Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
One of the more widely used therapeutic groups. Many of these agents possess
antipyretic, analgesic properties in addition to anti-inflammatory properties
which are useful in the treatment of a number of rheumatic disorders. On the
other hand, there are agents that possess analgesic-antipyretic properties but
are essentially devoid of anti-inflammatory activity. Additionally, agents that
possess uricosuric properties useful in the treatment of gout will also be
covered here.
Role of Chemical Mediators in Inflammation
Inflammation is a normal and essential response to any noxious stimulus that
threatens the host and may vary from a localized response to a generalized
response.
Inflammation can be summarized as follows:
1) Initial injury causing release of inflammatory mediators (e.g., histamine,
serotonin, leukokinins, SRS-A, lysosomal enzymes, Iymphokinins,
prostaglandins);
2) Vasodilation; Increased vascular permeability and exudation;
3) Leukocyte migration, chemotaxis and phagocytosis;
4) Proliferation of connective tissue cells.
The most common sources of chemical mediators include leukocytes, mast
cells, and platelets. Currently available agents relieve the symptoms of the
disease but are not curative.
Prostaglandins, Thromboxanes, Prostacyclin and Leukotrienes
Prostaglandins are naturally occurring 20-carbon cyclopentano-fatty acid
derivatives produced in mammalian tissue from polyunsaturated fatty acids.
They belong to the class of eicosanoids, a member of the group of autocoids
derived from membrane phospholipids.
The eicosanoids are derived from unsaturated fatty acids and include the fol-
lowing groups of compounds: prostaglandins, thromboxanes, prostacyclin and
leukotrienes.
67
, They have been found in essentially every compartment of the body.
The General Structure of the Prostaglandins (PGs)
All naturally occurring PGs possess this substitution pattern, a 15-hydroxy
group and a trans double bond at C-13.
- Unless a double bond occurs at the C-8, C-12 positions, the two side chains
(the carboxyl-bearing chain termed the -chain and the hydroxyl-hearing chain
termed the ß-chain) are of the trans stereochemistry depicted.
General structure of prostaglandins (PGs)
The PGs are classified by the capital letters A, B, C. D, E, F, G, H and I depending
on the nature and stereochemistry of oxygen substituents at the 9-and 11-po-
sitions.
Cyclic and Linear Metabolic Pathways of Arachidonic acid
Prostaglandins are derived biosynthetically from unsaturated fatty acid
precursors. The most common of these fatty acids in humans is arachidonic
acid.
Arachidonic acid is derived from dietary linoleic acid or is ingested from
the diet and esterified to phospholipids in cell membranes.
Various initiating factors interact with membrane receptors coupled to G
proteins (guanine nucleotide-binding regulatory proteins) activating
phospholipase A2 which, in turn, hydrolyzes membrane phospholipids resulting
in the release of arachidonic acid.
The steroidal anti-inflammatory agents (corticosteroids) appear to act,
in part, by inhibiting these phospholipases.
The liberated arachidonic acid may then be acted on by two major enzyme
systems:
1) Arachidonic acid cyclooxygenase (prostaglandin endoperoxide synthetase
or COX) to produce prostaglandins, thromboxanes and prostacyclin (cyclic
68
, metabolic pathways) or by
2) lipoxygenases to produce leukotrienes (linear metabolic pathway).
69
One of the more widely used therapeutic groups. Many of these agents possess
antipyretic, analgesic properties in addition to anti-inflammatory properties
which are useful in the treatment of a number of rheumatic disorders. On the
other hand, there are agents that possess analgesic-antipyretic properties but
are essentially devoid of anti-inflammatory activity. Additionally, agents that
possess uricosuric properties useful in the treatment of gout will also be
covered here.
Role of Chemical Mediators in Inflammation
Inflammation is a normal and essential response to any noxious stimulus that
threatens the host and may vary from a localized response to a generalized
response.
Inflammation can be summarized as follows:
1) Initial injury causing release of inflammatory mediators (e.g., histamine,
serotonin, leukokinins, SRS-A, lysosomal enzymes, Iymphokinins,
prostaglandins);
2) Vasodilation; Increased vascular permeability and exudation;
3) Leukocyte migration, chemotaxis and phagocytosis;
4) Proliferation of connective tissue cells.
The most common sources of chemical mediators include leukocytes, mast
cells, and platelets. Currently available agents relieve the symptoms of the
disease but are not curative.
Prostaglandins, Thromboxanes, Prostacyclin and Leukotrienes
Prostaglandins are naturally occurring 20-carbon cyclopentano-fatty acid
derivatives produced in mammalian tissue from polyunsaturated fatty acids.
They belong to the class of eicosanoids, a member of the group of autocoids
derived from membrane phospholipids.
The eicosanoids are derived from unsaturated fatty acids and include the fol-
lowing groups of compounds: prostaglandins, thromboxanes, prostacyclin and
leukotrienes.
67
, They have been found in essentially every compartment of the body.
The General Structure of the Prostaglandins (PGs)
All naturally occurring PGs possess this substitution pattern, a 15-hydroxy
group and a trans double bond at C-13.
- Unless a double bond occurs at the C-8, C-12 positions, the two side chains
(the carboxyl-bearing chain termed the -chain and the hydroxyl-hearing chain
termed the ß-chain) are of the trans stereochemistry depicted.
General structure of prostaglandins (PGs)
The PGs are classified by the capital letters A, B, C. D, E, F, G, H and I depending
on the nature and stereochemistry of oxygen substituents at the 9-and 11-po-
sitions.
Cyclic and Linear Metabolic Pathways of Arachidonic acid
Prostaglandins are derived biosynthetically from unsaturated fatty acid
precursors. The most common of these fatty acids in humans is arachidonic
acid.
Arachidonic acid is derived from dietary linoleic acid or is ingested from
the diet and esterified to phospholipids in cell membranes.
Various initiating factors interact with membrane receptors coupled to G
proteins (guanine nucleotide-binding regulatory proteins) activating
phospholipase A2 which, in turn, hydrolyzes membrane phospholipids resulting
in the release of arachidonic acid.
The steroidal anti-inflammatory agents (corticosteroids) appear to act,
in part, by inhibiting these phospholipases.
The liberated arachidonic acid may then be acted on by two major enzyme
systems:
1) Arachidonic acid cyclooxygenase (prostaglandin endoperoxide synthetase
or COX) to produce prostaglandins, thromboxanes and prostacyclin (cyclic
68
, metabolic pathways) or by
2) lipoxygenases to produce leukotrienes (linear metabolic pathway).
69
