chapter 17 sedative-hypnotic drugs. definition sedation:an effective sedative agent should reduce...
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Chapter 17
Sedative-Hypnotic Drugs
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Definition
Sedation:An effective sedative agent
should reduce anxiety and exert an
effect with little or no effect on motor or
mental functions.
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DefinitionHypnosis: 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.
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Phases of SleepPhases 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
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NREMNREM
• 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
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Specificity
1. Graded dose-dependent depression
of CNS function
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Type A sedation hypnosis anesthesia coma paralysis failure
Type B sedation hypnosis anesthesia?
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Specificity
2.Tolerance
metabolic tolerance (enzyme inducer)
pharmacodynamic tolerance(down-
regulation)
3. Dependence
Psychological dependence
Physiological dependence
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Classification
• Benzodiazepines(BZ)
• Barbiturates
• Other
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Section 1 Benzodiazepines
The most widely used Sedative-Hypnotics.
They are more effective and safer than
barbiturates.
Approximately 20 benzodiezepines are
currently available.
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Chemical Structure of BZ
1,4-benzodiazepines
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Classifications of BZs Drug T1/2(h)
Short-acting
Triazolam 2~4
Intermediate
lorazepam 6~14
Oxazepam 6~10
clonazepam
Long
Diazepam 30~60
Flurazepam 50~100
chlordiazepoxide
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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 )
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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.
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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
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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
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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.
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5.Others
Respiration
cardiovascular function
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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
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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
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Pharmacokinetics
★ Dutation of actions
half-lives important clinically
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Pharmacokinetics★ Fate
A. Biotransformation
metabolized by the liver to compounds that
are also active.
B. Excretion
excreted by kidey as glucuronides or
oxidized metabolites..
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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
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Adverse Reactions
CNS depression:
1.drowsiness, fatigue, dizziness;
2.ataxia;
3.coma ; inhibition of respiration
Inhibition of cardiovascular function
Tolerance and Dependence
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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
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Section 2 Barbiturates
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Pharmacokinetics
a. Absorbed easily following po, im
b. Duration of action of babiturates
depends on degree of lipid solubility.
Thiopental: redistribution
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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
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Mechanisms
• ↑GABAergic inhibition(↑duration of Cl-
channel opening)
• GABA mimetic(high dose)
• Inhibit exicitatory neurotransmitter
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Pharmacological Effects and Uses
Sedation and hypnosis
Anticonvulsant effects
Anesthesia and administration pre-
anesthesia thiopental(硫喷妥钠)
Enhance the effects of other CNS
depressants
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Adverse Drug Reactions
After effect
Tolerance and dependence
Inhibition of respiration function
Hepatic enzyme induction
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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.
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Section 3 Chloral hydrate (水合氯醛)Hypnosis
No influence on REM
Anticonvulsant effects
Irritation to mucous membrane
Inhibit cardiac contractility
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Buspirone
Uses:relief of anxietyMechanism: a partial agonist at brain 5-HT1A-R
Advantages: no sedative-hypnotic effects no psychomotor impairment no tolerance and dependence
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Melatonin
(褪黑素)
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Clinical uses of sedative-hypnotics.
For relief of anxietyFor insomniaFor sedation and amnesia before medical and surgical proceduresFor treatment of epilepsy and seizure statesAs a component of balanced anesthesia (intravenous administration)For control of ethanol or other sedative-hypnotic withdrawal statesFor muscle relaxation in specific neuromuscular disordersAs diagnostic aids or for treatment in psychiatry
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Respiratory center stimulants
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Nikethamide (尼可刹米) Coramin (可拉明 )
Stimulates the respiratory centerActivates carotid chemoreceptors
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Dimefline (二甲弗林,回苏灵)Stimulates the respiratory center
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Lobeline (洛贝林)Activates carotid chemoreceptorsUses:newborn suffocation
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Bemegride(贝美格 ) Megimide (美解眠)
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