Pharmacology - Anti-Inflammatory Drugs - Corticosteroid, NSAID, Leukotriene (Eicosanoids)

3/23/2020 introduction_to_eicosanoids [TUSOM | Pharmwiki]
Figure 1. Pathway of biosynthesis of eicosanoids from arachidonic acid, and drugs used to prevent their effects.
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3/23/2020 Analgesic, Antipyretic, and Antiinflammatory Drugs - Pharmacology - An Illustrated Review
Fig. 33.1 Nonsteroidal antiinflammatory drugs (NSAIDs).
NSAIDs inhibit prostaglandin metabolism by inhibiting both forms of the enzyme cyclooxygenase (COX-1 and COX-2). Cyclooxygenase
catalyzes the formation of prostaglandin H2 which is the most important step in prostaglandin production. The normal physiological effects of
COX-1 and COX-2 are shown. Because NSAIDs block these actions, they have an antiinflammatory effect (wanted), but they also block the
physiological effects of COX-1, which are the main cause of NSAID side effects. Glucocorticoids also inhibit prostaglandin (and leukotriene)
production by inhibiting phospholipase A2 and COX-2 (indirectly).
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Figure 4. COX, LOX and the therapeutic effects mediated by NSAIDs & Leukotriene pathway inhibitors.
Figure 2. The cyclooxygenase cascade. Arachidonic acid is converted by COX-1 or COX-2 to an unstable
intermediate prostaglandin H2 which is converted to different biologically active prostanoids depending on the
presence of different tissue-specific isomerases. Some of the tissues in which prostanoids exert their most
significant effects are listed. Modified from Fitzgeral (2003). Low dose aspirin has a selective effect to irreversibly
inhibit COX-1 (at higher doses, aspirin also irreversibly inhibits COX-2). Most non-aspirin NSAIDs are relatively
non-selective & reversibly inhibit both COX-1 & COX-2. Coxibs are a subclass of NSAIDs that selectively &
reversibly inhibit COX-2.
Figure 3. Signal transduction mechanisms responsible for mediating the effects of PGI2 (prostacyclin) and
TXA2(thromboxane). Prostacyclin is produced by endothelial cells of the cardiovascular system, while thromboxane
is produced by platelets. Prostacyclin stimulates IP receptors in vascular smooth muscle & platelets to produced a
decrease in intracellular calcium, resulting in vasodilation, and decreased platelet aggregation. In contrast,
thromboxane stimulates TXA2 receptors to produce an increase in intracellular calcium, resulting in vasoconstriction
in smooth muscle, and increased release of granules and aggregation in platelets. Thromboxane can also induce
changes in platelet shape (that contribute to increases of platelet aggregation) by effects on Rho kinase.
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Mechanisms of NSAID side effects.
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3/23/2020 Analgesic, Antipyretic, and Antiinflammatory Drugs - Pharmacology - An Illustrated Review
Fig. 33.2 Adverse effects of NSAIDs.
NSAID-induced inhibition of COX enzymes leads to decreased production of prostaglandins from arachidonic acid. This leads to gastric
mucosal damage and its sequelae and nephropathy. COX-2 inhibitors show a lower incidence of gastropathy. Inhibition of this side of the
arachidonic acid metabolic pathway may lead to increased leukotriene production, depending on arachidonic acid availability. This
proinflammatory mediator can cause asthma and bronchoconstriction.
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3/23/2020 eicosanoids_draft [TUSOM | Pharmwiki]
Figure 2. COX-2 Inhibitors & Cardiovascular Risk. The left graphic illustrates the normal balanced effect between
prostacyclin (PGI2) and Thromboxane (TXA2). PGI2 is produced primarily by COX-2 activity in the endothelial cell
wall. PGI2 produces vasodilation, and inhibits platelet activation. In contrast, TXA2 is produced primarily by COX-1
activity of platelets, and produces vasoconstriction and enhanced platelet aggregation. When their is a balanced
effect of both PGI2 & TXA2, normal vascular homeostasis is maintained. However, when the balance is tipped in
favor of TXA2 formation after selective inhibition of COX-2 (right graphic), vasoconstriction and platelet clumping
are more likely to occur, and there is an increased risk for cardiovascular events such as myocardial infarction and
stroke.
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3/23/2020 all_eicosanoid_drugs [TUSOM | Pharmwiki]
Figure 1. The prevailing hypothesis on the mechanism of action of acetaminophen. The enzyme responsible for synthesis of
prostnoids has been given several names, including prostaglandin H2-synthase (PGHS), but is now most commonly referred to as
cyclooxygenase (COX). This bifunctional enzyme contains two separate catalytic domains that are responsible for converting
arachidonic acid to PGH2: i) a cyclooxyginase domain that produces an unstable peroxide intermediate (PGG2), and ii) a
peroxidase (POX) domain containing a heme group that converts the unstable intermediate to PGH2. Experiments published by
Boutaud et al (2002, 2010) and Aronoff et al (2009) indicate that acetaminophen acts as a PGG2 cosubstrate & heme reducing
agent that inhibits the POX catalytic step by converting its heme group to an inactive reduced state (as illustrated in the box,
bottom right). Because acetaminophen acts as a heme reducing agent, its effects are nearly abolished in the presence of high
levels of lipid hydroperoxides (such as inflammatory HETEs) that oxidize the heme back to its active state. As a result,
acetaminophen is ineffective in tissues with high peroxide tone, such as in platelets or activated lymphocytes (e.g. inflammatory
conditions). However, acetaminophen is effective in inhibiting prostanoid synthesis in vascular endothelial cells and neurons that
have a low basal peroxide tone, which can account for its antipyretic and (central) analgesic effects.
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Pharmacology - Anti-Inflammatory Drugs - Corticosteroid, NSAID, Leukotriene (Eicosanoids)

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3/23/2020 introduction_to_eicosanoids [TUSOM | Pharmwiki]

Fig. 33.1 Nonsteroidal antiinflammatory drugs (NSAIDs).

Mechanisms of NSAID side effects.

Fig. 33.2 Adverse effects of NSAIDs.

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