??? Analgesics

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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.

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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.

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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 hasnt be certified, in order to
  avoid misdiagnosis.

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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
  brain barrier?hepatic metabolism?renal excretion

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Opiate alkaloids (??????)
Phenanthrene
Morphine (1806,10 of opium total base) Codeine
(1832,methyl-morphine) Heroin (1874,
acetomorphine, powerful addictive drugs)
H
O
Isoquinoline
O
Papaverine
C
H
N
3
H
O
morphine
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Poppy
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Fresh capsule of opium poppyP
Cut capsule showing latex exuding from cut
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Poppy
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Morphine

• Chemical constitution
• Structural features
• 17position R is -CH3agonists
• 17 position R is -CH2CHCH2antagonists
• 7 position NCH2CH-inreversible compound

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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

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Types and effects

• µ(mu) d(delta) ?(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

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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.

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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.
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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 ganglionanalgesia
• Nucleus ceruleuseuphoria
• Limbic system emotional reaction?Sedation
• NTStussis, stomach intestine

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Pharmacological effect of Morphine

• CNS
• Analgesia ? Sedation
• Inhibition of cough reflex
• Respiratory depression
• Euphoria
• Miosis?Nausea and vomiting

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Pharmacological effect of Morphine

• Gastrointestinal and biliary effects
• Constipation(increased intestinal smooth muscle
  tone)
• Increased biliary sphincter tone and pressure

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Pharmacological effect of Morphine

• Cardiovascular effects
• Postural hypotension and vasodilation
• Decreased myocardial oxygen demand

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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.

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Clinical application of morphine

• Analgesia acute sharp pain,serious trauma,
  adustum,myocardial infarct,terminal cancer
• Cardiac asthma AT
• Antidiarrheal
• Aombined anesthesia

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Morphine

• Untoward reaction
• Respiratory 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 sleepiness) morphine

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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.
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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 24h less
than morphine. Addiction is weaker than morphine.
?Application? Succedaneum of morphine
Analgesia, preanesthetic medication and induced
hibernation, cardiac asthma
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Pethidine (dolantin) Artificial

• Untoward reaction
• Addiction
• Respiratory depression

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Codeine(3-o-methyl derivative of morphine, ???)

• Characteristics
• Analgesia1/12 of morphine
• Preventing cough1/4 of morphine
• Addiction is weaker than morphine.
• Application
• central antitussive
• Moderate analgesicssimple recipe or mixture

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Dihyentophine (?????)

• Characteristics
• Strong opioid agonists,1000 times of morphine
• IM10 µg 515 min ? analgesia
• 
  last 6 hr
• Hypoglossis20 µg 520 min
• Use to traumatic occlusion pain, TCA, postop
  analgesia
• Tolerance, addiction
• Overdose?Respiratory depression

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Methadone (???)
?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
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Opioid antagonists Naloxone (???)
Competitive opioid receptor antagonist that can
rapidly reverse the effects of morphine and other
opioid agonists.
Application The treatment of opioid overdose and
the prevention The treatment of toxic shock
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Fentanyl(???)

• 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

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Pentazocine (???)

• Characteristics
• Mixed opioid agonist-antagonist, agonist ?,d,
  antagonistµ
• Analgesia is 1/4 of morphine
• Less addiction??Non-Narcotics
• Use to chronic pain

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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 12000 KMnO4
• artificial respiration,O2
• IM.naloxone
• Respiratory Stimulants

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Examples of Pain Scales
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•  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.

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Three-step Analgesic Ladder Mild to moderate
pain use of non-opioids (Aspirin,Ibuprofen,I
ndometacin) Moderate pain a combination of
opioids and non-opioids should be tried
(Codeine,Tramadol) Severe pain opioids should be
used (Morphine?Dihydroetorphine? Pethidine)
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Thanks!