Pharm 42
Physiology of Eicosanoid Metabolism
 Autacoids – substances rapidly synthesized in response to specific stimuli, act quickly in immediate environment,
and remain active for only short time before degradation
 Eicosanoids – family of autacoids mostly derived from arachidonic acid
o Centrally involved in metabolic pathways that exhibit diverse roles in inflammation and cellular
signaling; vast majority center on reactions involving metabolism of arachidonic acid
 Docosanoids – technically eicosanoids; resolvins, protectins, and maresins derived from docosahexaenoic acid
Generation of Arachidonic Acid and Omega-3 Fatty Acids
 Arachidonic acid must be biosynthesized from essential fatty acid precursor linoleic acid
 Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are precursors to resolvins, protectins, and
maresins; obtained from dietary sources or biotransformation of essential fatty acid precursor α-linolenic acid
o EPA, DHA, and α-linolenic acid are omega-3 fatty acids
 In cell, arachidonic acid doesn’t exist as free fatty acid, but is esterified to sn2 position of membrane
phospholipids, predominantly phosphatidylcholine and phosphatidylethanolamine
o Arachidonic acid released from cellular phospholipids by phospholipase A2; first step in arachidonic acid
cascade; overall rate-determining step in generation of eicosanoids
 Secretory phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2); existence of
multiple isoforms allows for calibrated regulation of enzyme in different tissues to achieve
selective biological responses
 Isoforms relevant to inflammation stimulated by cytokines (TNF-α, GM-CSF, and IFN-γ) and
growth factors (EGF and MAPK-PKC cascade)
o Glucocorticoids induce synthesis of lipocortins (family of phospholipase A2-regulatory proteins)
 Annexin 1 – lipocortin that mediates some anti-inflammatory actions of glucocorticoids
Cyclooxygenase Pathway
 Unesterified intracellular arachidonic acid converted by cyclooxygenase, lipoxygenase, or cytochrome-containing
epoxygenase enzymes
o Cyclooxygenase pathway leads to formation of prostaglandins, prostacyclin, and thromboxanes
o Lipoxygenase pathways lead to leukotrienes and lipoxins
o Epoxygenase pathways lead to epoxyeicosatetraenoic acids
 Cyclooxygenases – membrane-bound, heme-containing enzymes ubiquitous in animal cells
o Each COX catalyzes 2 sequential reqctions: first (COX step) is oxygen-dependent cyclization of
arachidonic acid to prostaglandin G2 (PGG2), and second (peroxidase step) is reduction of PGG2 to PGH2
o As result of differences in cellular localization, regulatory profile, tissue expression, and substrate
requirements, COX-1 and COX-2 ultimately produce different sets of eicosanoid products involved in
different pathways and functions
 Constitutively expressed COX-1 functions in physiologic housekeeping acitvities such as vascular
homeostasis, maintenance of renal and GI blood flow, renal function, intestinal mucosal
proliferation, platelet function, and antithrombogenesis
 As-needed functions attributed to products of inducible COX-2 enzyme, including inflammation,
fever, pain, transduction of painful stimuli in spinal cord, mitogenesis (particularly in GI
epithelium), renal adaptation to stresses, deposition of trabecular bone, ovulation, placentation,
and uterine contractions of labor
 Role of constitutive COX-2 expression in areas of nervous system (hippocampus,
hypothalamus, and amygdala) yet to be elucidated
 COX-3 isoform may be product of same gene as COX-1 but w/different protein characteristics
(alternative mRNA splicing or post-translational modification)
 Expressed primarily in CNS; potential site of action of acetaminophen
 Prostaglandins – large family of structurally similar compounds; all share chemical structure (prostanoid)
o Divided into 3 major subseries (PG1, PG2, and PG3); subscript numeral indicates number of double bonds
o PG2 series most biologically prevalent because these are direct derivatives of arachidonic acid
(eicosatetraenoic acid)
o PG1 series derive from arachidonic acid precursor DHGLA (eicosatrienoic acid)
o
o
PG3 series derive from an eicosapentaenoic acid
PGH2 represents critical juncture of COX pathway because it is immediate precursor to PGD2, PGE2,
PGF2α, thromboxane A2 (TxA2), and prostacyclin (PGI2)
o Distribution of eicosanoids in various tissues determined by expression pattern of different enzymes of
prostaglandin synthesis (i.e., PG synthases)
o Important in many physiologic processes (modulation of gastric mucosal acid secretion, mucus, and
blood flow)
o PGE2 – cytoprotective roles (gastric mucosa, myocardium, and renal parenchyma shielded from effects
of ischemia by PGE2-mediated vasodilation and overall regulation of blood flow); involved in
inflammatory cell activation
 PGE2 synthesized by COX-2 and PGE2 synthase in cells near hypothalamus has role in fever
 Platelets express high levels of thromboxane synthase but don’t contain prostacyclin synthase; TxA2 is chief
eicosanoid product of platelets
o TxA2 has half-life of 10-20 seconds before nonenzymatically hydrolyzed to inactive TxB2
o TxA2 signals via GPCR Gq mechanism; potent vasoconstrictor as well as promoter of platelet adhesion
and aggregation
 Vascular endothelium lacks thromboxane synthase but expresses prostacyclin synthase; PGI2 is primary
eicosanoid product of vascular endothelium
o PGI2 signals via Gs, functions as vasodilator, venodilatory, and inhibitor of platelet aggregation;
vasodilatory actions confer cytoprotective properties
 Local balance between TxA2 and PGI2 levels critical in regulation of systemic BP and thrombogenesis
o Imbalances lead to hypertension, ischemia, thrombosis, coagulopathy, MI, and stroke
o EPA converted into TxA3 and PGI3; vasoconstricting and platelet aggregating effects of TxA3 relatively
weak, so thromboxane-prostacyclin balance tipped toward vasodilation, platelet inhibition, and
antithrombogenesis
Lipoxygenase Pathway
 Lipoxygenase pathway leads to formation of leukotrienes and lipoxins
 Lipoxygenases – enzymes that catalyze insertion of O2 into arachidonic acid, using non-heme iron to generate
specific hydroperoxides
o 5-LOX, 12-LOX, and 15-LOX are major LOX isoforms in humans
o LOXs named for position in arachidonic acid on which they catalyze insertion of O2
o Immediate products of LOX reactions are HPETEs, which can be reduced to corresponding HETEs by GSPdependent enzymes
o 5-HPETE formed by 5-LOX is direct precursor to leukotriene A4 (LTA4), which is precursor to all bioactive
leukotrienes
o LOXs involved in converting 15-HETE and LTA4 to lipoxins
 Leukotriene biosynthesis begins w/5-LOX-mediated conversion of 5-HPETE to LTA4 (5-LOX catalyzes first 2 steps
in leukotriene biosynthesis)
o LTA4 then converted to either LTB4 or LTC4
 LTA4 hydrolase converts LTA4 to LTB4 in neutrophils and erythrocytes
 LTA4 conversion to LTC4 occurs in mast cells, basophils, eosinophils, and macrophages by
addition of glutathione
 LTC4, LTD4, LTE4, and LTF4 (cysteinyl leukotrienes) interconverted by removal of amino acid
portions of γ-glutamylcysteinylglycine tripeptide
 LTB4 acts via 2 G protein-coupled receptors (BLT1 and BLT2)
 Binding of LTB4 to BLT1 (expressed mainly in tissues involved in host defense and
inflammation leads to proinflammatory sequelae such as neutrophil chemotaxis,
aggregation, and transmigration across epithelium and endothelium)
 LTB4 upregulates neutrophlil lysosomal function and generates ROS, enhances cytokine
production, and potentiates actions of NK cells
 BLT2 binds COX product 12-HHT and evokes chemotaxis of leukocytes
 Cysteinyl leukotrienes (LTC4 and LTD4) bind to CysLT1 receptors to cause vasoconstriction,
bronchospasm, and increased vascular permeability

Responsible for hyperreactivity to stimuli and airway and vascular smooth muscle
contraction that occur in asthmatic, allergic, and hypersensitivity processes
 Together, both arms of leukotriene pathway (LTB4 and LTC4/LTD4) play key roles in psoriasis,
arthritis, and various inflammatory responses; key mediators in vascular disease
(atherosclerosis, obesity, and asthma)
 Lipoxins (lipoxygenase interaction products) – derivatives of arachidonic acid
o LXA4 and LXB4 modulate actions of leukotrienes and cytokines and are important in resolution of
inflammation
o At sites of inflammation, there is inverse relationship between amounts of lipoxin and leukotriene
present
o LXA4 receptors present on neutrophils and in lung, spleen, and blood vessels
o Lipoxins stop neutrophil chemotaxis, adhesion, and transmigration through endothelium by decreasing
P-selectin expression
 Limit eosinophil recruitment
 Stimulate vasodilation by inducing synthesis of PGI2 and PGE2
 Inhibit LTC4 and LTD4-stimulated vasoconstriction
 Inhibit LTB4 inflammatory effects
 Inhibit function of NK cells
 Stimulate uptake and clearance of apoptotic neutrophils by macrophages and thereby mediate
resolution of inflammatory response
o Imbalance in lipoxin-leukotriene homeostasis key factor in pathogenesis of inflammatory disease
 Resolvins, protectins, and maresins – chemical mediator families that control magnitude and duration of
inflammation; omega-3-derived mediators (especially from EPA and DHA)
o Limit neutrophil recruitment to sites of inflammation and stimulate macrophages to take up and remove
apoptotic cells from inflammatory site
o Resolvins and protectins also produced in bone marrow and brain, where they possess potent local
mediator actions
 Specialized pro-resolving mediators (SPM) – group that includes resolvins, protectins, maresins, and lipoxins
o Resolution is active process; defective or deficient resolution mechanisms underlie some chronic
inflammatory diseases
Epoxygenase Pathway
 Microsomal cytochrome P450 epoxygenases oxygenate arachidonic acid, resulting in formation of EET and
hydroxyacid derivatives
 Important in tissues that don’t express COX or LOX (certain cells in kidney)
 Epoxygenation of arachidonic acid produces EETs; dihydroxy derivatives of EETs formed by hydrolysis regulate
vascular tone by inhibiting Na+/K+-ATPase in vascular smooth muscle cells and affect renal function by regulating
ion absorption and secretion
Isoprostanes
 Phospholipid-esterified arachidonic acid susceptible to free-radical-mediated peroxidation; release of modified
lipids from phospholipid by phospholipase A2 gives rise to isoprostanes
 During oxidative stress, isoprostanes higher than COX products
 8-epi-PGF2α and 8-epi-PGE2 are potent vasoconstrictors
 Isoprostanes can activate NFκB, phospholipase Cγ, PKC, and calcium flux
 Rate of formation of isoprostanes depends on cellular oxidation conditions, so levels may be indicative of
oxidative stress in pathologic conditions
o Urinary isoprostanes levels used as biomarkers of oxidative stress in ischemic syndromes, reperfusion
injury, atherosclerosis, and hepatic diseases
Metabolic Inactivation of Local Eicosanoids
 Prostaglandins, leukotrienes, thromboxanes, and lipoxins inactivated by hydroxylation, β-oxidation (resulting in
loss of 2 carbons), or ω-oxidation (to dicarboxylic acid derivatives)
 Degradation processes render molecules more hydrophilic and excretable in urine
Integrated Inflammation Schema

Acute inflammation is result of intricate network of molecular and cellular interactions induced by responses to
variety of stimuli, such as trauma, ischemia, infectious agents, or antibody reactions
 Leukotrienes, lipoxins, thromboxanes, prostaglandins, and prostacyclins critical for generating, maintaining, and
mediating inflammatory responses
o Inflammatory cascade initiated when cells in particular region exposed to foreign substance or damaged
o Insult stimulates local cytokine cascade (ILs or TNF), which increases COX-2 mRNA and enzyme levels
o COX-2 facilitates production of proinflammatory and vasoactive eicosanoids
o Locally high concentrations of PGE2, LTB4, and cysteinyl leukotrienes promote accumulation and
infiltration of inflammatory cells by increasing blood flow and vascular permeability
 LTB4 and 5-HETE important in attracting and activating neutrophils
o LTB4 (synthesized and released by activated neutrophils at site of inflammation) recruits and activates
additional neutrophils and lymphocytes so they adhere to endothelial surfaces and transmigrate into
interstitial spaces
o Increased vascular permeability results in fluid leak and cellular infiltration, causing edema
 Transcellular biosynthesis – eicosanoid intermediates donated from one cell type to another to generate larger
diversity of local chemical mediators
 Feedback mechanisms
o Lipoxins help resolve inflammation and promote return of tissues, organs, and organism to homeostasis
o COX-2-derived eicosanoids function in wound healing and resolution
o PGE2 inhibits functions of B and T lymphocytes and NK cells
o LTB4 and cysteinyl leukotrienes regulate T-cell proliferation
o PGE2 and PGI2 are potent pain sensitizers; lipoxins reduce nociception
Pathophysiology of Asthma
 Symptoms result from chronic airway inflammation, hyperreactivity, constriction, and obstruction
 Antigens in lungs stimulate cytokine cascades leading to generation of prostaglandins and leukotrienes
o Elaboration of LTB4 attracts inflammatory cells and promotes cellular aggregation; particularly acts on B
lymphocytes, causing cell activation, proliferation, and differentiation
 LTB4 promotes expression of FcεRII receptors (receptors for constant chain of IgE released by
antigen-stimulated B lymphocytes) on mast cells and basophils
o LTC4 and LTD4 potent bronchoconstrictive compounds; cause airway epithelium to secrete mucus, while
impairing clearance of mucus by inhibiting beating of cilia on airway epithelium
 Mucus secretion exacerbated by neutrophils and eosinophils (become part of inflammatory
exudate clogging airways)
o LTD4 and LTE4 recruit eosinophils to airways
 Eosinophils integrate signals from T lymphocytes and, when activated, release factors that
damage airway epithelium and enhance local airway inflammation
Pathophysiology of Inflammatory Bowel Disease
 Crohn’s disease and ulcerative colitis – pathologically distinct, but in both, elevated LTB4 production in affected
mucosa results in abnormal leukocyte infiltration into parenchyma
 Chronic inflammation and leukocyte infiltration lead to progressive mucosal damage w/histological changes
 Crohn’s disease – focal damage, fissuring ulcers, and granulomas
 Ulcerative colitis – mucosal inflammation and colonic dilatation
 Both diseases increase risk of adenocarcinoma of colon in affected areas
 Stable analogues of lipoxin A4 effective treatments in mice
Rheumatoid Arthritis
 Chronic, systemic, autoimmune, and inflammatory disease that primarily attacks joints; affects skin,
cardiovascular system, lungs, and muscles
 Autoimmune targeting of normal joint proteins results in inflammation, with resultant local release of cytokines,
TNF, growth factors, and ILs, all of which induce COX-2 expression
o Levels of COX-2 and PGE2 marked elevated in synovial fluid of affected joints
o PGE2 stimulates pain pathways and other COX-2-derived eicosanoids
o 5-LOX-derived leukotrienes activate surrounding endothelium to recruit inflammatory cells
o
Macrophages release collagenase and proteases; lymphocyte activity leads to immune complex
formation; both further damage joint tissue and provide substrates that accelerate chronic inflammation
 Common findings include synovitis, leukocytosis, rheumatoid nodules, and presence of rheumatoid factor
(circulating antibody against IgG)
Pathophysiology of Glomerulonephritis
 Large group of inflammatory renal conditions that ultimately lead to renal failure through deterioration of renal
hemodynamics and glomerular filtration
 Local complement activation promotes neutrophil and macrophage infiltration; characteristic early pathologic
finding that correlates w/abnormal levels of LTB4 biosynthesized by LTA4 hydrolase in kidney mesangium;
facilitates neutrophil adhesion to glomerular mesangium and epithelium
o LTA4 is substrate for biosynthesis of LTC4 and LTD4, which work together w/LTE4 and LTF4 to promote
endothelial and mesangial proliferation
o Cysteinyl leukotrienes directly affect glomerular function
 LTC4 and LTD4 decrease renal blood flow and GFR by vasoconstricting arterioles and contracting
mesangial spaces
 LOX inhibitors administered at early stages of glomerulonephritis prevent glomerular inflammation and
evidence of structural damage
o Both LOX inhibitors and LTD4 receptor antagonists increase GFR and decrease proteinuria
 Kidney mesangium expresses LTA4 hydrolase and 12-LOX, conferring ability to synthesize either LTB4 or LXA4
from leukocyte-derived LTA4
o At low concentrations, LTA4 used primarily for LTB4 formation; corresponds to initiation of inflammation
or low level of chronic inflammation
o When LTA4 concentrations relatively high (long-standing inflammation), LTA4 mostly converted to LXA4,
which provides autoinhibitory counterregulatory impact on inflammatory response
o In glomerulus, LXA4 counteracts deleterious proinflammatory consequences of leukotrienes as well as
effect of leukotrienes on GFR, in part by raising afferent arteriolar flow via vasodilation
Pathophysiology of Cancer
 Correlation between chronic NSAID therapy and decreased incidence of colorectal cancer, gastric
adenocarcinomas, and breast tumors
 Colorectal adenomas and carcinomas express abundant COX-2
 In stomach and breast, COX-2 generates PGE2 and other eicosanoids that promotes tumor growth
o Perinuclear localization of COX-2 shows potential for intracellular function of eicosanoid products in
oncogenesis
o Some eicosanoid derivatives bind to homologues of retinoic acid receptor (RXR) family of transcription
factors, which are involved in regulation of cell growth and differentiation (among other things)
o Overexpression of COX-2 generates eicosanoids that flood RXR signaling pathways and provide excessive
growth stimuli
Pathophysiology of Cardiovascular Disease
 Platelet-derived thromboxane A2 – important mediator of thrombosis in acute coronary syndromes (unstable
angina, non-STEMI, and STEMI) and other cardiovascular diseases
 Aspirin effective antiplatelet agent in prophylaxis and treatment of cardiovascular diseases
 Intravascular leukotriene production during rupture of atheromatous plaques contributes to pathophysiology of
acute coronary syndromes
o 5-LOX, FLAP, and LTA4 hydrolase genetically linked to MI
Phospholipase Inhibitors
 Inhibition of phospholipase A2 prevents release of arachidonic acid from cellular phospholipids (rate-limiting
step in eicosanoid biosynthesis); in absence of proinflammatory mediators, inflammation limited
 Glucocorticoids (corticosteroids; includes prednisone, prednisolone, and dexamethasone) mainstay therapy of
autoimmune and inflammatory diseases
o Induce family of secreted Ca and phospholipid-dependent proteins (lipocortins), which interfere
w/action of phospholipase A2 and limit availability of arachidonic acid
 Annexins (annexin 1 and annexin 1-derived peptides) induced by glucocorticoids
o
Annexins act at G protein-coupled receptors on leukocytes to block proinflammatory responses and
enhance endogenous anti-inflammatory mechanisms (activation of lipoxin A4 receptor)
 Glucocorticoids inhibit action of COX-2 and formation of prostaglandins by repressing COX-2 gene and enzyme
expression, repressing expression of cytokines that activate COX-2, and limiting available pool of COX-2
substrate (arachidonic acid) by indirectly blocking phospholipase A2
Cyclooxygenase Inhibitors
 NSAIDs – combined anti-inflammatory, antipyretic, and analgesic properties
o Ultimate goal is to inhibit COX-mediated generation of proinflammatory eicosanoids and limit extent of
inflammation, fever, and pain
o Antipyretic activity related to ability to decrease levels of PGE2, particularly in region of brain
surrounding hypothalamus
o Only suppress signs of underlying inflammatory response, but may not reverse or resolve problem
o Except for aspirin, all NSAIDs act as reversible competitive inhibitors of COX; block hydrophobic channel
of COX protein where substrate arachidonic acid binds, preventing conversion of arachidonic acid to
PGG2
o Inhibit both COX-1 and COX-2 to different degrees
o Cytoprotective roles of COX-1 eicosanoid products eliminated, leading to spectrum of NSAID-induced
gastropathy (dyspepsia, gastrotoxicity, subepithelial damage and hemorrhage, gastric mucosal erosion,
frank ulceration, and gastric mucosal necrosis)
 Patients w/gastric ulceration can have bleeding into stomach, where reaction of Hgb w/stomach
acid results in hematemesis
 Regulation of blood flow to kidney perturbed, decreasing GFR and causing renal ischemia,
papillary necrosis, interstitial nephritis, and renal failure
o Organic acid functionality of NSAIDs confers important pharmacokinetic properties on drugs, including
near-complete absorption from gut, binding to plasma albumin, accumulation in cells at site of
inflammation, and efficient renal excretion
o NSAIDs w/long elimination half-lives include naproxen, salicylate, piroxicam, and phenylbutazone
o Salicylates – include aspirin and its derivatives
 Used to treat mild-to-moderate pain, headache, myalgia, and arthralgia
 Irreversibly acetylates active-site serine residue in both COX-1 and COX-2; destroys enzyme’s
cyclooxygenase activity, preventing formation of COX-1-derived prostaglandins, thromboxanes,
and prostacyclin
 May inhibit neutrophil oxidative burst by reducing NADPH oxidase activity
 Daily low-dose aspirin used as antithrombogenic agent for prophylaxis and postevent
management of acute coronary syndromes and ischemic stroke
 Platelets, lacking nuclei, can’t synthesize new COX-1, so platelets’ COX activity irreversibly
inhibited for their circulating lifetime (10 days)
 Endothelial cells can synthesize new COX and rapidly resume synthesis of PGI2
 Shifts vascular TxA2-PGI2 balance toward PGI2-mediated vasodilation, platelet inhibition,
and antithrombogenesis
 Inhibition of COX-2 prevents generation of prostaglandins; aspirin-modified COX-2 enzyme
retains part of catalytic activity and can form 15-(R)-HETE from arachidonic acid
 5-LOX converts 15-(R)-HETE to 15-epi-lipoxins, which are relatively stable stereoisomers
of lipoxins collectively called aspirin-triggered lipoxins (ATLs)
 15-epi-lipoxins mimic functions of lipoxins as anti-inflammatory agents; production
mediates part of anti-inflammatory effects of aspirin
 Long-term aspirin therapy can lead to GI ulceration and hemorrhage, nephrotoxicity, and
hepatic injury
 Use cautiously if at all in patients w/renal insufficiency and heart failure
 Aspirin-induced airway hyperreactivity in asthmatics – exposure to aspirin leads to ocular and
nasal congestion along w/severe airway obstruction (10% of asthma patients)
 Aspirin-sensitive patients also reactive to some other NSAIDs (indomethacin, naproxen,
ibuprofen, mefenamate, and phenylbutazone)


 Exposure leads to increased levels of leukotrienes implicated in pathogenesis of asthma
 Reye’s syndrome – hepatic encephalopathy and liver steatosis in young children
 Aspirin therapy during course of febrile viral infection implicated
o Proprionic acid NSAIDs – ibuprofen, naproxen, ketoprofen, and flurbiprofen
 Ibuprofen relatively potent analgesic used in rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, gout, and primary dysmenorrhea
 Naproxen has long half-life, is 20x more potent than aspirin, directly inhibits leukocyte function,
and causes less severe GI adverse effects than aspirin
o Acetic acid NSAIDs – indole acetic acids (indomethacin, sulindac, and etodolac) and phenylacetic acids
(diclofenac and ketorolac)
 Many promote incorporation of unesterified arachidonic acid into triglyceride, reducing
availability of substrate for COX and LOX
 Indomethacin – direct inhibitor of neutrophil motility; not tolerated as well as ibuprofen;
specific use in promoting closure of PDA in newborns by inhibiting vasodilatory eicosanoids PGE2
and PGI2
 Diclofenac reduces intracellular arachidonic acid concentrations by altering cellular fatty acid
transport; more potent anti-inflammatory than indomethacin and naproxen; widely used in Tx
of pain associated w/renal stones
 Ketorolac – primarily employed for strong analgesic properties, particularly in post-surgical
patients; used for no more than 3-5 days due to potency and adverse effects
 Mostly used to relieve symptoms in long-term treatment of RA, OA, ankylosing spondylitis, and
other musculoskeletal disorders
 Use causes GI ulceration and rarely hepatitis and jaundice
o Oxicam derivatives – piroxicam as efficacious as others in treatment of RA and OA but may be better
tolerated; additional effects in modulation of neutrophil function by inhibiting collagenase,
proteoglycanase, and oxidative burst
 Extremely long half-life, so administered once daily
 GI adverse effects (gastric ulceration) and prolongs bleeding time because of antiplatelet effect
o Fenamate derivatives – mefenamate and meclofenamate; inhibit COX and antagonize prostanoid
receptors to various degrees
 Less anti-inflammatory activity and are more toxic than aspirin
 Mefenamate used only for primary dysmenorrhea
 Meclofenamate used in treatment of RA and OA
o Ketone NSAIDs – nabumetone is ketone prodrug oxidized to active acid form
 Preferential activity against COX-2
 Incidence of GI adverse effects relatively low, but headache and dizziness frequently reported
o Adverse gastric effects of long-term NSAID therapy can be reduced by coadministration of histamine H2
receptor antagonists or proton pump inhibitors
Acetaminophen – has analgesic and antipyretic effects similar to aspirin, but anti-inflammatory effect
insignificant because of weak inhibition of COXs
o Valuable for patients at risk of adverse effects of aspirin
o Most important adverse effect is hepatotoxicity
o Modification of acetaminophen by cytochrome P450 enzymes produces reactive metabolite normally
detoxified by conjugation w/glutathione
o Overdose of acetaminophen can overwhelm glutathione stores, leading to cellular and oxidative damage
and in severe cases to acute hepatic necrosis
COX-2 selective inhibitors (celecoxib, rofecoxib, valdecoxib, and meloxicam) – sulfonic acid derivatives that
exhibit 100x greater selectivity for COX-2 than COX-1
o COX-2 has larger hydrophobic channel through which substrate enters active site
o Anti-inflammatory, antipyretic, and analgesic properties similar to NSAIDs but don’t share antiplatelet
actions of COX-1 inhibitors
o Only celecoxib approved in U.S.
o
Rofecoxib withdrawn from worldwide market in 2004 because of increase in thrombogenicity
w/prolonged use, manifesting as MI and stroke
o Increased thrombogenicity uncovered in clinical use due to prolonged inhibition of vascular COX-2 w/in
endothelial cells, leading to reduced PGI2 formation
o Inhibition of COX-2 may generate problems in wound healing, angiogenesis, and resolution of
inflammation
o Much more expensive than equivalent doses of NSAIDs
o Currently approved indications of celecoxib are OA, RA, juvenile RA, ankylosing spondylitis, acute pain in
adults, and primary dysmenorrhea
 Approved to reduce number of colorectal polyps in patients w/familial adenomatous polyposis
 Decreases activity of PPARδ (transcription factor that heterodimerizes w/RXR transcription
factors involved in growth regulation); prevents signaling through PPARδ pathway and thus
removes potent mitogenic stimulus that could promote development of colon cancer
 Increases risk of cardiovascular thrombotic events (MI & stroke), hypertension, edema, and
heart failure, particularly at higher doses
 Contraindicated in treatment of pain associated w/coronary artery bypass surgery
 Cytokine inhibitors – inhibit action of TNF-α and IL-1 (normally enhance prostaglandin productin and upregulate
COX-2), inhibiting process where stimulus activates COX-2 and initiates inflammatory response
o 5 antibody-based TNF-α antagonists currently available: etanercept, infliximab, adalimumab,
golimumab, and certolizumab
 Etanercept consists of extracellular domain of TNF-α receptor coupled to human IgG1
 Infliximab – humanized mouse monoclonal antibody directed against TNF-α
 Adalimumab, golimumab, and certolizumab – humanized monoclonal IgG1 antibodies or Fab
antibody fragments directed against TNF-α
o Treatment of RA – halt joint destruction and bone erosion, decrease pain, calm swollen tender joints,
and limit overall disease progression
o Approved for other autoimmune diseases (ankylosing spondylitis, psoriatic arthritis, plaque psoriasis,
juvenile idiopathic arthritis (>4 years of age for adalimumab, >2 for etanercept), Crohn’s disease
(adalimumab, certolizumab, and infliximab), and ulcerative colitis (infliximab)
o Years of experience has increased risk of serious infections (disseminated or extrapulmonary TB,
invasive fungal infections (Aspergillus, Histoplasma), HBV reactivation, and opportunistic infections)
 Patients routinely tested for latent TB prior to initiation of therapy and must be monitored for
active TB during treatment
o Small but possibly increased risk of lymphoma, demyelinating disease, heart failure, and pancytopenia
o Anakinra – recombinant form of human IL-1 receptor produced in E. coli; approved for patients w/RA
who have failed one or more disease-modifying antirheumatic agents
 Associated w/increased risk of serious infection
Thromboxane Antagonists
 Compounds such as dazoxiben and pirmagrel inhibit thromboxane synthase
 Ridogrel is TxA2 receptor antagonist
 Not yet found clinical utility because clinical benefit not significantly greater than that of aspirin, which is far less
expensive
Leukotriene Inhibition
 Suicide inhibitors of LOX (derivatives of arachidonic acid w/triple bonds instead of double bonds) become
covalently bound to active site of LOX, but aren’t available for clinical use
o Radical scavengers (catechols, BHT, and α-tocopherol) trap radical intermediates in LOX reaction and
prevent functioning of enzyme; nonspecific compounds that can’t be used clinically for LOX inhibition
o Only LOX inhibitor in clinical use is zileuton (benzothiopene derivative of N-hydroxyurea that inhibits 5LOX by chelating its nonheme iron)
 Induces bronchodilation in asthma, improves symptoms, and generates long-lasting
improvement in pulmonary function tests
 Effective in treatment of asthma induced by cold, drugs, and allergens
 Low bioavailability, low potency, and significant adverse effects (liver toxicity)

5-lipoxygenase activating protein (FLAP) inhibition – 5-LOX activated after enzyme translocates to nuclear
membrane and docks w/FLAP; FLAP binds arachidonic acid released by phospholipase A2 and shuttles it to 5-LOX
active site
o Inhibitors develops that prevent and reverse LOX binding to FLAP and block arachidonic acid binding
site, but none currently available for clinical use
 No specific inhibitors of enzymes involved in leukotriene synthesis available for clinical use
o Adenosine, acting via receptors on neutrophils, inhibits LTB4 biosynthesis by regulating arachidonic acid
release and interfering w/influx of Ca; has role in limiting cell and tissue injury during inflammation
 High cell turnover at inflammatory sites generates high local concentrations of adenosine, which
decrease LTB4 synthesis and reduce leukocyte recruitment and activation
 Leukotriene receptor antagonism – receptor-based mechanism for inhibiting leukotriene-mediated
bronchoconstriction and other effects
o Cysteinyl leukotriene receptor (CysLT1) antagonists effective against asthma induced by antigen,
exercise, cold, or aspirin; improve bronchial tone, pulmonary function tests, and asthma symptoms
 Montelukast and zafirlukast currently available; main clinical application is Tx of asthma
Lipoxins, Aspirin-Triggered Lipoxins, Resolvins/Protectins/Maresins, and Lipoxin-Stable Analogues
 Lipoxins, ATLs, and omega-3-derived resolvins, protectins, and maresins all antagonize inflammatory actions of
leukotrienes and other inflammatory mediators to promote resolution of inflammation
 Because lipoxins are endogenous regulators, they have selective actions w/few adverse effects