CHAPTER 19 Narcotic Analgesics. I General Consideration 【 action mechanism 】 ligands opioids...

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CHAPTER 19 Narcotic Analgesics

Transcript of CHAPTER 19 Narcotic Analgesics. I General Consideration 【 action mechanism 】 ligands opioids...

Page 1: CHAPTER 19 Narcotic Analgesics. I General Consideration 【 action mechanism 】 ligands opioids receptor Gi inhibiting adenylate cyclase increasing potassium.

CHAPTER 19

Narcotic Analgesics

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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

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1.Ligands

(1)endogenous:

• endorphins from pituitary

β-endorphin

dynorphin

• enkephalins from brain

M-enkephalin

L-enkephalin

(2)exogenous: drugs

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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

.

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【 analgesic characteristics 】• relieving pain without affecting other sen

ses and consciousness.

• high potency of analgesia.

• dependence.

【 clinical use 】 intense pain.

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【 classification of drug 】1.origin• natural opiates morphine, heroin, codeine, thebaine, paraverine• synthetic analgesics meperidine, methadone, fentanyl, anadol, etorphin

e, pentazocine.2.potency• strong agonist morphine,heroin,meperidine,methadone,fentanyl• moderate agonist codeine, propoxyphene.• mixed agonist-antagonist buprenorphine, pentazocine• antagonist: naloxone, naltrexone

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Ⅱ Natural Opiates

Morphine【 mechanism of action 】• Morphine activates opiate receptor to produce anal

gesic effect like endogenous opiate peptides.

• high affinity for μ receptors• varying affinities forδandκreceptors• low affinity for σ receptors in CNS and gast

rointestinal tract.*

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Sensory neuron second neuron

sp

sp sp

E

E

Enkephalin sp=substence P

Neuron E=enkephalin

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【 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.

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

ere pain.• analgesia with euphoria in partial patients.

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(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.

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2.cardiovascular effects

(1)peripheral vasodilation to cause orthostatic hypot

ension

• inhibition of vasomotor center.

• promotion of histamine release from mast cells.

(2)cerebral vasodilation to increase intracranial pres

sure

• depression of respiration to increase blood CO2.

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3. gastrointestinal effects

(1)relieves diarrhea or causes constipation• reducing peristalsis and stomach mobility• increasing spasmodic nonpropulsive contracti

on• decreasing biliary and pancreatic secretions t

o cause indigestion.

(2)increasing biliary pressure by constriction of

Oddi's sphincter to induce biliary colic.

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

of bladder.

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【 therapeutic uses 】1. analgesia. • acute sharp pain(intense pain)• anginal pectoris by analgesic, sedative and vasodi

lation• biliary and kidney colic etc., combined with atropin

e

2. acute pulmonary edema• vasodilation• sedative• inhibiting respiration

3. severe diarrhea.

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【 adverse effects 】1.common side effects• nausea, vomiting, constipation, biliary colic,• respiratory depression, • dysphoria, • hypotension, • acute urine retention.2.tolerance and physical dependencewithdrawal symptoms : autonomic, motor and psychological respon

ses (insomania, dysphoria, headache, sweating, vomiting, diarrhea, tremor, collapse).

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【 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.

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Codeine1.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 few

er gastrointestinal effects.5.use: mild to moderate pains and severe coug

h by oral administration.6.physical dependence in long administration.

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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.

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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.

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Methadone1.analgesic effect is equal to morphine in potency an

d 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.

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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.

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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.

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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.

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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

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CHAPTER 20 Central Stimulants

【 classification of drugs 】 1. cerebral stimulants: caffeine.

2. respiratory stimulants: nikethamide, lobeline.

3. spinal cord stimulants: strychnine.

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I Cerebral Stimulants

Caffeine

【 mechanism of action 】 caffeine→ blocking adenosine receptors, inhi

biting PDE → breakdown of cAMP↓ → central actions and some of peripheral actions.

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【 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

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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.

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【 therapeutic uses 】 1. central inhibition

2.headache in combination with aspirin, migraine in combination with ergotamine.

【 adverse effects 】 CNS excitement: insomnia, agitation, convul

sion etc..

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II Respiratory StimulantsNikethamide(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.

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Lobeline1.stimulating respiratory center by stimulation of ch

emoreceptors 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.

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Summary for this chapter1.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.

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CHAPTER 21

Antipyretic Analgesic andAntiinflammatory Drugs

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I General Consideration• Inflammation is a protective response to tissue injury.• Inflammation is triggered by the release of chemical med

iators from injured tissues and migrating cells.• Specific chemical mediators include histamine, 5-HT, P

Gs, LTs, brandykinin, interleukin-1.• nonsteroidal anti-inflammatory drugs(NSAID) or non-na

rcotic analgesics.• effects: antipyretic, analgesic and anti-inflamatory activit

ies.• differences: they all exert antipyretic and analgesic actio

ns, most also produce antiinflammatory action. • mechanisms of actions: reduction of PG biosynthesis by

inhibition of cyclooxygenase.*

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Phospholipids

↓ PLA2

AA

↓cyclooxygenase (-)

PGG2/PGH2↓

PGs↓

(PGD1, PGD2, PGE1, PGE2, PGFα, PGI2 etc.)

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

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1. antipyretic effects:Effect: • reduction of body temperature in patients with fe

ver• no effect on normal body temperatureMechanism: reduction of PGs biosynthesis via inhibition of c

yclo-oxygenase to lower body temperature in patients with fever. *

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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)

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Use: high fever.Differences in 2 aspects: effect action mechanism• Phenothiazides decrease both normal and high b

ody 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.

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2. analgesic effect Effect: • weak, only effective on mild to moderate dull

pain• little effect on colicky pain and sharp pain (in

tense pain)• no narcotic. Mechanism: • relieving pain via inhibition of PGs biosynthe

sis*

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injured or inflammatory tissue

PGs release autocoid release

(+) (e.g.bradykinin)

(+) (+)

pain receptors

pain

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Use: • common dull pains. e.g. headache, toothache, neuralgia, muscular pai

n, 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

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3. anti-inflammatory effect

Effect:

relieving inflammatory symptoms

(pain and swelling).

Mechanism:

inhibition of PG synthesis.*

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prostaglandins

  vasodilation autocoids release

histamine

serotonin

kinin  increased vascular permeability

  edema

  pain, swelling

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Use: rheumatic and rheumatoid arthritis etc..

Differences: NSAID---weak

SAID---strong

4.antiplatelet effect

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【 classification I 】 1. salicylates

aspirin

2. aminophenol derivatives

acetaminophen

3. pyrazolon

phenylbutazone

4. other organic acids

indomethacin etc.

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【 classification II 】1. non-selective COX inhibitors: aspirin etc.

antipyretic

analgetic

antiinflammatory

antiplatelet

2. COX-2 selective inhibitors: celecoxib,etoricoxib,meloxicam

antipyretic

analgetic

antiinflammatory

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Ⅱ Salicylates

Acetylsalicylic acid (ASA, aspirin)

【 pharmacokinetics 】• metabolized in liver by the hydrolyzation to salicy

late and acetic acid by esterases . • in oral small dose , metabolized in first-order ki

netics and half life is 3.5 h, in large dose (1g/time,>4g/day), metabolized in z

ero-order kinetics because hepatic metablic pathway becomes saturated, which prolong t1/2 of aspirin to 15 h or more to lead to toxication.

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【 pharmacologic effects 】• Aspirin is rapidly deacetylated by esterases in body, pro

ducing 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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5.other effects:• increasing alveolar ventilation • increasing gastric acid secretion and diminish

ing mucus protection to cause epigastric distress, ulceration, hemorrhage

• resulting in retention of sodium and water to cause edema and hyperkalemia

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【 therapeutic uses 】 DOSAGE1. 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, myocardi

al 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.*

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【 adverse effects 】1.gastrointestinal reaction: epigastric distress, nause

a, vomiting, gastric ulceration and bleeding. taking aspirin with meal or with sodium bicarb

onate, taking enteric- coated aspirin.2. hepatic damage: mild, reversible.3. prolonging bleeding time due to inhibition of platel

et 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.

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6.Reye’s syndrome: • seen during viral infectionsfatal, especially in chil

dren• manifestations: fulminating hepatitis with cerebra

l edema• children should use acetaminophen instead.7.Salicylate toxication (salicylism): • mild toxication: headache, mental confusion, dro

wsiness, difficulty in hearing, vomiting• severe toxication: hyperventilation, severe CNS

disturbulance, respiration depression and marked alteration in acid-base balance

Medication: discontinuation of salicylates, gastric lavage, relieving symptoms, intravenous infusion of NaHCO3 and dialysis.

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Ⅲ Aminophenol Derivatives Acetaminophen

Acetaminophen inhibits prostaglandin synthesis in CNS,but less effect on peripheral cyclooxygenase.

• antipyretic and analgesic effects are similar to aspirin in potency

• no anti-inflammatory activity. Use: dull pain and hyperpyrexia., choice for children wi

th viral infections or chicken pox. Adverse effects: skin rash and drug fever, hypoglycemi

c coma, renal tubular necrosis and renal failure in long-term administration, acute hepatic necrosis in large dose.

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Ⅳ Other Organic Acids

Indomethacin

【 pharmacologic effects 】• anti-inflammatory, analgesic and antipyretic effects• more potent than aspirin as an anti-inflammatory agent• inferior to the salisylates at dose tolerated by patients

with rheumatoid arthritis.

【 therapeutic uses 】 rheumatoid and rheumatic arthritis, not routinely for a

nalgesia and antipyresis because of its toxicity and side effects.

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【 adverse effects 】 35%-50% of patients report some adverse effect

s 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.

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Ibuprofen• anti-inflammatory, analgesic and antipyretic activity.• chronic treatment of rheumatoid and osteoarthritis.• less intense of gastrointestinal effects than that of as

pirin.

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Other drugs• Sulindac• fenamates (mefenamic acid, meclofenamate)• tolmetin• propionicacid derivatives (naproxen, fenoprofen, k

etoprofen, flurbiprofen)• piroxicam• nabumetone• etodolac, diclofenac, ketorolac• in single agent or in the compound preparations.

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Summary for this chapter• effects and uses of NSAID• mechanism of action of NSAID• pharmacological basis of small dose of aspirin for

prevention of thromboembolism• characterastics of aspirin, acetaminophen, indomet

hacin and ibuprofen