SEDATIVE-HYPNOTIC

DRUGS

A. Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

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 SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra-short
action action
Intermediate Short Buspirone
action action Chloral hydrate
Long Long Zaleplon
action action Zolpidem
Ezsopiclone
Ramelteon

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SEDATIVE-HYPNOTIC DRUGS

SEDATION
• Reduction of anxiety
• Calming effect
ANXIOLYTIC
• Drug that reduces anxiety
• Sedative
HYPNOSIS
• Induction of sleep

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Drug A
- Older sedative-hypnotics
(barbiturates and alcohols)
- An increase in dose higher than
that needed for hypnosis may lead
to general anesthesia
- At still higher doses may depress
respiratory and vasomotor centers
in the medulla, leading to coma and
death
Drug B
- Require proportionately greater
dosage increments to achieve CNS
depression more profound than
hypnosis
- Benzodiazepines and for certain
newer hypnotics
- Flatter dose response curve
- Greater margin of safety
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SEDATIVE-HYPNOTIC DRUGS

• Lipid solubility (CNS penetration)

– Triazolam, thiopental, eszopiclone,
zaleplon, zolpidem
• Absorbed well from the GIT
• Cross the placenta and detectable in breast milk
• Metabolized (Phase 1) before elimination by
conjugation (Phase 2) by hepatic enzymes

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BENZODIAZEPINES

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SEDATIVE-HYPNOTIC DRUGS

BENZODIAZEPINES
• Converted initially to active metabolites with long
half-lives
• Diazepam and flurazepam
 After several days of therapy accumulation of
active metabolites can lead to excessive
sedation

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BIOTRANSFORMATION OF
BENZODIAZEPINES

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SEDATIVE-HYPNOTIC DRUGS

BENZODIAZEPINES
• Bz receptors
 Form part of GABAA receptor-chloride ion channel
macromolecular structure
 Binding facilitates the inhibitory actions of GABA
 Increased GABA mediated chloride ion
conductance

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 GABA A receptor-chloride ion
channel macromolecular complex

GABA
-Interacts at two sites between α and
β subunits
-Triggers chloride channel opening
with resulting membrane
hyperpolarization
-Benzodiazepines and the newer
hypnotic drugs, zolpidem
-Flumazenil, benzodiazepine
antagonist also binds at this site and
can reverse the hypnotic effects
-Barbiturates binding sites are
distinct from those binding sites

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 BENZODIAZEPINE BINDING
LIGANDS

Three types of ligand-benzodiazepine receptor

interactions
(1)Agonists
•Facilitate GABA actions at multiple BZ binding sites
•Benzodiazepines, zolpidem, zaleplon, and eszopiclone
bind at BZ sites that contain an α1 subunit

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 BENZODIAZEPINE BINDING
LIGANDS

Three types of ligand-benzodiazepine receptor

interactions
(2) Antagonists
• Synthetic benzodiazepine derivative flumazenil
• Blocks the actions of benzodiazepines, eszopiclone,
zaleplon, and zolpidem
• Does not antagonize the actions of barbiturates,
meprobamate, ethanol

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 BENZODIAZEPINE BINDING
LIGANDS

Three types of ligand-benzodiazepine receptor interactions

(3) Inverse agonists
• Negative allosteric modulators of GABA-receptor function
• Can produce anxiety and seizures
• Beta carbolines

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SEDATIVE-HYPNOTIC DRUGS

BARBITURATES
• Extensively metabolized
• Depress the neuronal activity
• Facilitates and prolongs the inhibitory effects of
GABA and glycine
• Block the excitatory transmitter glutamic acid and
at high concentration, sodium channels

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 SEDATIVE-HYPNOTIC DRUGS

BARBITURATES
• Bind to multiple isoforms of GABAA receptor but at
different sites from those with which benzodiazepines
interact
• Not antagonize by flumazenil
• Increase the duration of GABA-mediated chloride ion
channel opening

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 SEDATIVE-HYPNOTIC DRUGS
BARBITURATES
• Thiopental
 Drug with highest lipid solubility enter the CNS
rapidly
 Used as induction agents in anesthesia
 CNS effects are terminated by rapid redistribution of
the drug from the brain to other highly perfused
tissues (skeletal muscles)
 Metabolism occur via oxidation and glucoronidation
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SEDATIVE-HYPNOTIC DRUGS

BARBITURATES
• Phenobarbital
 Goes to the liver to be oxidized
 Excreted partly unchanged in the urine
 Alkalinizes the urine
 Half-life of 4-5 days
 Requires loading dose

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SEDATIVE-HYPNOTIC DRUGS

OTHER DRUGS
• Buspirone
 Partial agonist at serotonin receptor (5-HT
receptor)
 Impairment of mental activity
 Psychomotor impairment
 Selective with minimal depressant effects on the
CNS

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SEDATIVE-HYPNOTIC DRUGS

OTHER DRUGS
• Zolpidem and zaleplon
 Exert their CNS effects via interaction with
benzodiazepine receptors
 Bind more selectively
 Antagonize by flumazenil

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Other drugs

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 ORGAN SYSTEM EFFECTS
1. Sedation
2. Hypnosis
• Promote sleep onset
• Increase the duration of the sleep state
(1) Latency of sleep onset is decreased (time to fall
asleep);
(2) Duration of stage 2 NREM (nonrapid eye
movement) sleep is increased;
(3) Duration of REM sleep is decreased;
(4) Duration of stage 4 NREM slow-wave sleep is
decreased
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ORGAN SYSTEM EFFECTS

3. Anesthesia
• Thiopental (barbiturate)
• Midazolam (benzodiazepine)
• Loss of consciousness, amnesia and suppression of
reflexes

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 ORGAN SYSTEM EFFECTS

4. Anticonvulsant actions
• Phenobarbital, clonazepam
 Suppression of seizure activity
 Selective because they do not cause severe
sedation
• Diazepam, lorazepam and phenobarbital
 Given IV
 Used in status epilepticus
 Heavy sedation is needed
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ORGAN SYSTEM EFFECTS

5. Muscle relaxation
• Diazepam
 Spasticity states
 Cerebral palsy

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ORGAN SYSTEM EFFECTS

6. Medullary depression
• High doses can lead to
 Respiratory arrest
 Hypotension
 CVS collapse
 Death in suicidal overdose

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 SEDATIVE-HYPNOTIC DRUGS
Tolerance and dependence
• Tolerance
 Decrease in responsiveness
 Used chronically or in high dosage
 Metabolic tolerance
 Occurs with phenobarbital
 Induces its own metabolism
 Decreases CNS response to the drug itself

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SEDATIVE-HYPNOTIC DRUGS
Tolerance and dependence
•Dependence
Physiologic
 State of response to a drug
 Removal of the drug evokes unpleasant
symptoms
 Opposite of the drug’s effects
 Leads to abstinence syndrome (withdrawal
state) when the drug is discontinued

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SEDATIVE-HYPNOTIC DRUGS

Tolerance and dependence

• Dependence
Physiologic
 Occur more commonly with short- acting drugs
 Pentobarbital and secobarbital
 Dependence is unlikely to occur with buspirone

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SEDATIVE-HYPNOTIC DRUGS

Tolerance and dependence

• Dependence
Psychological
 State of response to a drug
 Drug taker feels compelled to use the drug
 Suffers anxiety when separated from the drug

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SEDATIVE-HYPNOTIC DRUGS

CLINICAL USES
1. Anxiety states
• Benzodiazepines with intermediate or long
durations of action are favored
• Buspirone
 Used for generalized anxiety disorders
• Alprazolam
 Phobic and panic attacks

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SEDATIVE-HYPNOTIC DRUGS

CLINICAL USES
2. Sleep disorders
• Used to treat primary insomnia and other sleep
disorders
3. Sedation
• Prior to medical/surgical procedures
• Conscious sedation-anterograde amnesia

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SEDATIVE-HYPNOTIC DRUGS

CLINICAL USES
4. Treatment of seizures and convulsions
5. Detoxification of alcoholics
• Chlordiazepoxide
• Diazepam
6. Muscle relaxation
7. Manias, major depression, phobias

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CLINICAL USES

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SEDATIVE-HYPNOTIC DRUGS

TOXICITY
1. Psychomotor dysfunction
• Cognitive impairment
• Decreased psychomotor skills
• Unwanted daytime sedation

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SEDATIVE-HYPNOTIC DRUGS

TOXICITY
2. Additive CNS depression
• When used with
 Alcoholic beverages
 Antihistamines
 Antipsychotic drugs
 Opioid analgesics
 Tricyclic antidepressants

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SEDATIVE-HYPNOTIC DRUGS

TOXICITY
3. Overdosage causes severe respiratory and
cardiovascular depression
4. Terratogenic

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SEDATIVE-HYPNOTIC DRUGS

TOXICITY
3. Induce formation of liver microsomal enzymes
• Metabolize drugs multiple drug interactions
• Chloral hydrate displaces coumarin from protein
binding sites and increases anticoagulant effects

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