ReviewNeuroleptic drugs12Chapter 20Narcotic AnelgesicsObjectivesUnderstand the pharmacological effects, mechanism of actions, clinical uses, as well as adverse drug reactions of morphine.Identify the therapeutic effects and adverse drug reactions of codeine and pethidine. Section oneIntroduction451.2 Analgesics DefinitionDrugs that selectively inhibit the perception (sensation) of the pain Classification 1- Peripheral: - Causal: Atropine, NSAIDs - Non-causal2- Central: - Narcotic analgesicsPeripheral analgesics Causal -Treat the causeExample: Atropine (antispasmodic) Aspirin Non-causal- Not treat the causeExamples:1- Local anaesthetics (for superficial tumor)2- Counter-irritant (apply pain that counteract or mask the original one e.g. acupuncture)Narcotics NSAIDsExamplesMorphineAspirinSite of actionCortex & thalamusPeripheralAntagonistNaloxoneNo antagonistUsesSever & deep pain e.g. cancer, MI & anginal painDull pain e.g. headache, toothache & backachePotencyHighLowSide effectAddictionNo addiction. in bleeding tendency & ulcerMechanism stimulate opiates receptors (m, k , d) m, k , d) and relief the painInhibits PG synthesis by inhibition of COX-2The actions listed for antagonists are seen with the antagonist alone. All the correlations in this table are based on studies in rats and mice, which occasionally show species differences.10Section two MorphineNaturally occurring in the poppy (16%)- Only needs to be isolatedVery strong pain reliever but also very addictive (2nd to Heroin)Usually injected but can be smoked, sniffed or swallowedCommonly used in hospitals2.1 Introduction121) 3位位-OH的的H被被-CH3取代，取代，中枢抑制作用中枢抑制作用。如：。如：可待可待因（因（codeine)2) 3位和位和6位位-OH的的H同时被同时被-COCH3取代，取代，中枢抑制作中枢抑制作用用。如：。如：海洛因海洛因(heroin)3) 17位的位的-CH3被被-CH2CH=CH2取代，则变为取代，则变为吗啡受体的吗啡受体的部分激动药，部分激动药，如：丙烯吗啡如：丙烯吗啡(nalorphine)。若同时将若同时将6位的位的-OH变为变为=O，则变为，则变为吗啡受体的完全吗啡受体的完全拮抗药，拮抗药，如：如：纳洛酮纳洛酮 (naloxone)2.2 构效关系构效关系14152.3 Mechanisms of ActionuMost neurons react to opioids with a hyperpolarization, reflecting an increase in K+ conductance. uCa2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of transmitters and decreased synaptic activity.uDepending on the cell population affected, this synaptic inhibition translates into a depressant or excitant effect.Morphine and opioids produce analgesia, affect mood and rewarding behavior, and alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine function.2.4 Pharmacological effects and mechanisms172.4.1 Effects on the CNS(1) AnalgesiauMechanisms and Sites of Opioid-Induced Analgesia: The analgesic effects of opioids arise from their ability to directly inhibit the ascending transmission of nociceptive information from the spinal cord dorsal horn (脊髓背角) and to activate pain control circuits that descend from the midbrain via the rostral ventromedial medulla(延脑头端腹内侧区) to the spinal cord dorsal horn.18uCharacteristics: A significant feature of the analgesia is that it occurs without loss of consciousness.In addition to relief of distress, some patients experience sedation, euphoria, and rewarding properties.Continuous dull pain is relieved more effectively than sharp intermittent pain, but with sufficient amounts of opioid it is possible to relieve even the severe pain associated with renal or biliary colic.19(2) Respiration. The primary mechanism of respiratory depression by opioids involves a reduction in the responsiveness of the brainstem respiratory centers to carbon dioxide. The second mechanism of respiratory depression is via a direct effect on the brainstem respiratory centers. 20(3) Cough. Morphine and related opioids also depress the cough reflex at least in part by a direct effect on a cough center in the medulla.(4) Nauseant and Emetic Effects. Nausea and vomiting produced by morphine-like drugs are side effects caused by direct stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla.21(5) Miosis. Morphine and most and agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. After toxic doses of agonists, the miosis is marked, and pinpoint pupils are pathognomonic.瞳孔扩大瞳孔扩大 正常瞳孔正常瞳孔 针尖样瞳孔针尖样瞳孔22(6) Neuroendocrine Effects. Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and -endorphin.232.4.2 Effects on the peripheral smooth muscle(1) Stomach. Relatively low doses of morphine decrease gastric motility, thereby rolonging gastric emptying time.(2) Small Intestine. Morphine diminishes biliary, pancreatic, and intestinal secretions and delays digestion of food in the small intestine.The amplitude of the nonpropulsive type of rhythmic, segmental contractions usually is enhanced, but propulsive contractions are decreased markedly. 24(3) Large Intestine Propulsive peristaltic waves in the colon are diminished or abolished after administration of morphine.The tone of the anal (肝门）sphincter is augmented greatly, and reflex relaxation in response to rectal distension （直肠扩张） is reduced. Inattention to the normal sensory stimuli for defecation（通便） reflex owing to the central actions of the drug, contribute to morphine-induced constipation.(4) The sphincter of Oddi constricts, and the pressure in the common bile duct may rise.(5) Ureter （输尿管）（输尿管）and Urinary Bladder. Therapeutic doses of morphine may increase the tone and amplitude of contractions of the ureter, although the response is variable.(6) Uterus（子宫）（子宫）. If the uterus has been made hyperactive by oxytocics（催产素）, morphine tends to restore the tone, frequency, and amplitude of contractions to normal.(7) Morphine causes histamine release, which can cause bronchoconstriction and vasodilation.262.4.3 Cardiovascular System. Therapeutic doses of morphine like opioids do produce peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor（压力感受器）reflexes. Therefore, when supine patients assume the head-up position, orthostatic hypotension and fainting may occur.Morphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension.opioid-induced respiratory depression and CO2 retention can result in cerebral vasodilation and an increase in cerebrospinal（脑脊髓的） fluid pressure;272.4.4 Immune SystemThe overall effects of opioids appear to be immunosuppressive, and increased susceptibility to infection and tumor spread have been observed.2.5 Therapeutic Uses2.5.1 Analgesia. For the treatment of acute pain, trauma, cancer, nonmalignant chronic pain, and pain in children.Pain of Terminal Illness and Cancer Pain. the analgesia, tranquility, and even euphoria afforded by the use of opioids can make the final days far less distressing for the patient and family.In general, it is recommended that opioids always be combined with other analgesic agents, such as NSAIDs or acetaminophen. In this way, one can take advantage of additive analgesic effects and minimize the dose of opioids and thus undesirable side effects.28Fig. 19-3 The analgesic regimen recommended by WHO for cancer pain. 2.5.2 Dyspnea（呼吸困难）（呼吸困难） Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to intravenous morphine may be dramatic. It may involve an alteration of the patients reaction to impaired respiratory function and an indirect reduction of the work of the heart owing to reduced fear and apprehension（忧虑）. However, it is more probable that the major benefit is due to cardiovascular effects, such as decreased peripheral resistance and an increased capacity of the peripheral and splanchnic （内脏的）vascular compartments.2.5.3 Cough2.5.4 Diarrhea（腹泻）（腹泻）2.6 Side Effects2.6.1. Morphine has many side effects. The most dangerous is respiratory depression. -Naloxone2.6.2. With higher doses or in frail patients, the patient becomes increasingly sedated, and the pupils become very small. 2.6.3. Common side effects are nausea and vomiting due to a central action of morphine stimulating one of the centres in the brain concerned with vomiting called the chemotactic trigger zone. Side Effects2.6.4. Tolerance. With repeated administration of opioids, their CNS effects undergo habituation (adaptation). In the course of therapy, progressively larger doses are thus needed to achieve the same degree of pain relief.2.6.5. Other central nervous system side effects of morphine is addiction (dependence).-Methatone (opioid receptor agonist) -Clonidine ( 2-R agonist) Side Effects2.6.6. Morphine can also cause histamine release, which causes itching of the skin and nose and a mild flushing of the skin. 2.6.7. Morphine also has an effect on the muscle of the bowel and urinary tract, causing the sphincter to contract and reduce the peristalsis (the wavelike movements of the bowel muscle that propel its contents forwards). This results in a delayed emptying of the stomach, constipation, and may also lead to urinary retention.352.6.8. Acute opioid toxicity may result from clinical overdosage, accidental overdosage in addicts, or attempts at suicide.Symtoms: Three Cardinal Symptoms: coma, pinpoint pupils, and depressed respiration strongly suggests opioid poisoning. Others: blood pressure will fall progressively; hypoxia is severe and cyanosis may be present. urine formation is depressed. Treatment. The first step is to establish a patent airway and ventilate the patient. The antagonist naloxone (see below) is the treatment of choice.2.7 KineticsMorphine can be given orally or parenterally, as well as epidurally(硬脑膜外地) or intrathecally(鞘内地) in the spinal cord.Morphine is conjugated to glucuronic acid and excreted renally. Glucuronidation of the OH group at position 6, unlike that at position 3, does not affect affinity for the receptors.3637NauseavomittingPinpointpupilsSection 3Other analgesicsCodeineCodeine is considered a prodrug, since it is metabolised in vivo to the principal active analgesic agent morphine. It is, however, less potent than morphine since only about 10% of the codeine is converted.Uses of Codeine1. Cough, though its efficacy in low dose over the counter formulations has been disputed.2. Moderate to severe pain. Codeine is sometimes marketed in combination preparations with patacetamol (acetaminophen), with aspirin or with ibuprofen. These combinations provide greater pain relief than either agent (drug synergy).42 Pethidine (dolantin) In the treatment of mild-to-moderate pain.Pethidine can be used to treat labor pain and may cause less neonatal respiratory depression.43Common side effects of pethidine include nausea, vomiting, dizziness, dry mouth, sedation, and headache. Respiratory depression appears to be less than with equianalgesic doses of morphine, and the degree of constipation is less than that seen after equivalent doses of codeine.MethadoneCompared to most strong analgesics it is weaker.Has been synthesized to not have euphoric properties and mild withdrawal effects but is still addictive.Used as an analgesic but most commonly to help in the withdrawal for heroin addicts.45NaloxoneNaloxone is a drug used to counter the effects of opioid overdose, for example， heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system.46 常用镇痛药的作用比较常用镇痛药的作用比较药物药物 镇镇 镇镇 止止 抑制抑制 成瘾成瘾 呕呕 痛痛 静静 咳咳 呼吸呼吸 性性 吐吐吗啡吗啡 + + + + + +可待因可待因 + + + + + + 度冷丁度冷丁 + + + + +芬太尼芬太尼 + + + + +镇痛新镇痛新 + + + +美沙酮美沙酮 + + + + +罗通定罗通定 + + 47药药 名名 临临 床床 应应 用用吗吗 啡啡 其它镇痛药无效的锐痛其它镇痛药无效的锐痛、心性哮喘、心性哮喘、 心绞痛、止泻。心绞痛、止泻。可待因可待因 中等程度的疼痛、无痰干咳中等程度的疼痛、无痰干咳度冷丁度冷丁 各种锐痛、各种锐痛、心性哮喘、心性哮喘、分娩止痛分娩止痛、人人 工冬眠工冬眠、麻醉前给药。、麻醉前给药。芬太尼芬太尼 各种剧痛、麻醉辅助用药。各种剧痛、麻醉辅助用药。镇痛新镇痛新 各种慢性剧痛、术后止痛。各种慢性剧痛、术后止痛。美沙酮美沙酮 创伤、手术、晚期癌症等剧痛、创伤、手术、晚期癌症等剧痛、吸毒吸毒 成瘾者成瘾者。罗通定罗通定 慢性钝痛慢性钝痛、内脏疾病引起的、内脏疾病引起的钝痛。钝痛。常用镇痛药的用途常用镇痛药的用途