SEDATIVE-HYPNOTIC

DRUGS

Anita Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
 SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra
action action
Intermediate Short Buspirone
action action Chloral hydrate
Long Long Zaleplon
action action Zolpidem
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SEDATION
Reduction of anxiety
Calming effect
ANXIOLYTIC
Drug that reduces anxiety
Sedative
HYPNOSIS
Induction of sleep
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Lipid soluble
Absorbed well from the GIT
Good distribution to the brain
Metabolized before elimination from
the body by hepatic enzymes
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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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BENZODIAZEPINES
Lorazepam and oxazepam
Undergo extrahepatic conjugation
and do not form active metabolites
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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
SEDATIVE-HYPNOTIC DRUGS

BENZODIAZEPINES
Flumazenil
Reverses the CNS effects of
benzodiazepines
Antagonist at the Bz receptor
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BENZODIAZEPINES
Beta-carbolines
High affinity for Bz receptors
Can elicit anxiogenic and convulsant
effects
Inverse agonists
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BENZODIAZEPINES
Diazepam
desmathyldiazepam active
oxazepam metabolites
conjugation
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BENZODIAZEPINES
Chlorazepam
Estazolam immediately converted to
Oxazepam inactive metabolites
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BARBITURATES
Extensively metabolized
Depress the neuronal activity
Facilitates and prolongs the inhibitory
effects of GABA and glycine
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BARBITURATES
Bind to multiple isoforms of GABAA
receptor but at different sites from
those with which benzodiazepines
interact
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BARBITURATES
Not antagonize by flumazenil
Increase the duration of GABA-
mediated chloride ion channel
opening
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BARBITURATES
Block the excitatory transmitter glutamic
acid and at high concentration, sodium
channels
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BARBITURATES
Thiopental
Drug with highest lipid solubility enter
the CNS rapidly
Used as induction agents in anesthesia
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BARBITURATES
Thiopental
CNS effects are terminated by rapid
redistribution of the drug from the
brain to other highly perfused tissues
(skeletal muscles)
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BARBITURATES
Thiopental
Metabolism occur via oxidation
and glucoronidation
Converted to active metabolite
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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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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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OTHER DRUGS
Zolpidem and zaleplon
Exert their CNS effects via interaction
with benzodiazepine receptors
Bind more selectively
Antagonize by flumazenil
SEDATIVE-HYPNOTIC DRUGS
DRUG A

DRUG B

DRUG A - BARBITURATES dose = CNS depression

DRUG B - BENZODIAZEPINES
- flatter dose response curve
- greater margin of safety
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ORGAN SYSTEM EFFECTS
1. Sedation
2. Hypnosis
Promote sleep onset
Increase the duration of the sleep state
STAGES OF SLEEP
a. REM (Rapid eye movement)
Dream
Decreases at high doses
b. Non-REM
70-75%
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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
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ORGAN SYSTEM EFFECTS

4. Anticonvulsant actions
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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ORGAN SYSTEM EFFECTS

7. Tolerance and dependence
Tolerance
Decrease in responsiveness
Used chronically or in high dosage
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ORGAN SYSTEM EFFECTS

7. Tolerance and dependence
Tolerance
Metabolic tolerance
Occurs with phenobarbital
Induces its own metabolism
Decreases CNS response to the
drug itself
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ORGAN SYSTEM EFFECTS

7. Tolerance and dependence
Dependence
Physiologic
State of response to a drug
Removal of the drug evokes
unpleasant symptoms
Opposite of the drugs effects
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ORGAN SYSTEM EFFECTS

7. Tolerance and dependence
Dependence
Physiologic
Leads to abstinence syndrome
(withdrawal state) when the drug
is discontinued
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ORGAN SYSTEM EFFECTS

7. Tolerance and dependence
Dependence
Physiologic
Withdrawal signs
Anxiety
Tremors
Hyperreflexia
Seizures
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ORGAN SYSTEM EFFECTS
7. 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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ORGAN SYSTEM EFFECTS

7. 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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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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CLINICAL USES
2. Sleep disorders
Used to treat primary insomnia and
other sleep disorders
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CLINICAL USES
3. Sedation
Prior to medical/surgical procedures
Conscious sedation-anterograde
amnesia
4. Treatment of seizures and convulsions
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CLINICAL USES
4. Detoxification of alcoholics
Chlordiazepoxide
Diazepam
6. Muscle relaxation
7. Manias, major depression, phobias
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TOXICITY
1. Psychomotor dysfunction
Cognitive impairment
Decreased psychomotor skills
Unwanted daytime sedation
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TOXICITY
2. Additive CNS depression
When used with
Alcoholic beverages
Antihistamines
Antipsychotic drugs
Opioid analgesics
Tricyclic antidepressants
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TOXICITY
3. Overdosage causes severe respiratory
and cardiovascular depression
4. Terratogenic
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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