22 sedative hypnotic drugs

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

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

• Lipid soluble
• Absorbed well from the GIT
• Good distribution to the brain
• Metabolized before elimination from
the body by hepatic enzymes

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

BENZODIAZEPINES
• Lorazepam and oxazepam
 Undergo extrahepatic conjugation
and do not form active metabolites

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

BENZODIAZEPINES
• Flumazenil
 Reverses the CNS effects of
benzodiazepines
 Antagonist at the Bz receptor

BENZODIAZEPINES
• Beta-carbolines
 High affinity for Bz receptors
 Can elicit anxiogenic and convulsant
effects
 Inverse agonists

BENZODIAZEPINES
• Diazepam
desmathyldiazepam active
oxazepam metabolites
conjugation

BENZODIAZEPINES
• Chlorazepam
• Estazolam immediately converted to
• Oxazepam inactive metabolites

BARBITURATES
• Extensively metabolized
• Depress the neuronal activity
• Facilitates and prolongs the inhibitory
effects of GABA and glycine

BARBITURATES
• Bind to multiple isoforms of GABAA
receptor but at different sites from
those with which benzodiazepines
interact

BARBITURATES
• Not antagonize by flumazenil
• Increase the duration of GABA-
mediated chloride ion channel
opening

BARBITURATES
• Block the excitatory transmitter glutamic
acid and at high concentration, sodium
channels

BARBITURATES
• Thiopental
 Drug with highest lipid solubility enter
the CNS rapidly
 Used as induction agents in anesthesia

BARBITURATES
• Thiopental
 CNS effects are terminated by rapid
redistribution of the drug from the
brain to other highly perfused tissues
(skeletal muscles)

BARBITURATES
• Thiopental
 Metabolism occur via oxidation
and glucoronidation
 Converted to active metabolite

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

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

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

DRUG A - BARBITURATES dose = CNS
depression
DRUG B - BENZODIAZEPINES
- flatter dose response curve
- greater margin of safety
DRUG A
DRUG B

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%

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

4. Anticonvulsant actions
• Phenobarbital, clonazepam
 Suppression of seizure activity
 Selective because they do not
cause severe sedation

4. Anticonvulsant actions
• Diazepam, lorazepam and phenobarbital
 Given IV
 Used in status epilepticus
 Heavy sedation is needed

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

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

7. Tolerance and dependence
• Tolerance
 Decrease in responsiveness
 Used chronically or in high dosage

• Tolerance
 Metabolic tolerance
 Occurs with phenobarbital
 Induces its own metabolism
 Decreases CNS response to the
drug itself

• Dependence
Physiologic
 State of response to a drug
 Removal of the drug evokes
unpleasant symptoms
 Opposite of the drug’s effects

• Dependence
Physiologic
 Leads to abstinence syndrome
(withdrawal state) when the drug
is discontinued

ORGAN –SYSTEM EFFECTS
• Dependence
Physiologic
 Withdrawal signs
 Anxiety
 Tremors
 Hyperreflexia
 Seizures

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

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

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

CLINICAL USES
2. Sleep disorders
• Used to treat primary insomnia and
other sleep disorders

CLINICAL USES
3. Sedation
• Prior to medical/surgical procedures
• Conscious sedation-anterograde
amnesia
4. Treatment of seizures and convulsions

CLINICAL USES
4. Detoxification of alcoholics
• Chlordiazepoxide
• Diazepam
6. Muscle relaxation
7. Manias, major depression, phobias

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

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

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

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

22 sedative hypnotic drugs

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