第十五章抗精神失常藥

1、1,Depression and anxiety,Lou haiyan（婁海燕）Institute of PharmacologySchool of MedicineShandong Universitylouhaiyan@sdu.edu.cn,2,Depression,Common psychiatric disease, 11% WHO，Depression will become the main kil

2、ler to people in 21th century,BLUE FLU,3,,Depression is an illness that is characterized by a series of changes that gradually cause significant impairment of the activity of people concerned.It is more than feeli

3、ng blue, down in the dumps or sad about a particular issue or situation.It is a medical condition that requires diagnosis and treatment,4,Symptoms of Depression,FIVE OR MORE OF THE FOLLOWING FOR AT LEAST TWO WEEKS:Fee

4、lings of sadness, depressed mood and/or irritabilityLoss of interest or pleasure in activitiesChanges in weight or appetiteChanges in sleep pattern-not enough or too much,5,Symptoms of Depression,Feelings of guilt, ho

5、pelessness or worthlessnessInability to concentrate, remember things or make decisionsConstant fatigue or loss of energyRestlessness or decreased activityRecurrent thoughts of suicide or death,6,人很煩？愛發(fā)脾氣或?qū)δ愕挠H友漠不關(guān)心？,,

6、7,Hamilton rating scale for depression（漢密爾頓抑郁量表),8,Epidemiology,The most common psychiatric disorderDepression incidence Men: 13%Women: 21%Bipolar disorder: 1.3-1.8%Age of onset: 25-35 yearMajor risk factor: stres

7、s,9,Etiology,Biological factorsSocial factorsPsychological factors,10,Biological factors,GeneticHigh prevalence in first degree relativesHigh concordance with monozygotic twinsShort allele of serotonin transported g

8、ene,2003Medical illness: Parkinson's, Alzheimer's, cancer, diabetes or strokeVascular changes in the brain Chronic or severe painPrevious history of depressionSubstance abuse,11,Social factors,Loneliness, i

9、solation Recent bereavement Lack of a supportive social network,12,Psychological factors,Traumatic experiencesDamage to body image Fear of death Frustration with memory loss Role transitions,13,Neurobiology of depr

10、ession,The monoamine deficiency theoryDecreased levels or activity of nor-epinephrine and/or serotoninAbnormality in HPA axisHippocampus volume ↓,14,Treatment for Depression,Approximately 80% of people who rece

11、ive treatment for Depression improve.There are three types of treatment:PsychotherapyMedicationElectroconvulsive Therapy (ECT,電休克治療),15,Tricyclic antidepressants(TCAs) Monoamine oxidase inhibitors(MAOIs) Norepinep

12、hrine reuptake inhibitors(NARIs) Selective serotonin reuptake inhibitors( SSRIs) Serotonin and norepinephrine reuptake inhibitors(SNRIs),Antidepressant drugs,16,,,丙米嗪（imipramine）,氯米帕明（ clomipramine ）,,阿米替林（amitrip

13、tyline）,多塞平（doxepin）,三環(huán)類：,Ⅰ.Tricyclic antidepressants (TCA),17,1.CNS： produce inhibition on normal person, elevating the mood that is depressed　 slow onset:2-3w,Imipramine (丙米嗪，米帕明）,Mechanisms：

14、 block the uptake of NA and 5-HT,【Pharmacological effects and mechanism】,18,2. autonomic nervous system block M-R3. cardiovascular systemhypotension: block α1 –Rarrhythmias,tachycardia: NA↑ quinidi

15、ne-like inhibitory action on heart used with caution in patients with cardiovascular disease,【Pharmacological effects and mechanism】,19,【Clinical uses】 1. depressions caused by all kinds of reasons 2. enuresis(遺

16、尿癥) in children 3. anxiety and phobia (恐怖癥),【Adverse reactions】 1. atropine-like action 2. cardiovascular reaction,20,三環(huán)類抗抑郁藥的作用及機(jī)制,抑制突觸前膜對(duì)5-HT和NA的重?cái)z取,阻斷M-R,阻斷?1-R,阻斷H1-R,奎尼丁樣心肌抑制作用,抗抑郁,,,,心律失常,,,,口干、視力模糊、便秘、

17、尿潴留,,血壓,過度鎮(zhèn)靜,,,,,21,doxepin（多塞平，多慮平）,抗焦慮作用強(qiáng)，對(duì)伴有焦慮癥狀的抑郁 癥療效最佳。,22,Ⅱ Monoamine oxidase inhibitors(MAOIs) ：,,異煙肼（isoniazid）,異卡波肼（isocarboxazid）,嗎氯貝胺（moclobemide）,,,,Adverse reaction: hypertensive cris

18、is, liver injury,23,,【Pharmacological effects and mechanism】 Inhibit MAO, and reduce the degradation of monoamine.【Clincal uses】: atypical depression not first choice【Adverse reac

19、tions】 Severe: hypertension crisis,24,Ⅲ NA reuptake inhibitors,Desipramine (地昔帕明)Maprotiline (馬普替林)Nortriptyline (去甲替林) TCA Selectively reduce reuptake of NA Weak sedation and anticholinergic activity Onset rap

20、id,25,Ⅳ Selective 5-HT reuptake inhibitors (SSRIs),Fluoxetine (Prozac,氟西汀, 百憂解)Paroxetine (Paxil, 帕羅西汀, 賽洛特)Sertraline (Zoloft,舍曲林, 郁樂復(fù))Fluvoxamine (Luvox,氟伏沙明, 蘭釋)Citalopram (Celexa,西酞普蘭, 喜普妙 ),First line,26,氟西汀（f

21、luoxetine,百憂解）,selectively inhibit 5-HT reuptake no affinity to the receptors in CNS and periphery，less adverse reactions better tolerance and security than TCAs take effects after 2-6 weeks used for depr

22、ession , compulsion(強(qiáng)迫癥) polyphagia(貪食癥),27,Ⅴ 5-HT and NA reuptake inhibitors (SNRIs),Venlafaxine (文拉法辛,怡諾思） Duloxetine (度洛西?。〩ave advantages over SSRIsFaster onset of action (< 2 weeks)Used for depression

23、and anxiety,28,Electroconvulsive Therapy (ECT),Second-line treatment Faster acting than most medicationsIs used in life threatening situations to achieve fast reliefCan be used in combination with medicationSide effe

24、cts: short-term memory loss,29,Section 2 Anti-manic Drugs,30,Bipolar Disorder(Manic-depressive disorder),People with this type of illness change back and forth between periods of depression and periods of mania (a

25、n extreme high). Symptoms of mania may include:Less need for sleepOverconfidenceRacing thoughtsReckless behavior(行為魯莽）Increased energy,31,repeated episodes of mania or depression, alternating mania and depression

26、Mechanisms: 5-HT↓ NA↑ mania 5-HT↓ NA↓ depression,,,Manic-depressive disorder (躁狂抑郁癥) —bipolar affective disorder,32,Antimanic drug (mode stabilizing agents),Li

27、thium carbonateAntipsychotic agents(氯丙嗪、氟哌啶醇、氯氮平、利培酮)Antiepileptic agents(卡馬西平、丙戊酸鈉)Calcium blockers (維拉帕米),33,Lithium carbonate(碳酸鋰) —“Mood-stabilizing” agent,【Pharmacological effects an

28、d mechanism】 little impact on normal person, anti-mania, sometimes also effective for depression,34,碳酸鋰的可能作用機(jī)制,1.抑制腦內(nèi)神經(jīng)末　梢對(duì)NA、DA的釋放,突觸間隙單胺類遞質(zhì)減少,2.促進(jìn)NA、DA的重?cái)z取及滅活,3.抑制AC及PLC介導(dǎo)的反應(yīng),4.影響Na+、Ca2+、Mg2+ 轉(zhuǎn)運(yùn),

29、,,影響神經(jīng)功能,,,35,【Clinical uses】,manic-depressive psychosis especially for acute and mild mania (80%),36,Lithium toxicity therapeutic concentration: 0.8-1.5mmol/L toxic concentration: >2mmol/L monitor blo

30、od drug concentration, withdrawal at 1.6mmol/L,【Adverse reactions】,37,,nausea, vomit, abdominal pain, profuse diarrhea, and ataxia, mental confusion, hyper-reflexia, tremor, convulsionIntoxication can be usually r

31、eversed by osmotic diuresis or by dialysis (透析),38,Section 3 Anti-anxiety Drugs,39,Anxiety,Anxiety is an unpleasant emotional experience characterized by fear disproportionate to the severity of stressful factors

32、in the environment, or fear without cause.,40,Anti-anxiety drugs,BenzodiaepinesFirst-line drugsMechanism: binds to GABAA receptor and act as positive allosteric modulators.Buspirone(丁螺環(huán)酮）Psychotherapy,41,Buspirone (B

33、uSpar®),Partial agonist at the serotonin 1a receptor.Relieves anxiety without producing sedation, impairment of motor skills, or memory loss.Does not induce withdrawal symptoms upon discontinuation.Does not ac

34、t immediately.Can take up to 1 week to become effective.Used for chronic anxiety states.Pharmacokinetics:Rapidly absorbed orally.Rapid first-pass effect.Elimination half-life = 2-4 hrs.Metabolism is primarily hep