Download Morphine

镇痛药 Analgesics
北京协和医学院基础医学院药理学系
叶菜英
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.
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.
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.
Opium (阿片类药物)
【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 brain
barrier→hepatic metabolism→renal excretion
Opiate alkaloids (阿片生物碱类)
Phenanthrene
Morphine (1806，10% of opium total base）
Codeine （1832,methyl-morphine）
Heroin （1874, acetomorphine, powerful addictive drugs）
HO
Isoquinoline
O
Papaverine
N
HO
morphine
CH3
Poppy
阿片生物碱类
Fresh capsule of opium
poppyP
Cut capsule showing
latex exuding from cut
Poppy
镇痛药 阿片生物碱类
含阿片生物碱类植物： 罂粟
Morphine

Chemical constitution
 Structural features

17position R is －CH3……agonists

17 position R is －CH2CH＝CH2……antagonists

7 position NCH2CH－……inreversible compound
Mechanisms and Effects
Opioid receptor
In 1973, three American labs discovered 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)
Analgesia
κ(kappa)
above spinal cord level spinal cord level spinal cord level
＋＋
＋＋
＋
Pupil
myosis
myosis
－
Stomach intestine
decrease
decrease
－
SM spasm
＋＋
＋＋
－
Psychoactivity euphoria＋＋ euphoria＋＋ restlessness ＋
sedative＋＋ sedative＋＋ sedative＋
Physical dependence ＋＋
＋＋
＋
Respiratory depression
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 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 to alleviate pain principally at the
brainstem.
Mechanisms
Morphine
It binds to opioid recepters which are discretely
distributed 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
muscle 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.
Clinical application of morphine

Analgesia: acute sharp pain,serious trauma,
adustum,myocardial infarct,terminal cancer

Cardiac asthma AT

Antidiarrheal

Aombined anesthesia
Morphine
Untoward reaction

Respiratory depression
 Addiction
euphoria—morphine is a highly addictive
substance, both psychologically and physically.
withdrawal syndrome—stimulation, insomnia,
lacrimation, perspiration, thrill, vomit, diarrhea,
collapse, unconscious.
(feelings of “euphoria”, ambition, nervousness, relaxation,
drowsiness, or sleepiness) morphine
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
出汗
衰弱
头痛、
肌痉挛
腹泻
震颤
寒战
抑郁
渴求药物
镇痛药
阿片生物碱类
鸦片战争
Mechanism of morphine addiction
Nucleus ceruleus: intensive opioid and NA receptors.
Morphine and endogenous opioid 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.
Pethidine (dolantin）
【Pharmacologic action】
It interacts predominantly with the μ-opioid receptor.
CNS effects is similar with morphine but weaker than
morphine,action time is 2~4h less than morphine.
Addiction is weaker than morphine.
【Application】
Succedaneum of morphine
Analgesia, preanesthetic medication and induced
hibernation, cardiac asthma
Pethidine (dolantin) Artificial
Untoward reaction

Addiction
 Respiratory depression
Codeine（3-o-methyl derivative of
morphine, 可待因）
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
Dihyentophine (二氢埃托啡)
Characteristics

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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
Methadone (美沙酮)
【Pharmacologic action】
It interacts predominantly with the μ-opioid receptor.
CNS effects is similar with morphine, action time is longer
than morphine.
Addiction is weaker than morphine.
【Application】
Succedaneum of morphine
detoxification
Opioid antagonists
Naloxone (纳洛酮)
H3C HCH2C
OH
Competitive opioid receptor
antagonist that can rapidly
O
reverse the effects of morphine
and other opioid agonists.
N
O
Naloxone
Application
The treatment of opioid overdose and the prevention
The treatment of toxic shock
CH3
Fentanyl(芬太尼)
Characteristics:

Strong analgesic effect（100 times of morphine）
 Many kinds of pain, use with anesthetic
 Less addiction
 Untoward reactions are similar with morphine
Contraindication:

bronchial asthma，intracranial tumour and coma
caused by cerebral trauma
Pentazocine (镇痛新)
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
enhancing drug for a non-therapeutic or non-medical effect.
 Morphine: 3 times a day, last 1-2 weeks→addition
 Treatment of withdrawal syndrome: convince,
decrement step by step, use methadone, benzodiazepine
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 Ladder
 2000,WHO has developed a standardized cancer pain
treatment plan that is recognized and used worldwide.

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 refer 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!