抗精神失常药Antipsychotic Drugs.ppt

　　Antipsychotic Drugs 抗精神失常药

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　　Psychotropic Drugs

　　Classification： antipsychotic drugs 抗精神病药物 neurotropic drugs 神经安定剂 antimanic drugs 抗躁狂药物 antidepressants 抗抑郁药物 anxiolytics 抗焦虑药物

　　Antipsychotic drugs

　　Schizophrenia 精神分裂症 literal translation “split mind” separate emotional side from intellectual side emotional & cognitive processes don't function together a group of severe disorders characterized by: disorganized and delusional thinking(妄想) disturbed perceptions inappropriate emotions & action

　　Nature of psychosis /schizophrenia The dopamine hypothesis excessive dopaminergic activity plays a role in the disorder. The enhancement of function of 5-HT2 Dopaminergic Systems The nigrostriatal pathway (coordination of voluntary movement )

　　Mesolimbic- mesocortical ( behavior ) Tuberoinfundibular- pituitary system (endocrine) The medulla oblongata (vomit) Medullary - periventricular pathway ( eating behavior)

　　Antipsychotic drugs Classification： Phenothiazin 吩噻嗪类 (氯丙嗪 chloropromazine ) Thioxanthenes 硫杂蒽类 (chlorprothixene 氯普噻吨(泰尔登)) Butyrophenones 丁酰苯类 (haloperidol 氟哌啶醇) Others

　　Antipsychotic/Neuroleptics

　　Phenothiazin 吩噻嗪类 chlorpromazine 氯丙嗪 (wintermine 冬眠灵)

　　Pharmacologic effects blocking DA2 、α 、 M 、 5HT2 、 H1 receptors

　　neuroleptic effect (神经安定作用)

　　Blocking Mesolimbic system and mesocortical D2-R More effective for treating positive symptom Substantia nigra- corpus striatum ---- extrapyramidal effects 锥体外系反应 Node-funnel --- endocrine system action

　　powerful antiemetic action 镇吐作用 blocking CTZ 催吐化学感受区 D2-R (small dosage) directly inhibiting vomiting center 呕吐中枢 (large dosage) altering temperature-regulating mechanisms decrease temperature no matter normal or high temperature body temperature varies with the environment

　　autonomic NS effects blocking α-R vasodilatation “epinephrine reversal” blocking M-R atropine-like action endocrine system action increasing prolactin催乳素 secretion inhibiting gonadotropic hormone促性腺激素， growth hormone生长激素 secretion

　　Therapeutic uses

　　schizophrenia 精神分裂症 more effective in treating positive symptoms severe nausea and vomiting useful in the treatment of drug-induced nausea hypothermic anesthesia 低温麻醉 and artificial hibernation 人工冬眠 chlorpromazine – promethazine – pethidine (氯丙嗪 – 异丙嗪 – 哌替啶)

　　Adverse effects common adverse effects CNS depression (drowsiness, indifference) M-R block (blurred vision, dry mouth) α-R block (orthostatic hypotension 体位性低血压) extrapyramidal reaction 锥体外系反应 Parkinson's syndrom akathisia 静坐不能 acute dystonia 急性肌张力障碍 treated by antimuscarinic drugs (artane,安坦 )

　　tardive dyskinesia 迟发性运动障碍 treated by antidopamine drugs (clozapine,氯氮平) Neural antagonist severe symdrome drug-induced mind abnormality convulsion惊厥 and epilepsy癫痫 allergic reaction acute hypogranulocytosis (粒细胞减少症) cardiovascular and endocrine system reaction acute poisoning 急性中毒

　　Thioxanthenes 硫杂蒽类 chlorprothixene 氯普噻吨(泰尔登) Butyrophenones 丁酰苯类 haloperidol 氟哌啶醇 Others penfluridol 五氟利多 clozapine 氯氮平

　　Clozapine (氯氮平) Benzodiazepines Pharmacological effect Blocking 5-HT, D2 receptor Strong efficacy, rapidly No extrapyramidal reaction Blocking H1, M andαreceptor hypogranulocytosis

　　Antimanic drugs

　　Bipolar affective disorder (双极性情感障碍) Cyclic manic attacks (往复性躁狂发作) In high spirit (情绪高涨) Overactivity (过度活动) Paranoid thoughts (妄想)

　　Lithium Carbonate (碳酸锂)

　　Clinical use Based on the Li+ treatment for bipolar disorder manic phase particularly prophylactic Li may block both manic and depressive

　　Adverse effects GI tract nausea, vomiting, diarrhea mental confusion, tremor, aphasia 失语症, choreoathetosis 舞蹈症, coma Management of Li overdosage: peritoneal dialysis腹膜透析or hemodialysis iv NaCl

　　ANTIDEPRESSANTS

　　DEPRESSION

　　Types Symptoms Diagnosis Causes Treatment

　　TYPES OF DEPRESSION

　　Major depression Chronic depression (Dysthymia) Atypical depression Bipolar disorder/Manic depression Seasonal depression (SAD)

　　CAUSES OF DEPRESSION

　　Genetics Death/Abuse Medications

　　SYMPTOMS

　　persistently sad, anxious, or empty moods loss of pleasure in usual activities (anhedonia) feelings of helplessness, guilt, or worthlessness crying, hopelessness, or persistent pessimism fatigue or decreased energy loss of memory, concentration, or decision-making capability restlessness, irritability sleep disturbances change in appetite or weight physical symptoms that defy diagnosis and do not respond to treatment (especially pain and gastrointestinal complaints) thoughts of suicide or death, or suicide attempts poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)

　　More than 50 % of patients with depressive disorders don’t realize that they have any psychological problems and complain only on certain somatic discharges

　　Most frequent complaints of patients with depression Feeling of hopelessness, indifference, fear, panic Tiredness, weakness, headache, dizziness, dream disorders, dyspepsia, unpleasant feelings and pain in different parts of the body Depressive conditions “mask” as vegetovascular, neurocirculative dystonia (various vegetative disorders), gastro-intestinal pathology, pathology of cardio-vascular, respiratory systems, manifest as diskinesia, functional motor disorders, insomnia, toothache, disorders of sexual activity, recidivate eczema and many other disorders

　　TREATMENT FOR DEPRESSION

　　Psychotherapy Electroconvulsive therapy Natural alternatives Medication SSRIs MAOIs TCAs SNRIs NDRIs TeCAs

　　ANTIDEPRESSANTS

　　Drugs which inhibit neuronal uptake of monoamines Nonselective action (block uptake of noradrenaline and serotonine): imisin, amitriptilin Selective action: а) heterocyclic compounds (block neuronal uptake of noradrenaline): amoxapin, maprotilin (ludiomil); б) selective blockers of neuronal uptake of serotonin: fluoxetin (prozak, framex), sertralin (zoloft), paroxetin (rexetin) Inhibitors of monoaminoxidase (IMAO) nonselective (block МАО-А and МАО-В): а) irreversible action – nialamid; b) reversible action – transamin Selective ?МАО (block МАО-А): moklobemid, pirasidol

　　TCAS MECHANISM OF ACTION

　　TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake TCAs also allow for the down regulation of post-synaptic receptors All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

　　TCAS SIDE EFFECTS

　　Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence Histamine H1 receptor antagonism - sedation and weight gain Adrenergic α receptor antagonism - postural hypotension Direct membrane effects - reduced seizure threshold, arrhythmia Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

　　TCAS SIDE EFFECTS

　　Nonselectivity results in greater side effects TCAs can also lead to cardiotoxicity Increased LDH leakage Slow cardiac conduction High potency can lead to mania Contraindicated with persons with bipolar disorder or manic depression

　　MONOAMINE OXIDASE (MAO) AND DEPRESSION

　　MAO catalyze deamination of intracellular monoamines MAO-A oxidizes epinephrine, norepinephrine, serotonin MAO-B oxidizes phenylethylamine Both oxidize dopamine nonpreferentially MAO transporters reuptake extracellular monoamine

　　MAOIS MECHANISM OF ACTION

　　MAO contains a cysteinyl-linked flavin MAOIs covalently bind to N-5 of the flavin residue of the enzyme

　　Blockers of neuronal uptake of serotonin

　　Modern point of view on mechanism of development of depression Primary deficiency of serotonin in synaptic gap Compensatory growing of quantity and sensitivity of postsynaptic 5-НТ2 receptors Compensatory decreasing of quantity and sensitivity of presynaptic 5-НТ1 receptors in hippocampus and nuclei row (these structures play an important role ?n development of depression)

　　Blockers of neuronal uptake of serotoninfluoxetin, sertralin, paroxetin

　　Mechanism of action Increasing of active concentration of serotonin in synaptic gap on a level of postsynaptic 5-НТ2 serotonin receptors of cerebral structures

　　Blockers of neuronal uptake of serotoninfluoxetin, sertralin, paroxetin

　　SSRIs SIDE EFFECTS

　　Anhedonia (disambiguation) Apathy Nausea/vomiting Drowsiness or somnolence Headache Bruxism (involuntarily grinding of the teeth) Extremely vivid and strange dreams Dizziness Fatigue Changes in sexual behavior Suicidal thoughts

　　SSRIs SIDE EFFECTS

　　Many disappear within 4 weeks (adaption phase) Side effects more manageable compared to MAOIs and TCAs Sexual side effects are common SSRI cessation syndrome Brain zaps Sexual dysfunction

　　SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)

　　Slightly greater efficacy than SSRIs Slightly fewer adverse effects than SSRIs Current drugs Venlafaxine (Effexor) Duloxetine (Cymbalta) Mechanism of Action Very similar to SSRIs Works on both neurotransmitters Side effects Similar to SSRIs Suicide

　　Usage of antidepressants

　　Schizophrenia, Bipolar disease Atherosclerosis of brain Reactive depressions Parkinsonism Organic diseases of CNS Oncology patients General somatic diseases

　　Psychotropic action of antidepressants

　　Drugs with psychosedative action: Аmitriptilin, maprotilin, asafen, fluvoxamin 2. Drugs with psychostimulative action: Imisin, nialamid, fluoxetin 3. Drugs with regulative influence Pirasidol

　　Principles of antidepressants usage

　　Endogen depression – the deeper it is, the larger doses, rate of their increasing and duration of treatment should be administered Step-by-step dose increasing till obtaining of effect, administration of effective dose during 4-6 weeks – 3-6 months, gradual decreasing of dose (during 5-6 weeks) Effect can appear only after 7-14 days after beginning of therapy (this fact should be taken into consideration in patients with suicidal dispositions) In case of rapid abolishing withdrawal syndrome may develop

　　Side effects of antidepressants

　　М-cholinoblocking action: dry mouth, increasing of intraocular pressure, disturbance of accommodation, constipation, ischuria (important in a case of adenoma of prostatic gland!), tremor, hallucinations, disorders of consciousness, excitation Alpha-adrenoblocking, papaverine-like effect: sharp hypotension, orthostatic collapse (especially in combination of amitriptiline with clopheline), for correction of which adrenomimetics can’t be used (it is necessary to increase volume of circulating blood, put the legs up)

　　Side effects of antidepressants

　　Acute attacks of epilepsy Cardiotoxic action (sudden death), three- cyclic antidepressants increase arrhythmogenic activity of drugs for general anesthesia, antihistamines etc. Combination of three-cyclic antidepressants with IMAO is absolutely contraindicated: danger of development of hypertensive crisis, seizures, rapid excitation, tachycardia, cardiac arrhythmias, increasing of temperature

　　Rules of transferring from one kind of antidepressants to another

　　From three-cyclic to IMAO – break time– 2-3 days From IMAO to three-cyclic – break time – not less than 2 weeks

　　It is absolutely contraindicated to administer adreno(sympato)mimetics in case of treatment with antidepressants

　　Even small doses of adrenomimetic (sympatomimetic) substances in such patient can cause hypertensive crisis: Nose drops for rhinitis If few drops were added to solutions of local anesthetics In case of administration of drugs which contain pseudoephedrine

　　Diet in case of administration of IMAO

　　It is necessary to exclude such products which contain DOPA and thiramine (which is formed from casein during the process of transforming under the influence of bacteria) aged cheese, kefir Marinated herring Smoked meat, fish Red vine, beer, yeast Beans Any BAA are also dangerous In case of treatment with IMAO new products should be introduced into ration very carefully

　　In case of administration of inhibitors of uptake of serotonin the previously indicated side effects are observed much more rarely Administration of antidepressants with any other drugs should be performed only after precise studying of possible negative consequences of their interaction

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