Analgesics（镇痛药）

Yin Ming

2011.11.1

Pain

an unpleasant sensation often caused by intense or damaging stimuli

the most common reason for physician consultation

interfering with a person's quality of life and general functioning

protective response of human body

Pain killers

Opiates and morphinomimetics ( 阿片类及类似物）NSAIDs: son-selective cyclooxygenases (COX-1 and COX-2) inhibitors: aspirin, ibuprofen, …

COX-2 inhibitors: celecoxib ( 塞来昔布） , …

Flupirtine （氟吡汀） : K+ channel opener with weak NMDA antagonist properties

other and specific agents: amitriptyline, cabamazepine, rotundine, ziconotide, …

Drug classification

Opioid analgesics

Natural• phenanthrene

• morphine 10% （吗啡） • codeine 0.5% （可待因）

semisynthetic • heroin （海洛因）， not used

clinically• Buprenorphine （丁丙诺啡） ,

partial agonistsynthetic

• Pethidine （哌替啶） • Methadone （美沙酮） • Fentanyl （芬太尼）• Remifentanil （瑞芬太尼） • Oxygodone （羟考酮）

Opiate receptors and opioid peptides

1962, Zou Gang （邹冈） , morphine injected into periaqueductal gray matter （中脑导水管周围灰质） , sites found

1973, Snyder, radioligand binding （放射配基结合） and autoradiography （放射自显影） , opiate receptors found

1975, enkephalins isolated

Endorphins and dynorphins, … found

阿片受体分类及其效应

受体分类

效 应 配体的受体选择性

镇痛作用部位

呼吸抑制

缩瞳 抑制胃肠蠕动

欣快 镇静 躯体依赖

β内啡肽

亮氨酸脑啡肽

强啡肽

吗啡

μ 脑、脊髓、外周

+++ ++ ++ +++ ++ +++ +++ + ++ +++

δ 脊髓 ++ － ++ － － － +++ +++ + +

外周、脊髓

+ + + － ++烦躁

+ +++ － +++ ++

Receptor classification and functions

Mu μ• P hysical dependence

• E uphoria

• A nalgesia (supraspinal)

• R espiratory depression

Kappa κ• S edation

• A nalgesia (spinal)

• M iosis

Delta δ• analgesia (spinal & supraspinal) • release of growth hormone   

Sigma Σ• dysphoria (opposite of euphoria) • hallucination (both visual & auditory)• respiratory and vasomotor stimulation • mydriasis

OPIOID receptors

CNS distribution is not uniformthey are at areas concerned with painreceptor locations beginning with highest concentration areas

1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord

Extracellular

Cytoplasmic

NH 2Extracellular

Cytoplasmic

NH 2

HOOC

Pharmacokinetics

readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route

Distributed to breast

CNS action of morphine

analgesia

sedation

euphoria

mood change

mental cloudiness

Morphine analgesia

Changes our reaction and our perception of pain

severe cancer pain is tolerated more when person is given morphine relieves all types of pain, but most effective against continuous dull aching pain sharp, stabbing, shooting pain also relieved by morphine

Morphine given to a pain free individual first experience is dysphoric not experienced in person in pain

Morphine sedation - morphine causes sedation effect, but no loss of consciousness

Morphine euphoria

sense of well being

reason why morphine is abused

Effects of morphine on respiration

a primary and continuous depression of respiration related to dose

decrease rate

decrease volume

decrease tidal exchange

Effects on respiration

mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression

CNS becomes less responsive to pCO2 thereby causing a build up of CO2

• irregular breathing patterns; • periods of apnea

nausea and vomiting – Stimulation of CTZ, in the area postrema of medulla

stimulation by stretch receptors causes nausea and vomiting

receiving afferents from gut and ear

involved in motion sickness

pupil size

morphine causes miosis (pinpoint pupils) kappa receptor effect pinpoint pupils still responsive to bright light oculomotor nerve is stimulated by kappa receptor site if kappa receptor is blocked, mydriasis from sigma effect will appearatropine partially blocks effect indicating parasympathetic system involved

Cardiovascular effects

Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure

morphine causes the release of histamine and

suppression of central adrenergic tone and

suppression of reflex vasoconstriction

effects on gastrointestinal system

increase in tone and decrease in mobility leads to constipation （便秘）decreased concentration of HCl secretion increased tone in stomach, small and large intestinedelay of passage of food (gastric contents) , so more reabsorption of watertolerance does not develop (i.e. same amount of effect each time) to this constipation effect

effects on various smooth muscles

billiary tract • marked increase in the pressure in the billiary tract • 10 fold increase over normal (normal is 20 mm H20 pr

essure) • increase due to contraction of sphincter of Oddi

urinary bladder • tone of detrusor muscle increased • feel urinary urgency • urinary retention due to increased muscle tone wher

e sphincter shrinks bronchial muscle

• bronchoconstriction• contraindicated in asthma, particularly before surger

y uterus

• contraction of uterus results in prolonged labor

Neuroendocrine Effects

release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF) inhibited

↓decreased circulating luteinizing hormone (LH),

follicle-stimulating hormone (FSH), ACTH, and β- endorphin

↓concentrations of testosterone and cortisol in

plasma declined

Therapeutic uses of morphine

relief of severe pain preoperative medications postoperative medications acute pulmonary edema constipating effect cough

Tolerance to morphine

nausea analgesia sedation respiratory depression         cardiovascular euphoric not to:• miosis • constipation

Dependence and withdrawal syndrome

Strong cravings Nausea Cramps Sweating Chills Goose bumps Vomiting Diarrhea Shakes Irritation Agitation Anxiety Muscle aches Runny nose Yawning Insomnia Dilated pupils

physical dependence; psychological dependence

Animals will self-administer drugs

Results obtained from animals thatself-administer drugs

can be compared with animals thatreceive the same drug given passively

Acute toxicity of morphine

acute overdose respiratory depression pinpoint pupils (miosis) coma

Treatment establishing adequate ventilation giving OPIOID antagonist (naloxone)

Naloxone

no agonist activity

displacing morphine from all receptors, reversing all of the effects of morphine

effects immediate (3-5 min)

lasting 30-45 minutes, then reinjected

Other opiate drugs

Codeineone tenth the potency of morphine

withdrawal from codeine is mild in relation to morphine

antitussive drug for cough

pethidine （哌替啶）same CNS actions as morphine often used clinically

Fentanyl ( 芬太尼）

different structure than morphine 80 to 100 times more potent than morphine rapidly acting drug and short acting (30-45 min) often used as preoperative medication highly abused, known as china white as street name

analogue: remifentanil （瑞芬太尼）

Methadone

pharmacological activity similar to morphine, same potency as morphine orally absorbed well 16 to 20 hour duration of actionused in treatment of opioid dependence

Non-opioid analgesics

Rotundine （罗通定）Alkaloid isolated from plant Stephania

As a mild pain reliever, used in visceral pain and other mild pain.

Flupirtine （氟吡汀）Potassium channel opener and mild NMDA antagonist

Used for acute and chronic pain, in moderate to severe cases

癌症患者止痛的阶梯疗法 轻度疼痛：非甾体镇痛药阿司匹林、布洛芬等 中度疼痛：可待因、曲马多等 重度疼痛：吗啡、哌替啶、芬太尼、美沙酮等。

不易产生依赖性

《麻醉药品和精神药品管理条例》（国务院令第442 号） 2005 年 08 月 03 日 发布

Antagonists of opiates

Naloxone （纳洛酮） naltrexone ( 纳曲酮 )

Used for treatment of opiate intoxication and diagnosis of opiate dependence

Suggested reading

Fareed A, Vayalapalli S, Stout S, Casarella J, Drexler K, Bailey SP. Effect of methadone maintenance treatment on heroin craving, a literature review. J Addict Dis. 2011 Jan; 30(1):27-38.