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Antipsychotic agents ----Schizophrenia (精神分裂症), is a particular kind of psychosis characterized by a clear sensorium but a marked thinking disturbance Case Study • W.G, 19 years old, undergraduate, member of rowing team of school, was found staying by himself, avoiding the company of friends and skipping school and athletic training. Later, he was heard speaking to himself as he sat isolated in his room, mumbling and smiling. Then he confided to his roommate that he had uncovered a grand conspiracy to rob him of his athletic abilities and that he could hear the conspirator’s voices as they planed to destroy him. Finally, he accused his roommate of being a part of the conspiracy. Epidemiology • Incidence consistent worldwide --1% general population --10% siblings , parents / offspring, dizygotic twins --50% monozygotic twins • Environmental factors implicated --Prenatal stress - infection, famine, war, death of spouse --Season of birth - winter > summer --Urban setting > rural setting • Age of onset --Men 17 - 27, Women 17 - 37 --Childhood onset extremely rare: 1 in 10,000-100,000 • Outcome --10% good - optimistic --80% remission(缓和) without full recovery --10% no remission Signs & Symptoms 1. Positive symptoms • Delusions (错觉)- fixed false beliefs outside cultural norm (bizarre vs. non bizarre) • Hallucinations (幻觉)- perceptual (hearing), have no outside source •“Like my voice” • Not an illusion (幻想,a mistaken perception for which there is an actual external stimulus) • Disorganization – pattern of speech/thought/behavior, making up words without a meaning (neologisms) Signs & Symptoms 2. Negative symptoms • Affective flattening (absence of emotional expressiveness) • Avolition/Amotivation (decreased motivation) • Autistic behaviors (social withdrawal) • Anhedonia (inability to experience pleasure ) • Ambivalence (coexistence of opposing attitudes or feelings) • Anosognosia (impaired awareness of illness ) Historical Perspective • Chlorpromazine (氯丙嗪) made in 1950 in France, used to treat pre-operative anxiety • 1952 Delay and Deniker published the first report of Chlorpromazine's efficacy in psychosis • 1963 Carlsson and Lindquist report that Haloperidol and Chlorpromazine result in accumulation of DA metabolites • D2 hypothesis (excessive dopaminergic activity plays a role in the disorder) - 1976 Seeman et. al. and Creese et. al. report that “potency” of DA antagonism at D2 related to efficacy • Refs: http://www.bedrugfree.net/Schizophrenia.pdf Film: One Flew Over the Cuckoo’s Nest (1975) Classification of antipsychotics Typical: • Phenothiazines (吩噻嗪类): chlorpromazine • Thioxanthenes (硫杂蒽类): chlorprothixene • Butyrophenones (丁酰苯类): haloperidol Atypical: • Clozapine(氯氮平), olanzapine(奥氮平), risperidone(利培酮) Available Medications • Typical medications (D2 receptor antagonists) – Low potency agents - Chlorpromazine (sedation) – High potency agents - Haloperidol (motor problems – extrapyramidal effects) • Atypical agents – Clozapine – 5-HT2 and D4 receptor antagonist, great efficacy – Olanzapine (奥氮平)– 5-HT2, D1, D2, M, H, αreceptor antagonist, good – Risperidone (利培酮)– 5-HT2 and D2 receptor antagonist, good Typical Antipsychotics • Good ability to treat hallucinations and delusions in most people within approximately 2 months • Limited effect on negative symptoms – Flat affect – Avolition – Anhedonia – Alogia – Attentional impairment (Cognition) Dopaminergic pathways in CNS and drugs for schizophrenia A. mesolimbic and mesocortical pathways related with psychological activities and the therapeutic effects of drugs. B. nigrostriatal pathway related with extrapyramidal adverse effects of drugs C. Tuberohypophyseal pathway related with hypothalamus endocrine adverse effects of drugs Chlorpromazine 1. Pharmacological effects (1) Central effects a) Antipsychotic effects (neuroleptic effects) -- controls excitation and then hallucinations (slow, weeks to months) b) Antiemetic effects -- inhibits chemoreceptor trigger zone (CTZ) in the medulla Chlorpromazine c) Poikilothermic effects (comparison with NSAIDs) -- hypothermic anesthesia -- artificial hibernation (with meperidine哌替啶, promethazine异丙嗪) d) Extrapyramidal effects (nigrostriatal pathway blockade) -- primary adverse effects e) Potentiating the effects of central depressants -- sedative-hypnotics, analgesics, general anesthetics, ethanol Chlorpromazine (2) Effects on autonomic nervous system a) Hypotensive effects receptor blockade, postural hypotension b) Anticholinergic effects dry mouth, constipation, blurred vision, urinary retention, increased intraocular pressure, etc. Chlorpromazine (3) Endocrine effects (Tuberohypophyseal pathway blockade) Prolactin Estrogen, progestin, ACTH, growth hormone Chlorpromazine 2. Clinical uses (1) Treatment and prevention of acute schizophrenia and mania (2) Treatment of emesis and hiccough but ineffective on motion sickness (3) Hypothermic anesthesia and artificial hibernation combined with lowering room temperature Chlorpromazine 3. Side effects • Motor - proportional to D2 blockade of nigrostriatal pathway – EPS (extrapyramidal syndrome) - misnomer, stiffness, tremor (parkinsonism), akathisia (inability to sit still ), acute dystonia (twisting and repetitive movements or abnormal postures) • TD (tardive dyskinesia)- licking, sucking, chewing (twitching of the muscles around the mouth), described before meds existed, exacerbated in some, may be irreversible Chlorpromazine 3. Side effects • NMS (neuroleptic malignant syndrome, induced by excessive blocking of DAergic system): high fever, hypertension, tonus, autonomic system disorder, even death. Treatment: DA agonists (eg bromocriptine), DA releasers (eg amantadine), and muscular relaxants (eg scoline) Chlorpromazine 3. Side effects • • • • • • Sedation Cardiac - lengthen QT interval Seizures Endocrine - prolactin elevations Drooling(流涎) Weight gain Haloperidol 氟哌啶醇 • • • • • • High efficacy for positive symptoms Weaker sedative effect Weaker and M receptor antagonism More severe EPS Also can be used for anxiety, hiccup, vomiting Terotogenicity (Class C, should be given only if the potential benefit justifies the potential risk to the fetus) Then came clozapine(氯氮平) • • • • • Worked better than the rest (on some patients) Relatively weak binding at dopamine D2 receptor Better efficacy at lower D2 receptor occupancy Relatively stronger binding at serotonin receptors “Dirty” drug - acts at many different types of receptors (D4, D2, 5-HT2) Other atypical antipsychotics: olanzapine(奥氮平), loxapine(洛沙平), risperidone(利培酮), aripirazole(阿立哌 唑), etc. “Atypical” Antipsychotics Many definitions: • Work better on positive symptoms ? - No • Work for “negative symptoms” ? – Some • Better cognitive effect- No • Less hormonal side effects ? - Prolactin Sometimes • More easily tolerated? - equivocal, likely dose dependent • Less motor side effects ? - Yes Case study --continued W.G. was taken to see a psychiatrist. He was diagnosed schizophrenia and hospitalized. Haloperidol was started at a dose of 10 mg/d. On the second day, he was found to develop a “seizure”. His neck was strained backward with his face turned upward toward the ceiling. He was having difficulty speaking but was quite conscious of his surroundings. The attending physician recognized this as an acute dystonia and ordered an immediate injection of benztropine. Haloperidol was replaced with loxapine accompanied with benztropine. 3 weeks later, his delusions and hallucinations disappeared and he developed insight into his problems. One month later, he left the hospital and resumed his academic life. Compliance with Medication • Studies show that 50% of all people do not consistently take medications as prescribed all illnesses. • Some studies have found as few as 20% of people take antipsychotics as recommended. • Severe consequences to stopping medication • Most significant advances on the horizon are likely going to involve improved compliance interventions Antidepressant Agents Depression (抑郁症) is a kind of mood disorders (mania, depression, anxiety) with symptoms such as intense feelings of sadness, hopelessness, despair, and inability to experience pleasure in usual activity. Lecture Outline • Depression • Neurotransmitter systems associated with the disease and the treatment • Classifications of antidepressant drugs - chemical structure - efficacy, side effects, toxicity - mechanism of action • Other therapy for depression Leading Sources of Disease Burden* • • • • • • • Ischemic Heart Disease Unipolar Major Depression Cardiovascular Disease Alcohol Use Traffic Accidents Lung and other cancers Dementia and Neurodegenerative Disorders *based on DALY’s (Disability Adjusted Life Years, WHO) which measure lost years of healthy life due to premature death or disability Criteria for Diagnosis of Major Depression • Depressed Mood • Fatigue or loss of energy • Loss of interest or pleasure in almost all activities • Feelings of worthlessness or inappropriate guilt • Significant weight loss or gain or change in appetite nearly every day • Diminished ability to think or concentrate; indecisiveness • Insomnia or hypersomnia • Psychomotor agitation or retardation • Recurrent thoughts of or attempts at suicide; wishing one were dead At least 2 weeks of ≥5 of the above features, which are present most of the day or nearly every day; must include depressed mood or loss of interest or pleasure. Monoamine Hypothesis of Depression • Functional deficiency of Norepinephrine (NE) or Serotonin (5-Hydroxytryptamine, 5-HT) in the brain is key to the pathology and behavioral manifestations associated with depression. 中缝核 兰斑核 Classifications of Antidepressants • Tricyclic Antidepressants (TCAs,三环类抗抑郁药) and heterocyclics • Selective Serotonin Reuptake Inhibitors (SSRIs) • Selective Norepinephrine Reuptake Inhibitors (NRIs) • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) • Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) • Monoamine Oxidase Inhibitors (MAOIs) • Norepinephrin-Serotonin Releasers TCA’s are highly related in their chemical structures 丙咪嗪 Doxepin 多塞平 氯丙咪嗪 阿米替林 去甲替林 地昔帕明 NRIs TCAs Mechanisms: Non-selective monoamines (mainly NE and 5-HT) reuptake inhibitors Clinical uses: depression, anxiety, obsessive compulsive disorder, panic disorder, neuropathic pain, enuresis Side effects Toxicity - Narrow dose response range. Normal plasma levels 0.1-0.2 mg/ml Toxic effects are seen at 1.0 mg/ml Anticholinergic - dry mouth, constipation, dizziness, blurred vision, tachycardia, urinary retention Hypotension and Sedation - due to adrenergic blocking properties and/or anti-histaminergic Selective norepinephrine reuptake inhibitors For severe depression 尼索西汀 地昔帕明 托莫西汀 去甲替林 瑞波西汀 Amoxapine 阿莫沙平 Selective serotonin reuptake inhibitors: used for both anxiety and depression 氟西汀,百忧解 舍曲林 帕罗西汀 茚达品 氟伏沙明 西酞普兰 Side effects • GI upset, weight gain and low libido • Serotonin Syndrome: - Occurs when switching among SSRIs or to other drug classes - Potential for over-activation of central serotonin receptors - Features: abdominal pain, diarrhea, sweating, fever, tachycardia, increased blood pressure, tremor and altered mental state, or even coma and death Eric Harris Fluvoxamine taker (Luvox) Dylan Klebold Columbine High School massacre Norepinephrine-dopamine reuptake inhibitors Bupropion 安非他酮 • Glaxo Wellcome product • Inhibits NE, DA and serotonin reuptake • No weight gain or sexual dysfunction Serotonin-norepinephrine reuptake inhibitors 度洛西汀 文拉法辛 Used for depression and generalized anxiety disorder obsessive compulsive disorder panic attacks neuropathic pain (duloxetine) Adverse effects: GI upset, headache, insomnia Monoamine Oxidase Inhibitors (MAOIs) MAO: ---Regulates free intraneuronal concentration of NE or 5-HT ---Regulates inactivation of endogenous and ingested amines Side effects: few anticholinergic, adrenergic side effects but toxicity associated with dietary interactions (tyramine) 司来吉兰 吗氯贝胺 MAOIs and Dietary Interactions • Tyramine is normally metabolized by MAO • Tyramine is sympathomimetic (it acutely displaces NE from terminals to activate receptors) • Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomiting • Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc. Norepinephrin-serotonin releaser - Mirtazapine (米氮平) - Blocks presynaptic 2 receptor - Promotes the release of NA and 5-HT - Weight gain and postural hypotension are main adverse effects Clinical Pharmacology of Antidepressants • Depression: antidepressants, lithium • Panic disorder: benzodiazepine, SSRIs, MAOIs • Obsessive-compulsive disorders: selective and mixed serotonin reuptake inhibitors • Enuresis: tricyclics • Neuropathic pain: tricyclics, norepinephrine reuptake inhibitors Individualized therapy • Drug choice • Dosages: from small doses • Maintenance treatment: 6-8months after remission, gradually withdraw • Monitoring plasma concentrations • Unresponsive patients: diagnosis, drug, dose, duration of treatment (6-8wks), and different treatments Alternative Treatments for Depression • Herbal Therapy- St. Johns wort (Hypericum perforatum) • Electroconvulsive Therapy • Transcranial Magnetic Stimulation • Exercise Herbal Therapy St. Johns wort (Hypericum perforatum) • Used extensively in Europe for mild to moderate depression • British Study - found St. John’s Wort as effective as Paxil (Paroxetine) • NIH - 3year study found no significant antidepressant effect Electroconvulsive Therapy • Brief electrical pulse to the scalp under anesthesia • Neurons are excited causing them to fire in unison and produce a seizure • Mechanism of effectiveness is unknown Electroconvulsive Therapy • 1930s: used for numerous psychiatric illnesses • 1970s: improved treatment delivery, increased safety and comfort resulted in increased use • Most effective in severe depression and medication response failure • Treatments are administered 3X week for a course of 6-12 treatments total • Effects can be seen more rapidly (1-2 weeks) than typical pharmacotherapy (3-6 weeks) Transcranial Magnetic Stimulation • Safe and noninvasive means of getting electrical energy into brain • Procedure involves discharge of a large current (5000 amps) through a copper-wire coil • Magnetic field produces currents in the induced electrical field lying parallel to the plane of the coil • Currents can excite axons lying in the plane of the induced field in a manner similar to that achieved with direct cortical stimulation with electrodes Transcranial Magnetic Stimulation • Repetitive TMS (rTMS) • Similar to ECT but less intense and given over specific areas of the brain for a longer time than ECT • No anesthesia or seizure production Exercise Exercise as an augmenting Treatment for major Depressive Disorder: A Pilot Study Friedman. R., et al, Society for Neuroscience 2003 Abstract 851.9 *treadmill, walking or cycling for 12 weeks, 30 min for most days of the week Appendix Drugs for mania - Lithium carbonate - Antiphsychotics - Antiepileptics - Calcium channel blockers Appendix Drugs for mania Lithium carbonate • Lithium is an anti-mania drug with narrow TI; • Start with small dosage. Dosage regimens should be individually titrated to desired concentrations and clinical response of the patients; • The toxicity should be monitored regularly; • The patients and/or their families should be educated. Therapeutic range of lithium Disease or condition Therapeutic range Acute mania 0.5-1.2 mmol/L 1.2-1.5 mmol/L may be required in selected patients Prophylaxis of mania and/or depression 0.6-0.8 mmol/L Concentration-related toxicity of lithium Potential side effects under therapeutic concentrations: Agitation, cogwheel rigidity, confusion, delirium, dysarthria, increased deep tendon reflexes, memory impairment, seizures. Mild toxicity (>1.5 mmol/L): Fatigue, fine tremors of the limbs, gastrointestinal disturbances, muscle weakness Moderate toxicity (1.5-2.5 mmol/L): Ataxia, coarse tremors, dysarthria, headaches, hyperthermia, impaired sensorium, increased deep tendon reflexes, lethargy, nystagmus, sedation Severe toxicity (>2.5 mmol/L): Basal ganglia dysfunction, coarse tremors, delirium, respiratory complication, seizures, death Pharmacological Treatment of Parkinson’s Disease Parkinson’s disease, one of movement disorders, is a degenerative disease of the brain that often impairs motor skills, speech, and other functions Parkinson’s disease (PD) Tremor of one hand Parkinsonism: -Muscle rigidity -Tremor -Bradykinesia (slowness of motion), or even akinesia (loss of motor function) -Postural instability (propulsion, retropulsion). Dopaminergic neuronal loss in the substantia nigra Substantia nigra (striatum) Substantia nigra Imbalance of DA/ACh neuronal functions in extrapyramidal system of Parkinson’s disease Dopamine Acetylcholine How to reach the desired goal of pharmacological therapies for Parkinson’s disease? Different approaches including: I Increases in dopamine synthesis capacity (L-DOPA) II Direct activation of post-synaptic receptors III Inhibition of dopamine metabolism (MAOIs) IV Alteration of the interaction/balance with other neurotransmitters (Ach) V Dopamine releasers VI L-DOPA metabolism inhibitors (adjuvant) Note: All therapies treat the symptoms of the disease; none is neuroprotective and none slows the progression of the disease How to increase dopamine synthesis capacity? Provide DA precursor: L-DOPA (Levodopa ) OH OH OH Rationale for L-DOPA Precursor Loading: OH (AAAD) L-DOPA decarboxylase B6 O • Striatal dopamine levels are low OH NH L-Dopa in PD. • Dopamine does not pass BBB and, hence, has no therapeutic effect in PD. • L-DOPA , an amino acid, the immediate precursor to dopamine, is transported across BBB. 2 NH2 Dopamine What happens to L-DOPA in the periphery? L-DOPA peripheral metabolism How to reduce peripheral metabolism of L-DOPA? - peripheral decarboxylase inhibitor Carbidopa, a peripheral decarboxylase (AAAD) inhibitor, increases L-DOPA bioavailability; and decreases its adverse effects by allowing lower L-DOPA dosages to be used. BBB 息 宁 Periphery CNS L-DOPA L-DOPA AAAD AAAD Carbidopa - dopamine Peripheral adverse effects dopamine Therapeutic effects + What are the major adverse effects of L-DOPA? Early • Gastrointestinal effect: nausea or vomiting • Cardiovascular effect: tachycardia, hypertension, orthostatic hypotension • Emotional depression/ psychosis (clozapine) What are the major adverse effects of L-DOPA? Late – • Fluctuation of response: end-of-dose/“wearing off” periods; on/off periods (sudden loss of symptom control, akinesia alternates improved mobility). • Dyskinesia (months to years after, up to 80%, increase of involuntary movements: chorea, ballismus, athetosis, dystonia, myoclonus, tics, and tremor, any part of the body may be involved). How to reduce peripheral metabolism of L-DOPA? -- peripheral COMT inhibition HO O H HO C N C C CN O2N Entacapone • Reduces metabolism of L-DOPA in the periphery but not the CNS • Used as adjuvant with Sinemet (note: only effective when combined with L-DOPA) • May reduce “on-off” fluctuations and dyskinesias BBB 息 宁 3-OMD Periphery CNS L-DOPA L-DOPA Entacapone AAAD AAAD Carbidopa - dopamine Peripheral adverse effects dopamine Therapeutic effects + II. How to activate post-synaptic DA receptors? - Dopamine receptor agonists 1st generation agonists: (ergot derivatives) bromocriptine* (D2 agonist) (t1/2 ~ 12 h) pergolide* (D2/D3 agonist)(t1/2 ~ 24 h) 溴麦角环肽和培高利特 2nd generation agonists: ropinirole (t1/2 ~ 6 h) (D2/D3 agonist) pramipexole (D2 agonist) Bromocriptine N (t1/2 ~ 8 -12 h) 罗平尼咯和普拉克索 N Can be used as monotherapy for mild Ropinrole H parkinsonism, or combined with levodopa for N advanced disease, permitting the dose of H2N S levodopa to be reduced and smoothing out response fluctuations and dyskinesias. Pramipexole O N H 麦角生物碱类 Ergot Alkaloids (background) -isolated from the fungus Claviceps purpurea found on rye and wheat and other grains. -ergotism can cause nausea, and mild symptoms: diarrhea severe symptoms: hallucinations, delirium and seizures - main sites of action: 5-HT receptors, dopamine receptors and alpha 1 adrenergic receptors - causes uterine contraction, vasoconstriction, dopamine receptor agonist activity What are the major adverse effects of DA receptor agonists? • Dyskinesia and response fluctuation (lower incidence) • Some individuals develop a troubling sleep disorder, with sudden attacks of sleep (突然昏睡) during ordinary daytime activities (the second generation agonists) • Postural hypotension • Dose-related psychiatric side effects (similar to L-DOPA but may occur more frequently, especially in elderly) • Nausea or vomiting (drugs active at chemotrigger zone (CTZ) ) Dopamine Agonists Apomorphine (Apokyn)阿朴吗啡 - is a short-acting non-ergoline dopamine agonist (t1/2 ~ 40 min) at D1 and D2 receptors -can provide rapid “rescue” within 4 - 8 min after injection for an undermedicated or “frozen” state; indicated for the acute, intermittent treatment of hypomobility, "end-of-dose/wearing off" and unpredictable "on/off" episodes associated with advanced Parkinson’s disease. - morphine structural analog but lacks any analgesic actions or risk for causing dependence or addiction III. How to inhibit dopamine metabolism? - Selective MAO-B inhibition CH N Selegiline Rasagiline • MAO-B is the predominant form in the striatum and is responsible for the oxidative metabolism of dopamine. • At low therapeutic concentrations, these drugs irreversibly inhibit MAO-B selectively in the CNS • Peripheral metabolism of catecholamines (mostly through MAO-A) is unaffected. • Drug interactions (potentiation) with SSRIs & TCAs (reuptake blockers) (recall: MAO-A mostly outside brain; MAO-B > MAO-A in the brain) IV. How to alter the interaction/balance with other neurotransmitters (DA-ACh) ? “Balance” Hypothesis of DA-ACh Striatal Interactions Imbalance of dopamine and acetylcholine in Parkinson's disease. Effects of Parkinson's disease therapy. Muscarinic Receptor Antagonists N NCH2CH2COH Trihexyphenidyl CH3 C6 H 5 OCH Benztropine C6H5 • Weak efficacy (mostly for tremor) • Potential adverse effects: • neuropsychiatric: sedation, poor concentration/memory, confusional state. • blurred near vision due to mydriasis and cycloplegia. • dry mouth • constipation • urinary retention Note: antihistamines (eg., diphenhydramine: H1-antagonist) also have muscarinic antagonist properties V. How to increase DA release? NH2 Amantadine Used for mild Parkinson’s disease, as an early monotherapy • Mechanisms of action: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist) • The dose should be reduced with renal impairment. • Potential adverse effects: - CNS reactions (dizziness, anxiety, impaired coordination) - hyperkinesias - nausea, vomiting, etc DRUG THERAPY Review • Main Line Agents: • L-DOPA plus carbidopa (Sinemet®) • Dopamine receptor agonists (ropinirole) • Lower Efficacy/Second Line or Adjuvant Agents: • Anticholinergics • Reuptake inhibitor or releaser (amantadine) • COMT inhibitor (entacapone) • MAO B inhibitors (rasagiline, selegiline) Drug-Induced Parkinsonism • Reserpine, which depletes brain catecholamines, induces Parkinson’s disease symptoms • Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists. • N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine. MPTP first came to medical attention because it produced symptoms similar to Parkinson’s disease. Beyond Pharmacotherapy Striatum - mesencephalic fetal cell transplantation - genetically engineered cells, infusion of growth factors - viral vector therapy (deliver genes for tyrosine hydroxylase, and/or amino acid decarboxylase; neurotrophic factors - stem cells Surgery - radiofrequency lesion – pallidotomy - deep brain stimulation – subthalamic nucleus Photograph showing an electrode being inserted during deep brain stimulation Opioid analgesics (narcotic analgesics) and antagonists Crude opium Opium flowers Collecting resin of opium poppy Seeds of opium poppy 1. Classification of opiates • Natural opiates: morphine, codeine, papaverine and thebaine; • Semi-synthetic opiates: hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (Heroin), nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine; • Fully synthetic opioids: fentanyl, pethidine, methadone, tramadol and propoxyphene; • Endogenous opioid peptides: endorphins, enkephalins, dynorphins, and endomorphins. 2. Opioid receptors 2. Opioid receptors 2.1 Distribution and physiological effects: A Certain cells in the CNS: Brainstem: mediate respiration, cough, nausea and vomiting, maintain blood pressure, pupillary diameter and control of stomach secretions. Medial thalamus: modulate deep pain that is poorly localized and emotionally influenced. 2. Opioid receptors 2.1 Distribution and physiological effects : A Certain cells in the CNS: Spinal cord: involved in the reception and integration of incoming sensory information and attenuate painful afferent stimulation. Hypothalamus: affect neuroendocrine secretion. Limbic system: influence emotional behavior. 2. Opioid receptors 2.1 Distribution and physiological effects : B Periphery: --- Inhibit the release of excitatory, proinflammatory substances from nerve endings, which contribute to the antiinflammatory effect of opioids. C Immune cells: immune depression 2. Opioid receptors 2.2 Signal transduction: In the Spinal Cord 2. Opioid receptors In the Brain Stem 3. Opioids Summary of opioid analgesics and antagonists: Strong agonists: fentanyl, heroin, pethidine, methadone, morphine Moderate agonists: codeine Mixed agonist-antagonists: pentazocine Antagonists: naloxone, naltrexone Mainly agonist action at μ receptors, but some actions on other receptors •Morphine •Heroin •Codeine •Fentanyl ⊕ μ opioid receptor ⊕ κ opioid receptor Agonist action at κ receptors, with partial antagonist action at μ receptors •Pentazocine ⊕ opioid receptor Analgesia Analgesia Analgesia Respiratory depression Sedation/dysphoria Euphoria/sedation Pupil constriction Physical dependence Decreased GI motility Antagonist act at μ, κ, receptors Pupil constriction •Naloxone •Naltrexone Efficacy high Addiction/abuse low Morphine Pethidine Methadone Fentanyl Codeine A comparison of the maximum efficacy and addiction/abuse liability of commonly used narcotic analgesics Time to peak effect Duration of action Morphine Pethidine Fentanyl 20min 4 hours 15min 2 hours 5min 45min Time to peak effect and duration of action of several opioids administered intravenously 4. Morphine 4.1 Pharmacological effects: A Analgesia: - Raises the pain threshold at the spinal cord level, alters nociception in the brain. - Relieves anxiety and fear 解热镇痛药与阿片类镇痛药镇痛作用比较 阿片类镇痛药 解热镇痛药 作用部位 中枢 外周(主) 作用机制 激动阿片受体 抑制环氧酶, 使PG合成减少 镇痛特点 强大,伴有镇静作 用及欣快感 中等强度,无镇静作用 及欣快感 适应证 不良反应 用其他药无效的急性锐痛 易成瘾,抑制呼吸 慢性钝痛 无成瘾性及呼吸抑制 4. Morphine B Euphoria: - Produces a powerful sense of contentment and wellbeing by stimulation of the ventral tegmentum腹侧被盖. C Respiration: - Causes respiration depression by reduction of the sensitivity of respiratory center neurons to CO2. D Depression of cough reflex: - May allow accumulation of secretions and thus lead to airway obstruction and atelectasis (肺不张). - Replaced by other safer antitussives . 4. Morphine E Miosis: - The pinpoint pupil is the characteristic of morphine use, little tolerance. F Emesis: - Causes vomiting by stimulating the CTZ in the medulla but with no unpleasant sensations. 4. Morphine G Sedation: - Causes drowsiness and clouding of mentation, even disrupting sleep H Gastrointestinal effect: - Decreases motility of smooth muscle and increases tone, which causes constipation and increases pressure in the biliary tract (worsens abdominal colic, eg. Sphincter oddi contraction). 4. Morphine I Cardiovascular : - Has no major effects on the cardiovascular system. - Is usually contraindicated in individuals with severe brain injury (because that increased PCO2 induced by respiration depression leads to cerebral vasodilation and consequential increase in cerebral blood flow and intracranial pressure). - Causes postural hypotension sometimes. 4. Pharmacodynamics- morphine J Histamine release: - Causes pruritus搔痒症, urticaria荨麻疹, sweating, vasodilation and bronchoconstriction. K Hormonal actions: - Inhibits release of LH (黄体生成素). - Increases GRH (促生长激素), ADH (抗利尿激素), PRL (催乳素) M Immune depression 4. Morphine 4.2 Therapeutic uses: A Analgesia: - Used for various pain, especially acute, obstinate constant pain (e.g. burn, cancer pain); - Fixed interval of administration reduces tolerance and dependence; - Severe pain of renal and biliary colic + MR blockers. 4. Morphine B Cardiac asthma: - Acute left ventricular heart failure induces pulmonary edema - Reduces anxiety, cardiac preload and afterload. - Particularly useful for painful myocardial ischemia with pulmonary edema. C Treatment of diarrhea: synthetic surrogates (eg. 地芬 诺酯). 4. Morphine D Relief of cough: synthetic antitussives(eg. 右美沙芬) E Premeditate drugs before anesthesia : sedative, anxiolytic, and analgesic properties. For high-risk surgery administered systemically; for local (epidural) anesthesia. Caution: respiratory suppression 4. Morphine 4.3 Adverse effects: - Respiratory depression - Vomiting, constipation, biliary colic - Dysphoria - Allergy-enhanced or postural hypotensive effects - Urinary retention (prostatic hypertrophy) - Elevation of intracranial pressure (head injury) - Immune depression 4. Morphine Tolerance and Physical Dependence • Repeated use produces tolerance to the respiratory depression, analgesic, euphoric and sedative effects, but not to pupil-constricting and constipating effects. • Physical and psychologic dependence readily occur for strong μagonists, especially used on necessities. 4. Morphine Tolerance and Physical Dependence • Withdrawal symptoms: a series of autonomic, motor and psychological response that incapacitate the individual (rhinorrhea, lacrimation, yawning, chills, gooseflesh, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility). Druggy Malformation 4. Morphine 4.4 Contraindications: • Women during labor or lactation • New-born infants • Chronic obstructive pulmonary disease (COPD) • Asthma 5. Pethidine (meperidine) 5.1 Actions and mechanisms: • Binds to opioid receptors, particularly receptor. • Actions similar to but less potent than morphine. ----Transient decrease of gastro-intestinal motility and increase of the tone ---- Indistinctly central depression of cough reflex. 5. Pethidine (meperidine) 5.2 Therapeutic uses: • Analgesia: various severe pain, including during obstetric labor (less depression of respiration in newborn infants) • Cardiac asthma • Administration before anesthesia and artificial hibernation, combined with chlorpromazine (氯丙嗪) and promethazine (异丙嗪) 6. Pentazocine • An agonist on receptor, but a weak antagonist at and receptors (partial agonist). • Actions (less potent than morphine): analgesia and respiratory depression, indistinct euphoria and dependence. Dysphoria, hallucinations and hypertension in high dose • Used for moderate or chronic pain. 7. Naloxone • Competitive blocker of opioid receptor, with ten-fold higher affinity for receptor than for . • Actions: --- precipitates withdrawal symptoms; ---reverses the coma and respiratory depression of opioid overdose (short action duration! Naltrexone with much longer action duration); --- eliminates some adverse effects with opioids 8. Other analgesics • Tramadol: weak receptor agonist, inhibits uptake of NA and 5-HT, effective on moderate to severe acute and chronic pain. • Tetrahydropalmatine (延胡索乙素): effective on persistent blunt pain Guidelines for neuropathic pain WHO guidelines for cancer pain