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 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 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(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 T 1/2 (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, C max 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 anxiety  Mechanism:  a partial agonist at brain 5-HT 1A -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）