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.
