Chapter 21 Opioid-analgesics

• opium receptor agonists; • opium receptor partial agonists;• others.

Classification of analgesics basied on their mechanism of action:

[Mechanism of action]

• Opioid agonists produce analgesia by binding to specific receptors, located primarily in brain and spinal corbrain and spinal cord regionsd regions involved in the transmission and modulation transmission and modulation of pain.of pain.

• Receptor types: The major classes of receptors are µ (mu for morphine) delta(δ), and kappa(κ). All are members of the G-protein-coupled family of receptors.

• Analgesia, as well as the euphoriant, respiratory depressant, and physiologic dependence properties of morphine result principally from actions at mu receptors.Most of the currently available opioid analgesics act primarily at the mu receptor.

Opioid Analgesics

含阿片生物碱类植物： 罂粟含阿片生物碱类植物： 罂粟

• [Source] • Opium is obtained from the opium

poppy by incision of the seed pod after the petals of the flower have dropped.The white latex that oozes out turns brown and hardens on standing.

• This sticky brown gum is opium. It contains about 20 alkaloids, including morphine, codeine etc.The principal alkaloid in opium is morphine,present in a concentration of about 10%.

Opioid Analgesics

• Central effects

• Peripheral effects

Opioid Analgesics---Narcotic analgesics

[Pharmacological Effects]

Morphine 吗啡

• 1.Analgesia:

• Pain consists of both sensory and affective(emotional) components.

• 2.Sedation and change in mood

• After a dose of morphine, a patient in pain or an addict experiences a pleasant floating sensation and freedom from anxiety and distress.However,other patients and some normal subjects(not in pain) experience dysphoria rather than pleasant effects after a dose of opioid analgesics.

Opioid Analgesics---Morphine[Central effects]

• 3.Respiratory depression:

• All of the opioid analgesics can produce significant respiratory depression by inhibiting the sensitivity of brain stem respiratory center to CO2 .

• 4.Cough suppression:

• Opioids directly suppress the cough center in medulla.

• 5.Emesis

• Nausea and vomiting are an unpleasant side effect by direct stimulation of CTZ.

• 6.Miosis:

• It is valuable in the diagnosis of opioid overdose.

Opioid Analgesics---Morphine

• 1. Histamine release• Causing peripheral arteriolar,venous dilation,and bronchoconstriction. • 2. Effects on smooth muscles• (1) Gastrointestinal tract: Constipation has long been recognized as an

effect of opioids.motility(rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase, particularly in the central portion.

• (2) Biliary （胆道的） tract: The opioids constrictconstrict biliary smooth muscle and sphincter of Oddi, which may result in biliary colic( 绞痛） .

• (3) Other smooth muscle: Uterus ( 子宫 ) tone is decreased and duration of childbirth is prolonged. Genitourinary tract: Ureteral( 输尿管 ) and bladder tone are increased by t

herapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate （加重） urinary retention,especially in postoperative patients.

Bronchial smooth muscle can constrict in higher dose of morphine, which may precipitate bronchial asthmia.

Opioid Analgesics---Morphine

[Peripheral effects ]

[Clinical use of opioid analgesics]

• 1.pain • Opioids relieve moderate to severe acute pain from various causes.• 2.Dyspnea • The relief produced by intravenous morphine in dyspnea(呼吸困难 ) from

pulmonary edema associated with left ventricular failure is remarkable.• The mechanism probably include:• (1) reduction of the patient anxious and fear due to the sedative effects of

opioids;• (2) decrease in cardiac preload and afterload by lowering peripheral resis

tance due to opioid-induced histamine releasing;• (3)decrease of the sensitivity of respiratory center to CO2 and relief of sh

allow breathing.• 3.Diarrhea• 4.Anesthesia

Opioid Analgesics---Morphine

[untoward effects]

• 1. Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting and constrespiratory depression, nausea, vomiting and constipation...ipation...

• 2. Tolerance2. Tolerance

• 3.Physical dependence3.Physical dependence:

Failture to continue administering the drug results in a abstinence syndrome( 戒断症状 ), including mydriasis, muscular aches, vomiting, diarrhea, anxiety.

Opioid Analgesics---Morphine

吗啡耐受和依赖性的产生机制受体向下调节（脱敏）

SYMPTOMS OF WITHDRAWAL

3. Acute morphine poisoning :coma, severe respiratory depression and miosis with blood pressure decreased, and urinary retention.

Respiratory paralysis often is the mainly lethal reason.

Treatment: respiratory support and intrvenous injection of naloxone.

Opioid Analgesics---Morphine

[Toxicity ]

[contraindication and Cautions in therapy]

• 1. Use in patients with head in injuries: Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation; in patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.

• 2. Use in patients with impaired pulmonary function : The respiratory depression properties of the opioid analgesics may lead to acute respiratory failure.

• 3. Use during pregnancy and delivery :Since the opioid analgesia readily traverse the placenta,their use for obstetric analgesia can result in delivery of an infant with depressed respiration.

• 4. Use in patients with impaired hepatic or renal function.

Characterization of individual narcortic agonists

• A.strong agonists• 1.Morphine• 2.meperidine and fentanyl• B.Moderate agonists• 1.codeine• 2.propoxyphene• C.Mixed agonist-antagonist(MAA)• Buprenorphine

• Pethidine/meperidine and fentanyl( 芬太尼 ) are the most widely used agents in this family of synthetic opioids.

• The principal effects of pethidine with affinity for mu receptors are on the central nervous system.

Opioid Analgesics--- Pethidine ( 哌替啶 )

[Pharmacological Effects]

The pharmacological effects of Pethidine is similar to morphine, primarily at the mu receptor.It has less potent analgesics than morphine,and has a shorter duration of action. Pethidine dosn`t delay delivery.

Clincal Use

• 1. Analgesia : Pethedine which be considered as a replacement for morphine is used for wound, postoperative and terminal cancer pain, etc.

• 2. Acute pulmonary edema (cardiac asthma ) • 3. (1)Applications in anesthesia It is used as premedicant drugs before anesthesia a

nd surgery . (2) artificial hibernation:with chlorpromazine an

d promethazine( 异丙嗪 )

The Opioid Antagonists

• The opioid antagonist drugs naloxone and naltrexone are morphine derivatives.

• When given in the absence of an agonist drug these antagonists are almost inert at doses that produce marked antagonism of agonist effects.

• When given intravenously to a morphine-treated subject,the antagonist will completely and dramatically reverse the opioid effects within 1-3 min.

Clincal Use

• The major application of naloxone is in the treatment of acute opioid overdose.

• In individuals who are acutely depressed by an overdose of an opioid,the antagonist will effectively normalize respiration,level of consciousness,pupil size.

• More recently,considerable interest has been aroused by reports that naltrexone decreases craving for alcohol in chronic alcoholics,and it has been approved by the FDA for this purpose.

The Opioid Antagonists