51.

CYCLOOXYGENASE INHIBITORS: ASPIRIN,

PARACETAMOL
52. CYCLOOXYGENASE INHIBITORS: PYRAZOLONS,
PROPIONIC ACID DERIVATIVES, INDOLE DERIVATIVES
AND OTHERS. COX-2 INHIBITORS
Overview
-

cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs, NSAIDs) inhibit

cyclooxygenase (COX), thus inhibiting the formation of prostaglandins and thromboxanes
(see 35)
there are 3 types of COX
TYPE
COX-1

DESCRIPTION
Location
- most tissues
Effect
- normal tissue homeostasis

COX-2

Location
- inflammatory cells
Effect
- edema (vasodilation and potentiation of the
effect of the inflammatory mediators that
cause increased capillary permeability)
- pain (potentiation of the effect of the
inflammatory mediators that cause irritation of
afferent C nerve fibers)
- fever (increase in the hypothalamic
temperature set point in response to bacterial
endotoxins)

COX-3

Location
- CNS
Effect
- pain (cerebral vasodilation)
- induction of fever (see above)

COX inhibitors are primarily administered to obliterate the effects of COX-2 and COX-3
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, thus the general medical uses of COX inhibitors include

MEDICAL USE
TREATMENT OF INFLAMMATION
TREATMENT OF PAIN
TREATMENT OF FEVER

however, most COX inhibitors are non-selective reversible inhibitors of COX, thus also
inhibiting COX-1
the effects of COX-1 inhibition are usually considered side effects, and include
ORGAN
GI TRACT

SIDE EFFECT
Increased gastric acid production and
decreased mucous production
- dyspepsia
- diarrhea/constipation
- nausea
- vomiting
- peptic ulcers

KIDNEYS

Vasoconstriction and following renal ischemia

- acute renal insufficiency
- chronic nephritis
- renal papillary necrosis

SKIN

Increased arachidonic acid available for 5lipoxygenase and following increased

leukotriene production (see 35)
- rashes
- urticaria (hives)
- photosensitivity

Relevant Drugs
-

6 categories
1) SALICYLIC ACID DERIVATIVES
- salicylic acid derivatives are non-selective irreversible COX inhibitors
- 1 type
DRUG NAME

DESCRIPTION

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ASPIRIN

General information
- acetylsalicylic acid
- administered orally
- severe side effects (irreversible COX
inhibition)
Medical uses
- see above
- treatment of thrombosis, DIC and emboli
(inhibition of platelet aggregation, due to
irreversible COX-1 inhibition)
- treatment of radiation-induced diarrhea
- prophylaxis of colonic- and rectal cancer
- prophylaxis of alzheimers disease
Side effects
- see above
- hemorrhages (inhibition of platelet
aggregation)
- salicylism (deafness, tinnitus and vertigo, due
to repeated administration of large doses of
aspirin)
- salicylate poisoning (respiratory acidosis (due
to respiratory center depression), metabolic
acidosis (due to uncoupling of oxidative
phosphorylation), hyperpyrexia (due to
uncoupling of oxidative phosphorylation and
following increased metabolic rate) and finally
coma, due to aspirin overdose)
- reyes syndrome (hepatic insufficiency and
encephalopathy in children, due to aspirin
administration during a viral infection)

2) ACETIC ACID DERIVATIVES

- indole derivatives
- 3 types
DRUG NAME
INDOMETACIN

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DESCRIPTION
General information
- potent COX inhibitor
- has severe side effects (potent COX
inhibitor)
- also inhibits phagocytosis of urate crystals by
neutrophils
- administered orally

Medical uses
- see above
- treatment of gout (inhibition of urate crystal
phagocytosis)
SULINDAC

General information
- pro-drug
- administered orally

DICLOFENAC

General information
- accumulates in synovial fluid
- administered orally or IV
Medical uses
- see above
- treatment of rheumatoid arthritis
(accumulates in synovial fluid)

3) PROPIONIC ACID DERIVATIVES

- 3 types
DRUG NAME
IBUPROFEN

DESCRIPTION
General information
- weak COX inhibitor
- has little or no side effects (weak COX
inhibitor)

KETOPROFEN
FENOPROFEN

General information
- pro-drug

4) ENOLIC ACID DERIVATIVES

- pyrazolon derivatives
- 1 type
DRUG NAME
PHENYLBUTAZONE

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DESCRIPTION
General information
- potent COX inhibitor
- has severe side effects (potent COX
inhibitor)

5) COXIBS
- COX-2 inhibitors
- coxibs are selective reversible COX-2 inhibitors
- 3 types
DRUG NAME
CELECOXIB

DESCRIPTION
General information
- has little or no side effects (selective COX-2
inhibitor)
- administered orally

ROFECOXIB

General information
- same as celecoxib

PARECOXIB

General information
- same as celecoxib
- administered orally or parenterally

6) ANILINE DERIVATIVES
- COX-3 inhibitors
- aniline derivatives are selective reversible COX-3 inhibitors
- 1 type
DRUG NAME
PARACETAMOL

DESCRIPTION
General information
- acetaminophen
- has little or no anti-inflammatory effect
(selective COX-3 inhibitor)
- has little or no side effects in therapeutic
doses (selective COX-3 inhibitor)
- administered orally
- metabolized by the liver by glucoronidation
and/or sulfation
Medical uses
- treatment of pain
- treatment of fever
Side effects
- paracetamol overdose (nausea and vomiting
followed by hepatic- and renal tubular
necrosis, due to saturation of the hepatic

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enzymes responsible for its metabolism and

following metabolism by the cytochrome P450
enzyme system leading to the formation of a
toxic metabolite (n-acetyl-p-benzoquinone
imine))

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