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CHAPTER 19 Narcotic Analgesics

CHAPTER 19 Narcotic Analgesics. I General Consideration. 【action mechanism】 ligands opioids receptor Gi inhibiting adenylate cyclase increasing potassium ion efflux or reducing calcium ion influx impeding neuronal firing and transmitter release . 1.Ligands

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CHAPTER 19 Narcotic Analgesics

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  1. CHAPTER 19 Narcotic Analgesics

  2. I General Consideration 【action mechanism】 ligands opioids receptor Gi inhibiting adenylate cyclase increasing potassium ion efflux or reducing calcium ion influx impeding neuronal firing and transmitter release

  3. 1.Ligands (1)endogenous: • endorphins from pituitary β-endorphin dynorphin • enkephalins from brain M-enkephalin L-enkephalin (2)exogenous: drugs

  4. 2.Receptor (1)classification of opioid receptors μ, κ, σ,δ analgesic effect: mediated by μ,κreceptors (2)location of opioid receptors: • CNS • nerve terminals in periphery • cells of gastrointestinal tract .

  5. 【analgesic characteristics】 • relieving pain without affecting other senses and consciousness. • high potency of analgesia. • dependence. 【clinical use】 intense pain.

  6. 【classification of drug】 1.origin • natural opiates morphine, heroin, codeine, thebaine, paraverine • synthetic analgesics meperidine, methadone, fentanyl, anadol, etorphine, pentazocine. 2.potency • strong agonist morphine,heroin,meperidine,methadone,fentanyl • moderate agonist codeine, propoxyphene. • mixed agonist-antagonist buprenorphine, pentazocine • antagonist: naloxone, naltrexone

  7. Ⅱ Natural Opiates Morphine 【mechanism of action】 • Morphine activates opiate receptor to produce analgesic effect like endogenous opiate peptides. • high affinity for μ receptors • varying affinities forδandκreceptors • low affinity for σ receptors in CNS and gastrointestinal tract.*

  8. Sensory neuron second neuron sp sp sp E E Enkephalin sp=substence P Neuron E=enkephalin

  9. 【pharmacokinetics】 • good absorption from gastrointestinal tract • significant first-pass effect • subcutaneous injection is commonly used. • rapidly entering to all body tissues, including fetuses of pregnant women. • not used for analgesia during labor. • duration of action is 4 - 6 h.

  10. 【pharmacologic effects】 1. effects on CNS (1) analgesia and sedation: prominent effect. characteristics: • strong analgesia • effective on various pains chronic dull pain, colic andacute sharp pain. • no effect on other senses and consciousness. • sedation relieving anxiety and stress accompanied with severe pain. • analgesia with euphoria in partial patients.

  11. (2) emesis by direct stimulation of CTZ to cause nausea and vomiting. (3) respiratory depression by reducing response of respiratory centers to blood CO2. (4) suppression of cough by direct inhibition of cough center. (5) miosis by stimulating Edinger-Wesphal nucleus, pinpoint pupils are indicative of toxic dosage.

  12. 2.cardiovascular effects (1)peripheral vasodilation to cause orthostatic hypotension • inhibition of vasomotor center. • promotion of histamine release from mast cells. (2)cerebral vasodilation to increase intracranial pressure • depression of respiration to increase blood CO2.

  13. 3. gastrointestinal effects (1)relieves diarrhea or causes constipation • reducing peristalsis and stomach mobility • increasing spasmodic nonpropulsive contraction • decreasing biliary and pancreatic secretions to cause indigestion. (2)increasing biliary pressure by constriction of Oddi's sphincter to induce biliary colic.

  14. 4.other effects • bronchoconstriction by histamine. • retention of urine by increasing sphincter tone of bladder.

  15. 【therapeutic uses】 1. analgesia. • acute sharp pain(intense pain) • anginal pectoris by analgesic, sedative and vasodilation • biliary and kidney colic etc., combined with atropine 2. acute pulmonary edema • vasodilation • sedative • inhibiting respiration 3. severe diarrhea.

  16. 【adverse effects】 1.common side effects • nausea, vomiting, constipation, biliary colic, • respiratory depression, • dysphoria, • hypotension, • acute urine retention. 2.tolerance and physical dependence withdrawal symptoms： autonomic, motor and psychological responses (insomania, dysphoria, headache, sweating, vomiting, diarrhea, tremor, collapse).

  17. 【contraindication】 1.women in delivery and lactation. 2.patients with bronchial asthma and pulmonary heart disease. 3.patients with cranial injury and high cranial pressure.

  18. Codeine 1.codeine is 3-methyl ether of morphine. 2.pharmacologic effects are similar to morphine, but its analgesic potency is 1/12 of morphine, cough depressant potency is 1/4 of morphine. 3.analgesic effect is strongr than aspirin. 30mg of codeine is equivalent to 600mg of aspirin. 4.less sedation, respiratory depression and fewer gastrointestinal effects. 5.use: mild to moderate pains and severe cough by oral administration. 6.physical dependence in long administration.

  19. Ⅲ Synthetic Analgesics Pethidine (Meperidine,Dolantin) 1.activating opioid receptors, particularlyκreceptors. 2.pharmacologic effects are similar to morphine • less potency and shorter duration in analgesis, sedative and respiratory depression. • no effect on cough, bronchial and gastrointestinal smooth muscles.

  20. 3.use • to replace morphine to relieve intense pains, • to treat acute pulmonary edema, • to induce artificial hibernation. • not useful for diarrhea or cough. 4.mild adverse effects similar to morphine 5.tolerance: being cross with the other opioids. dependence: in long use.

  21. Methadone 1.analgesic effect is equal to morphine in potency and action duration, but more effective in oral administration than morphine. 2.use: • analgesia • suppression of withdrawal syndrome • treatment of heroin user. • orally administered, methadone is substituted for injected opioids and patient is then slowly weaned from methadone. 3.physical dependence occurs slowly and withdrawal syndrome is mild.

  22. Fentanyl 1.effects analgesic effect is 80-100 times as effective as morphine with short duration(15 to 30 min) and rapid onset. 2.use anesthesia or anesthesic adjunct.

  23. Alfentanil • effects Alfentanil has a more rapid onset of action and shorter duration of narcotic effect than fentanyl. • uses adjunct to general anesthetics anesthetic inducing agent.

  24. Ⅳ Opioid Receptor Antagonists 1.partial antagonists to precipitate a withdrawal syndrome in opioid addicts (nalorphine, pentazocine, butorphanol, nalbuphine, buprenorphine). 2. full antagonists naloxone and naltrexone. naloxone may reverse the acute poisoning effects of opioid agonists and precipitate a withdrawal syndrome in opioid addicts.

  25. Summary for this chapter • effects and uses of morphine and dolantin • contraindication of morphine • dependence • characteristics of other analgesics • drug name of opiate receptor antagonists

  26. CHAPTER 20 Central Stimulants 【classification of drugs】 1. cerebral stimulants: caffeine. 2. respiratory stimulants: nikethamide, lobeline. 3. spinal cord stimulants: strychnine.

  27. I Cerebral Stimulants Caffeine 【mechanism of action 】 caffeine→ blocking adenosine receptors, inhibiting PDE → breakdown of cAMP↓ → central actions and some of peripheral actions.

  28. 【pharmacologic effects】 1.CNS small dose stimulating cerebral cortex vigorous loss of sleepiness medullary bulb respiratory--- hyperpnea vasomotor centers--- BP ↑ large dose spinal cord---convulsion

  29. 2.cardiovascular system (1)direct effects: cardiac excitement and vascular dilation. (2)indirect effects: cardiac inhibition and vascular contriction by stimulating vasomotor center and vagal center. In overall, little changes in heart rate and blood pressure in normal cardiovascular state, increasing heart rate and blood pressure in cardiovascular hypofunction. 3.other systems: relaxing bronchial smooth muscle, diuretic effect and stimulating secretion of gastric acid.

  30. 【therapeutic uses】 1. central inhibition 2.headache in combination with aspirin, migraine in combination with ergotamine. 【adverse effects】 CNS excitement: insomnia, agitation, convulsion etc..

  31. II Respiratory Stimulants Nikethamide(coramine) 1.stimulating respiration: short and modest effect. direct stimulation of respiratory center reflex-mediated stimulation of respiratory center by stimulating chemoreceptor in carotid body increasing sensitivity of respiratory center to CO2 2.use: central respiratory depression, no effective for peripheral respiratory depression. 3. wide margin of safety. tachycardia and blood pressure increase in the large dose.

  32. Lobeline 1.stimulating respiratory center by stimulation of chemoreceptors in carotid and aortic bodies. 2.short effect and wide margin of safety. hardly producing convulsion in large dose. 3.use: asphyxia in the newborn CO toxication respiratory failure caused by infectious diseases in children.

  33. Summary for this chapter 1.Clinical uses of caffeine. 2.Action mechanisms, uses of nikethamide and lobeline. 3.Pay attention of dosage of caffeine, nikethamide and lobeline in clinical uses.

  34. CHAPTER 21 Antipyretic Analgesic andAntiinflammatory Drugs

  35. I General Consideration • Inflammation is a protective response to tissue injury. • Inflammation is triggered by the release of chemical mediators from injured tissues and migrating cells. • Specific chemical mediators include histamine, 5-HT, PGs, LTs, brandykinin, interleukin-1. • nonsteroidal anti-inflammatory drugs(NSAID) or non-narcotic analgesics. • effects: antipyretic, analgesic and anti-inflamatory activities. • differences: they all exert antipyretic and analgesic actions, most also produce antiinflammatory action. • mechanisms of actions: reduction of PG biosynthesis by inhibition of cyclooxygenase.*

  36. Phospholipids ↓ PLA2 AA ↓cyclooxygenase (-) PGG2/PGH2↓ ↓ PGs↓ (PGD1, PGD2, PGE1, PGE2, PGFα, PGI2 etc.)

  37. COX COX-1: gastrointestinal tract, kidney, platelet COX-2: EC etc.

  38. 1. antipyretic effects: Effect: • reduction of body temperature in patients with fever • no effect on normal body temperature Mechanism: reduction of PGs biosynthesis via inhibition of cyclo-oxygenase to lower body temperature in patients with fever. *

  39. pathogens or toxins ↓(+) PMNs ↓ pyrogen release ↓(+) hypothalamus ↓ PG E2 synthesis and release ↓(+) body temperature-regulating center in hypothalamus ↓ set point for body temperature↑ ↓ heat production↑and heat dissipation↓ ↓ body temperature↑(fever)

  40. Use: high fever. Differences in 2 aspects: effect action mechanism • Phenothiazides decrease both normal and high body temperature by direct inhibition of temperature-regulating center in CNS. • Antipyretics decreases only high body temperature by inhibition of PGs biosynthesis and has no effect on normal body temperature.

  41. 2. analgesic effect Effect: • weak, only effective on mild to moderate dull pain • little effect on colicky pain and sharp pain (intense pain) • no narcotic. Mechanism: • relieving pain via inhibition of PGs biosynthesis*

  42. injured or inflammatory tissue PGs release autocoid release (+) (e.g.bradykinin) (+) (+) pain receptors pain

  43. Use: • common dull pains. e.g. headache, toothache, neuralgia, muscular pain, arthralgia and dysmenorrhea etc. Differences: • narcotic analgesics: potency: strong analgesic effect action site: CNS mechanism: activation of opiate receptors use: mainly for sharp pain • non-narcotic analgesics: potency: weak analgesic effect action site: peripheral tissue mechanism: inhibition of PGs biosynthesis use: mainly for dull pain

  44. 3. anti-inflammatory effect Effect: relieving inflammatory symptoms (pain and swelling). Mechanism: inhibition of PG synthesis.*

  45. prostaglandins vasodilation autocoids release histamine serotonin kinin  increased vascular permeability edema pain, swelling

  46. Use: rheumatic and rheumatoid arthritis etc.. Differences: NSAID---weak SAID---strong 4.antiplatelet effect

  47. 【classification I】 1. salicylates aspirin 2. aminophenol derivatives acetaminophen 3. pyrazolon phenylbutazone 4. other organic acids indomethacin etc.

  48. 【classification II】 1. non-selective COX inhibitors: aspirin etc. antipyretic analgetic antiinflammatory antiplatelet 2. COX-2 selective inhibitors: celecoxib,etoricoxib,meloxicam antipyretic analgetic antiinflammatory

  49. Ⅱ Salicylates Acetylsalicylic acid (ASA, aspirin) 【pharmacokinetics】 • metabolized in liver by the hydrolyzation to salicylate and acetic acid by esterases . • in oral small dose，metabolized in first-order kinetics and half life is 3.5 h, in large dose (1g/time,>4g/day), metabolized in zero-order kinetics because hepatic metablic pathway becomes saturated, which prolong t1/2 of aspirin to 15 h or more to lead to toxication.

  50. 【pharmacologic effects】 • Aspirin is rapidly deacetylated by esterases in body, producing salicylate which has anti-inflammatory, analgesic,and antipyretic effects. • Aspirin irreversibly acetylates cyclooxygenase to inhibit the enzyme activity. 1. antipyretic action: rapid and moderate in potency. 2. analgesic effects: effective for mild, moderate dull pain. 3. antiinflammatory effects: to treat rheumatoid and rheumatic arthritis, symptomatic relief. 4.antiplatelet effects: to inhibit platelet aggregation and secondary release of ADP from activated platelets by inhibition of TXA2 production.*

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