolarization

B. Stimulation of NE

C. Transient decrease in permeability of chloride

D. Hyperpolarization

D. Hyperpolarization

Which part of the limbic system is most closely associated with processing of fear and anxiety?

A. Hippocampus

B. Amygdala

C. Thalamus

D. Hypothalmamus

B. Amygdala

T/F GABA_A receptors are members of the superfamily of neurotransmitter gated ion channel

True

What drugs are in the Benzodiazepines class?

• Estazolam

• Flurazepam

• Quazepam

• Temazepam

• Triazolam

• Diazepam

• Alprazolam

• Midazolam

Bind to GABA_A receptors

What must bind for benzodiazepines to activate GABA_A?

Benzodiazepines do not activate native GABA_A receptor in the absence of GABA

Two molecules of GABA has to bind between Alfa and Beta subunits to activate the molecule.

Benzodiazepine act as an agonist and favor channel opening.

Inhibitory neurotransmitter in CNS, decrease neuronal excitability

Benzodiazepine-GABA-chloride ion channel complex

What is the role of Benzodiazepine?

Benzodiazepine act as positive allosteric modulator by enhancing the presence of GABA

What are the effects of benzodiazepines?

• Reduction of anxiety

• Sedative and hypnotic actions

• Anticonvulsant

• Muscle relaxant

• Ethanol Withdrawal syndromes

What effects of benzodiazepines are mediated by alpha 1-GABA_A and alpha 2-GABA_A )

alpha 1-GABA_A → Sedative and hypnotic actions, anticonvulsant

alpha 2-GABA_A → at high does it acts as muscle relaxant

Diazepam (Valium)

• Long acting

• Anxiolytic- used to treat chronic and severe anxiety

• Anti-epileptic, muscle relaxant

Alprazolam (Xanax)

• Intermediate acting

• Mitigate chronic, severe anxiety and the anxiety associated with some forms of depression and schizophrenia

Midazolam

• Rapid-onset

• Short acting - anxiolytic/sedative/amnestic

What happens when benzodiazepines are combined with opioids?

A synergistic potentiation of both sedation and respiratory depression can occur

Estazolam

flurazepam

Quazepam

Temazepam

Triazolam

• Facilitate sleep onset and increase the overall duration of sleep

• Increase the length of Non-REM sleep and decrease the length of REM sleep

Flurazepam

Long acting, half-life 74 hours, accumulation of active metabolite may cause daytime sedation

Triazolam

Fast onset, short duration of action

Clonazepam (Klonopin)

Anticonvulsant effect, panic disorder

Compare the duration of action of Benzodiazepines

Metabolism of Benzodiazepines

Metabolized by cytochrome P450 (CYP3A4)

Examples of CYP3A4 Inhibitors and effect?

• Ketoconazole

• macrolide antibiotics

Enhance benzodiazepine’s effect

Examples of CYP3A4 Enhancers and effect?

• rifampicin, omeprazole, nifedipine

reduce benzodiazepine’s effect

What happens when Benzodiazepines are taken at high doses?

• Prevents activities that require fine motor coordination (driving an automobile)

• Cognitive impairment, drowsiness, confusion, amnesia, ataxia

• Respiratory or cardiovascular depression (patients with pulmonary or cardiovascular disease)

• Sedation (patients who have suffered brain damage from stroke or head trauma)

• May increase the risk of Alzheimer's disease

High doses can cause death when administered with other drugs such as ethanol, CNS depressants, opioid analgesics, or tricyclic antidepressants

What effects of Triazolam are seen with stopping?

Short acting drug- severe withdrawal problems

Rapid elimination, rapid development of tolerance, early morning insomnia, daytime anxiety

Flumazenil - How can an overdose be Reversed?

• Overdose can be reversed by antagonist by competing for occupancy of high affinity benzodiazepine sites on GABAA receptor

• Rapid action, short duration, half-life 1 hour

Brand Name + Duration of Action + Clinical Yse

T/F Benzodiazepines and barbiturates bind at the same site of GABAA receptor

False

Which of the following drugs act as an allosteric modulator in GABAergic neurotransmission?

A. Alprazolam

B. Diazepam

C. Midazolam

D. Flurazepam

E. All of the above

F. None of the above

E. All of the above

Which of the following drugs may increase the sedative effects of diazepam when taken concurrently?

A. Ibuprofen

B. Paracetamol

C. Alcohol

D. Amoxicillin

C. Alcohol

What is the potential interaction between diazepam and cimetidine (H2RA)?

A. Cimetidine increases diazepam clearance

B. Cimetidine decreases diazepam levels

C. Cimetidine inhibits diazepam metabolism, increasing its effects

D. No interactions

C. Cimetidine inhibits diazepam metabolism, increasing its effects

Which of the following drugs show higher GABAergic transmission?

A. Midazolam

B. Phenobarbital

C. Lorazepam

D. Tamazepam

B. Phenobartbital