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Analgesics. Zhang, Bin. PGs. BK. 5-HT. K + 、 H +. mood effect, the affective aspect of pain. Limbic system. Somato-sensory cortex. the sensory aspect of pain. Primary afferent fibres. Dorsal horn. Noxious stimuli. Spinal cord. nociceptor. Pain transmission pathway.

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analgesics

Analgesics

Zhang, Bin

slide2

PGs

BK

5-HT

K+、H+

mood effect, the affective aspect of pain

Limbic system

Somato-sensory cortex

the sensory aspect of pain

Primary afferent fibres

Dorsal horn

Noxious stimuli

Spinal cord

nociceptor

Pain transmission pathway

slide3

Drug treatment of pain

Local anaesthetics

cholinoceptor-blocking drugs

vasodilator drugs

(eg. Nitroglycerin)

Carbamazepine

slide4

Cortex

Ventral caudal thalamus

Opioids

NSAIDs

Dorsal horn

PGs

BK

Spinal cord

5-HT

K+、H+

Sites of action of different drugs

slide5

Freedom from cancer pain

WHO analgesic ladder

e.g. morphine, fentanyl, methadone

Strong Opioids for severe pain

Pain persisting

or increasing

e.g. codeine, tramadol

Weak Opioids for moderate pain

Pain persisting

or increasing

NSAIDs e.g. aspirin, acetaminophen

Non-opioid for mild pain

Three steps analgesia therapy for cancer patients

slide7

Opium (阿片)is the dried exudate obtained from unripe seedpods of the poppy Papaver somniferum, containing morphine, codeine, and other alkaloid substances.

Opiate(阿片剂) means that a substance is extracted from opium or is similar in structure to natural substances present in opium.

Opioid(阿片样物质) is a term that designates substances that are not derived from opium. It refers particularly to opioid peptides, i.e. endogenous compounds that bind to opioid receptors and mimic the effect of morphine-like compounds.

Widely use term

slide8

Opium (阿片)

Opium

The flower of papaver

The plant of joy

opiate
Opiate (阿片剂)
  • Morphine
  • Codeine
  • Papaverine

… …

slide10

Opioid (阿片样物质)

Endogenous opioid peptides:

  • Enkephalins
  • Endorphins
  • Dynorphins
  • Nociceptin and nocistatin
  • Endomorphin-1/2

Others:

slide11

Research history

1992~1993

Cloned opioid receptors: μκδ

1975

isolated the first “endogenous opioid peptide” and named enkephalin

1973

put forward “receptors” for opiate analgesics in brain

1962

analgesic site is laminae III of periventricular and periaqueductal gray area

slide12

Opioid receptors

NH2

Extracellular

Cytoplasmic

HOOC

G protein-coupled receptors

the cellular mechanisms
The cellular mechanisms
  • Presynaptic inhibition: activation of opioid receptors on presynaptic nerve terminals. Close a voltage-gated Ca2+ channel, decrease Ca2+ input, and thereby reduce transmitter release (Ach, NA, Glu, 5-HT, P).
  • Postsynaptic inhibition: activation of postsynaptic opioid receptors. Open K+ channels on postsynaptic neurons, increase K+ output , and thereby cause hyperpolarization and thus reduce postsynaptic neuronal excitability.
slide14

Presynaptic terminal

Ca2+

Postsynaptic neuron

Ca2+

Dorsal horn

enkephalins

enkephalins

Spinal cord

slide15

morphine

Presynaptic terminal

Postsynaptic neuron

enkephalins

The cellular mechanisms

slide16

Pharmacological actions

  • CNS
  • Smooth muscles

3. Cardiovascular system

4. Others

slide17
1.CNS effects: principal effects
  • Analgesia
  • Sedation & euphoria
  • Respiratory depression
  • Cough suppression
  • Others: miosis, nausea, hormone
slide18
2.Smooth muscle system

Gastrointestinal system

Biliary tract

Urinary system

genital system

slide19

3. Cardiovascular system

(1)

peripheral arterial and venous dilatation

orthostatic hypotension

Mechanisms:

release of histamine

vasomotor center

(2) intracranial pressure

secondary to respiratory depression

clinical uses
Clinical uses
  • Analgesia
  • Cardiac asthma
  • Antidiarrhea
  • Antitussive
slide21

Analgesia (severe pain)

  • terminal cancer
  • myocardial infarction
  • renal and biliary colic (atropine)
  • trauma, burn, operation
  • at regular time and quantity
slide22

2. Cardiac asthma

Reduce cardiac preload and afterload

morphine

Reduce the sensitivity of the respiratory center to increased CO2

Sedation

Acute left ventricular dysfunction

Pulmonary edema

Alveolar hypoventilation

CO2 retention

dyspnea

short of breath (respiratory center)

anxiety and distress

Cardiac asthmaand morphine therapy

opioid analgesic drugs
Opioid analgesic drugs

Morphine (吗啡)

Codeine (可待因)

Pethidine (哌替啶)

Methadone (美沙酮)

Fentanyl (芬太尼)

Tramadol (曲马多)

slide24

little cross the BBB, but enough for its function

placental fetus

kidney,breast

sc. im.

morphine-6-glucuronide

First pass elimination

oral

metabolism

Morphine

distribution

excretion

absorption

blood

free drug

iv.

active

liver

Bioavailability25-30%

slide25
美施康定(硫酸吗啡控释片)

1. 强效,作用持续12 hr。主要用于晚期癌症患者第三阶梯止痛。

2. 抑制呼吸,可引起恶心、呕吐、便秘及排尿困难,长期应用可产生耐受性、身体依赖性和成瘾性。

slide26

Codeine

1. has a higheroralefficacy, demethylation to morphine

2. lower efficacy than morphine

3. mainly use as antitussive, severedry cough.

联邦止咳露 :麻黄碱+可待因+氯苯那敏+氯化铵

  • 抑制支气管腺体分泌,使痰液粘稠难以咳出,不宜用于痰多粘稠者。连续应用不宜2周,因久用可成瘾。7岁儿童禁用。

注意事项

pethidine dolantin
Pethidine (dolantin)
  • Synthetic substance
  • Weaker potency than Morphine, no antitussive action
  • More sedative, more rapid onset and shorter duration (2-4h) than morphine
  • Metabolite: normeperidine  convulsion
  • Lyticcocktail
slide28

Methadone

1. synthetic compound, oral bioavailability is 80%

2. milder physical abstinence syndrome

3. routinely used in detoxification of the morphine and heroin addicts

slide29

Fentanyl

1. more analgesic potentcy than morphine: 100 times

2. rapid onset and short duration of action

3.fentanyl, alfentanil, remifentanil: adjunctive drug for general anaesthesia

4. breakthrough cancer pain:

癌症患者的突发性疼痛,突然出现,不能被患者的常规疼痛治疗方案缓解。

oral transmucosal fentanyl citrate otfc

Fentanyl lollipop

口腔经粘膜芬太尼拘橼酸盐(Oral Transmucosal Fentanyl Citrate, OTFC)

ACTIQ

芬太尼口腔粘膜贴片(Fentanyl sublingual tablets)

ABSTRAL

适应证:年龄18岁以上,已连续24小时使用阿片类药,对高剂量阿片类药物耐受者。

tramadol
Tramadol
  • Atypical opioid
  • Weak μactivation, also interacts with monoaminergic systems
  • Alternative to traditional opioid analgesics (improved side effect profile)
slide32

Adverse effects

1. Tolerance

2. Dependence

  • physical dependence:

withdrawal syndrome

  • psychological denpendence:

compulsive drug- seeking behavior

When are used for the relief of pain, tolerance and dependence are not significant and prevalent problem

slide35

Naloxone

1. competitive full antagonist for opioid R (μ)

2. Uses: opioid overdose

3. short t1/2 (1h) , repeated injections

slide36

Contraindications

  • obstetric labor, breasting period
  • obstructive airway disease, bronchial asthma
  • head injuries
  • seriously impaired hepatic or renal function
mode of administration of opioids
Mode of administration of opioids
  • Oral administration
  • Sublingual administration
  • Rectal administration
  • Intravenous administration
  • Intramuscular administration
  • Intrathecal and epidural administration
  • Transdermal patch administration

Patient Controlled Analgesia (病人自控镇痛,PCA)

introduction
Introduction

Non-steroidal anti-inflammatory

drugs (NSAIDs)

Antipyretic-analgesic and anti-

inflammatory drugs

Aspirin-like drugs

slide40
共同作用机制:

Inhibition of cyclo-oxygenase enzymes

(COX), and resulting inhibition of the

synthesis of prostaglandins (PGs)

slide41
花生四烯酸的代谢途径及主要代谢产物的生物活性花生四烯酸的代谢途径及主要代谢产物的生物活性

保护胃粘膜

three major actions of nsaids
【Three major actions of NSAIDs】

Antipyretic effect

Analgesic effect

Anti-inflammatory effect

slide45

coxNSAIDs

Antipyretic effect

pathogen and toxins

neutrophils

endogenous pyrogens (ILs, TNF)

PGE2(hypothalamus)

heat production

body

temperature

set point

heat dissipation

characteristics
Characteristics

①Central

② “Elevated” temperature — reduced

“Normal ” temperature — no influence

Clinical applications

symptomatic treatment

slide47

PGs

BK

5-HT

K+、H+

Limbic system

Somato-sensory cortex

Analgesic

effect

NSAIDs

Dorsal horn

Noxious stimuli

Spinal cord

nociceptor

Pain transmission pathway

characteristics1
Characteristics

① Peripheral (probably also inhibit pain stimuli at a subcortical site)

② mild to moderate pain

③ No addiction or respiratory inhibition

clinical applications
Clinical applications

① have good effects on chronic dull pain— headache , toothache, neuralgia, muscle

pain, arthralgia, dysmenorrhea

② are not very effective for traumatic pain, severe visceral pain—myocardial infarction or renal or biliary colic

Three steps analgesia therapy for cancer patients

nsaids

morphine

(+)opium

receptor

CNS

periphery

(-)PG

synthesis

aspirin

比较NSAIDs和吗啡的镇痛作用
  • powerful
  • dull and sharp pain
  • inflammatory pain
  • cause euphoria and

addiction

  • respiratory inhibition
  • moderate
  • chronic dull pain
  • cancer pain
  • not addictive
  • norespiratory

inhibition

slide51

Anti-inflammatory effect :

Mechanism of inflammation:

phospholipids

injury

factor PLA2

neutrophilic arachidonic acid

granulocyte

cytokines induce COX-2

( ILs, TNF)

PGs

inflammation

( redness, swelling, heat and pain )

nsaids classifications
【 NSAIDs classifications 】
  • According to selectivity for COX:

①Non-selective COX inhibitors

②Selective COX-2 inhibitors

  • According to chemical structures :
aspirin acetylsalicylic acid
Aspirin (Acetylsalicylic acid)

(1) Antipyretic-analgesic effect

(2) Anti-inflammatory and antirheumatic effects

(3) Platelet effect

slide56
AA

血小板

血管内皮

PGI2

TXA2

(-) platelet aggregation

vascular dilation

(+) plateletaggregation

vascular constriction

slide57

Aspirin小剂量

thrombosis inhibition:

AA

血小板

血管内皮

PGI2

TXA2

(-)platelet aggregation

vascular dilation

(+)plateletaggregation

vascular constriction

slide58

Aspirin大剂量

血管内皮

血小板

PGI2

TXA2

(-)platelet aggregation

vascular dilation

(+)plateletaggregation

vascular constriction

AA

slide59
Aspirin irreversibly acetylates and blocks platelet COX1

→ TXA2 biosynthesis(-) → platelet aggregation(-) →

thrombosis (-).

TXA2↓

Low dose thrombosis is inhibited

PGI2 not affected

TXA2↓

High dose unbeneficial for thrombosis inhibition

PGI2↓

slide60
Clinical uses:

① low dose (40~100mg) is recommended

② prevent thrombosis:

cardiac or brain ischemic diseases

angioplasty(血管成形术 )

coronary artery bypass grafting

③ Pregnancy-induced hypertension syndrome (PIH)

adverse effects
【Adverse effects】

Gastrointestinal side effects

Disturbance of blood coagulation

Salicylism reaction

Hypersensitivity reactions

Reye’s syndrome

Nephrotoxicity

slide62
Salicylism reaction
  • Large dosage (>5g/d)
  • headache, vertigo, nausea, vomiting, tinnitus, decreased vision and hearing;hyperpnea, acid-base disturbance, insanity.
  • Therapy: ① aspirin must be stopped at once

② sodium bicarbonate infusions.

reye s syndrome
Reye’s syndrome

Severe hepatic dysfunction with

complication of encephalopathy

  • Substitute aspirin with acetaminophen

Nephrotoxicity

acute renal failure by reducing renal blood flow.

chronic renal failure due to development of interstitial nephritis.

复方药物滥用

acetaminophen paracetamol
Acetaminophen (paracetamol):
  • Similar antipyretic and analgesic effects to aspirin,no significant anti-inflammatory effect
  • Less frequent gastrointestinal irritation
  • Toxicity to liver and kidney after prolonged use

Paracetamol overdose is treated with N-acetylcysteine

slide65
Acetaminophen (paracetamol):

对乙酰氨基酚是现在常用感冒药的主要成分

slide66
常用复方制剂

白加黑:白片:扑热息痛+盐酸伪麻黄碱+氢溴酸右美沙芬

黑片:白片+苯海拉明

slide67
Ibuprofen(布洛芬):

Anti-inflammatory, analgesic, antipyreticeffectssimilar to Asp

It can be slowlyreleased into synovial fluidand remains there with a high concentration

Widely used in RA and osteoarthritis, mild and moderate pain

Less frequent gastrointestinal irritation

芬必得布洛芬缓释胶囊

芬必得布洛芬乳膏

芬必得酚咖片新头痛装

selective cox 2 inhibitors
Selective COX-2 inhibitors

Celecoxib (塞来昔布)

Rofecoxib(罗非昔布)

Nimesulide(尼美舒利)

slide69
2004年9月30日,由于“连续服用18个月会增加病人心血管事件的风险”,美国默沙东公司宣布将其治疗风湿性关节炎的王牌药物“万络”(罗非昔布)实施全球召回。

美国辉瑞公司“西乐葆”(塞来昔布)

被披露存在同样的安全隐患。

Attention

  • The security of selectiveCOX-2 inhibitors is not absolute !