ANALGESIC &

ANTI INFLAMMATORY
AGENTS
Nur permatasari

The 5 Cardinal Signs of

Heat

Redness Swelling

Pain Loss Of Func.

Nursing management: assessment,

diagnosis, planning, intervention,
evaluation

pain classification
ACUTE AND CHRONIC
SOMATIC AND VISCERAL
NEUROPATIC PAIN
NOCICEPTIVE PAIN
DISREGULATION PAIN
PSICHOSOMATIC

Sensitization of Peripheral Nociceptors

Chemical Mediators:
Vasoactive

amines - Histamine, Serotonin

Complement system C1 C9 (Classic/alt)
Kinin System Kallikrein Bradykinin
Clotting system FXII, FX, Fibrin, Plasmin
Arachidonic acid metabolites:
Prostaglandins - (cyclooxigenase)
Leukotrienes (Lipoxigenase)
Lipoxins anti-inflammatory.
PAF,

Cytokines (interleukins), Chemokines.

H2o2, Nitric Oxide, Lysozymes,O2 free
radicals

PROSES INFLAMASI
PADA SENDI
DETEKSI

INJURI

MIGRASI LEKOSIT
AKTIVASI LEKOSIT
IL-1
SEL PMN

CHONDROSIT

TNF ALFA
SEL MAST

SEL SINOVIUM

ELASTASE
CAPTESIN G COLLAGENASE
GELATINASE
STROMELYSIN TRYPTASE
CHYMASE
CAPTESIN D CAPTESIN L DAN B

DESTRUKSI TULANG RAWAN

Uses
Anti-

inflammatory
agent.
Analgesics.
Antipyretics.
Antithrombotics

Arthritis
Back pain
Soft tissue injuries
(sprains & strains)
Dental pain
Post-operative pain
Menstrual pain
Migraine
Delaying onset of
premature labour.

NSAID (non steroid anti inflammation drugs)

NSAID

a. Anti-Inflammatory Actions
Inflammation

is characterised by redness,
pain and swelling.
These are thought to be caused by
increased levels of prostaglandins.
NSAIDs reduce the prostaglandin levels
therefore reducing the symptoms of
inflammation.
They have varying degrees of antiinflammatory properties.

b. Antipyretic Actions

Pyrogens increase the body temperature by

activating macrophages & other cells to produce
cytokines.
These increase prostaglandin E2 synthesis in the
hypothalmus (the bodys thermostat) which in turn
increases the body temperature.
NSAIDs inhibit prostaglandin E2 synthesis and
lower the body temperature.
All NSAIDs have antipyretic properties. Aspirin,
ibuprofen and paracetamol are most commonly
used for this purpose.

c. Analgesic Actions
Prostaglandins

cause sensitisation of
nerve cells to pain.
They sensitise nociceptor fibres to
bradykinins and 5HT.
The pain relieving properties of
NSAIDs are thought to be due to the
inhibition of prostaglandins,
particularly PGE2 & PGF2

d. Antithrombotic Actions
The body maintains a balance between
Thromboxane A2 (TXA2), produced by platelets
& Prostaglandin I2 (PGI2), produced by the
vascular endothelium.
This allows adequate platelet aggregation
within the body.
NSAIDs reduce both TXA2 & PGI2 levels.

Platelets cant synthesise cyclo-oxygenase

enzymes & so become inactive.
This causes the prostaglandin levels to
increase & reduces platelet aggregation.

Anti thrombotic effect of aspirin

Differential Actions of
Cyclooxygenases
Unwanted sideeffects
COX1

Constitutive

NSAIDs
Inducible
Inflammatory

COX2

Therapeutic antiinflammatory effects

PGI2
PGE2
TXA2
PGE2
PGF2
Proteases

Housekeeping
Endothelial integrity
Vascular patency
Gastric mucosal
integrity
Bronchodilation
Renal function
Platelet function

Inflammation

Side effects

Gastric irritation and ulceration.

COX 1 produces prostaglandins that have a
protective effect on the stomach lining. NSAIDs
inhibit this enzyme & so it loses its function. Risk
factors for NSAID ulcers ??

Acute

kidney failure.

The kidneys are rarely damaged in normal people.

Patients with heart failure, cirrhosis of the liver,
renal disease or who are taking diuretics should
not take NSAIDs as they cause kidney failure.

Side effects (cont)

Bleeding

problems.
Bronchospasm can occur (may make
asthma worse).
Liver function abnormalities.
Headaches, Vertigo, Tinnitus, Dizziness
(Salicylism)
Metabolism.
Salt & Water Retention.

Hypersensitivity reaction

bronchospasm

Classes of NSAIDs

Table showing the different classes of NSAIDs and some examples.

Analgesia without Anti-inflammation

Acetaminophen
Does not have significant anti-inflammatory
properties
and as a result is not considered a true
NSAID.
Inhibits COX-3
Does not have the same degree of
complications from
the development of ulcerations. One of the
first
drugs of choicein the management of
mild to moderate
chronic pain.
Conventional oral dose is 325 to 1000 mg.

Acetaminophen-Pharmacokinetics
A small percentage undergoes cytochrome
P450 mediated
N-hydroxylation forming a highly reactive
intermediate.
Associated with hepatoxicity when taken in
large doses
(10 to 15 g).
Neutralized with the sulphydryl reducing
agent
N-acetylcysteine*

COX-II Selective NSAIDS

O
N N
O
H2 N

CF3

O
O

celecoxib

rofecoxib

Celecoxib
Approved for osteo and rheumatoid arthritis
Long term trial (CLASS) shows no difference in ulcerations between celecoxib
and diclofenac or ibuprofen
Slightly better than ibuprofen with respect to GI irritation
Rofecoxib
Approved for osteo and rheumatoid arthritis
Long term trial (VIGOR) shows significant improvement in ulcerations and GI
irritation between rofecoxib and naproxen
However, the incidence of thrombotic cardiovascular events is significantly
higher (overall incidence still less than 2%)

COX-II Selective NSAIDS

N
Cl

O
H2N

valdecoxib

Valdecoxib
First second generation coxib
Approved for rheumatoid and osteoarthritis
8 to 10 h half life
Etoricoxib
In Phase 3 Trials
Second Generation
15 to 20 h half life

etoricoxib

COX-2 Inhibitors - Do they meet

expectations?
Renal and cardiac complications at least as great as
conventional NSAIDS

No anti-thrombic activity

Gastrointestinal ulcerations reduced in short-term

studies (approximately 1-2 years), long-term benefit results still are not clear

Side effects

Pharmacokinetics

Binding to the glucocorticoid receptor complex prevents translocation af NFkappa B to

the nucleus.
( NFkappa B is agent that can stimulate the expressions of
proinflammatory protein) . So, glucocorticoids inhibit the expression of genes encoding
for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor).

Glucorticoid principle
and adverse effects

Regimens for prevention of

adrenocortical atrophy
a) Circadian administration and
The daily dose of glucocorticoid is given in
the morning. Endogenous cortisol
production will have already begun, the
regulatory centers being relatively
insensitive to inhibition.
b) Alternate-day therapy:
Twice the daily dose is given on alternate
mornings.On the off day, endogenous
cortisol production is allowed to occur.

Gout
NH2
N

N
H
adenine
adenine
deaminase
OH
N
N
N

N
H
hypoxanthine
xanthine
oxidase
OH
N
N
N

OH
N

N
H2 N
N
guanine
N
H
H
deaminase
guanine
xanthine
xanthine
oxidase

HO

OH
N

N
HO
N
H
uric acid

OH

Gout Treatment Strategies

Treatment of Acute Gout:

indomethacin or other NSAID

corticosteroids (rarely used today)
colchicine second line therapy

Treatment of Chronic Gout:

1) Increase uric acid excretion
uricosuric agents - probenecid
2) Decrease uric acid production
metabolic inhibition - allopurinol
3) Decrease inflammatory response
colchicine (low dose)

Uricosuric Agents
O
N S
O

O
OH

Probenecid
O
S

O
O

Sulfinpyrazone

N
N

Benzbromarone

Agents decrease reabsorption of uric acid at the middle of the proximal tubule in the kidney

Common Adverse Effects.

Probenecid is well tolerated. Approximately 2% of
patients develop mild gastrointestinal irritation. It is
ineffective in patients with renal insufficiency and should
be avoided in those with creatinine clearance of <50
ml/minute.
Substantial overdosage with probenecid results in CNS
stimulation, convulsions, and death from respiratory
failure.
Sulfinpyrazone :
Preferably given with meals or milk; a liberal fluid intake
should be maintained. Larger doses are tolerated poorly
and unlikely to produce a further uricosuric effect in
resistant patients.
Sulfinpyrazone is ineffective in patients with renal
insufficiency and should be avoided in those with
creatinine clearance of <50 ml/minute.

Allopurinol & Rasburicase

OH
N

N
N
N
H
allopurinol

xanthine
oxidase

OH
N

N
N
HO
N
H
alloxanthine

Rasburicase : catalizes the enzymatic oxidation of

uric acid into the soluble and inactive metabolite
allantoin

Nursing assessment:
The goal of therapy is to reduce the plasma uric acid
concentration to less than 6 mg/dl (equivalent to 360
mmol).
Fluid intake should be sufficient to maintain daily urinary
volume of more than 2 liters; slightly alkaline urine is
preferred.
The most common adverse effects are hypersensitivity
reactions (cutaneous reaction caused by allopurinol is
predominantly a pruritic, erythematous, or maculopapular
eruption, but occasionally the lesion is urticarial or
purpuric.

Colchicine

O
O

NH
O

O
O

Functions by blocking polymerization of tubulin to

microtubules
Blocks leukocyte migration and phagocytosis
Relieves pain in 12-24 h for acute attacks
Also used to prevent future attacks
Colchicine now is considered second-line therapy because it
has a narrow therapeutic window and a high rate of side
effects, particularly at higher doses.

Toxic Effects.
Nausea, vomiting, diarrhea, and abdominal pain
are the most common untoward effects of
colchicine
Bone marrow suppression, particularly from the
third to eighth days. There is a tendency toward
leukocytosis with appearance of less mature forms.
Chronic colchicine use may lead to agranulocytosis.
Thrombocytopenia
also
can
occur,
and
disseminated intravascular coagulation has been
reported in cases of severe poisoning.
Chronic use is associated with a proximal
myopathy. Ascending paralysis of the CNS has been
reported with acute poisoning.
Proteinuria, hematuria, and acute tubular necrosis

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

The term DMARD is a latex concept that can

be stretched to cover a heterologous group of
agents with unrelated chemical structures and
different mechanisms of action. Included in
this category are methotrexate,
sulfasalazine, gold compounds,
penicillamine and chloroquine
The DMARDs were often referred to as secondline drugs, with the implication that they are
only resorted to when other therapies (e.g.
NSAIDs) failed. Today, however, DMARD
therapy may be initiated as soon as a definite
diagnosis has been reached.
DMARD has potentially serious adverse effects.