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ANTI-INFLAMMATORY
DRUGS
( NSAIDs)
KUSWINARTI
DEPARTMENT OF PHARMACOLOGY AND THERAPY
MEDICAL SCHOOL
UNIVERSITAS PADJADJARAN
INTRODUCTION
Inflammation is a normal, protective response
to tissue injury caused by physical trauma,
noxious chemicals, or microbiologic agents
ARACHIDONIC ACID
NSAIDs - Cyclooxygenase
PGG2
Hydroperoxidase
PGF2
SYNTHESIS OF PROSTAGLANDINS
INTRODUCTION (CONTINUED)
In contrast, acetaminophen (paracetamol),
although an excellent analgesic and antipyretic,
does not possess anti-inflammatory activity
In the treatment of rheumatoid arthritis, the
NSAIDs and the salicylates are the drugs of first
choice.
Besides their use in rheumatoid arthritis, many
of the NSAIDs are also useful in the treatment of
acute gout
Unlike narcotics, these agents have no
tolerance or addiction liability
NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs)
Actions :
1. Anti-inflammatory actions :
Aspirin inhibits inflammation in arthritis
Acetaminophen, although a useful analgesic and antipyretic,
has weak anti-inflammatory activity rheumatoid arthritis
2. Analgesic action :
By decreasing Prostaglandin E2 (PGE2) synthesis, aspirin and
other NSAIDs repress the sensation of pain.
The salicylates are used mainly for the management of pain of
low to moderate
3. Antipyretic action :
The salicylates lower body temperature in patients with
fever by impeding PGE2 synthesis and release.
Aspirin resets the thermostat toward normal and
rapidly lowers the body temperature of febrile patients by
increasing heat dissipation as a result of peripheral
vasodilation and sweating. Aspirin has no effect on
normal body temperature
4. Respiratory actions :
At therapeutic doses, aspirin increases alveolar
ventilation
At higher doses hyperventilation
At toxic levels central respiratory paralysis
5. Gastrointestinal effects :
Aspirin increase gastric acid secretion and diminished
mucus protection may cause epigastric distress,
ulceration, and or/hemorrhage
6. Effects on platelets :
Aspirin platelet aggregation is reduced
anticoagulant effects prolonged bleeding time
NSAIDs
STRONG
Analgesic Antipyretic
b. External applications :
Salicylic acid To treat corns, epidermophytosis
Methyl salicylate is used externally as a cutaneous counterirritant in liniment
c. Cardiovascular applications :
Low doses of aspirin are used prophylactically to decrease the
incidence of ischemic attack ,unstable angina , coronary artery
thrombosis
d. Colon cancer
Chronic use of aspirin reduces the incidence of colorectal cancer
PHARMACOKINETICS
ADMINISTRATION AND DISTRIBUTION :
Salicylates, especially Methyl salicylate are absorbed through intact
skin.
After oral adm : salicylates absorbed from the stomach and the
small intestine.
Rectal absorption slow and unreliable
Salicylates (except for diflunisal) cross both the BBB and the
placenta
DOSAGE :
The salicylates exhibit analgesic activity at low doses, only at higher
doses do these drugs show anti-inflammatory activity
PHARMACOKINETICS (CONTINUED)
FATE :
Aspirin (low doses) salicylate + acetic acid
Salicylate is converted by the liver to watersoluble conjugates that
are rapidly cleared by the kidney (serum half life of 3,5 hours)
At anti-inflammatory dosages ( > 4 g/day) T1/2 : >15 hours
At low doses of aspirin uric acid secretion
At high doses uric acid secretion
(Alkalinization of the urine promotes excretion)
ADVERSE EFFECTS
GI : epigastric distress, nausea, vomiting
Reyes Syndrome
DRUGS INTERACTING WITH SALICYLATES
DRUGS :
INDOMETHACIN
SULINDAC
ETODOLAC
All have anti-inflammatory, analgesic,
antipyretic activity
They act by reversibly inhibiting
cyclooxygenase
INDOMETHACIN
Therapeutic uses :
- control of pain associated with uveitis and
postoperative opthalmic procedures
- antipyretic for Hodgkins disease
- like aspirin, indomethacin can delay labor
by suppressing uterine contractions
PHARMACOKINETICS :
- rapidly and almost completely absorbed from the upper
GI tract after oral adm. metabolized by the liver
excreted in bile and urine (unchanged drug and
metabolites)
ADVERSE EFFECTS :
-GI complaints : nausea, vomiting, anorexia, diarrhea, abdominal
pain, ulceration / hemorrhage
-CNS : Headache, dizziness, vertigo, mental confusion
-Hematopoietic reactions : neutropenia, thrombocytopenia, aplastic
anemia
-Hypersensitivity reactions : rashes, urticaria, itching, acute attacks
of asthma.
-Others : acute pancreatitis, hepatic effects
DRUGS INTERACTION
Furosemide
Thiazide diuretics
Beta-blocking drugs
ACE inhibitors
SULINDAC
- Inactive pro-drug active form
Hepatic microsomal enzymes of the drug
Therapeutic uses :
- rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis, acute gout
ETODOLAC
DRUGS INTERACTION :
May increase the serum levels and thus raise the risk of
adverse reactions caused by digoxin, lithium,
methotrexate, and enhance the nephrotoxicity of
cyclosporine
OXICAM DERIVATES :
PIROXICAM
Therapeutic uses :
Rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis
Half-life : 50 hours adm : once a day
FENAMATES
Mefenamic acid & Meclofenamate
Have no advantages over the other NSAIDs
SE : diarrhea, hemolytic anemia
PHENYLBUTAZONE
Has powerful anti-inflammatory effect but weak analgesic and
antipyretic activities
Therapeutic uses :
Acute gout & acute rheumatoid arthritis (toxicity short-term
therapy)
Use : up to 1 week only
Pharmacokinetics :
PO / rectal rapidly and completely absorbed
Active Metabolite : oxyphenbutazone
Interaction : warfarin, oral hypoglycemic agents,
sulfonamides (Bound to PP displacement free drugs )
SE :
Agranulocytosis, aplastic anemia, nausea, vomiting, skin
rashes, epigastric discomfort, fluid and electrolyte retention,
diarrhea, vertigo, insomnia, blurred vision, euphoria,
nervousness, hematuria
OTHER AGENTS
DICLOFENAC :
More potent than indomethacin or naproxen
Therapeutic uses : Rheumatoid arthritis, Osteoarthritis,
Ankylosing spondilitis
KETOROLAC
Route of drug adm : PO, IM (Post operative pain), Topically
(allergic conjunctivitis)
ACETAMINOPHEN
PHENACETIN
PHARMACOKINETICS :
Rapidly absorbed from GIT
First pass metabolism in intestine & hepatocytes
Phenacetin Acetaminophen conjugated with
glucoronic or sulfat / hydroxylated Excreted in urine
ADVERSE EFFECTS :
Salycylates :
Upper GI disturbances Aspirin
Low cost ; long
history of safety
Salicylate salts
Diflunisal
Less GI irritation
Pyrazoles :
No antipyretic effect than aspirin
Phenylbutazone
Indoleacetic acids :
Indomethacin
Sulindac Long half-life permits daily
Tolmetin or twice daily dosing
Very potent : should be
V only after less toxic
used Propionic acids :
e
agents have proven Ibuprofen
Lower toxicity and
r
ineffective Naproxen
better acceptance
y Ketoprofen
CNS disturbances
Fenoprofen
in some patients
common
Oxicam :
Piroxicam
Fenamates :
Mefenamic acid
Meclofenamic acid