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
(1)endogenous:
endorphins from pituitary
-endorphin
dynorphin
enkephalins from brain
M-enkephalin
L-enkephalin
(2)exogenous: drugs

2.Receptor
(1)classification of opioid receptors
, , ,
analgesic effect: mediated by
,receptors
(2)location of opioid receptors:
CNS
nerve terminals in periphery
cells of gastrointestinal tract
.
analgesic characteristics
relieving pain without affecting other
senses and consciousness.
high potency of analgesia.
dependence.

clinical use
intense pain.
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
Natural Opiates
Morphine
mechanism of action
Morphine activates opiate receptor to produce
analgesic effect like endogenous opiate peptides.
high affinity for receptors
varying affinities forandreceptors
low affinity for receptors in CNS and
gastrointestinal tract.*



Sensory neuron second neuron

sp
sp sp
E

E
Enkephalin sp=substence P
Neuron E=enkephalin

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.
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
severe pain.
analgesia with euphoria in partial patients.
(2) emesis by direct stimulation of CTZ to cause
nausea and vomiting.
(3) respiratory depression by reducing response of
respiratory centers to blood CO
2
.
(4) suppression of cough by direct inhibition of cough
center.
(5) miosis by stimulating Edinger-Wesphal nucleus,
pinpoint pupils are indicative of toxic dosage.
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 CO
2
.
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.

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

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.
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).
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.

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.
Synthetic Analgesics
Pethidine (Meperidine,Dolantin)

1.activating opioid receptors, particularlyreceptors.
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.
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.
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.
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.


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.

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.
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

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

I Cerebral Stimulants

Caffeine
mechanism of action
caffeine blocking adenosine receptors,
inhibiting PDE breakdown of cAMP
central actions and some of peripheral
actions.

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


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.
therapeutic uses
1. central inhibition
2.headache in combination with aspirin,
migraine in combination with ergotamine.

adverse effects
CNS excitement: insomnia, agitation,
convulsion etc..

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 CO
2

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.
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.
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.

CHAPTER 21

Antipyretic Analgesic and
Antiinflammatory Drugs
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.*
Phospholipids
PLA
2

AA
cyclooxygenase (-)
PGG
2
/PGH
2


PGs
(PGD
1
, PGD
2
, PGE
1
, PGE
2
, PGF, PGI
2
etc.)


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

pathogens or toxins
(+)
PMNs

pyrogen release
(+)
hypothalamus

PG E
2
synthesis and release
(+)
body temperature-regulating center in hypothalamus

set point for body temperature

heat productionand heat dissipation

body temperature(fever)

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.
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*

injured or inflammatory tissue

PGs release autocoid release
(+) (e.g.bradykinin)
(+) (+)
pain receptors

pain

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

prostaglandins

vasodilation autocoids release
histamine
serotonin
kinin
increased vascular permeability

edema

pain, swelling


Use: rheumatic and rheumatoid arthritis etc..
Differences: NSAID---weak
SAID---strong


4.antiplatelet effect

classification I
1. salicylates
aspirin
2. aminophenol derivatives
acetaminophen
3. pyrazolon
phenylbutazone
4. other organic acids
indomethacin etc.
classification II
1. non-selective COX inhibitors: aspirin etc.
antipyretic
analgetic
antiinflammatory
antiplatelet
2. COX-2 selective inhibitors:
celecoxib,etoricoxib,meloxicam
antipyretic
analgetic
antiinflammatory
Salicylates
Acetylsalicylic acid (ASA, aspirin)
pharmacokinetics
metabolized in liver by the hydrolyzation to
salicylate and acetic acid by esterases .
in oral small dosemetabolized 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 t
1/2

of aspirin to 15 h or more to lead to toxication.
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 TXA
2
production.*
5.other effects:
increasing alveolar ventilation
increasing gastric acid secretion and
diminishing mucus protection to cause
epigastric distress, ulceration, hemorrhage
resulting in retention of sodium and water to
cause edema and hyperkalemia

therapeutic uses
DOSAGE
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.*
adverse effects
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.
6.Reyes syndrome:
seen during viral infectionsfatal, especially in
children
manifestations: fulminating hepatitis with
cerebral edema
children should use acetaminophen instead.
7.Salicylate toxication (salicylism):
mild toxication: headache, mental confusion,
drowsiness, 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 NaHCO
3
and dialysis.
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
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.
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
analgesia and antipyresis because of its toxicity and
side effects.
adverse 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.
Ibuprofen
anti-inflammatory, analgesic and antipyretic activity.
chronic treatment of rheumatoid and osteoarthritis.
less intense of gastrointestinal effects than that of
aspirin.

Other drugs
Sulindac
fenamates (mefenamic acid, meclofenamate)
tolmetin
propionicacid derivatives (naproxen, fenoprofen,
ketoprofen, flurbiprofen)
piroxicam
nabumetone
etodolac, diclofenac, ketorolac
in single agent or in the compound preparations.

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,
indomethacin and ibuprofen