Pharmacology of Eicosanoids and NSAIDs

Arachidonic acid

The most abundant precursor of eicosanoids, stored in cell membrane lipids.

COX pathway

Metabolic pathway for producing prostanoids like prostaglandins, thromboxane, and prostacyclin.

LOX pathway

Metabolic pathway using 5-Lipoxygenases to produce leukotrienes.

COX-1 prostanoids

Constitutively expressed prostanoids that provide cytoprotection for the gastric and cardiovascular system.

COX-2 prostanoids

Activated in inflammation and cancer, induced expression, and modulate cardiovascular and renal function.

EET

Produced via CYP epoxygenase (CYP2C and CYP2J), modulating cardiovascular and renal function.

Prostaglandins (PG)

Potent vasodilators that inhibit platelet aggregation, increase renal blood flow, induce diuresis, natriuresis, kaliuresis, and renin release.

PGI2

A potent vasodilator that increases heart blood flow and is involved in tumorigenesis.

PGF2alpha

Induces uterine contractions, amenorrhea, labor, and parturition, and is used to lower glaucoma.

Thromboxane (TXA2)

A potent vasoconstrictor that induces platelet aggregation and tumorigenesis.

Leukotriene

Induces hypotension, bronchoconstriction via LTC4 and LTD4, and is targeted by drugs like Zileuton, Zafirlukast, and Montelukast.

COX-1

Constitutively expressed in many cells, with housekeeping roles in maintaining epithelial barriers and renal blood flow.

COX-2

Activated/inducible expression in inflammation, pain, fever, ovulation, uterine contractions, and placental functions.

Aspirin

Irreversibly inhibits COX-1 and COX-2 by acetylation, with cardioprotective effects through COX-1 blockade in platelets and COX-2 recovery mechanisms.

Acetaminophen (APAP)

An antipyretic and analgesic drug with low gastric toxicity, metabolized in the liver by CYP enzymes.

Celecoxib

A selective COX-2 inhibitor with advantages in GI effects but associated with cardiovascular side effects and renal toxicity.

Indomethacin

A nonselective COX-inhibitor with analgesic, antipyretic, and anti-inflammatory properties, highly protein-bound.

Sulindac

A prodrug similar to indomethacin but less potent, also highly protein-bound.

Ketorolac

A potent analgesic with mild anti-inflammatory effects, rapid and short-acting, and highly protein-bound.

Diclofenac

An analgesic, anti-pyretic, and anti-inflammatory drug with COX-2 preference over COX-1, associated with increased hepatic enzymes and CV side effects.

Etodolac

An anti-inflammatory drug with lower GI toxicity, highly protein-bound, and 100% bioavailable.

Pharmacokinetics

The study of drug absorption, distribution, metabolism, and excretion in the body.

Toxicity

The degree to which a substance can damage an organism, often related to overdose or adverse effects.

Hyperuricemia

High levels of uric acid in the blood, leading to the formation of urate crystals in joints, a key factor in gout.

Gout

A condition characterized by recurrent inflammation due to the accumulation of urate crystals in joints, caused by hyperuricemia.

Allopurinol

Purine analog that inhibits Xanthine oxidase, leading to decreased uric acid levels

Probenecid

Drug that inhibits organic acid transport, increasing uric acid excretion and inhibiting renal secretion of glucuronide metabolites of NSAIDs

Colchicine

Medication that binds to intracellular protein tubulin, inhibiting leukocyte migration and phagocytosis to relieve inflammation in gout

Febuxostat

Non-purine inhibitor of xanthine oxidase used to inhibit urate crystal formation and safer than allopurinol for chronic kidney disease

Pegloticase

PEGylated uricase that promotes uric acid excretion by inhibiting organic acid transport and renal secretion of glucuronide metabolites of NSAIDs

NSAIDs

Drugs that inhibit prostaglandin synthesis to reduce inflammation and pain, also inhibiting urate crystal phagocytosis

Glucocorticoids in gout

Inhibit NF-kappa B to reduce inflammation and pain by inhibiting inflammatory cascades at multiple points

DMARDs

Disease-modifying antirheumatic drugs that reduce disease activity, retard tissue destruction, and block pro-inflammatory immune cell recruitment

Methotrexate

Anti-proliferation agent that inhibits dihydrofolate reductase, reducing purine nucleotide and thymidine synthesis, DNA replication, and cell-mediated immune reactions

Azathioprine

Antimetabolite that inhibits de novo purine synthesis, reducing B and T cell function, immunoglobulin production, and IL-2 secretion

Hydroxychloroquine

Anti-malarial/anti-rheumatic drug that suppresses T-cell response and leukocyte chemotaxis, inhibiting DNA and RNA synthesis

Cyclosporine and Tacrolimus

Calcineurin inhibitors that block T-cell activation by inhibiting calcineurin activity and prevent production of IL-2, TNF-α, and IFN-γ

Tofacitinib

Janus kinase (JAK) inhibitor that blocks cytokine signaling pathways, reducing production of various interleukins

Leflunomide

Antimetabolite that inhibits pyrimidine synthesis, reducing T-lymphocyte activity

Cyclophosphamide

Cytotoxic agent that causes DNA strand breakage and cell death in rapidly proliferating tissues

Infliximab

Chimeric monoclonal antibody that blocks TNF-α binding to its receptor, used in autoimmune diseases

Etanercept

Fusion protein that binds to free TNF-α, preventing its interaction with receptors

Adalimumab

Human monoclonal antibody that blocks TNF-α binding to its receptor

Anakinra

Recombinant human IL-1 receptor antagonist that blocks IL-1 signaling

Rilonacept

Soluble decoy receptor that traps and neutralizes IL-1

Canakinumab

Human monoclonal antibody that neutralizes IL-1β

Secukinumab

Monoclonal antibody that blocks IL-17A

Tocilizumab and Sirukumab

Monoclonal antibodies that block the IL-6 receptor

Vedolizumab

Drug that blocks alpha4beta7 integrin, preventing leukocyte binding and extravasation into tissues

Abatacept

CTLA4-Ig fusion protein that inhibits T-cell activation by blocking CD28 interaction

Brodalumab, Ixekizumab, Guselkumab, Ustekinumab, Risankizumab

Biologics targeting different interleukins for psoriasis and psoriatic arthritis

Ligand Blockade

Involves agents that bind to a ligand to prevent its interaction with its receptor

Receptor Blockade

Involves agents that bind to the receptor, blocking the ligand from binding