Beruflich Dokumente
Kultur Dokumente
Perioperative Period
dr. Asmin Lubis, DAF, Sp.An,
KAP, KMN
Pediatric Anesthesia Consultant and Pain
Management
Anesthesiology and Intensive Department
Faculty of Medicine
Universitas Sumatera Utara
What is Pain
An
unpleasant
emotional
with
sensory
experience
actual
or
and
associated
potential
tissue
Multimodal Analgesia
Combinations of varying agents for pain
control
Always consider multimodal analgesia when
treating pain
Different drugs with different mechanisms/sites
of action along pain pathway
Each with a lower dose than if used alone
Can provide additive or synergistic effects
Provides better analgesia with less side effects
(mainly opiate related S/E)
Categorized:
Characteristic of NSAIDs
Suitability (contra-indication)
Availability
Pharmacokinetics and drug interaction
Daily cost
Evidence based medicine
Drug issues
Efficacy
Tolerability
Safety
Dosage
Cost
BENEFITS
efficacy
RISKS
safety
Patient issues
Type, severity
Risk factors: GI,
platelet, renal and
cerebro-cardiovascular
system.
Co-prescription.
Co-morbidity.
Compliance.
phospholipids
arachidonic acid
COX-2
COX
COX-1
cyclic
endoperoxides
PGI2
stimulates platelet
aggregation,
vasoconstriction
hyperalgesia
PGD2
inhibits platelet
aggregation,
vasodilator
5-HPETE
TXA2
inhibits platelet
aggregation,
vasodilator,
PGE2
vasodilator,
LOX
PGF2alfa
bronchodilatation
myometrial contr.
hyperalgesia hyperalgesia
LTA4
LTB4
chemotaxis
LTC4
LTD4
LTE4
brochoconstriction
increase
vascular
permeability
COX-1 or COX-2
The detrimental effects of some NSAIDs
(eg, renal dysfunction, gastrointestinal
mucosal compromise, platelet inhibition)
are mediated by inhibition COX-1
The
analgetic
effect
and
antiinflammatory effects are attributable
primarily to inhibition of COX-2
Experimental
evidence
showing
that
prostaglandin E2 (PGE2), which is generated
by the COX-2 pathways, plays a critical
role in the induction of both peripheral
and central sensitization
Bronchospam
Hepatotoxic
Bleeding
Allergy
Color blindness
CHF
UGIB
UGIB
Nephrotoxic
Tocolytic
Mechanism of = Mechanism of
therapeutic effects
adverse effects
platelet
aggregation
COX-1
inhibitor
platelet
aggregation
hemorrhagic stroke
GI
bleeding
bleeding
COX-2
inhibitor
GI
bleeding
blood coagulation
Lelo, 2000
Pref.
COX-2
non
selective
Pref.
COX-1
COX-1
selective
analgesic
anti-inflammation
COX 1 SELECTIVE
Ketorolac
COX 1 SELECTIVE
Ketorolac
<65 years
20 mg (orally), then 10 mg every 4-6 hours
(not to exceed 40 mg/24 hours)
Given parenterally
60 mg IM followed by 30 mg every 6 hours
Or 30 mg IV every 6 hours
Available as ocular preparation 0.25%, 1
drop every 6 hours
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
COX 1 SELECTIVE
Ketoprofen
Pharmacokinetics
Peak plasma 1-2 hours, Half life 2 hours
Protein binding 98%
Half-life in plasma of about 2 hours except in the elderly, in whom it
is slightly prolonged
Conjugated with glucuronic acid in the liver, and the conjugate is
excreted in the urine. Patients with impaired renal function eliminate
the drug more slowly.
Dose
Analgesia: 25 mg (3-4 times/day)
Antiinflammatory: 50-75 mg 3-4 times/day
Pref. COX-1
Ibuprofen
Pharmacokinetics
Absorbed rapidly, bound avidly to protein, and undergoes hepatic
metabolism
Renal excretion of metabolites.
Peak 15-30 minutes, half-life is roughly 2-4 hours
Slow equilibration with the synovial space means that its antiarthritic
effects may persist after plasma levels decline
In experimental animals, ibuprofen and its metabolites readily cross the
placenta
Dose
Analgesia 200-400 mg every 4-6 hours
Antiinflammatory 300 mg every 6-8 hours or 400-800 mg 3-4 times/day
Common adverse effects
5% to 15% of patients experience gastrointestinal side effects.
Can be used occasionally by pregnant women; however, the concerns
apply regarding third-trimester effects, including delay of parturition
Excretion into breast milk is thought to be minimal, so ibuprofen also can
be used with caution by women who are breastfeeding.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
non Mefenamic
selective
Acid
Pharmacological Properties
Peak plasma 2-4 hours, half life 3-4 hours
May have central action
The fenamates are a family of NSAIDs first discovered in the 1950s that are
derivatives of N-phenylanthranilic acid. They include mefenamic,
meclofenamic, and flufenamic acids.
The fenamates are typical tNSAIDs. Mefenamic acid has central and
peripheral actions, and meclofenamic acid (and perhaps other fenamates)
may antagonize directly certain effects of prostaglandins, although it is not
clear that receptor blockade is attained at therapeutic concentrations.
These drugs are absorbed rapidly and short durations of action.
Approximately 50% of a dose of mefenamic acid is excreted in the urine
Twenty percent of the drug is recovered in the feces
,Dose
500-mg load, then 250 mg every 6 hours
Common Adverse Effects and Precautions
Approximately 25% of users develop gastrointestinal side effects at
therapeutic doses.
The fenamates are contraindicated in patients with a history of
gastrointestinal disease
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
non
selective
Piroxicam
Pharmacological Properties
Piroxicam is effective as an antiinflammatory agent
Absorbed completely after oral administration and undergoes
enterohepatic recirculation;
Peak concentrations in plasma 3-5 hours, Half life 45-50
minutes
Food may delay absorption
Estimates of the half-life in plasma have been variable; the average is
roughly 50 hours
Extensively (99%) bound to plasma proteins
Less than 5% of the drug is excreted into the urine unchanged
60% of the drug excreted in the urine and feces.
Dose
The usual daily dose is 20 mg and because of the long half-life,
steady-state blood levels are not reached for 7 to 12 days
Common adverse effects
Toxicity includes gastrointestinal symptoms (20% of patients),
dizziness, tinnitus, headache, and rash. When piroxicam is used in
dosages higher than 20 mg/d, an increased incidence of peptic ulcer
and bleeding is encountered.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
Pref.
COX-2
Meloxicam
Pharmacological Properties
Some COX-2 selectivity, especially at
lower doses
Peak 5-10 hours, Hall life 15-20 hours
Protein binding 99%
Meatbolisme di hati melalui Hydroxylation
Dose
7.5-15 mg/day
7.5 to 15 mg once daily for osteoarthritis
and 15 mg once daily for rheumatoid
arthritis
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
Pref.
COX-2
Celecoxib
Pharmacological Properties
Peak 2-4 hours, Half-life 6-12 hours, protein binding 97%
Metabolites Carboxylic acid and glucuronide conjugates
Celecoxib is metabolized predominantly by CYP2C9.
Little drug is excreted unchanged; most is excreted as carboxylic acid and glucuronide
metabolites in the urine and feces
Renal insufficiency is associated with a modest, clinically insignificant decrease in
plasma concentration
Dose
Celecoxib is approved in the United States for the treatment of osteoarthritis and
rheumatoid arthritis
The recommended dose for treating osteoarthritis is 200 mg per day as a single dose or
as two 100-mg doses.
Common Adverse Effects and Precautions
Studies in mice and some epidemiological evidence suggest that the likelihood of
hypertension on NSAIDs reflects the degree of inhibition of COX-2 and the selectivity
with which it is attained.
Risk of thrombosis, hypertension, and accelerated atherogenesis are
mechanistically integrated. The coxibs should be avoided in patients prone to
cardiovascular or cerebrovascular disease.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
Pref.
COX-2
Diclofenac
Pharmacological Properties
Diclofenac has analgesic, antipyretic, and antiinflammatory
activities
Diclofenac has rapid absorption , Peak 2-3 hours, a short half-life,
Half-life 1-2 hours
There is a substantial first-pass effect, such that only about 50% of
diclofenac is available systemically.
Diclofenac accumulates in synovial fluid after oral administration,
which may explain why its duration of therapeutic effect is considerably
longer than the plasma half-life
Diclofenac is metabolized in the liver
Metabolites are excreted in the urine (65%) and bile (35%)
Dose
100 to 200 mg, given in several divided doses
50 mg 3 times/day or 75 mg 2 times/day
short-term treatment of acute musculoskeletal pain, postoperative
pain, and dysmenorrhea
Common Adverse Effects
Diclofenac produces side effects (particularly gastrointestinal) in about
20% of patients
Modest elevation of hepatic transaminases in plasma occurs in 5% to
15% of patients
CNS effects, rashes, allergic reactions, fluid retention, and edema, and
rarely impairment of renal
function.
Goodman
& gilman's the pharmacological basis of therapeutics - 11th ed. (2006)
Paracetamol
Pharmacological Properties
Analgesic-antipyretic agent
Weak COX-1 and COX-2 inhibitor and no significant anti-inflammatory effect
Peak blood in 30-60 minutes, half-life is 2-3 hours
Relatively unaffected by renal function.
With toxic doses or liver disease, the half-life may be increased twofold or
more.
Less than 5% is excreted unchanged.
Dose
10-15 mg/kg every 4 hours (maximum of 5 doses/24 hours)
Common Adverse Effects and Precautions
Rash and other allergic reactions occur occasionally
The use of acetaminophen has been associated anecdotally with
neutropenia, thrombocytopenia, and pancytopenia.
Overdosage: Fatal hepatic necrosis.
Renal tubular necrosis and hypoglycemic coma also may occur.
rapid onset
but short duration
long
duration
but slow onset
Effective concentration
Time
Acute
Slowly Chronic
Acute
o
r
long duration e
but slow onset ng
a
D
increased
By increasing the dose ???:
?
onset!becomes earlier
the dose
c
i
but adverse effects enhanced
h
t
E
Effective concentration
?
e
v
Sa
?
l
a
Time
n
o
i
t
Slowly
Chronic
a
R
Gastrointestinal Risk
Thrombosis,
Myocardial Infarction
Bleeding Ulcer
Complications
Discontinuation
Discontinuation
Et
or
ic
Ro oxi
b
fe
co
xi
b
C
Di ele
cl c
of ox
en ib
ac
Ib
up
ro
fe
n
Na
pr
ox
en
Blood Pressure
Increase
COX-2
COX-1
Degree of Selectivity
Adapted from Antman EM, et al. Circulation. 2007;115:1634-