药理学教学课件：Chapter15 Sedative-Hypnotics

1、 Chapter 15 Sedative-Hypnotics Definition : Drugs which can selectively inhibit CNS and cause sedation and hypnosis . Classifications: I. Benzodiazepines： Diazepam 、Chlordiazepoxide、 Triazolam II. Barbiturates： Phenobarbital、Amobarbital 、 Sodium pentothal III. Others： Chloral hydrate The physiologic

2、al significance of sleep l People must study and work in the wake - a clear head , high efficiency The body must have sufficient sleep to relief the body from fatigue , get rest. lMaintain and promote the development of brain function . lGet consolidation of memory and ensure the best brain function

3、s. lPromote the growth of the body, resist aging lEnhance the bodys immune function Sedative-Hypnotics Inhibit CNS in a dose-dependent manner lLow dose : l Relief patients irritability sedation lSuitable increment : l Induce sleep. deepen and extend the role of hypnosis . lLarge dose： Deepen central

4、 inhibition anticonvulsant 、anesthesia. Poisoning dose : central inhibition death. Benzodiazepines ( BZ) Categories l Long-acting： Diazepam （T1/2 20-80 hr） l Chlordiazepoxide （T1/2 15-40 hr） l Middle-acting： （T1/2 10-20 hr） l Short-acting： （T1/2 2-3 hr） l Advantages： Effective, safe, fewer side effe

5、cts Diazepam N N Cl O CH3 N C N O O H C l H N Cl Cl N N N H3C 【The In Vivo Process】 Absorbed quickly, such as diazapam , etc. The speed of absorption and the extent of plasma binding are in equilibrium with liposolubility . lMetabolized to a range of active substances by liver drug enzyme , t 1 / 2

6、longer than the mother nuclide . lLong-acting：slow elimination ，long t1/2 ， repeated administration accumulation lThe majority of drugs are oxygenized in the body (such as diazapam) affected by many factors , such as liver disease t 1 / 2 extended lSome enter hepatoenteral circulation effects last a

7、ccumulation 【Pharmacological Effects and Uses】 Anti-anxiety Effect Advantages: high selectivity, wide safety margin , slow elimination , lasting effects, low dependence and light withdrawal symptoms. Clinical Applications: anxiety with compulsive disorder, gastrointestinal neurosis , heart neurosis

8、. Sedation and hypnosis : A. Have no obviously influence to FWS， Do not cause anesthesia in large dose B. Clinical applications： Treat insomnia difficult to fall asleep , wake up easily and early. Preanesthetic medication calm Central muscle relaxant: Clinical Applications: muscle cramps , spinal co

9、rd injuries and lumbar muscle strain anticonvulsant Used in treating the convulsions due to tetanus、 children with high fever and drug poisoning. Strychnine and other drugs cause seizures. Anti Epilepsy Diazepam is of choice in treating lasting- state of epilepsy by i.v. 【Mechanism of Action】 BZ Dru

10、gs （）（）BZ receptor Promote the Combination of GABA and the Receptor， Opening frequency of Cl Channel Cl （ （ chloridion ）Internal Flow， Hyperpolarization，Inhibitory Effects . 【Adverse Reaction】 lTherapeutic dose ：drowsiness ，dizziness , fatigue , memory decline . lLarge dose ：ataxia Overdose ： intoxa

11、tion coma , respiratory depression death lLong term use ：tolerance ，addiction l ethanol strengthen toxicity lThrough the placenta : teratogenicity role lWithdrawal symptoms： psychological and physiological dependence after long-term use . Sudden withdrawal symptoms ： nervous , trembling , appetite a

12、nd sleep disorders. Barbiturates 【Chemical strcture】 NH2 HOOC NHOC H O C CH2 OC (2) (5) C NH2 HOOC NHOC H lBarbituric acid is condensed by urea and malonate . lShow hypnotic when C5 is substituted by different groups . lC5-two H substituted barbiturates C5-benzene ringanticonvulsant phenobarbital C5

13、-side chain has branchesamobarbital lC2-O substituted by S Classifications Long-acting： Middle-Acting : A Short-Acting: S Ultra-Short-Acting: T Comparison of Barbiturates Main drugs Liposolubility Effect time Eliminated way Pheno- low slow some destroyed in liver， barbital some eliminated from kidne

14、y slightly low slightly faster destroyed in liver higherfaster destroyed in liver highest fastest Store fat，destroyed in liver 【The In Vivo Process】 lOral and intramuscular injection l Absorbed Distribute all over the body, body fluid Brain lOf high liposolubility（metabolized by liver drug enzyme）el

15、iminated by kidney （short maintenance time） lOf low liposolubility eliminated in original form（long maintenance time） 【Pharmacological Effects and Uses】 l Sedation & Hypnosis Low dose sedation Middle dose hypnosis , shorten time to fall asleep , extend sleeping time Long term use rebound phenomenon

16、（ nightmare ） when stop medication quickly, dependence , addiction. lAnticonvulsant and antiepilepsia strong action for convulsions due to tetanus , children with high fever , meningitis and convulsion caused by central stimulants . lPreanesthetic medication and anesthesia Thiopental : intravenous a

17、nesthesia， induction of anesthesia . Phenobarbitol ：anesthetic medication lEnhance the function of central depressant lBarbiturates of sedative dose combined with antipyretic analgesic drugs can augment the analgesic effect of the latter . Characteristics of pharmacological action lBarbiturates gene

18、rally inhibit the CNS . It has sedative , hypnotic , anticonvulsant , antiepileptic and anaesthetic effect at different doses from low to large , respectively . lInhibit cardiovascular system at large dose . l10 times of hypnosis dose can cause respiratory paralysis and death . lPoor safety，easy to

19、cause dependence . lThe application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia . 【Mechanism of Action】 l Barbiturates can function as GABA in the absence of GABA , which can increase the permeability of Cl channel , leading to the cell membrane hyperpola

20、rization . Different from BZ drugs which increase Cl channel opening frequence ，barbiturates mainly extend the Cl channel opening time . l In addition ，barbiturates can weaken or block the excited reaction of brain stem reticular structure and inhibit the CNS . 【Adverse Reaction】 After effect : dizz

21、iness , drowsiness , fine uncoordinate movement Allergic response : nettle rash , angioneuroedema , etc. Tolerance Dependence Acute intoxication: significant inhibit respiration center 【Attention】 l The drug is a inducer of liver drug- metabolizing enzymes and promote metabolism of other drugs . l T

22、he main cause of death of barbiturates is deep respiratory inhibition . l Patients who have fever , hypotension , heart 、 liver 、 kidney dysfunction and old people with mental disease should take the drug with caution . l Patients with respiratory inhibition, severe liver dysfunction, uncontrolled d

23、iabetes and who is allergic are forbidden to take . 【Acute intoxation treatment】 lIntoxation : deep coma , high respiratory inhibition , blood pressure drop , body temperature drop , shock and renal failure. Treating Methods lBreath maintenance , O2 , trachea cannula , artificial breathing , transfu

24、sion , central stimulants. lGastric lavage ，Alkaline drugs such as sodium bicarbonate , dialysis . l l 40 40 l NREM l 30 30 l l 20 20 l 10 10 REM （dayday） l l medication medication stop stop go go onon LD50 ED50 LD50/ /ED50 lPhenobarbital 242 26 9.3 lDiazepam 970 2 485 Barbiturates Coma Anesthesia H

25、ypnosis Benzodiazepines Sedation Increasing dose Other Drugs Chloral hydrate Chloral hydrate lHypnosis refractory insomnia lAnti-convulsion tetanus , convulsion of epilepsia lTake 10% solution orally or per rectum generally in order to reduce stimulating . 【Adverse effects】 l Gastrointestinal reacti

26、on : strong stimulation of gastric mucous membrane causes nausea , vomiting and epigastric discomfort . lOverdose cause damage to heart , liver and kidney . So patients with liver or kidney disease are forbidden to take . lAllergic reactions occur occasionally , such as dermatitis, erythema, urticar

27、ia, and so on. l Zopiclone l Show effects quickly and improve the quality of sleep. Chapter 16 Anti-Epileptic Drugs and Anticonvulsants Anti-Epileptic Drugs Epilepsy is a family of different recurrent seizure disorders that have in common the sudden , excessive, and synchronous discharge of cerebral

28、 neurons. Psychomotor Seizures Small Seizures Grand Seizures Lasting State of Grand Seizures C C O NH N CONa Phenytoin Sodium 【Pharmacological Effects 】 Prevent transmission of diseased tissue of abnormal discharge to normal brain tissue Reduce permeability of cell membrane to Na+、Ca+ Inhibit the fo

29、rmation of PTP 【Clinical Uses 】 1 Grand Seizures、 Psychomotor Seizures of choice 2 Trigeminal neuralgia、 Glossopharyngeal neuralgia 3 Ventricular Arrhythmia 【The In Vivo Process】 Strong alkaline； Irregularly absorption by p.o. ； Elimination according to first-order kinetics when blood drug concentra

30、tion is below 10 g/ml 【Adverse Reaction】 Toxic reaction related to doses: overdose by p.o. Ataxia overdose by iv Arrhythmia、BP down over 40ug/ml Insanity over 50ug/ml Coma Chronic toxic reaction Gingival hyperplasia seen in 20 of patients, often seen in Teenagers； Peripheral neuritis seen in 30 of p

31、atients, Mental abnormality Hypocalcemia Can be prevented by vitamin D Male breast development rarely seen Inhibiting the absorption of folic acid when medication for a long time. Allergic reaction Itch，Rash，Granulocyte Platelet， Inducing deformity Inducing the activity of liver drug enzyme Carbamaz

32、epine 【Pharmacological Effects and Uses】 Grand Seizures、 Psychomotor Seizures of choice Treating Central neuropathic pain Better than Phenytoin sodium Anti- Depression very strong Phenobarbital 【Pharmacological Effects and Uses】 Inhibiting the abnormal discharge and prevent transmission of diseased

33、tissue of abnormal discharge to normal brain tissue Used mainly in treating “Grand Seizures” and “Lasting State of Grand Seizures” Ethosuximide A Absorption entirely by p.o. ，used in preventing and curing small Seizure，of choice because of the less side-effects and tolerance； B Inhibiting T type Ca ion cha