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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inhibiting adenylate cyclase
increasing potassium ion efflux or reducing calcium ion influx
impeding neuronal firing and
(1)classification of opioid receptors
μ, κ, σ,δ
analgesic effect: mediated by μ,κreceptors
(2)location of opioid receptors:
morphine, heroin, codeine, thebaine, paraverine
meperidine, methadone, fentanyl, anadol, etorphine, pentazocine.
【mechanism of action】
Sensory neuron second neuron
Enkephalin sp=substence P
1. effects on CNS
(1) analgesia and sedation: prominent effect.
chronic dull pain, colic andacute sharp pain.
relieving anxiety and stress accompanied with severe pain.
(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.
(1)peripheral vasodilation to cause orthostatic hypotension
(2)cerebral vasodilation to increase intracranial pressure
(1)relieves diarrhea or causes constipation
(2)increasing biliary pressure by constriction of
Oddi's sphincter to induce biliary colic.
2. acute pulmonary edema
3. severe diarrhea.
1.common side effects
2.tolerance and physical dependence
autonomic, motor and psychological responses (insomania, dysphoria, headache, sweating, vomiting, diarrhea, tremor, collapse).
1.women in delivery and lactation.
2.patients with bronchial asthma and pulmonary
3.patients with cranial injury and high cranial
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.
1.activating opioid receptors, particularlyκreceptors.
2.pharmacologic effects are similar to morphine
sedative and respiratory depression.
4.mild adverse effects similar to morphine
5.tolerance: being cross with the other opioids.
dependence: in long use.
1.analgesic effect is equal to morphine in potency and action duration, but more effective in oral
administration than morphine.
3.physical dependence occurs slowly and withdrawal syndrome is mild.
analgesic effect is 80-100 times as effective as morphine with short duration(15 to 30 min) and rapid onset.
anesthesia or anesthesic adjunct.
Alfentanil has a more rapid onset of action and shorter duration of narcotic effect than fentanyl.
adjunct to general anesthetics
anesthetic inducing agent.
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.
【classification of drugs】
1. cerebral stimulants: caffeine.
2. respiratory stimulants: nikethamide, lobeline.
3. spinal cord stimulants: strychnine.
【mechanism of action 】
caffeine→ blocking adenosine receptors, inhibiting PDE → breakdown of cAMP↓ → central actions and some of peripheral actions.
small dose stimulating cerebral cortex
loss of sleepiness
vasomotor centers--- BP ↑
large dose spinal cord---convulsion
(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.
1. central inhibition
2.headache in combination with aspirin, migraine in combination with ergotamine.
CNS excitement: insomnia, agitation, convulsion etc..
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.
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.
asphyxia in the newborn
respiratory failure caused by infectious diseases in
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.
(PGD1, PGD2, PGE1, PGE2, PGFα, PGI2 etc.)
COX-1: gastrointestinal tract, kidney, platelet
COX-2: EC etc.
reduction of PGs biosynthesis via inhibition of cyclo-oxygenase to lower body temperature in patients with fever. *
PG E2 synthesis and release
body temperature-regulating center in hypothalamus
set point for body temperature↑
heat production↑and heat dissipation↓
Differences in 2 aspects:
PGs release autocoid release
e.g. headache, toothache, neuralgia, muscular pain, arthralgia and dysmenorrhea etc.
potency: strong analgesic effect
action site: CNS
mechanism: activation of opiate receptors
use: mainly for sharp pain
potency: weak analgesic effect
action site: peripheral tissue
mechanism: inhibition of PGs biosynthesis
use: mainly for dull pain
relieving inflammatory symptoms
(pain and swelling).
inhibition of PG synthesis.*
vasodilation autocoids release
kinin increased vascular permeability
2. aminophenol derivatives
4. other organic acids
1. non-selective COX inhibitors: aspirin etc.
2. COX-2 selective inhibitors: celecoxib,etoricoxib,meloxicam
Acetylsalicylic acid (ASA, aspirin)
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.
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.*
1. hyperpyrexia: middle dose.
2.dull pain: e.g. headache, arthritis, dysmenorrhea etc. middle dose.
3.rheumatic fever and rheumatoid arthritis (first-line drugs) in relatively large dose.
4. prevention of thromboembolism, stroke, myocardial infarction in small dose. decreasing incidence of transient ischemic attack and unstable angina as well as that of coronary artery thrombosis.
5.chronic use of aspirin reduces incidence of colorectal cancer.*
1.gastrointestinal reaction: epigastric distress, nausea, vomiting, gastric ulceration and bleeding.
taking aspirin with meal or with sodium bicarbonate, taking enteric- coated aspirin.
2. hepatic damage: mild, reversible.
3. prolonging bleeding time due to inhibition of platelet functions in small dose and reduction of plasma prothrombin level in large dose.
4.large dose of aspirin uncouples oxidative phosphorylation. Energy normally used for production of ATP is dissipated as heat, which explains hyperthermia caused by salicylates when taken in toxic quantities.
5.hypersensitivity or allergy.
7.Salicylate toxication (salicylism):
Medication: discontinuation of salicylates, gastric lavage, relieving symptoms, intravenous infusion of NaHCO3 and dialysis.
Acetaminophen inhibits prostaglandin synthesis in CNS,but less effect on peripheral cyclooxygenase.
Use: dull pain and hyperpyrexia., choice for children with viral infections or chicken pox.
Adverse effects: skin rash and drug fever, hypoglycemic coma, renal tubular necrosis and renal failure in long-term administration, acute hepatic necrosis in large dose.
rheumatoid and rheumatic arthritis, not routinely for analgesia and antipyresis because of its toxicity and side effects.
35%-50% of patients report some adverse effects and most adverse effects are dose-related.
1. gastrointestinal complains.
2. CNS effects: frontal headache, dizziness, vertigo, mental confusion etc.
3. hematologic effects: neutropenia, thrombocytopenia, inpaired platelet functions, rare aplastic anemia.
4. contraindication: in pregnancy or nursing women, patients with psychiatric disorders, epilepsy, parkinsonism, renal diseases, peptic ulcers and machine operators.