1、麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)1ReviewNeuroleptic drugs麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)2Narcotic Narcotic AnelgesicsAnelgesics麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Objectives Understand the pharmacological effects, mechanism of actions, clinical uses, as well as adverse drug reactions of morphine. Identify the therapeutic effects and

2、 adverse drug reactions of codeine and pethidine. 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)4Section oneIntroduction麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)5麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)1.2 Analgesics DefinitionDrugs that selectively inhibit the perception (sensation) of the pain Classification 1- Peripheral: - Causal: Atropine, NSAIDs - Non-c

3、ausal2- Central: - Narcotic analgesics麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Peripheral analgesics Causal -Treat the causeExample: Atropine (antispasmodic) Aspirin Non-causal- Not treat the causeExamples:1- Local anaesthetics (for superficial tumor)2- Counter-irritant (apply pain that counteract or mask the original

4、 one e.g. acupuncture)麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Narcotics NSAIDsExamplesMorphineAspirinSite of actionCortex & thalamusPeripheralAntagonistNaloxoneNo antagonistUsesSever & deep pain e.g. cancer, MI & anginal painDull pain e.g. headache, toothache & backachePotencyHighLowSide effectAddicti

5、onNo addiction. in bleeding tendency & ulcerMechanism stimulate opiates receptors (m, k , d) m, k , d) and relief the painInhibits PG synthesis by inhibition of COX-2麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)The actions listed for antagonists are seen with the antagonist alone. All the correlations in this table ar

6、e based on studies in rats and mice, which occasionally show species differences.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)10Section two Morphine麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料) Naturally occurring in the poppy (16%)- Only needs to be isolated Very strong pain reliever but also very addictive (2nd to Heroin) Usually injected but

7、 can be smoked, sniffed or swallowed Commonly used in hospitals2.1 Introduction麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)121) 3位位-OH的的H被被-CH3取代，取代，中樞抑制作用中樞抑制作用。如：。如：可待可待因（因（codeine)2) 3位和位和6位位-OH的的H同時被同時被-COCH3取代，取代，中樞抑制作中樞抑制作用用。如：。如：海洛因海洛因(heroin)3) 17位的位的-CH3被被-CH2CH=CH2取代，則變為取代，則變為嗎啡受體的嗎啡受體的部分激動藥，部分激動藥，如：丙烯嗎啡如：丙烯嗎啡(

8、nalorphine)。若同時將若同時將6位的位的-OH變為變為=O，則變為則變為嗎啡受體的完全拮嗎啡受體的完全拮抗藥，抗藥，如：如：納洛酮納洛酮 (naloxone)2.2 構效關系構效關系OHOHNHCH3HO12345678910111213141516Morphine (Astramorph)HO- Group is needed for activityHO- Group not important to activity麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)14麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)152.3 Mechanis

9、ms of ActionuMost neurons react to opioids with a hyperpolarization, reflecting an increase in K+ conductance. uCa2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of transmitters and decreased synaptic activity.uDepending on the cell population affected,

10、this synaptic inhibition translates into a depressant or excitant effect.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料) Morphine and opioids produce analgesia, affect mood and rewarding behavior, and alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine function.2.4 Pharmacological effects and mechanisms麻

11、醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)172.4.1 Effects on the CNS(1) Analgesiau Mechanisms and Sites of Opioid-Induced Analgesia: The analgesic effects of opioids arise from their ability to directly inhibit the ascending transmission of nociceptive information from the spinal cord dorsal horn (脊髓背角) and to activate

12、pain control circuits that descend from the midbrain via the rostral ventromedial medulla(延腦頭端腹內側區) to the spinal cord dorsal horn.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)18uCharacteristics: A significant feature of the analgesia is that it occurs without loss of consciousness.In addition to relief of distress, some

13、patients experience sedation, euphoria, and rewarding properties.Continuous dull pain is relieved more effectively than sharp intermittent pain, but with sufficient amounts of opioid it is possible to relieve even the severe pain associated with renal or biliary colic.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)19(2) Res

14、piration. The primary mechanism of respiratory depression by opioids involves a reduction in the responsiveness of the brainstem respiratory centers to carbon dioxide. The second mechanism of respiratory depression is via a direct effect on the brainstem respiratory centers. 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)20

15、(3) Cough. Morphine and related opioids also depress the cough reflex at least in part by a direct effect on a cough center in the medulla.(4) Nauseant and Emetic Effects. Nausea and vomiting produced by morphine-like drugs are side effects caused by direct stimulation of the chemoreceptor trigger z

16、one for emesis in the area postrema of the medulla.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)21(5) Miosis. Morphine and most and agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. After toxic doses of agonists, the miosis is marked, and pinpoint pupils a

17、re pathognomonic.瞳孔擴大瞳孔擴大 正常瞳孔正常瞳孔 針尖樣瞳孔針尖樣瞳孔麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)22(6) Neuroendocrine Effects. Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH), thus decreasing circulating concentrations of luteinizing horm

18、one (LH), follicle-stimulating hormone (FSH), ACTH, and -endorphin.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)232.4.2 Effects on the peripheral smooth muscle(1) Stomach. Relatively low doses of morphine decrease gastric motility, thereby rolonging gastric emptying time.(2) Small Intestine. Morphine diminishes biliary, p

19、ancreatic, and intestinal secretions and delays digestion of food in the small intestine. The amplitude of the nonpropulsive type of rhythmic, segmental contractions usually is enhanced, but propulsive contractions are decreased markedly. 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)24(3) Large Intestine Propulsive perist

20、altic waves in the colon are diminished or abolished after administration of morphine. The tone of the anal (肝門）sphincter is augmented greatly, and reflex relaxation in response to rectal distension （直腸擴張） is reduced. Inattention to the normal sensory stimuli for defecation（通便） reflex owing to the c

21、entral actions of the drug, contribute to morphine-induced constipation.(4) The sphincter of Oddi constricts, and the pressure in the common bile duct may rise.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)(5) Ureter （輸尿管）（輸尿管）and Urinary Bladder. Therapeutic doses of morphine may increase the tone and amplitude of contrac

22、tions of the ureter, although the response is variable.(6) Uterus（子宮）（子宮）. If the uterus has been made hyperactive by oxytocics（催產素）, morphine tends to restore the tone, frequency, and amplitude of contractions to normal.(7) Morphine causes histamine release, which can cause bronchoconstriction and

23、vasodilation.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)262.4.3 Cardiovascular System. Therapeutic doses of morphine like opioids do produce peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor（壓力感受器）reflexes. Therefore, when supine patients assume the head-up position, orthostatic h

24、ypotension and fainting may occur.Morphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension.opioid-induced respiratory depression and CO2 retention can result in cerebral vasodilation and an increase in cerebrospinal（腦脊髓的） fluid pressure;麻醉性鎮

25、痛藥麻醉性鎮痛藥(學習資料學習資料)272.4.4 Immune SystemThe overall effects of opioids appear to be immunosuppressive, and increased susceptibility to infection and tumor spread have been observed.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)282.5 Therapeutic Uses2.5.1 Analgesia. For the treatment of acute pain, trauma, cancer, nonmaligna

26、nt chronic pain, and pain in children.Pain of Terminal Illness and Cancer Pain. the analgesia, tranquility, and even euphoria afforded by the use of opioids can make the final days far less distressing for the patient and family.In general, it is recommended that opioids always be combined with othe

27、r analgesic agents, such as NSAIDs or acetaminophen. In this way, one can take advantage of additive analgesic effects and minimize the dose of opioids and thus undesirable side effects.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Fig. 19-3 The analgesic regimen recommended by WHO for cancer pain. 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)2.

28、5.2 Dyspnea（呼吸困難）（呼吸困難） Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to intravenous morphine may be dramatic. It may involve an alteration of the patients reaction to impaired respiratory function and an indirect reduction of the w

29、ork of the heart owing to reduced fear and apprehension（憂慮）. However, it is more probable that the major benefit is due to cardiovascular effects, such as decreased peripheral resistance and an increased capacity of the peripheral and splanchnic （內臟的）vascular compartments.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)2.5.3

30、 Cough2.5.4 Diarrhea（腹瀉）（腹瀉）麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)2.6 Side Effects2.6.1. Morphine has many side effects. The most dangerous is respiratory depression. -Naloxone2.6.2. With higher doses or in frail patients, the patient becomes increasingly sedated, and the pupils become very small. 2.6.3. Common sid

31、e effects are nausea and vomiting due to a central action of morphine stimulating one of the centres in the brain concerned with vomiting called the chemotactic trigger zone. 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Side Effects2.6.4. Tolerance. With repeated administration of opioids, their CNS effects undergo habitu

32、ation (adaptation). In the course of therapy, progressively larger doses are thus needed to achieve the same degree of pain relief.2.6.5. Other central nervous system side effects of morphine is addiction (dependence).-Methatone (opioid receptor agonist) -Clonidine ( 2-R agonist) 麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習

33、資料)Side Effects2.6.6. Morphine can also cause histamine release, which causes itching of the skin and nose and a mild flushing of the skin. 2.6.7. Morphine also has an effect on the muscle of the bowel and urinary tract, causing the sphincter to contract and reduce the peristalsis (the wavelike move

34、ments of the bowel muscle that propel its contents forwards). This results in a delayed emptying of the stomach, constipation, and may also lead to urinary retention.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)352.6.8. Acute opioid toxicity may result from clinical overdosage, accidental overdosage in addicts, or attempt

35、s at suicide. Symtoms: Three Cardinal Symptoms: coma, pinpoint pupils, and depressed respiration strongly suggests opioid poisoning. Others: blood pressure will fall progressively; hypoxia is severe and cyanosis may be present. urine formation is depressed. Treatment. The first step is to establish

36、a patent airway and ventilate the patient. The antagonist naloxone (see below) is the treatment of choice.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)2.7 Kinetics Morphine can be given orally or parenterally, as well as epidurally(硬腦膜外地) or intrathecally(鞘內地) in the spinal cord. Morphine is conjugated to glucuronic acid

37、and excreted renally. Glucuronidation of the OH group at position 6, unlike that at position 3, does not affect affinity for the receptors.36麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)37NauseavomittingPinpointpupils麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Section 3Other analgesics麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)CodeineOHOHNHCH3HO1234567891011121314

38、1516Morphine (Astramorph)HO- Group is needed for activityHO- Group not important to activityOHOHNHCH3CH3OCodeine (5X LESS potent than morphine)Inefficiently converted to HO group in the liver麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料) Codeine is considered a prodrug, since it is metabolised in vivo to the principal acti

39、ve analgesic agent morphine. It is, however, less potent than morphine since only about 10% of the codeine is converted.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)Uses of Codeine1. Cough, though its efficacy in low dose over the counter formulations has been disputed.2. Moderate to severe pain. Codeine is sometimes mark

40、eted in combination preparations with patacetamol (acetaminophen), with aspirin or with ibuprofen. These combinations provide greater pain relief than either agent (drug synergy).麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)42 Pethidine (dolantin) In the treatment of mild-to-moderate pain. Pethidine can be used to treat labor pain and may cause less neonatal respiratory depression.麻醉性鎮痛藥麻醉性鎮痛藥(學習資料學習資料)43Common side eff