Sedative-Hypnotic and Anxiolytic Drugs Quiz

Sedative-Hypnotic and Anxiolytic Drugs

• Sedatives and anxiolytics are central nervous system (CNS) depressants, calming the patient without drowsiness
• Hypnotics are a type of CNS depressant inducing sleep for insomnia
• Ideal anxiolytics calm patients without daytime sedation or dependence
• Ideal hypnotics induce quick sleep, maintaining sufficient quality and duration, leaving the patient refreshed without lingering effects
• Insomnia encompasses various sleep disturbances, including difficulty falling asleep, frequent awakenings, and feeling unrefreshed after sleep
• Causes of insomnia include: psychic diseases, CNS stimulants (like caffeine), chronic alcoholism, drug addiction, and endocrine abnormalities (like menopause)

Neurochemical Changes During Insomnia

• Increased dopamine and norepinephrine in the reticular activating system (RAS) leads to sleep initiation failure
• Reduced serotonin in the brainstem leads to disrupted sleep maintenance

GABAergic Action

• GABA_A receptor activation increases chloride ion influx, causing membrane hyperpolarization
• GABA_B receptor activation increases potassium ion efflux, causing membrane hyperpolarization
• Sedative-hypnotics enhance GABA's effects, which is a major inhibitory neurotransmitter in the CNS

GABA_A Receptor-Chloride Channel Complex

• GABA_A receptors have a pentameric structure with binding sites for benzodiazepines (BZ) and other drugs (like barbiturates and ethanol)

Pharmacological Treatment of Insomnia and Anxiety

• Benzodiazepines
• Barbiturates
• Other Sedative-Hypnotic Drugs
  • Non-Benzodiazepines (Zolpidem and Zaleplon)
  • Melatonin
  • Antihistamines (first generation)
  • Older hypnotics (Chloral Hydrate)
• Non-sedating anxiolytic Drugs
  • Buspirone
  • Propranolol

1- Benzodiazepines

• Commonly used anxiolytics and sedative-hypnotics with a wide safety margin
• Chlordiazepoxide was an early example
• They are lipophilic, easily absorbed orally, and rapidly penetrate the CNS
• Divided into short-, intermediate-, and long-acting groups based on duration of action
• Longer-acting agents form active metabolites, extending their duration of action (e.g., diazepam)
• Short-acting agents are metabolized by conjugation, followed by renal clearance
• Dependence, both psychological and physical, can develop with high doses and prolonged use
• Abrupt cessation can lead to withdrawal symptoms

Classification of Benzodiazepines

• Short-acting (t_1/2 < 8 hours): triazolam, midazolam
• Intermediate-acting (t_1/2 10-20 hours): alprazolam, lorazepam
• Long-acting (t_1/2 > 24 hours): diazepam, clonazepam

Mechanism of Action of Benzodiazepines

• BZ receptors are closely associated with GABA receptors, the major inhibitory neurotransmitter
• BZ enhance GABA neurotransmission by indirectly regulating chloride ion channels entry into postsynaptic cells
• BZ increase the frequency of GABA-induced channel openings
• Besides GABA, BZ inhibit neuronal adenosine reuptake, increasing adenosine's inhibitory effects on acetylcholine release; this effect relates to excitement/awakening

Pharmacological Effects of Benzodiazepines

• Anxiety reduction (low doses)
• Sedative/Hypnotic effects (higher doses)
• Amnesia (high doses)
• Anticonvulsant effects (partially mediated by GABA_A receptors)
• Skeletal muscle relaxation (via GABA_A receptors in the spinal cord)
• Therapeutic uses include anxiety disorders, insomnia, muscle spasms, surgical procedures, preanesthetic medications, and seizure disorders

Specific Benzodiazepines

• Alprazolam (Xanax)
• Diazepam (Valium)
• Lorazepam (Ativan)
• Triazolam
• Chlordiazepoxide (Librium)
• Flurazepam
• Oxazepam (Serax)
• Temazepam
• Clonazepam (Rivotril)
• Flumazenil (Anexate)

2- Barbiturates

• Synthesized from urea and malonic acid
• Less selective; higher doses produce more generalized CNS and medullary depression
• Replaced by benzodiazepines due to higher selectivity, less side effects, and antidote availability
• Classified into long-acting, intermediate-acting, short-acting, and ultra-short-acting groups based on duration of action
• Lipid-soluble drugs are rapidly absorbed and distributed, impacting duration of action (e.g., pentobarbitol; thiopentone)
• They act on GABA_A receptors, increasing the affinity of GABA and duration of chloride channel opening
• They lack a ceiling effect; higher doses progressively depress CNS (causing respiratory depression, coma, and death)
• May cause hangover, daytime sedation, tolerance, physical dependence, and withdrawal syndromes

3- Other Sedative-Hypnotic Drugs (Z-drugs)

• Newer class of hypnotics
• Structurally unrelated to benzodiazepines but with similar pharmacological properties
• They bind to GABA_A receptors, facilitating GABA-mediated inhibition
• More selective as hypnotics with no anticonvulsant/muscle relaxant effects
• Less respiratory depression effects than benzodiazepines
• Reduced tolerance and dependence, fewer daytime effects
• Examples include zolpidem and zaleplon

4- Melatonin

• Hormone interacting with MT1 and MT2 receptors in the CNS
• Acts as a circadian rhythm regulator and involved in seasonal/reproductive cycles
• Rammelteon (Rozerem) is a melatonin receptor agonist
• Effective for jet lag and insomnia, especially shift-worker insomnia and elderly patients

3- Antihistamines

• Some antihistamines cross the blood-brain barrier, inducing sedation
• Used in treating mild insomnia and anxiety disorders (examples: doxylamine and diphenhydramine)

4- Other Older Hypnotic (Chloral Hydrate)

• A prodrug metabolized into trichloroethanol
• Potentiated by alcohol
• Hypnotic effects lasting about 6 hours
• Used primarily for children and elderly patients before minor procedures

IV- Non-sedating Anxiolytic Drugs (Buspirone)

• Partial serotonin 5-HT_1A receptor agonist primarily used for chronic anxiety
• Relatively slow onset of action (3-4 weeks to reach maximal effect), avoiding rapid tolerance and dependence
• Mild side effects like headache/dizziness/tachycardia

Propranolol (β-blocker)

• β-adrenergic receptor antagonist
• Used to prevent physiological symptoms of stage fright, performance anxiety (especially when taken before the event)
• Reduces tachycardia and other anxiety-related symptoms by blocking norepinephrine effects

Adverse Effects

• Sedation, drowsiness, dizziness, motor incoordination, impaired concentration and judgment
• Possible respiratory depression, coma, or death, especially with other CNS depressants
• Tolerance & physical dependence with prolonged use; withdrawal syndrome with abrupt cessation
• Contraindicated during pregnancy

Interactions

• Barbiturates induce cytochrome P450 enzymes, leading to accelerated metabolism of themselves and other drugs