Transcript amnesia(短暂性记忆缺失)

Chapter 17
Sedative-Hypnotic Drugs
Definition
Sedation:An
effective
sedative
agent
should reduce anxiety and exert an
effect with little or no effect on motor or
mental functions.
Definition
Hypnosis: A hypnotic drug should produce
drowsiness and encourage the onset and
maintenance of a state of sleep that as far as
possible resembles the natural sleep state.
Hypnotic effects can be achieved with
most sedative drugs simply by increasing
the dose.
Phases of Sleep
• REM(rapid eye movement sleep), 25% of
the total sleep, about lasts30 min dream
• NREM(non-rapid eye movement sleep),
about 75% of total sleep, about 90 min
In man, the physiological sleep consists
of 4-5 cycles of alternative REM and NREM
sleep
NREM
• Stage 1 dozing and drowsiness
• Stage 2 major fraction, 50% of sleep
• Stage 3 deep sleep transition
slow wove sleep
• Stage 4 “cerebral” sleep
somnambulism and nightmare
Specificity
1. Graded dose-dependent depression
of CNS function
Type A sedation  hypnosis  anesthesia 
coma paralysis  failure
Type B sedation  hypnosis  anesthesia?
Specificity
2.Tolerance
metabolic tolerance (enzyme inducer)
pharmacodynamic tolerance(downregulation)
3. Dependence
Psychological dependence
Physiological dependence
Classification
• Benzodiazepines(BZ)
• Barbiturates
• Other
Section 1
Benzodiazepines
 The most widely used Sedative-Hypnotics.
 They are more effective and safer
than
barbiturates.
 Approximately
20
currently available.
benzodiezepines
are
Chemical Structure of BZ
 1,4-benzodiazepines
Classifications of BZs
 Drug
Short-acting
Triazolam
Intermediate
lorazepam
Oxazepam
clonazepam
Long
Diazepam
Flurazepam
chlordiazepoxide
T1/2(h)
2~4
6~14
6~10
30~60
50~100
Pharmacological Effects and Uses
1.Anti-anxiety
anxiety: nervous, anxious, excite
◆at the lowest effective doses
◆ used for relieving of anxiety states, including
restlessness,worry,stress that accompanies some forms
of depression and schizophrenia.
◆ selectively inhibits neuronal circuits in the limbic
system of the brain.
amnesia(短暂性记忆缺失)
2. Sedation
used prior to general anesthesis to
relieve the stress of patients.
◆ amnesia(短暂性记忆缺失)
used
for
patients
undergoing
tracheoscopy and electric defibrillation
before the treatment or examination.
Pharmacological Effects and Uses
2.Hypnosis
reduces both sleep-induction time and the
number of awakenings, and increases
the duration of sleep.
prolong stage 2 sleep, shorten stage 4 sleep,
little influence on REM
little rebound
Uses: insomnia
3. Anticonvulsant effect and antiepileptic effect
Inhibit the development and spread of
epileptiform activity in the CNS and
are useful in the treatment of convulsion
and status epilepticus.
diazepam:continuous seizure
first choice
4. Central muscle relaxation
Relax the spasticity of skeletal mucle,
probably by increasing presynaptic
inhibition in the spinal cord.
◆ Useful in the treatment of skeletal
mucle spasms such as occur in mucle
stain,and in treating spasticity from
degenerative disorders,such as multiple
sclerosis and cerebral palsy.
5.Others
Respiration
cardiovascular function
Mechanisms of action
 Increase the efficiency of
γ-aminobutyric acid (GABAergic) inhibition
enhance R affinity for GABA
increase the frequency of Cl- channel opening
do not substitute for GABA
Pharmacokinetics
★ Absorption
the oral absorption well, Cmax about 1 hour:
rapid triazolam
★ Distribution
high plasma protein binding
lipid solubility plays a major role
placental barrier/breast milk
Pharmacokinetics
★ Dutation of actions
half-lives
important clinically
Pharmacokinetics
★ Fate
 A. Biotransformation
 metabolized by the liver to compounds that
are also active.
 B. Excretion
 excreted by kidey as glucuronides or
oxidized metabolites..
Advantages of BZs
1. Higher therapeutic index, no anesthesia
in large dose
2. ↓The duration of slow-wave sleep
little influences on REM
3. Do not induce hepatic enzyme
4. Light dependence
5. Low after effect
Adverse Reactions
CNS depression:
1.drowsiness, fatigue, dizziness;
2.ataxia;
3.coma ; inhibition of respiration
Inhibition of cardiovascular function
Tolerance and Dependence
Benzodiazepine Antagonist
Flumazenil（氟马西尼）
 The only antagonist available
 Use for diagnosis and therapy of BZ overdose
 First-pass elimination
 A short half life, so requiring repeated
administration
Section 2
Barbiturates
Pharmacokinetics
a. Absorbed easily following po, im
b. Duration of action of babiturates
depends on degree of lipid solubility.
Thiopental: redistribution
Pharmacokinetics
C.Biotransformation and excretion
 Metabolites lack activity
 Drugs with high lipophilicity: liver metabolism
 Drugs with low lipophilicity: kidney excretion
 Alkalinization of urine promotes excretion of
babiturates.
 Phenobarbital intoxication: alkalinization
of the urine
Mechanisms
• ↑GABAergic inhibition(↑duration of Clchannel opening)
• GABA mimetic(high dose)
• Inhibit exicitatory neurotransmitter
Pharmacological Effects and Uses
Sedation and hypnosis
Anticonvulsant effects
Anesthesia and administration preanesthesia
thiopental（硫喷妥钠）
Enhance the effects of other CNS
depressants
Adverse Drug Reactions
After effect
Tolerance and dependence
Inhibition of respiration function
Hepatic enzyme induction
Adverse Drug Reactions
Poisoning
An overdose can result in coma, severe
respiratory depression.
supporting respiration and
circulation,purging the stomach
Alkalization of the urine often aids in the
elimination of phenobarbital.
Section 3
Chloral hydrate
（水合氯醛）
Hypnosis
No influence on REM
Anticonvulsant effects
Irritation to mucous membrane
Inhibit cardiac contractility
Buspirone
Uses:relief of anxiety
Mechanism:
 a partial agonist at brain 5-HT1A-R
Advantages:
 no sedative-hypnotic effects
 no psychomotor impairment
 no tolerance and dependence
Melatonin
（褪黑素）
Clinical uses of
sedative-hypnotics.
For relief of anxiety
For insomnia
For sedation and amnesia before medical and surgical procedures
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous administration)
For control of ethanol or other sedative-hypnotic withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry
Respiratory center stimulants
Nikethamide（尼可刹米）
Coramin (可拉明)
Stimulates the respiratory center
Activates carotid chemoreceptors
Dimefline（二甲弗林，回苏灵）
Stimulates the respiratory center
Lobeline（洛贝林）
Activates carotid chemoreceptors
Uses:newborn suffocation
Bemegride(贝美格)
Megimide （美解眠）