3rd Level
Pharmacology
Sedative, Hypnotics and Anxiolytic drugs.
Dr. Safa 2nd Lecture
The sedative-hypnotics produce dose-dependent CNS depressant effects.
They include: Benzodiazepines, Barbiturates and other agents like Carbamates, Alcohols and Cyclic Ethers.
Newer drugs are the anxiolytic Buspirone and hypnotics like ( Zolpidem,Eszopiclone, Zaleplon ) and Ramelteon which
is used in sleep disorders.
Classification of Sedative-Hypnotics:
• Benzodiazepines:
Short action, Intermediate action, long action.
• Barbiturates:
Ultra-short action, short action, long action.
• Miscellaneous Agents:
Buspirone, Chloral Hydrate, Eszopiclone, Ramelteon, Zaleplon, Zolpidem .
Pharmacokinetics
• Absorption And Distribution:
Most sedative-hypnotic drugs are lipid soluble and are absorbed from the GIT, with good distribution to the brain.
Thiopental has high lipid solubility, enters the CNS rapidly and can be used as an induction agent in anesthesia.
• Metabolism And Excretion:
Sedative-Hypnotics are metabolized before elimination from the body by hepatic enzymes.
Mechanism Of Action
A. Benzodiazepines:
They act on BZ receptors which present in the thalamus, limbic structures and the cerebral cortex which facilitate the
inhibitory actions of GABA.
Flumazenil reverses the CNS effects of benzodiazepines and is called antagonist at BZ receptors.
B. Barbiturates:
They depress neuronal activity in the mid brain reticular formation, facilitating and prolonging the inhibitory effects of
GABA. Their actions are not antagonized by flumazenil..
C. Other Drugs:
The hypnotics; zolpidem, zaleplon and eszopiclone are not benzodiazepines, but have CNS depressant effects.
Their CNS depressant effects can be antagonized by flumazenil.
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Pharmacodynamics
The CNS effects of sedative-hypnotics depend on dose.
1) Sedation
Sedative actions, relief of anxiety and impairment of psychomotor functions.
2) Hypnosis
Promote sleep onset and increase the duration of sleep state.
3) Anesthesia
Loss of consciousness amnesia and suppression of reflexes.
Anesthesia can be produced by most Barbiturates (thiopental) and certain Benzodiazepines (midazolam).
4) Anti-Convulsant Actions
Suppression of seizure activity, by barbiturates and benzodiazepines.
5) Muscle Relaxation
Relaxation of skeletal muscles for specific spasticity states including cerebral palsy.
Meprobamate has selectivity as a muscle relaxant.
6) Medullary Depression
High doses of Alcohol and Barbiturates cause depression of medullary neurones leading to respiratory arrest,
hypotension and cardiovascular collapse.
7) Tolerance And Dependence
Tolerance (a decrease in responsiveness) occurs when sedative-hypnotics are used chronically or in high dose.
Psychological Dependence occurs with most sedative-hypnotics and is manifested by the compulsive use of the drugs
to reduce anxiety.
Physiological Dependence leads to an abstinence syndrome (withdrawal state) when the drug is discontinued.
Withdrawal Symptoms are anxiety, tremors, hyper-reflexia and seizures.
Clinical Uses
A. Anxiety States:
Benzodiazepines are favored in the treatment of acute anxiety states and for rapid control of panic and phobic states
(clonazepam, alprazolam).
B. Sleep Disorders:
Benzodiazepines (estazolam, flur-azepam and triazolam) are used in insomnia and sleep disorders.
C. Other Uses:
• Thiopental is used for induction of anesthesia and certain Benzodiazepines (diazepam, midazolam)
• Treatment of muscle spasticity (diazepam).
• Long acting benzodiazepines (chlordiazepoxide, diazepam) for the management of withdrawal states
in persons physiologically dependent on ethanol and other sedative-hypnotics.
Toxicity
A. Psychomotor Dysfunction:
Cognitive impairment, decreased psychomotor skills and unwanted day time sedation(diazepam, flurazepam ).
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B. Additive CNS Depression:
This occurs when sedative-hypnotics are used with drugs in the same class and with alcoholic beverages, anti-
histamines, anti-psychotics, opioids and TCA.
C. Over Dosage:
This causes severe respiratory and cardiovascular depression. More likely occurs with alcohols, barbiturates and
carbamates than with benzodiazepines or newer hypnotics such as zolpidem.
Treatment requires maintain a patent airway and ventilatory support.
Flumazenil reverses CNS depressant effects of benzodiazepines, eszopiclone, zolpidem and zaleplon.
D. Other Adverse Effects:
Barbiturates and Carbamates (but not Benzodiazepines and newer agents) induce liver microsomal enzymes that
metabolize drugs, this will lead to multiple drug interactions.
Atypical Sedative-Hypnotics
A. Buspirone:
It is a selective anxiolytic with minimal CNS depressant effects, it does not affect driving skills and has no
anti-convulsant or muscle relaxant properties.
Side effects: tachycardia, paresthesia, pupillary constriction, GIT disorders.
It is safe in pregnancy.
B. Ramelteon:
New hypnotic drug, used in sleep disorders, with minimal rebound insomnia and withdrawal symptoms.
Adverse effects: dizziness, fatigue, endocrine changes including decreased testosterone and increased prolactin.
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