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 Wake FWS, REM SWS, NREM (2025)The physiological significance of sleepThe physiological significance of sleepll People must study and work in the wake - a People must study and work in the wake - a clear head , high efficiencyclear 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 functions.lPromote the growth of the body, resist aginglEnhance the bodys immune function Sedative-HypnoticsInhibit CNS in a dose-dependent mannerlLow dose : l Relief patients irritability sedationlSuitable increment : l Induce sleep. deepen and extend the role of hypnosis .lLarge dose： Deepen central inhibition anticonvulsant 、anesthesia. Poisoning dose : central inhibition death. Benzodiazepines ( BZ) Categoriesl Long-acting： Diazepam （T1/2 20-80 hr）l Chlordiazepoxide （T1/2 15-40 hr） l Middle-acting： OxazepamOxazepam （T1/2 10-20 hr）l Short-acting： TriazolamTriazolam （T1/2 2-3 hr）l Advantages： Effective, safe, fewer side effects Diazepam OxazepamOxazepam TriazolamTriazolam【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 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 extendedlSome enter hepatoenteral circulation effects last accumulation【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 . 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 cord 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 Drugs （）（）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 ： intoxation coma , respiratory depression deathlLong term use ：tolerance ，addictionl ethanol strengthen toxicitylThrough the placenta : teratogenicity rolelWithdrawal symptoms： psychological and physiological dependence after long-term use . Sudden withdrawal symptoms ：nervous , trembling , appetite and sleep disorders.Barbiturates【Chemical strcture】 NH2 HOOC NHOC H O C CH2 OC (2) (5) C NH2 HOOC NHOC HlBarbituric 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-side chain has branchesamobarbitallC2-O substituted by Sthiopentalthiopental Classifications Long-acting：Phenobarbital 68 h Middle-Acting : Amobarbital 36 h Short-Acting: Secobarbital 23 h Ultra-Short-Acting: Thiopental 0.5 h Comparison of BarbituratesMain drugs Liposolubility Effect time Eliminated wayPheno- low slow some destroyed in liver，barbital some eliminated from kidneyA Amobarbitalmobarbital slightly low slightly faster destroyed in liverSecobarbitalSecobarbital higherfaster destroyed in liverT Thiopentalhiopental highest fastest Store fat，destroyed in liver【The In Vivo Process】lOral and intramuscular injectionl Absorbed Distribute all over the body, body fluid BrainlOf high liposolubility（metabolized by liver drug enzyme） eliminated 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 （ 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 anesthesia， induction of anesthesia . Phenobarbitol ：anesthetic medicationlEnhance 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 generally 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 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 Clchannel , leading to the cell membrane hyperpolarization . 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 : dizziness , 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 The 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 diabetes 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 MethodslBreath maintenance , O2 , trachea cannula , artificial breathing , transfusion , central stimulants.lGastric lavage ，Alkaline drugs such as sodium bicarbonate , dialysis .The Effects of Barbiturateson the Sleep Phasell ll 40 40 40 40ll NREMNREMll 30 30 30 30ll ll 20 20 20 20ll 10 10 10 10 REMREM （daydaydayday）ll ll medication medication medication medication stop stop stop stop go ongo ongo ongo on Comparison of Safety LD50 ED50 LD50/ /ED50lPhenobarbital 242 26 9.3lDiazepam 970 2 485 BarbituratesBarbiturates Coma Coma Anesthesia Anesthesia Hypnosis Hypnosis BenzodiazepinesBenzodiazepines Sedation Sedation Increasing dose Increasing dose Other Drugs Chloral hydrate Chloral hydratelHypnosis refractory insomnialAnti-convulsion tetanus , convulsion of epilepsialTake 10% solution orally or per rectum generally in order to reduce stimulating .【Adverse effects】l Gastrointestinal reaction : 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, urticaria, 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 neurons. Psychomotor Seizures Small Seizures Grand Seizures Lasting State of Grand Seizures 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 formation of PTP 【Clinical Uses 】 1 Grand Seizures、 Psychomotor Seizures of choice2 Trigeminal neuralgia、 Glossopharyngeal neuralgia3 Ventricular Arrhythmia【The In Vivo Process】Strong alkaline；Irregularly absorption by p.o. ；Elimination according to first-order kinetics when blood drug concentration 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 ComaChronic toxic reactionGingival hyperplasia seen in 20 of patients, often seen in Teenagers；Peripheral neuritis seen in 30 of patients,Mental abnormalityHypocalcemia 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 Carbamazepine【Pharmacological Effects and Uses】 Grand Seizures、 Psychomotor Seizures of choice Treating Central neuropathic pain Better than Phenytoin sodiumAnti- Depression very strong Phenobarbital【Pharmacological Effects and Uses】 Inhibiting the abnormal discharge and prevent transmission of diseased tissue of abnormal discharge to normal brain tissue Used mainly in treating “Grand Seizures” and “Lasting State of Grand Seizures” EthosuximideA 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 channel，So the abnormal discharge of Thalamus is inhibited；C Side effects often seen include gastrointestinal reaction，central nervous system symptoms and so on. Be carefully used in the patients with the history of nerve disease. Sodium valproate Used widely ，especially in treating small Seizure and has better effects than ethosuximide， Not of choice due to liver toxicity Benzodiazepine （BZ ）Diazepam Treating “Lasting State of Grand Seizures” ， is of choiceApplication Note:1 Select drug acorrding to the type of seizure.2 Combined medication is often applied，and interaction should be pay attention to.3 Medication should begin with a small dose and increase the dose gradually .Can not stop medication suddenly and change drugs at will.4 Medication should keep in a long period and check hemogram and liver function regularly.Anticonvulsants Magnesium sulfate Similar in chemical features with Ca ion and block the effects of Ca ion specificly . Anticonvulsant，also used in BP crisis. Medication by injection and the safety margin is narrow. Calcium chlorideshould be prepared before use.