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

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 Sertürner ；

During the 1950s, a series of morphine-like potent analgesics were synthesized,such as

pethidine,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 and

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

hasn`t be certified ， in order to avoid misdiagnosis.

阿片类药物 Opium

Classification ： chemical constitution affinity and intrinsic activity Agonists ： morphine,Pethidine,adanton……

Antagonists ： Naloxone,Naltrexone

Partial agonist ： Pentazocine ， Nalorphine

Physiological disposition ： take orally, injection→pass through the blood brai

n barrier→hepatic metabolism→renal excretion

HO

HO

O

N CH3

吗啡 吗啡 morphinemorphine

阿片阿片 (opium)(opium) 生物碱类生物碱类 (opiate alkaloids)(opiate alkaloids)

Morphine Morphine (1806(1806 ，， 10% of opium 10% of opium total base ））CodeineCodeine （（ 1832,1832,methyl-morphine ））HeroinHeroin （（ 1874, acetomorphine 1874, acetomorphine ，， powerful addictive drugs powerful addictive drugs ））

PhenanthrenePhenanthrene

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 (poppy ）

镇痛药 阿片生物碱类

含阿片生物碱类植物： 罂粟含阿片生物碱类植物： 罂粟

吗啡 morphine

Chemical constitution Structural features 17position R is － CH3……agonists

17 position R is － CH2CH ＝ CH2……antagonists

7 position NCH2CH －…… inreversible compound

HO

HO

O

N CH3

Mechanisms and Effects 阿片受体 opioid receptor In 1973,three American labs dicovered the receptor

at the same time. Exist on cell membrane, glycoprotein 。 High affinity Saturability Stereospecificity Distribution of definite area Specificity antagonists

Types and effects

μ(mu) δ(delta) κ(kappa)

Analgesia above spinal cord level spinal cord level spinal cord level

Respiratory depression ＋＋ ＋＋ ＋Pupil myosis myosis －Stomach intestine 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 tract

Mechanism ： Inhibit sensory nerve ending to release SP ， thus preventing transmission of pain impulses to CNS.

Enkephalin and painWhen 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 to alleviate pain principally at the brainstem.

Mechanisms

Morphine It binds to opioid recepters which are discretely di

stributed in the human brain, exerts its principal pharmacological effect like internal opioid peptides

Cerebral ganglion——analgesia Nucleus ceruleus——euphoria Limbic system—— emotional reaction 、 Sedation NTS——tussis 、 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 smooth m

uscle tone)

Increased biliary sphincter tone and pressure

Pharmacological effect of Morphine

Cardiovascular effects:

Postural hypotension and vasodilation

Decreased myocardial oxygen demand

Pharmacological effect of Morphine

Immune system effects: Immune suppression Inhibit proliferation of lymphocytes,reduce

secretion of cytokines. Inhibit the immune reaction which induced

by HIV protein.

吗啡 morphine

Clinical application

Analgesia ： acute sharp pain,serious trauma 、 adustum,myocardial infarct,terminal cancer

Cardiac asthma AT

Antidiarrheal

Aombined anesthesia

吗啡 morphine

Untoward reaction Respiratory depression Addiction euphoria—morphine is a highly addictive substance, bo

th psychologically and physically. withdrawal syndrome—stimulation 、 insomnia 、 lacr

imation 、 perspiration 、 thrill 、 vomit 、 diarrhea 、collapse 、 unconscious 。

(feelings of “euphoria”,ambition, nervousness, relaxation, drowsiness, or sleepiness) 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

不良反应不良反应 反复应用（一般剂量连用反复应用（一般剂量连用 1w1w 左右）引起成瘾左右）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

腹泻腹泻

出汗出汗

抑郁抑郁

震颤震颤

衰弱衰弱

肌痉挛肌痉挛

寒战寒战

渴求药物渴求药物

头痛、头痛、

镇痛药 阿片生物碱类 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 NA receptors

Morphine and endogenous opioid peptides inhibit the

firings of nucleus ceruleus ， the firings of addicts a

re decrease significantly.The firings of nucleus cerule

us are increase when addicts stop using morphine,

naergic neurons are hyperfunction ， withdrawal sy

mptom appearance.

镇痛药 人工合成类 哌替啶

哌替啶 pethidine (dolantin, 度冷丁）Pharmacologic action

Applicationsuccedaneum of morphinesuccedaneum of morphineanalgesia analgesia 、、 preanesthetic medication and induced preanesthetic medication and induced hibernationhibernation 、、 cardiac asthmacardiac asthma

It interacts It interacts predominantlypredominantly with the with the μ-opioid receptor. μ-opioid receptor.

CNS effects is similar with morphine but weaker than CNS effects is similar with morphine but weaker than

morphine,action time is 2~4h less than morphine.Addiction morphine,action time is 2~4h less than morphine.Addiction

is weaker than morphine.is weaker than 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 Moderate analgesics:simple recipe or mixture

（如氨酚待因片）（如氨酚待因片）

二氢埃托啡 dihyentophine

Characteristics: Strong opioid agonists,1000 times of morphine IM10 μg 5~15 min → analgesia

last 6 hr Hypoglossis20 μg 5~20 min Use to traumatic occlusion pain ， TCA ， postop.

analgesia tolerance ， addiction overdose→Respiratory depression

镇痛药 人工合成类 哌替啶

美沙酮 methadone

Pharmacologic action

Application succedaneum of morphinesuccedaneum of morphine detoxificationdetoxification

It interacts It interacts predominantlypredominantly with the with the μ-opioid receptor. μ-opioid receptor. CNS effects is similar with morphine , action time is longer tCNS effects is similar with morphine , action time is longer than morphine. han morphine. Addiction is weaker than morphine.Addiction is weaker than morphine.

镇痛药 阿片受体拮抗剂

Opioid antagonistsOpioid antagonists

纳洛酮 纳洛酮 naloxonenaloxone

Application The treatment of opioid overdose and the preventionThe treatment of opioid overdose and the prevention The treatment of toxic shockThe treatment of toxic shock

Competitive opioid receptor antCompetitive opioid receptor ant

agonist that can rapidly reverse agonist that can rapidly reverse

the effects of morphine and othethe effects of morphine and othe

r opioid agonistsr opioid agonists 。。

CH3N

O

HCH2C

O

H3C

OH

Naloxone

芬太尼 fentanyl

Characteristics: Strong analgesic effect （ 100 times of morphin

e ） Many kinds of pain 、 use with anesthetic Less addiction Untoward reactions are similar with morphine

Contraindication: bronchial asthma ， intracranial tumour and coma c

aused by cerebral trauma

镇痛新 (Pentazocine)

Characteristics: Mixed opioid agonist-antagonist,agonist κ 、

δ ， antagonistμ Analgesia is 1/4 of morphine Less addiction――Non-Narcotics Use to chronic pain

Abuse analgesics Drug abuse:take a psychoactive drug or performance enha

ncing drug for a non-therapeutic or non-medical effect. Morphine ： 3 times a day ， last 1-2 weeks→addition Treatment of withdrawal syndrome ： convince ， d

ecrement step by step ， use methadone 、 benzodiazepine to relieve symptoms.

detoxificationdetoxification ： 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、绞痛按疼痛的性质分类：锐痛、纯痛、绞痛

 Three-Step Analgesic Ladder

2000,WHO has developed a standardized cancer pain treatme

nt plan that is recognized and used worldwide.

April 1991, Ministry of Public Health announced that our conu

try should develop Three-Step Analgesic Ladder in cancer pai

n therapy.

It is based on the idea that analgesic (pain reliever) drug thera

py provides the most effective pain relief for cancer patients. T

he three different steps refer to different combinations of analg

esics.

Three-step Analgesic Ladder

mild to moderate pain:use of non-opioids

（ Aspirin,Ibuprofen,Indometacin ）

moderate pain:a combination of opioids and non-op

ioids should be tried

（ Codeine,Tramadol ）

severe pain:opioids should be used

（ Morphine 、 Dihydroetorphine 、 Pethidin

e ）

Thanks!