Analgesics
Zhang, Bin
Pain transmission pathway
Noxious stimuli
PGs
K+ 、 H+
BK
5-HT
Primary afferent fibres
nociceptor
Spinal cord
Limbic system
Somato-sensory cortex
mood effect, the affective aspect of pain
the sensory aspect of pain
Dorsal horn
severe pain Opioids (eg. Morphine)
inflammatory pain NSAIDs (eg. Aspirin)
local anaesthesia
smooth muscle colic
angina pectoris induced by coronary artery spasm
trigeminal pain
Drug treatment of pain
cholinoceptor-blocking drugs
vasodilator drugs (eg. Nitroglycerin)
Carbamazepine
Local anaesthetics
Cortex
Spinal cord
Dorsal horn
Ventral caudal thalamus
PGs
K+ 、 H+
BK
5-HT
NSAIDs
Opioids
Sites of action of different drugs
Non-opioid for mild pain
Pain persisting or increasing
Weak Opioids for moderate pain
Pain persisting or increasing
Strong Opioids for severe pain
Freedom from cancer pain
NSAIDs e.g. aspirin, acetaminophen
e.g. codeine ,tramadol
e.g. morphine, fentanyl, methadone
WHO analgesic ladder
Three steps analgesia therapy for cancer patientsThree steps analgesia therapy for cancer patients
opioid analgesics(narcotic analgesic, addictive analgesics)
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
Opium
The flower of papaver
The plant of joy
Opium ( 阿片 )
Opiate (阿片剂 )
• Morphine• Codeine• Papaverine … …
Opioid ( 阿片样物质 )
Endogenous opioid peptides:
Enkephalins
Endorphins
Dynorphins
Nociceptin and nocistatin
Endomorphin-1/2
Others:
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 opioid receptors: μ κ δ
Research history
Extracellular
Cytoplasmic
NH2
HOOC
Opioid receptors
G protein-coupled receptors
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.
Spinal cord
Dorsal hornenkephalins
Ca2+
Ca2+
Presynaptic terminal
Postsynaptic neuron
enkephalins
enkephalins
Presynaptic terminal
Postsynaptic neuron
The cellular mechanisms
morphine
Pharmacological actions
1. CNS
2. Smooth muscles
3. Cardiovascular system
4. Others
1.CNS effects: principal effects
Analgesia Sedation & euphoria Respiratory depression Cough suppression Others: miosis, nausea, hormone
2. Smooth muscle system
Gastrointestinal system
Biliary tract
Urinary system
genital system
orthostatic hypotension
Mechanisms:
release of histamine
vasomotor center
3. Cardiovascular system
(1) peripheral arterial and venous dilatation
(2) intracranial pressure
secondary to respiratory depression
Clinical uses
• Analgesia
• Cardiac asthma
• Antidiarrhea
• Antitussive
1.Analgesia (severe pain)
terminal cancer
myocardial infarction
renal and biliary colic (atropine)
trauma, burn, operation
• at regular time and quantity
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
2. Cardiac asthma
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 )
absorption 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, breastiv.
activeBioavailability25-30%
Morphine
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。
Codeine
1. has a higher1. has a higher oral efficacy, demethylation to efficacy, demethylation to morphinemorphine
2. lower efficacy than morphinelower efficacy than morphine
3. 3. mainly use as antitussive, severe severe dry cough. cough.
联邦止咳露联邦止咳露 :麻黄碱 + 可待因 + 氯苯那敏 + 氯化铵
注意事项• 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。
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
Methadone
1. synthetic compound, oral bioavailability is 80%
2. milder physical abstinence syndrome
3. routinely used in detoxification of the morphine
and heroin addicts
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。
口腔经粘膜芬太尼拘橼酸盐(Oral Transmucosal Fentanyl Citrate, OTFC)
Fentanyl lollipop
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
• Atypical opioid
• Weak μ activation, also interacts with monoaminergic systems
• Alternative to traditional opioid analgesics (improved side effect profile)
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
Adverse effects
3. General adverse effects
1 Constipation 5 Respiratory depression
2 Biliary colic 6 Postural hypotension
3Nausea and
vomiting7 Increased intracranial pressure
4 Urinary retention 8 Dysphoria
• 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 :
4. Acute Morphine Poisoning
Naloxone
1. competitive full antagonist for opioid R (μ)
2. Uses: opioid overdose
3. short t1/2 (1h) , repeated injections
Contraindications
obstetric labor, breasting period
obstructive airway disease, bronchial
asthma
head injuries
seriously impaired hepatic or renal function
Mode of administration of opioids
• Oral administration
• Sublingual administration
• Rectal administration
• Intravenous administration
• Intramuscular administration
• Intrathecal and epidural administration
• Transdermal patch administrationPatient Controlled Analgesia
( 病人自控镇痛, PCA)
Non-opioid analgesics
Introduction Non-steroidal anti-inflammatory
drugs (NSAIDs)
Antipyretic-analgesic and anti-
inflammatory drugs
Aspirin-like drugs
共同作用机制 :
Inhibition of cyclo-oxygenase enzymes (COX), and resulting inhibition of the
synthesis of prostaglandins (PGs)
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
比较 COX-1 & COX-2生物学作用
COX-1 COX-2
类型 结构型 ( 血管,肾脏,胃 ) 诱导型作用 保护胃粘膜 调节血小板聚集 发热、疼痛、致炎 调节外周血管阻力 调节肾血流量作用类型 生理性作用 病理性作用 NSAIDs 不良反应 解热、镇痛、抗炎
【 COX isoforms: 】 COX-1 COX-2
production Constitutive Inducible
functions
Physiological : GI protection
Regulation of platelet aggregation
Regulation of kidney blood flow
Regulation of peripheral vascular
resistance
Pathological : Inflammation
Pain
Fever
NSAIDs effects
Side effectsTherapeutic effects
【 Three major actions of NSAIDs 】
Antipyretic effect
Analgesic effect
Anti-inflammatory effect
heat production
heat dissipation
pathogen and toxins
neutrophils
endogenous pyrogens (ILs, TNF)
set point body temperature
cox NSAIDsPGE2 (hypothalamus)
Antipyretic effect
Characteristics
① Central
② “Elevated” temperature — reduced
“Normal ” temperature — no influence
Clinical applications symptomatic treatment
Pain transmission pathway
Noxious stimuli
PGs
K+ 、 H+
BK
5-HT
nociceptor
Spinal cord
Limbic system
Somato-sensory cortex
Dorsal horn
NSAIDs
Analgesic effect
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
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 patientsThree steps analgesia therapy for cancer patients
Drug location mechanism characteristics representative
Analgesics
NSAIDs
CNS
periphery
(+)opium receptor
(-)PG synthesis
morphine
aspirin
powerful dull and sharp pain inflammatory pain cause euphoria and addiction respiratory inhibition
moderate chronic dull pain cancer pain not addictive no respiratory inhibition
比较 NSAIDs 和吗啡的镇痛作用
Mechanism of inflammation:Mechanism of inflammation: phospholipids injury factor PLA2
neutrophilic arachidonic acid granulocyte cytokines induce COX-2
( ILs, TNF) PGs
inflammation ( redness, swelling, heat and pain )
Anti-inflammatory effect :
According to selectivity for COX:
①Non-selective COX inhibitors
②Selective COX-2 inhibitors
According to chemical structures :
【 NSAIDs classifications 】
化学分类 非选择性 COX 抑制药 选择性 COX-2 抑制药
水杨酸类 阿 司 匹 林苯胺类 对乙酰氨基酚吲哚类 吲哚美辛 依托度酸芳基丙酸类 布洛芬 芳基乙酸类 双氯芬酸烯醇酸类 吡罗昔康 美洛昔康吡唑酮类 保泰松烷酮类 奈丁美酮二芳基吡唑类 塞来昔布二芳基呋喃酮类 罗非昔布磺酰苯胺类 尼美舒利
(1) Antipyretic-analgesic effect
(2) Anti-inflammatory and antirheumatic effects
(3) Platelet effect
Aspirin (Acetylsalicylic acid)
PGI2 TXA2
Platelet effect : thrombosis inhibition
AA
TXA2PGI2
(-) platelet aggregation vascular dilation
(+) platelet aggregation vascular constriction
血小板血管内皮
AA
TXA2PGI2
(-)platelet aggregation vascular dilation
(+)platelet aggregation vascular constriction
血小板血管内皮
Aspirin小剂量
thrombosis inhibition:
AA
TXA2PGI2
(-)platelet aggregation vascular dilation
(+)platelet aggregation vascular constriction
血小板血管内皮
Aspirin大剂量
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↓
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 】
Gastrointestinal side effects
Disturbance of blood coagulation
Salicylism reaction
Hypersensitivity reactions
Reye’s syndrome
Nephrotoxicity
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
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
Similar antipyretic and analgesic effects to aspirin, no significant anti-inflammatory effect
Less frequent gastrointestinal irritationToxicity to liver and kidney after
prolonged use
Acetaminophen (paracetamol):
Paracetamol overdose is treated with N-acetylcysteine
Acetaminophen (paracetamol):
对乙酰氨基酚是现在常用感冒药的主要成分
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
Ibuprofen( 布洛芬 ) : Anti-inflammatory, analgesic, antipyretic effects similar
to Asp It can be slowly released into synovial fluid and
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
Celecoxib ( 塞来昔布 )
Rofecoxib( 罗非昔布 )
Nimesulide( 尼美舒利 )
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。
• The security of selective COX-2 inhibitors is not absolute !
Attention