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.

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.

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

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

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(down-

regulation)

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 benzodiezepines are

currently available.

Chemical Structure of BZ

1,4-benzodiazepines

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

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 Cl-

channel opening)

• GABA mimetic(high dose)

• Inhibit exicitatory neurotransmitter

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

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 anxietyMechanism: 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 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

Respiratory center stimulants

Nikethamide （尼可刹米） Coramin (可拉明 )

Stimulates the respiratory centerActivates carotid chemoreceptors

Dimefline （二甲弗林，回苏灵）Stimulates the respiratory center

Lobeline （洛贝林）Activates carotid chemoreceptorsUses:newborn suffocation

Bemegride(贝美格 ) Megimide （美解眠）