Chapter 17 Opioid ['əupiɔid] analgesics [ænəl’dʒi:ziks] 阿片类镇痛药

Transmission of pain stimuli

Opioid receptors 阿片受体 1 μ-receptor: be responsible for analgesic effects and some adverse effects e.g. respiratory ([‘resp(ə)rət(ə)rɪ]呼吸的) depression； 2 δ-receptor: similar to μ-receptor, more important in the periphery ； 3 к-receptor: contribute to analgesia ([,æn(ə)l‘dʒiːzɪə]止痛) at the spinal ([’spaɪn(ə)l]脊髓的) level, elicit sedation ([sɪ‘deɪʃ(ə)n]镇静) and dysphoria ([dɪs'fɔrɪə] 烦躁不安)； 4 σ-receptor: the site of action of psychomimetic ([,psaɪkəʊmɪ‘metɪk]引起幻觉) drug, account for the dysphoria by some opioids (not selective opioid receptors)

Opioid analgesic drugs Morphine [‘mɔ:fi:n] 吗啡

Mechanism of action:作用机制 Morphine and most other clinically used opioid agonists exert their effects by mimicking endogenous ([en'dɔdʒənəs]内生的) opioid peptides (or endorphins [en'dɔːfɪn]内啡肽; 脑内啡): agonist action at opioid receptor, especially μ-receptor.

Route of administration Orally: 70% removed by first pass metabolism Rectally Intravenously Intramuscularly

Effects of morphine: Central Nervous System Effects 1 Analgesia ([,æn(ə)l'dʒiːzɪə]止痛) 2 Euphoria ([[juː'fɔːrɪə]欣快感) /dysphoria ([dɪs'fɔːrɪə]烦躁不安) 3 Sedation 4 Respiratory inhibition 5 Suppression of cough 6 Miosis 7 Nausea ([ˈnɔ:ziə] 恶心) and emesis ([‘emɪsɪs] 呕吐)

Cardiovascular system 1 Vasodilation and hypotension; 2 Increased intracranial ([,ɪntrə‘krenɪəl]颅内的) pressure: due to increased cerebral ([sə’ribrəl]大脑的) blood flow

Smooth muscle 1 Intestine smooth muscle tension ↑ → constipation [,kɔnsti'peiʃən]便秘 2 Increase urethral ([jʊ'riθrəl]尿道的), and bladder sphincter tone ↑ → urinary retention 3 Constrict biliary ([‘bɪlɪərɪ]胆的) smooth muscle and Oddi’s sphincter (奥狄括约肌) →increased biliary pressure.

Therapeutic Uses (Clinical application/use) 临床应用 1 Severe and constant pain (particularly visceral [‘vɪs(ə)r(ə)l] 内脏的, postoperative or cancer related) ； 2 Acute pulmonary ([‘pʌlmən(ə)rɪ]肺的) edema associated with left ventricular heart failure: reducing anxiety (perception of shortness of breath); reducing cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). 3 Diarrhea ([,daɪə'riə]腹泻);

Toxicity & Undesired Effects 1 Central adverse reactions （1）Drowsiness, and sedation （2） Respiratory inhibition （3）Tolerance and dependence （4）Vomiting

2 Peripheral adverse action Constipation urinary retention Increased biliary tract pressure

Intravenous injection of naloxone; Respiratory support. Diagnosis and treatment of opioid overdosage Intravenous injection of naloxone; Respiratory support.

Opioid analgesic drugs Codeine ['kəʊdiːn] 可待因

Analgesic potency =1/12 as morphine Uses: Cough Mild to moderate pain

Opioid analgesic drugs Pethidine (['pɛθədin]) 哌替啶

Synthetic analgesic drugs Effects： Central action 1 Analgesia 2 Respiratory inhibition

Cardiovascular 1 Vasodilation 2 Hypotension 3 Increased intracranial pressure Smooth muscle Constrict biliary smooth muscle and Oddi’s sphincter →increased biliary pressure

Clinical uses 1 Analgesia 2 Premedication for surgical operation 3 Artificial hibernation 4 Cardiogenic asthma

Adverse reaction 1 Respiratory inhibition 2 Tolerance and dependence 3 Others: vomiting, dizziness, tachycardia, postural hypotension

Opioid antagonist 阿片受体拮抗剂 Naloxone ([næl'ɔksəun]纳洛酮 ) Naltrexone ([næl'treksəun]纳曲酮) Mechanism: antagonize opioid receptors Route of administration: intravenously

Clinical uses 1 Respiratory depression induced by overdose of opioid agonists or newborn 2 Babies that have been affected by the opioids given to their mother.

Adverse effects 1 Withdrawal syndrome in those with physical dependence on opioids 2 Increased sensitivity to painful stimuli 3 Cardiotoxicity [,kɑ:diəu‘tɒksɪsətɪ] 心脏毒性

Supplementary reading Severe, constant pain is usually relieved with opioid analgesics with high intrinsic activity; whereas sharp, intermittent [ɪntə‘mɪt(ə)nt] 间歇性的 pain does not appear to be as effectively controlled. The pain associated with cancer and other terminal illnesses 绝症 must be treated aggressively and often requires a multidisciplinary多种学科的approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. Research in the hospice 收容所 movement has demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. New dosage forms of opioids that allow slower release of the drug are now available, eg, sustained-release forms of morphine. Their purported 据说的advantage is a longer and more stable level of analgesia. If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl 芬太尼transdermal [træns‘dɚməl] 经皮的system (fentanyl patch) can be used over long periods. Administration of strong opioids by nasal insufflation has been shown to be effective, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain. Opioid analgesics are often used during obstetric [əb‘stetrɪk]产科的 labor 分娩. Because opioids cross the placental [plə’sɛntl] barrier and reach the fetus [‘fiːtəs]胎儿, care must be taken to minimize neonatal [,niːə(ʊ)’neɪt(ə)l]新生儿 depression. If it occurs, immediate injection of the antagonist naloxone will reverse the depression. The phenylpiperidine苯基哌啶drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine; this may justify their use in obstetric practice. The acute, severe pain of renal and biliary colic ['kɒlɪk]急腹痛often requires a strong agonist opioid for adequate relief. However, the drug-induced increase in smooth muscle tone may cause a paradoxical矛盾的increase in pain secondary to increased spasm ['spæz(ə)m] 痉挛. An increase in the dose of opioid is usually successful in providing adequate analgesia.

大纲要求 1 掌握吗啡、哌替啶的作用、作用机理、用途、不良反应。 2 了解可待因及其它人工合成镇痛药的作用特点。

Glossary Opioid analgesics Respiratory depression Analgesia Morphine Endogenous Endorphins Euphoria /dysphoria Suppression of cough Nausea/emesis Cerebral blood flow Constipation Biliary Acute pulmonary edema Diarrhea Codeine Pethidine Cardiogenic asthma Cardiotoxicity