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Questions and Answers
What mechanism allows benzodiazepines to enhance GABA neurotransmission?
What mechanism allows benzodiazepines to enhance GABA neurotransmission?
Which of the following is NOT a classification of benzodiazepines based on their duration of action?
Which of the following is NOT a classification of benzodiazepines based on their duration of action?
What consequence may result from the abrupt discontinuation of benzodiazepines after long-term use?
What consequence may result from the abrupt discontinuation of benzodiazepines after long-term use?
Which of the following benzodiazepines is classified as long-acting?
Which of the following benzodiazepines is classified as long-acting?
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How do benzodiazepines contribute to hyperpolarization of postsynaptic cells?
How do benzodiazepines contribute to hyperpolarization of postsynaptic cells?
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What is a primary characteristic of an ideal anxiolytic drug?
What is a primary characteristic of an ideal anxiolytic drug?
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Which of the following is NOT a cause of insomnia?
Which of the following is NOT a cause of insomnia?
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Which class of drugs includes Zolpidem and Zaleplon?
Which class of drugs includes Zolpidem and Zaleplon?
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What happens to neurotransmitters in the brain during insomnia?
What happens to neurotransmitters in the brain during insomnia?
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Which of the following best describes the GABAA receptor's role in sedation?
Which of the following best describes the GABAA receptor's role in sedation?
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Study Notes
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
- GABAA receptor activation increases chloride ion influx, causing membrane hyperpolarization
- GABAB receptor activation increases potassium ion efflux, causing membrane hyperpolarization
- Sedative-hypnotics enhance GABA's effects, which is a major inhibitory neurotransmitter in the CNS
GABAA Receptor-Chloride Channel Complex
- GABAA 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 (t1/2 < 8 hours): triazolam, midazolam
- Intermediate-acting (t1/2 10-20 hours): alprazolam, lorazepam
- Long-acting (t1/2 > 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 GABAA receptors)
- Skeletal muscle relaxation (via GABAA 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 GABAA 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 GABAA 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-HT1A 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
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Description
Test your knowledge on sedative-hypnotic and anxiolytic drugs, their functions, and implications in treating insomnia. This quiz explores neurochemical changes associated with insomnia and ideal characteristics of these medications. Evaluate your understanding of how these drugs affect the CNS and their role in sleep disorders.
