1 Welcome to Pharmacology. 2 Chapter 21 Analgesics.

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Welcome to Pharmacology

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Chapter 21 Analgesics

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Overview

Section 1

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two components

somatic sensation

affective (emotion)

1. Concept

52. Pain transmission pathway

Noxious stimuli

PGs

K+ 、 H+

BK

5-HT

Primary afferent fibres (C/Aδ)

nociceptor

Spinal cord

Limbic system

Somato-sensory cortex

mood effect, the affective aspect of pain

the sensory aspect of pain

Medulla

Midbrain

Dorsal horn

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Descending pain inhibitorypathways

Local inhibitory interneuron in spinal cord

Pain

Ascending pain transmission pathways

Endogenous opioid peptides

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Medulla

Midbrain

Cortex

Spinal cord

Dorsal horn

Ventral caudal thalamus

PGs

K+ 、 H＋

BK

5-HT

NSAIDs

Local anesthetics

Opioid analgesics ， Antidepressants and General

anaesthetics

Sites of action of different drugs

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Pain

a. Acute pain (sharp pain), superficial pai

n, quick response of sudden onset, con

ducted by A nerve fibers

b. Chronic pain (dull pain), more lingerin

g and aching, conducted

by C nerve fibers

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severe, sharp painopioid analgesics

(eg. Morphine)

inflammation, elevated temperature, chronic- dull pain

NSAIDs

(eg. Aspirin)

smooth muscle colic

(eg. biliary or renal colic)

angina pectoris induced by coronary artery spasm

trigeminal pain

3. Durg treatment of pain

cholinoceptor-blocking drugs (eg. Atropine)

vasodilator drugs (eg. Nitroglycerin)

Carbamazepine

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Analgesics

Drugs which act on CNS , could rel

ieve or alleviate severe pain and un

happy mood without affecting othe

r sense perception, and consciousn

ess

1. Concept

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Full agonist of opioid receptors

Partial agonist of opioid receptors

Other analgesics

2. Classification

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Section 2Section 2

Full agonist of opioid receptors

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Opium Alkaloids

• Phenanthrenes

morphine, codeine

• Benzylisoquimolines

papaverine

--has no analgesic effect

--dilates the vessel

14 The flower of papaver somniferum

15Opium

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Morphine

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1803 Serturner isolated a pure active alkaline substance from opium .

He proposed the name“morphine”for it after Morpheus.

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structure-activity relationshipstructure-activity relationship

海洛因

吗啡

纳洛酮

OH

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Pharmacokineticsabsorption excretion distribution

free drug

oral First pass elimination

sc. im.

blood

liver

placental fetuslittle cross

the BBB, but enough for its function

metabolism

morphine-6-glucuronide

kidney, breast

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Pharmacological actions

1. CNS

2. Smooth muscles

3. Cardiovascular system

4. Others

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Pharmacological actions

1.CNS effects :principal effects

analgesia

euphoria

sedation

respiratory depression

tolerance

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(1) Analgesia powerful pain-relieving effect

all types of pains:

* constant, dull ﹥intermittent, sharp

poor efficiency on neuropathic pain

without affecting consciousness and

other sense perception

duration ： 4-6h

1. CNS

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(2) Sedation and euphoria

tolerance of pain

drowsiness and clouding of mentation

sleep induced and aroused easily

*Euphoria

a sense of contentment and well-being

relieve anxiety and distress

Sedation

the main reason for drug abuse

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Activate the opioid receptor at limbic sy

stem and locus ceruleus ( 蓝斑）

Mechanisms:

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respiratory rate ， tidal volume

occurs at ordinary doses, dose-related

the most common cause of death from acute

poisoning

Mechanisms:

the sensitivity of respiratory center to increased

CO2 tension

respiratory modulatory center

(3) Respiratory depression

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(4) Cough suppression

by inhibiting cough center directly

Has antitussive effectHas antitussive effect

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Miosis:

pinpoint pupils is characteristic of acute poisoning

blocked by naloxone and atropine

(5) Others

Nausea and vomiting:

activate the brain stem CTZ

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(5) Others• ↓release of gonadotropin-releasing hormone

(GnRH)

• ↓ release of corticotropin-releasing hormone

(CRF)

• ↓concentration of luteinizing hormone (LH) ,fol

licle-stimulating hormone(FSH)

• ↓adrenocorticotropic hormone(ACTH)

• ↑prolactin release

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Pharmacological actions

• 2. SM Stimulating

Gastrointestinal system

Biliary tract

Urinary

Bronchia

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(1) Gastrointestinal tract

delays passage

2. Smooth muscle system

secretion of digestive gland indigestion

central inhibition a call of nature

defecation reflex

sphincter tone

GIT tone GIT motility

absorption of water

constipationClinical uses?

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biliary colic

constrict biliary smooth muscle

constrict Oddi's sphincte

r

pressure in the biliary tract

(2) Biliary tract

Medicine?

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(3) Other smooth muscle

① constrict ureteral smooth muscle

constrict bladder sphincter

urinary retention

③ antagonize oxytocin ( 缩宫素） uterine tone

prolong labor

② constrict bronchial smooth muscle

bronchial asthma

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orthostatic hypotension

Mechanisms:

release of histamine

vasomotor center

3. Cardiovascular system

(1) peripheral arterial and venous dilatation

(2) intracranial pressure

secondary to respiratory depression

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4. Other actions

inhibit immune system

histamine release

bronchospasm

flushing

arteriolar dilatation

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1992~1993

1973

1962

1975

analgesic site is laminae III of periventricular and periaqueductal gray area

put forward “receptors” for opiate analgesics in brain

isolated the first “endogenous opioid peptide” and named enkephalin

cloned three opioid receptors: μ κ δ

Research on analgesic mechanisms

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Sites of analgesia

Supraspinal areas: thalamus, periventricular,

periaqueductal gray area

Spinal cord: substantia gelatinosa

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Opioid receptors

supraspinal analgesia, sedation, euphoria, respir

atory depression, miosis, dependence

spinal analgesia, sedation

dysphoria, hallucination

spinal analgesia, respiratory depression,

sedation, euphoria, dependence

**::

:

:

:

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Extracellular

Cytoplasmic

NH2

HOOC

Opioid receptors

G protein-coupled receptors

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Endogenous opioid peptides

Three main families:

Enkephalinsmet-enkephalin

leu-enkephalin

Endorphins: β-endorphine

Dynorphins: dynorphine A, B

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Mechanisms of analgesia

Supraspinal areas:

combined with receptors, activate desending i

nhibitory system

Spinal cord ：

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Spinal cord

Dorsal hornenkephalins

Ca2+

Ca2+

谷氨酸

神经肽

Presynaptic terminal

Postsynaptic neuron

enkephalins

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enkephalins

Presynaptic terminal

Postsynaptic neuron

The cellular mechanisms of analgesia

morphine

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Presynaptic inhibition: activation of opioid receptors o

n presynaptic nerve terminals. Close a voltage-gated C

a2+ channel, decrease Ca2+ input, and thereby reduce t

ransmitter release.

The cellular mechanisms of analgesia

Postsynaptic inhibition: activation of postsynaptic opi

oid receptors. Open K+ channels on postsynaptic neur

ons, increase K+ output , and thereby cause hyperpola

rization and thus inhibit postsynaptic neurons.

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Clinical uses1.Analgesia

acute, severe pain, particularly in

terminal cancer

myocardial infarction

renal and biliary colic （ atropine)

short-term use only when others failed

2. *Cardiac asthma

3. Antidiarrhea

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Pulmonary edema

dyspnea

Acute left ventricular dysfunction

short of breath (respiratory center)

CO2 retention

anxiety and distress

Alveolar hypoventilation

morphine

Reduce cardiac preload and afterload

Reduce the sensitivity of the respiratory center to increased CO2

Sedation

Cardiac asthma and morphine therapy

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(1) Mechanisms:

① peripheral arterial and venous dilation

preload and afterload pulmonary edema

② sedation anxiety and distress

oxygen consumption

③ the sensitivity of respiratory center to CO2

shortness of breath

Cardiac asthma

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1. General adverse effects

1 dysphoria 5 Biliary colic

2Respiratory depression

6 Urinary retention

3Nausea and

vomiting7

Postural hypotension accentuated by hypovolemia

4 Constipation 8 Increased intracranial pressure

Adverse effects

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• Clinical overdose• Accidental poisoning in addicts• 30mg – toxic threshold• 120mg – lethal threshold

Pinpoint pupilsDeep respiratory depressionComa

Treatments: Establish patent airway Adequate ventilation Naloxone Iv.

The triad ：

2. Acute Morphine Poisoning

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3. Tolerance and dependence(1) Tolerance a gradual loss in effectiveness in CNS with

frequently repeated administration, need larger

doses to achieve the same clinical effect.

Characteristic:

ordinary therapeutic doses 2-3 w

large doses at short intervals readily

develop not to miosis , constipation

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physical dependence ： withdrawal syndrome

psychological denpendence:

euphoria promote compulsive use

and craving

(2) Dependence

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rhinorrhea lacrimation chills

gooseflesh (piloerection)

yawning sweating

muscular aches vomiting diarrhea

anxiety hostility hyperventilation

Withdrawalsyndrome of Opioid

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Contraindications

reasons that result in pain are not clear

obstetric labor, breasting period

cor pulmonale , bronchial asthma

head injuries

seriously impaired hepatic or renal function

newborn infant, infant

biliary and renal colic

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Codeine (methyl － morphine)

Characteristics:

1. has a higher1. has a higher oral efficacyefficacy

2. weaker analgesia, abouweaker analgesia, abou

t 1/10t 1/10 －－ 1/121/12 ， ， antitussiveantitussive ：： 1/41/4

3. used in moderate pain 3. used in moderate pain

4. maily use as antitussive, severe severe dry cough. cough.

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Pethidine (dolantin, meperidin)

analgesia: weaker(1/7-1/10) and shorter(2-4h)

sedation, euphoria, respiratory depression: equal

no antitussive action

1. Metabolisms

normeperidine muscle tremors, witches, convulsion

2. Pharmacological properties

(1) CNS

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(3) Cardiovascular system

similar to morphine

(2) smooth muscle

less constipation and urinary retention

do not prolong labor

may induce biliary colic

large doses

the contraction of bronchial smooth muscle

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3. Clinical uses

(1) Analgesia

obstetric labor

but should not be used in 2 - 4 h before labor

do not longtime use in chronic pain .

(2) Cardiac asthma

(3) Premedication in anesthesia

sedative, anxiolytic, and analgesia

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(4) Artificial hibernation

pethidine chlorpromazine promethazine

lytic cocktailⅠ4. Adverse effects(1) CNS excitatory symptoms

muscle tremors, twitches, convulsion should be combined with anticonvulsive drugs when treat overdose poisoning

(2) some symptoms like atropine

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Increased CNS depression, particularly respiratory depression

Opioid analgesics

MAOIs

Tricyclic antidepressants

chlorpromazine promethazine

Sedative- hypnotics

Absolute contraindication to pethidine , relative contraindication to other opioid analgesics , because of high incidence of hyperpyretic coma

Drug – Drug interactions

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MethadoneCharacteristics:

1. analgesia: equal to morphine

2. give reliable effects orally, longer duration of action

3. tolerance and physical dependence more slowly

4. withdrawal signs attenuated but protracted

5. detoxification of the morphine and heroin

dependent addict

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Fentanyl Characteristics: 1. more analgesic potentcy than morphine:100 times

2. has a rapid onset and short duration of action

3. high lipid- soluble, transdermal administration

4. + droperidol ( 氟哌利多） neuroleptanalgesia( 神经阻滞镇痛术） or usually combined with anaesthetics

5. high dose cause truncal rigidity

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Short acting

fentanyl sufentanil alfentanil

Agonistsmixed Agonists /Antagonists

Antagonists

WEAK: codeine pentazocine

STRONG:methadone morphine pethidine

buprenorphine nalbuphinelong

actingnaltrexone

naloxone

Classification of opioid analgesics

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Section 2 Partial agonists of opioid receptor

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PentazocineCharacteristic:

κ, σ agonist , μ weak antagonist

1. CNS

analgesia: 1/3

respiratory depression : 1/2

* psychomimetic action (60-90mg)

dysphoric and hallucination (action on σ)

2. Smooth muscle: weaker

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Pentazocine3. Cardiovascular systemCardiovascular system

high doses

*increase blood pressure and cause tachycardia

(catecholamine )

not use in myocardial infarction

4. weak action on μ * little addictive liability * precipitate the withdrawal syndrome of a morphine abuser 5. various chronic pain

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Section 4 Other analgesics

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Tramadol

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Section 5Antagonists of opioid receptors

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Naloxone

Characteristics:

1. competitive antagonist for opioid receptors:

potency μ κ δ﹥ ﹥ reverse the opioid effects

2. iv.

3. rapid onset (1~3 min), short duration of

action

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Naloxone

4. acute opioid poisoning : reverses the coma and respiratory depression

5. differential diagnosis in morphine or heroin

abuser : precipitates withdrawal symptom

6. As a tool agent in pharmacological research

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Three step analgesia Three step analgesia therapy for cancer patientstherapy for cancer patients

AppendixAppendix

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Non-opioid for mild pain

Pain persisting or increasing

Opioid for moderate pain

Pain persisting or increasing

Opioid for severe pain

Freedom from cancer pain

Pain

NSAIDs e.g. aspirin, acetaminophen

e.g. codeine ， tramadol

e.g. morphine, pethidine

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病例：

张某 , 男 , 30 岁 , 因车祸伤导致左下肢疼痛不能活动送入急症科。查体发现基本生命体征平稳 , 病人痛苦貌 , 多处皮肤擦伤 , 左小腿前侧有一长约 20 厘米的皮肤裂伤 , 伴有骨折端外露 , 病人左上腹部亦有轻微疼痛感但较软无明显压痛。随即行双下肢 , 骨盆 x 线检查 , 提示左胫腓骨粉碎性骨折。病人检查过程中自觉腹部及小腿疼痛加剧 , 不能配合清创 , 于是值班医生给予度冷丁 50mg 肌肉注射 , 病人疼痛感减轻 , 并行简单清创后将病人推往手术室行骨折修复手术 . 问：这个给病人应用度冷丁合适么 ?

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病人转入手术室以后准备行手术治疗 , 麻醉前测量血压发现病人血压 80/50mmhg 睑结膜 ,

口唇苍白 , 四肢冷且苍白 , 骨外科主任医师立即详细询问急症值班医生有关处理后立即行腹腔穿刺 , 穿出大量不凝血性液体 . 立即给予快速多通道补液输血治疗 , 并请普外科医师会诊 , 考虑脾脏破裂 , 随即给予手术修补治疗 .

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