Sedative-Hypnotic Drugs镇静催眠药

Department of Pharmacology, CSU

Zhang xiaojie

Sedative & Hypnotics

Sedative : Drugs that decrease activity, clam the p

atient and reduce anxiety without inducing sleep.

Hypnotic : Drugs that produce drowsiness, initiat

e and maintain the normal sleep.

Depress the function of the central nervous system (CNS) in a dose-dependent fashion: with dose increasing, progressively producing calming, sleep, anticonvulsant, unconsciousness, coma, surgical anesthesia, and death (barbiturates)

Physiology of sleepSleep can be divided into two phases based on EE

G and eye movement non-rapid eye movement sleep (NREMS ）

slow wave sleep ， SWSnightterror, sleepwalking

BDZ : stage 2, SWS

rapid eye movement sleep (REMS) 1.eyeballs keep moving fast, 50-60 times/min

2.EEG similar to that of awaking(fast brain wave)

3.Most dreaming occurs in this phase

NREMS 90min REMS 20 ～ 30minCycle 3 ～ 4 times a night

Barbiturates: REMS, if withdraw suddenly, reboundof REMS nightmare, insomnia dependence

Physiological significance of NREMSIn this phase the growth hormone secretion is increased significantly, so it is essential for body growing and can relief the body from fatigue

Physiological significance of REMSBrain activity is increasedPromote the development of brain functionConsolidation of memory and ensure the best brain functions

Chemical Classification of Drugs

1. Benzodiazepines ( BDZ ) don't lead general anesthesia, rarely result death

2. Barbiturates the older sedative-hypnotics, in large dose can lead to coma and death

3. Miscellaneous ( non BDZ non barbiturate drugs) Zolpidem Zaleplon

Ⅰ.Benzodiazepines

Derivatives of 1,4- benzodiazepines. About 20 agents are available for clinical use. They are basically similar in their pharmacological actions

Long-acting agents ： T1/2>24hr Diazepam Nitrazepam Flurazepam

Middle-acting agents ： T1/2 6-24hr Estazolam Lorazepam Oxazepam

Short-acting agents ： T1/2<6hr Triazolam

ClassificationsAccording to Duration of Action :

Pharmacological actions

1. Anti-anxiety effect

2. Sedation and hypnosis

4. Central muscle relaxant effect

3. Anticonvalsant and antiseizure effects

1. Anti-anxiety effect high selectivity , small dose less than sedative

dose can significantly relieve symptoms such as nervous, depressive , frightened and insomnia

Mechanismselectively activate the BDZ receptor of limbic system and depress the firing of action potential of neurons in hippocampus and nucleus amygdalae

Diazepam is the first choice for anxiety

2. Sedation and hypnosis decrease sleep latency diminsh the number of awakings prolong the duration of sleeping

NREMS stage2

NREMS stage 3 and 4(SWS)

Advantages as hypnotics:(1) great margin of safety; without effect on r

espiration in normal subjects(2) little effect on REM sleep(3)Without inducing hepatic microsomal dru

g-metabolizing enzymes(4) slight physiologic and psychologic depende

nce and withdrawal syndrome(5) less adverse effects such as residual drowsi

ness and incoordination movement

3. Anticonvulsants and antiseizure effects

highly effective against chemically induced convulsions caused by leptazol

enhance GABA-mediated synaptic systems and inhibit excitatory transmission

Anticonvulsants: tetanus, eclampsia, febrile convulsion

Antiseizure: Diazepam, midazolam, and lorazepam for

status epilepticus

Clonazepam for myoclonic disorders

4. Central muscle relaxant effect

Clinical applications:muscle cramps , cerebral vascular accident , spinal cord injuries and lumbar muscle strain

Effect:

inhibitory effects on polysynaptic reflexes and internuncial transmission in CNS, leading to muscle relaxation

Mechanism:Mechanism:Promote GABA receptor functionPromote GABA receptor function

γ- butylamino acid, GABA GABA A receptor consists of

twoα1,two β2 and one γ2 subu

nits. GABA A receptor, which fu

nctions as a chloride ion chan

nel, is activated by the inhibit

ory neurotransmitter GABA .

GABA appears to interact

with αorβsubunits triggeri

ng chloride channel openin

g with resultant membrane

hyperpolarization.

The binding site for BDZs

(BDZ-receptor) is located

between αandγsubunit.

BDZs appear to increase the efficiency of GABAergic synaptic inhibition.

The enhancement in chloride ion conductance induced by the interaction of BDZs with GABA takes the form of an increase in the frequency of channel-opening events.

BZs can also increase the frequency of chloride channel opening, facilitate Cl- flowing into cell resulting membrane hyperpolarization

BZs promote GABA binding with GABA receptors chloride channels opening

chloride influx membrane hyperpolarization inhibition of propagation of action potential

inhibitory effect on different sites of the brain especially motor cortex, and limbic system.

Absorption, Fate, and Excretion

Highly lipophilic : absorbed rapidly and completely when administered orally and easily crosses the blood-brain and blood-placental barriers

More than 90% binding to plasma protein

Metabolized in the liver microsomal system , then glucuronide conjugated and excreted in the urine

Metabolites are active, with longer elimination Metabolites are active, with longer elimination half life than their parent drugshalf life than their parent drugs

Adverse effects ： Therapeutic dose ： drowsiness, dizziness , fatigue , memory decline

Large dose ： ataxia (motor incoordination)

Overdose : coma

Long term use ：tolerance ， addiction

Drug Interactions

strengthen the inhibition of other central inhibitors (such as ethanol ,barbiturates) ,may cause severe depression, even death

Cause ：diazepam ＋ lorazepam ＋ midazolam ＋ propofol

Death of Michael Jackson

Contraindications

1.Old or individuals who suffer liver or kidney diseases

2.Glaucoma or myasthenia

3.Pregnant or Lactating women

Ⅱ.BARBITURATES

Classification

(1)Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental: anesthesia

(2)Short-acting barbiturates: have a duration of action of about 2h. The principal use of Secobarbital : sleep-inducing hypnotics.

Ⅱ.BARBITURATESClassification

(3)Intermediate-acting barbiturates: have and effect lasting 3-5h. The principal use of Amobarbital is as hypnotics.

(4)Long-acting barbiturates: have a duration of action greater than 6h. Such as Barbital and Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents at low doses.

Pharmacological actions1. Sedation & hypnosisLow dose: sedation

Middle dose: hypnosis , shorten time to fall asleep , extend sleeping time

Long term use —— rebound phenomenon , dependence , addiction.

BARBITURATES

Barbiturates depress the CNS at all level in a dose-dependent fashion. Now it mainly used in anaesthesia and treatment of epilepsy; use as sedative-hypnotic agents is no longer recommended.

Disadvantage as hypnotics(1) have a narrow therapeutic-to-toxic dosage range.

(2) suppress REM sleep

(3) Tolerance develops relatively quickly

(4) have a high potential for physical dependence and ab

use.

(5) potent inducers of hepatic drug-metabolising enzyme

2. Anticonvulsant and antiepilepsia

strong action for tetanus , febrile convulsion, eclampsia , meningitis , encephalitis and convulsion caused by central stimulants .

3. Preanesthetic medication and anesthesia

Thiopental : intravenous anesthesia ， induction of anesthesia .

Phenolbarbitol ： anesthetic medication

Mechanism of action The centrol role is related to the activation of GA

BA receptors Barbiturates increase the permeability of Cl -chan

nel , leading to the cell membrane hyperpolarization . Different from BZs which increase the frequency of Cl- channel opening ， barbiturates mainly prolong the Cl- channel opening time .

In addition, barbiturates can weaken or block the glumatic acid's exciting effect and inhibit the CNS .

Pharmacokinetics High lipid solubility allows rapid transport acr

oss the blood-brain barrier and results in a short onset.

Removal from the brain occurs via redistribution to the other tissues results in short duration of action (thiopental)

Barbiturates and their metabolites excreted by the renal r. Alkalinization of the urine expedites the excretion of barbiturates. Treatment of acute overdosage: Sodium bicarbonate.

Adverse effects

After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation.

Tolerance: decreased responsiveness to a drug following repeated exposure because of down-regulation of receptors and induction of hepatic drug-metabolising enzymes

Dependence: including psychologic and physiologic dependence. Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions

Treatment of acute overdosage 10 times of hypnosis dose can result in deep c

oma, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure.

Treatment:

(1) supporting respiration and circulation

(2) Gastric lavage , alkalinizing the urine by sodium bicarbonate

(3) Hemodialysis or peritoneal dialysis.

Newer sedative/hypnotic drugsBuspirone

Partial agonist at the serotonin receptor

Relieves anxiety without producing sedation, impairment of motor skills, or memory loss

Does not induce withdrawal symptoms upon discontinuation

Does not act immediately Can take up to 1 week to become effective Used for chronic anxiety states

Zolpidem Produces sedative properties by binding selectively t

o GABA receptor Same site that also binds benzodiazepines. Evidence – pharmacological effects blocked by fl

umazenil. Structurally unrelated to benzodiazepines.

Only hypnotic effect, used clinically for treatment of insomnia. Minimal muscle relaxing and anticonvulsant effec

ts. Less potential for dependence and withdrawal.