1、镇痛药 Analgesics,北京协和医学院基础医学院药理学系 叶菜英,镇痛药Analgesics,Primary effect on CNS，eliminate or ease pain selectively，to lessen the nervous of patients ，these agents relieve pain without producing a loss of consciousness。They are used primarily to relieve acute and chronicity pain of any origin.,镇痛药Analgesics,
2、It has been know for centuries that extracts of the opium poppy can be used to relieve pain and treat diarrhea。 In 1806, Morphine was first isolated from the juice of the opium poppy by German pharmacist Friedrich Sertrner； During the 1950s, a series of morphine-like potent analgesics were synthesiz
3、ed,such aspethidine,methadone,etorphine,fentanyl.,镇痛药Analgesics,Pain is a complex subjective sensation ，and a kind of protective response when organism suffer the nociceptive stimulus; Pain is also the basis for the doctors diagnosing diseases。 It usually accompany anxiety,dread,horror, discomfort a
4、nd so on,to cause the patients disorder,even shock。 Acute pain that has been made a definite diagnosis,should use analgesics immediately; But it is inadvisable to use narcotic analgesics when a pain hasnt be certified ，in order to avoid misdiagnosis.,阿片类药物Opium,Classification： chemical constitution
5、affinity and intrinsic activity Agonists：morphine,Pethidine,adanton Antagonists：Naloxone,Naltrexone Partial agonist：Pentazocine，Nalorphine Physiological disposition： take orally, injectionpass through the blood brain barrierhepatic metabolismrenal excretion,H,O,H,O,O,N,C,H,3,吗啡 morphine,阿片(opium)生物碱
6、类(opiate alkaloids),Morphine (1806，10% of opium total base） Codeine （1832,methyl-morphine） Heroin （1874, acetomorphine ，powerful addictive drugs ）,Phenanthrene,Isoquinoline,Papaverine,阿片生物碱类,镇痛药 阿片生物碱类 罂粟(poppy）,Fresh capsule of opium poppy,Cut capsule showing latex exuding from cut,镇痛药 阿片生物碱类 罂粟(po
7、ppy）,镇痛药 阿片生物碱类,含阿片生物碱类植物： 罂粟,吗啡 morphine,Chemical constitution Structural features 17position R is CH3agonists17 position R is CH2CHCH2antagonists7 position NCH2CHinreversible compound,Mechanisms and Effects,阿片受体 opioid receptorIn 1973,three American labs dicovered the receptor at the same time. Ex
8、ist on cell membrane, glycoprotein。 High affinity Saturability Stereospecificity Distribution of definite area Specificity antagonists,Types and effects,(mu) (delta) (kappa)Analgesia above spinal cord level spinal cord level spinal cord level Respiratory depression Pupil myosis myosis Stomach intest
9、ine decrease decrease SM spasm Psychoactivity euphoria euphoria restlessness sedative sedative sedative Physical dependence ,Mechanisms and Effects,endopioid peptide Regulate algesthesia Endogenous pain control system Effects on angiocarpy and gastrointestinal tractMechanism：Inhibit sensory nerve en
10、ding to release SP，thus preventing transmission of pain impulses to CNS.,Enkephalin and pain When a person is injured, pain impulses travel up the spinal cord to the brain, which then releases endorphins and enkephalins. Enkephalins block pain signals in the spinal cord, while endorphins are thought
11、 to alleviate pain principally at the brainstem.,Mechanisms,MorphineIt binds to opioid recepters which are discretely distributed in the human brain, exerts its principal pharmacological effect like internal opioid peptides Cerebral ganglionanalgesia Nucleus ceruleuseuphoria Limbic system emotional
12、reaction、Sedation NTStussis、stomach intestine,Pharmacological effect of Morphine,CNS： Analgesia 、 Sedation Inhibition of cough reflex Respiratory depression Euphoria Miosis、Nausea and vomiting,Pharmacological effect of Morphine,Gastrointestinal and biliary effects Constipation(increased intestinal s
13、mooth muscle tone)Increased biliary sphincter tone and pressure,Pharmacological effect of Morphine,Cardiovascular effects:Postural hypotension and vasodilationDecreased myocardial oxygen demand,Pharmacological effect of Morphine,Immune system effects:Immune suppression Inhibit proliferation of lymph
14、ocytes,reduce secretion of cytokines. Inhibit the immune reaction which induced by HIV protein.,吗啡morphine,Clinical applicationAnalgesia：acute sharp pain,serious trauma、adustum,myocardial infarct,terminal cancerCardiac asthma ATAntidiarrheal Aombined anesthesia,吗啡morphine,Untoward reaction Respirato
15、ry depression Addiction euphoriamorphine is a highly addictive substance, both psychologically and physically.withdrawal syndromestimulation、insomnia、lacrimation、perspiration、thrill、vomit、diarrhea、collapse、unconscious。 (feelings of “euphoria”,ambition, nervousness, relaxation, drowsiness, or sleepin
16、ess) morphine(吗啡)一词来源于西腊文Morpheus(梦之神)。,镇痛药 阿片生物碱类 吗啡 不良反应,不良反应,反复应用（一般剂量连用1w左右）引起成瘾！,镇痛药 阿片生物碱类 成瘾性,镇痛药 阿片生物碱类 成瘾性,戒断综合症状 SYMPTOMS OF WITHDRAWAL,腹泻,出汗,抑郁,震颤,衰弱,肌痉挛,寒战,渴求药物,头痛、,镇痛药 阿片生物碱类 鸦片战争,鸦片战争,镇痛药 阿片生物碱类 吗啡成瘾机制,吗啡成瘾机制,Nucleus ceruleus:intensive opioid and NA receptors Morphine and endogenous op
17、ioid peptides inhibit the firings of nucleus ceruleus ，the firings of addicts are decrease significantly.The firings of nucleus ceruleus are increase when addicts stop using morphine, naergic neurons are hyperfunction，withdrawal symptom appearance.,镇痛药 人工合成类 哌替啶,哌替啶 pethidine (dolantin, 度冷丁）,Pharmac
18、ologic action,Application succedaneum of morphine analgesia 、preanesthetic medication and induced hibernation、cardiac asthma,It interacts predominantly with the -opioid receptor. CNS effects is similar with morphine but weaker than morphine,action time is 24h less than morphine.Addiction is weaker t
19、han morphine.,度冷丁dolantin （哌替啶pethidine）Artificial,Untoward reaction Addiction Respiratory depression,可待因codeine（3-o-methyl derivative of morphine）,Characteristics： Analgesia:1/12 of morphine Preventing cough:1/4 of morphine Addiction is weaker than morphine. Application： central antitussive Moderat
20、e analgesics:simple recipe or mixture（如氨酚待因片）,二氢埃托啡 dihyentophine,Characteristics: Strong opioid agonists,1000 times of morphine IM10 g 515 min analgesialast 6 hr Hypoglossis20 g 520 min Use to traumatic occlusion pain，TCA，postop. analgesia tolerance，addiction overdoseRespiratory depression,镇痛药 人工合成
21、类 哌替啶,美沙酮 methadone,Pharmacologic action,Applicationsuccedaneum of morphinedetoxification,It interacts predominantly with the -opioid receptor. CNS effects is similar with morphine , action time is longer than morphine. Addiction is weaker than morphine.,镇痛药 阿片受体拮抗剂,Opioid antagonists 纳洛酮 naloxone,A
22、pplicationThe treatment of opioid overdose and the preventionThe treatment of toxic shock,Competitive opioid receptor antagonist that can rapidly reverse the effects of morphine and other opioid agonists。,芬太尼 fentanyl,Characteristics: Strong analgesic effect（100 times of morphine） Many kinds of pain
23、、use with anesthetic Less addiction Untoward reactions are similar with morphine Contraindication: bronchial asthma，intracranial tumour and coma caused by cerebral trauma,镇痛新 (Pentazocine),Characteristics: Mixed opioid agonist-antagonist,agonist 、， antagonist Analgesia is 1/4 of morphine Less addict
24、ionNon-Narcotics Use to chronic pain,Abuse analgesics,Drug abuse:take a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. Morphine：3 times a day，last 1-2 weeksaddition Treatment of withdrawal syndrome ：convince，decrement step by step，use methadone 、benzodia
25、zepine to relieve symptoms. detoxification ： gastric lavage by 1:2000 KMnO4 artificial respiration，O2 IM.naloxone Respiratory Stimulants,Examples of Pain Scales,按疼痛的性质分类：锐痛、纯痛、绞痛,Three-Step Analgesic Ladder2000,WHO has developed a standardized cancer pain treatment plan that is recognized and used w
26、orldwide. April 1991, Ministry of Public Health announced that our conutry should develop Three-Step Analgesic Ladder in cancer pain therapy.It is based on the idea that analgesic (pain reliever) drug therapy provides the most effective pain relief for cancer patients. The three different steps refe
27、r to different combinations of analgesics.,Three-step Analgesic Ladder mild to moderate pain:use of non-opioids （Aspirin,Ibuprofen,Indometacin） moderate pain:a combination of opioids and non-opioids should be tried（Codeine,Tramadol） severe pain:opioids should be used（Morphine、Dihydroetorphine、 Pethidine）,Thanks!,
