Part 8. Anti-psychiatric disorders ( 抗精神失常药 ). Outline 1.Concept of mental disorders: Mental disorder = Psychiatric disorder (1)Morbidity ( 发病率 )of mental disorder in our country: 16 million 1982: 12.67 ‰, 70’: 3.20 ‰, 1993: 13.47 ‰, 80’: 9.33 ‰,
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1.Concept of mental disorders:
(1)Morbidity (发病率)of mental disorder
in our country: 16 million
1982: 12.67 ‰, 70’: 3.20 ‰,
1993: 13.47 ‰, 80’: 9.33 ‰,
2000: 15.56 ‰. 90’: 10.67 ‰,
in Guangdong:16.36 ‰,
in Beijing:34.34 ‰,
in Shanghai:38.46 ‰.
2006/3/27: inZhejiang, 17.3 ‰.
▲ Genetic factor(遗传因素):
▲ Diathetic factor(素质因素):
▲ Social psychogenic factor
▲ Age and sex(年龄和性别)
Ⅰ. Concept of Schizophrenia (精神分裂症)
Ⅱ. Distribution ofD2 receptor in CNS
Ⅲ. Specific drugs:
Schizophrenia (精神分裂症) is the most common kind of psychosis, more than 50% of psychosis.
Schizophrenia frequently occurring in puberty (青春期), fall ill rarely after 40 years old.
The causes of illness are not clear, probably owing to genetic factors and environmental factors together.
Schizophrenia can be divided into 2 types: TypeⅠ and TypeⅡ.
Functional disorder of CNSneurotransmitter andreceptors, especially CNStransmitterDopamineincreased.
Experimental study showed that the symptoms of schizophrenia exacerbated when Dopamine in CNS increased, and the symptoms of schizophrenia abated when Dopaminein CNS decreased.
There are 4 subtypes of dopamine receptor in CNS, they are D1, D2, D3, D4 receptor.
The most effective anti-schizophrenia drugs are blocking agents of D2 receptor.
Ⅱ. Distribution ofD2 receptorin CNS
①Chemoreceptor trigger zone(CTZ)of the medulla oblongata(延脑的催吐化学感受区);
②Heat-regulatingcenter of hypo-thalamus(下丘脑体温调节中枢)
The effects of anti-schizophrenia drugs blockingD2 receptorof other regions are adverse reaction, such as extrapyramidal symptoms(锥体外系症状).
1. Pharmacological effects :
Effects ofChlorpromazine includeCNS effects&Peripheral effects.
CNS effects:block D2 receptor of CNS, those effects are therapeutic effect or adverse reaction.
Peripheral effects:block receptorand M receptor of periphery, mainly cause adverse reaction.
Chlorpromazine block D2 receptor ofMeso-cortical pathway (中脑-皮质通路) and Meso-limbic pathway (中脑-边缘系统通路), to inhibit the mental activity of psychosis patients selectively.
Therearemarkedlycurativeeffects in acute psychosis of unknown etiology, including acute idiopathic psychosis (特发性精神病) and acute exacerbations of schizophrenia (精神分裂急性发作).
It is also effective to mania (躁狂症).
to block D2 receptor of CTZ(催吐化学感受区) of the medulla oblongata (延髓), it can be used to treat emesis (呕吐).
③Affecting body heat regulation(影响体温调节作用)
to block D2 receptor of heat-regulating center (体温调节中枢).
This action is different to anti-pyretics (解热药).
Owing toblocking D2 receptor of Nigro-striatal pathway (黑质-纹状体通路).
if taking chlorpromazine for long time, the functions of cholinergic nerve of CNS will be predominant:
Chlorpromazineblocking D2 receptor of tubero-infundibular pathway (结节-漏斗通路), to affect functions of hypothalamus (下丘脑) endocrine. `
—— Adverse reaction: menstrual (月经) disorder, feminization and lactation (女性化症状), exacerbation of breast cancer.
—— Clinical use: to treat gigantism (巨人症), owing to reduce the secretion of pituitary (垂体) growth hormone.
Vasodilatation, Blood pressure .
Owing to tolerance, not be used to treat hypertension.
ADRs:dry in the mouth(口干), constipation(便秘), blurred vision(视力模糊), etc.
(1)to treat psychosis
★ Various typeschizophrenia (精神分裂).including acute and chronic patients, especially acute type.
★ Mania (躁狂).
★Other psychosis with exciting, tension and delusion.
But Chlorpromazineis ineffective for depression (抑郁).
The conditionofsome patients with depression will exacerbate after takingchlorpromazine.
to treat various causative emesis, includingemesisresultofgastroenteritis, cancer, radiationdisease,uremia (尿毒症) and drug induced emesis.
But, it is in-effective to emesis of car sickness and sea sickness.
beside anti-emetic effect, also used to intractable hiccough(顽固性呃逆).
Mechanism of anti-emetic effect:
Small dose:blocking D2 receptor inCTZ of the medulla oblongata (延髓催吐化学感受区);
Large dose:directlyinhibiting emetic center (呕吐中枢).
★ Hypothermic anesthesia(低温麻醉)
when anesthesia, injected Chlorpromazinewith physical cooling(ice bath), Body temperature
≤ 30℃. 15~20 min,
Deep hypothermic anesthesia(深低温麻醉):≤ 18℃. 45~60 min,
★ Artificial hibernation(人工冬眠)
(1)Extra-pyramidal effects (锥体外系)
Can be treated with central anti-cholinergic agents—— Artane(安坦),or
Scopolamine(东莨菪碱),but can not be treated withL-dopa.
Skin rash, dermatitis, leukopenia (白细胞减少), and obstructive jaundice (黄疸), etc.
(3)Others:M and receptor blockade,andorthostatic hypotension (体位性低血压).
Epilepsy (癫痫), glaucoma, cardiovascular disorders, severe hepatic damage, etc.
Its anti-schizophrenic (精神分裂) effects is weaker, but with marked anti-depression and anti-anxiety (抗焦虑) effects.
used to schizophrenia with anxiety and anxiety-depression.
Its anti-schizophrenic effects and extra-pyramidal effects arestronger,and with stronger effects of anti-mania(抗躁狂), anti-hallucination(抗幻觉), and anti-delusion(抗妄想).
1. To treat schizophrenia with exciting, hallucination and delusion,
2. To treat mania as well.
longer-acting anti-psychoticeffects,by po. 1 time / 1 week.
to treat chronic patients for long-term.
ADR and extra-pyramidal effects are less,
to treat acute and chronic schizophrenia for long-term, and effective to depression.
1. Effects and characteristics:
It is a new type of anti-psychotic drug, its anti-psychotic effect is high potency.
It can not block D2 receptor, but can block D4 receptor.
Its CNS anti-cholinergic effect is stronger, therefore, there is not extra-pyramidal effect almost.
2. Adverse reaction:
5-HT (5 - 羟色胺) in the brainis the basis ofMania-depression,
when 5-HT , NA :Mania
when5-HT , NA :Depression
Antiepileptic drug——Carbamazepine (卡马西平),
Antipsychotic drug——Chlorpromazine (氯丙嗪) andHaloperidol (氟哌啶醇), there are marked anti-manic effects.
Let’sintroduce another anti-manic drug now:
1. Pharmacological effects:
therapeutic dose(1~2g/day, po)to normal subjects: no affection; to manic patients: marked curative effect.
Mechanisms of anti-manic effects:
inhibiting the release of NA and DA, promoting NA and DA reuptake,to decrease the concentration of the neurotransmitters in the synaptic cleft (突触间隙).
(2)Manic-depressive psychosis(躁狂抑郁症) —— mood-stabilizing(情绪稳定药).
(3)Manic symptomsofschizophrenia (有躁狂症状的精神分裂症).
3. Adverse reaction:
GI reaction and CNS reaction
(Cp) and drug reaction
0.8~1.2mEq/L Therapeutic concentration
1.6~2.0mEq/L GI reaction, include: nausea,
emesis, diarrhea, etc.
＞ 2.0 mEq / L CNS toxicity, include:
blood concentration monitoring, to control dosage.
Imipamine (米帕明, 丙咪嗪)
1. Pharmacological effects:
to normal subjects:
sleepiness, light headache, slight fall in blood pressure, and certain anti-cholinergic effects.
It can elevate mood markedly, mental stimulation—— marked anti-depressive effect.
The effect is different to CNS stimulants(such as caffeine), therefore, the mental stimulant effect of imipamine (米帕明) is selective.
①direct action: inhibiting heart,
——cardiac contractility , BP :
inhibiting NAreuptake of sympa-thetic nervous ending of heart,NA in synaptic cleft, activating 1 receptor of heart.
——ectopic cardiac rhythm and arrhythmia (心率失常).
Experiments show thatTCAs (三环类药物) can block the reuptake of NA and 5-HT, to increase the concentration of NA and 5-HT in thesynaptic cleft (突触间隙), to promotethe transmission function of synapse, to exert anti-depressive effects.
The curative effects are well to endogenous(内源性), reactive, and involutional(更年期) depression.
Depressive state of schizophrenia, the curative effect is bad.
(3)Anxiety and Phobia(恐惧症)
Thirsty, constipation (便秘), blurred vision.
Hypotension, tachycardia (心动过速), arrhythmia.
Other tricyclic drugs (三环类药物):
Amitriptyline(阿米替林), Clomipramine (氯米帕明), Doxepin(多塞平, 多虑平), etc.
The drugs of this kind can selectively inhibit NA reuptake, increase the concentration of NA in synaptic cleft of CNS.
The curative effects of the drugs take place faster and ADRs are less.
Such as Desipramine(地昔帕明), Maprotiline(马普替林), Nortriptyline (去甲替林), Protroptyline(普罗替林), Amoapine(阿莫沙平), etc.
The drugs of this kind can selectively inhibit 5-HT reuptake, increase the concentration of 5-HT in synaptic cleft of CNS.
Those drugs are effective to the patients whose 5-HT decreased in brain.
Such as Fluoxetine(氟西汀), Paro-xetine(帕罗西汀), Sertraline(舍曲林), etc.
There are many other anti-depressants mechanism, such as tryptophan (色氨酸), it is the pro-amino acid of 5-HT, can be used to treat some intractable(难治性的) depressant patients at abroad.
★ Classification ofanalgesics:
1. Opioid analgesics(阿片类镇痛药)
(2)Synthetic opioid analgesics(人工合成的阿片类镇痛药类)
2. Antipyretic, analgesic, and anti-inflammatory drugs(解热镇痛抗炎药)
(B)Synthetic opioid analgesics:
(D)Antagonist of opium receptors:
Opium alkaloids extracted from opium (阿片);
Opium(阿片)came from poppy(罂粟).
Opium as therapeutic drugs, it is called “阿片”;
as dope(毒品),it is called “鸦片”, “大烟” 或 “烟土”.
There are more than20 alkaloids in opium,the alkaloidsaccount for 25% ofopium.
Morphine(吗啡)is 10% ofopium,
Codeine(可待因)is 0.5% ofopium.
Sertürner(German) extracted from opium in 1806. “Morphine” came fromGreece“morpheus” ––––Greekgodofdream (梦之神).
1. Pharmacological effects:
①Analgesia (镇痛) and sedation (镇静):
(a)Analgesia: effective to various pain, including “sharp pain”(锐痛) and ‘‘Dull pain”(钝痛);
(c)Improving mood: euphoria(欣快感).
Mechanisms of analgesic effects:
Morphineand opioids canactivate opium receptor of different regions in CNS to effect analgesia.
There are 4 subtypes of opium receptor in CNS at least:
receptor,与脊髓以上水平的镇痛, 以及缩瞳、呼 吸抑制、改善情绪、欣快感和精神依赖性有关;
receptor,与脊髓以上水平的镇痛, 缩瞳, 欣快感有关, 还与胃肠道平滑肌兴奋, 张力提高和活动减少有关;
receptor,与镇痛无关, 兴奋可引起幻觉, 焦虑和 烦躁不安.
There aremore than 20 kinds of endogenous opioid peptides, such as:
Morphinewith affinity and intrinsic activity to opium receptor.
Peripheral mechanisms of pain
sensory neuron receiving neuron
neuron contained enkephalin (脑啡肽)
The therapeutic doses of morphine slightly inhibit respiratory center, to decrease sensitivity to CO2, to slow down respiratory frequency, the large doses markedly inhibit respiratory center.
▲ stimulating receptor, to depress respiratory center.
▲ at least in part by virtue of direct effect on the brainstem respiratory centers.
to depress coughing center.
Morphine and other receptor agonists can cause constriction of the pupil by an excitatory action on the parasympathetic nerve (副交感神经) innervating (支配) the pupil.
when morphine intoxication:
Morphine can stimulate receptor of smooth muscle(circular muscle), and diminish gland secretions.
▲Anti-diarrhea and constipation:
owing to decrease of gland secretion and propulsive peristalsis(推进性蠕动) ;
and owing to CNS depression.
▲Pressure in biliary tract (胆道) :
inducing biliary colic (胆绞痛).
▲Peripheralsmall vessels dilatation
● promoting histamine release, dilating peripheral small vessels, including arteriolar and venous dilatation.
● stimulating opium receptor of nucleus of solitary tract(孤束核) in CNS, tone of vasomotor centers (血管舒缩中心) , BP.
orthostatic hypotension(体位性低血压) and syncope(晕厥).
▲ Cerebral vasodilatation(脑血管扩张)
Respiratory depression, CO2,cerebral blood dilatation intracranial pressure (颅内压) ,
therefore, contraindication for the patients of craniocerebral injury (颅脑外伤).
▲Ureteral (输尿管) and vesical sphincter (膀胱括约肌) tension:
urinary retention (尿潴留)
because of releasing histamine, to contract smooth muscle of bronchus directly / large dose.
①inhibiting cellular immunity
Morphine can depress the activity of NK cell, inhibit T cell proliferation by ConA, inhibit phagocytic function etc.
②depressing humoral immunity
Morphine can affect the synthesis and release of cytokines(细胞因子), such as:
IL(interleukin, 白细胞介素): IL-1, IL-2, IL-10;
TNF(tumor necrosis factor, 肿瘤坏死因子): TNF-, TNF-, etc.
2. Clinical uses:
Fast and potency, effective for various pain(except biliary colic 胆绞痛).
Because it is very easy to addiction,
①Only treat toacute megalgia(急性剧痛),such as severe wound, large area of burn, etc.
The aim is to prevent painful shock, but contraindication for shock.
②Treat to pain of later period of cancer also.
(2)Cardiac asthma (心源性哮喘)
(acute ventricular (心室) failure):
Mechanism of therapeutic effects:
Peripheral resistance , and returned blood volume , heart load .
②Sedation (镇静) and euphoria (兴奋):
Alleviatingfrighten and worry, oxygen consumption , alleviating anoxia (缺氧) of patients.
Small dose of morphine slightly inhibit respiratory center, decrease sensitivity to CO2, let frequency of respiration change from fast and short to slow and deep.
Effective to acute and chronic functional diarrhea(non-infective).
Tinctureofopium(阿片酊: 1%morphine, 3% alcohol) or compound tincture of camphor(复方樟脑酊, 含5%的阿片酊).
now most in use:
Compound diphenoxylate(复方地芬诺酯, 复方苯乙哌啶): content diphenoxylate 2.5 mg,atropine 0.025mg/ tablet, 1~2#, po, tid.
3. Characteristics of ADME:
①easy absorption, but fast pass eliminationismarked,bioavailabilityislow(25%);
②therefore, administration by subcutaneous injection(sc) (皮下注射).
①Morphine is difficultly pass throughBBB,butheroin(海洛因, 二乙酰吗啡) very easily pass through BBB;
②easily pass through placenta;
③Morphine is a basic drug, can diffuse from blood to stomach, therefore, can detoxify by gastric lavage (洗胃排毒).
4. Adverse reaction:
(1)General adverse reactions:
Vertigo (眩晕), somnolence (睡意), slight respiratory inhibition, nausea, vomiting, constipation, immunosuppression, orthostatic hypotension, retention of urine, biliary colic, etc.
Acute intoxication/overdose: hypotension,coma (昏迷), serious respiratory depression,and pin-point pupil.
Acute toxicity can be antagonized by antagonist——Naloxone (纳洛酮) or Naltrexone (纳曲酮).
(3)Serious adverse reaction:
Tolerance, dependence and addiction.
Dependenceand addiction isthe most serious adverse reaction of morphine.
Dependence can be divided into physical dependence and mental dependence.
Physical dependence is a state that develops as a result of the tolerance.
Mental dependence is a state that develops as a result of euphoria (欣快感).
Withdrawal syndrome of morphine——abstinence syndrome(戒断症状).
Its analgesic (镇痛) effect is 1/10~1/12 of morphine, the antitussive (镇咳) effect is 1/4ofmorphine,therefore, its antitussive is relatively stronger.
And its addiction is relatively less.
It is mainly used to treat the dry cough (without sputum).
Addiction of opium alkaloidsis stronger, therefore, to synthesize opioid analgesics, the addiction is relatively less,
such as: Pethidine (哌替啶), Fentanyl (芬太尼), Methadone (美沙酮), Pentazocine (喷他佐辛), etc.
1. Pharmacological effects:
The same tomorphine,but weaker than morphine.
Potency of analgesic effect is 1/7 ~ 1/10 ofmorphine;
Analgesic term is shorter thanmorphine,about 2~4 hr, the analgesic term ofmorphineis about 4~6 hr.
The difference tomorphine, pethidine has no effects againt cough and diarrhea.
2. Clinical uses:
Use to treatvary acute severe pain, such as fracture, burn, pain of cut after operation,andpain of later cancer.
Tocolic of viscera (内脏绞痛),such asbiliary colic, colic of kidney,ought to administrate with spamolysics together, such asNitroglycerin(硝酸甘油)or Atropine.
Not use to thepain of childbirth.
Not use tochronic painalso, because of avoiding addiction.
(2)Preanesthetic medication and artificial hibernation (人工冬眠):
①dispel tension (消除紧张情绪), frightened mood of patients before operation, and reduce the dosage of general anesthetics.
②withchlorpromazine(wintermin, 氯丙嗪)andpromethazine(异丙嗪)together composemixture of hibernation(人工冬眠合剂).
It can be used to treat cardiac asthmareplacingmorphine.
3. Adverse reactions:
As morphine, it is easy to addiction too, therefore, it should be strictly controlled to use.
(2)Central exciting effect:
Normeperidine(去甲哌啶)is the metabolic product of pethadine,with marked central exciting effect, and its t1/2(15~ 20 h) is longer thanpethadine(t1/2, 3 h),therefore, it can’t be used for long time.
Potent and short-acting of analgesia,the analgesic effect is 100 times than morphine.
im. to take effect in 15 min, maintain 1~2 h, addiction less.
(1)variousacute megalgia (剧痛);
(2)Compatibility with droperidol(氟哌利多),neuroleptic analgesia(神经松弛镇痛),be used to redress wound of large area in burn patients.
Potency of analgesiceffectisthesame asmorphine,itseffectivetimeisthesame asmorphine too.
(1) Effective by po;
(2) Addiction is less thanmorphine,and appear slower thanmorphine.
Its abstinence syndrome is lighter, and easier to be treated, therefore, methadone as a surrogate(代用品)isused to abstain (戒除) addiction in USA .
Abstinence syndromein24~48h after withdraw drug, 3rd day upward to peak, 6~7 weeks later disappear.
Analgesic effect is weaker than morphine, about 1/3 of Morphine, but stronger than pethidine, about 3 times of pethidine, there are no addiction almost.
Pentazocine is - and -receptor agonist,-receptor antagonist.
Only use pentazocine, the analgesic effect come from excite -receptor;
Use it with morphine, pentazocine will weaken the analgesic effect of morphinebecause of blocking -receptor.
Owing to activating -receptor, to cause hallucination (幻觉), large dose will cause mental disorder, so that it is not encouraged now.
The types and nature of pain are the basis of clinical diagnosis.
To severe pain that is not diagnosed clearly, such as acute abdomen(急腹痛), should rapidly find out the causes of illness first,then treat patients with analgesics, in order to avoid covering up the states of illness owing to analgesics, to miss diagnosis of illness and treatment in time.
Rotundinis levorotatory tetrahydro-palmatine(左旋四氢巴马丁), a composition extracted from the stem tuber of a herb named 延胡索. In addition to analgesic effect,there are sedation (镇静) and hypnosis (催眠).
1. Analgesic action is stronger than aspirin and weaker thanpethadine.
Used in chronic continuous dull pain, such asheadache, dysmenorrhea(月经痛), effective to the pain of GI too.
2. Used in sedation and hypnosis also,
especially suited to insomnia (失眠) caused by pain.
3. No addiction, no tolerance:
Rotundincan be used for long-term.
4. There is no respiratory inhibition in therapeutic dose.
Adverse reaction: less
Occasionally dizziness, weary, nausea, etc.
They are antagonist of opium receptor, can block 4 types ofopium receptor, itself has no pharmacological effect.
1. To treat intoxication of opioid overdose, can eliminate respiratory inhibition in 1~2 minutes, increase respiratory frequency; also be used to treat various respiratory inhibition.
2. Tool agent for study in laboratory;
3. To stimulate addiction breaking up.