Steroidal and Non-Steroidal Anti-Inflammatory Agents and Uric Acid Metabolism

Metabolism and Physiological Effects of Glucocorticoids (GC)

Carbohydrate and Protein Metabolism: * Decrease ( $\downarrow$ ) glucose utilization in muscle and adipose tissue. * Increase ( $\uparrow$ ) blood glucose levels. * Increase ( $\uparrow$ ) gluconeogenesis and glycogen synthesis in the liver. * Decrease ( $\downarrow$ ) protein synthesis in muscle, connective tissue, and skin.
Lipid Metabolism: * Increase ( $\uparrow$ ) both lipolysis and lipogenesis.
Water and Electrolyte Balance: * Increase ( $\uparrow$ ) water and $Na^+$ reabsorption. * Increase ( $\uparrow$ ) $K^+$ excretion in urine.
Bone Health: * Decrease ( $\downarrow$ ) osteoblast formation. * Enchances bone resorption.
Gastrointestinal Tract (GIT): * Increase ( $\uparrow$ ) secretion of hydrochloric acid ( $HCl$ ) and pepsin.
Inflammatory and Immune Response: * Decrease ( $\downarrow$ ) tissue inflammatory response via inhibition of specific gene expression. * Decrease ( $\downarrow$ ) cytokine formation. * Decrease ( $\downarrow$ ) T-lymphocyte ( $T ext{-ly}$ ) activation and proliferation. * Decrease ( $\downarrow$ ) macrophage phagocytic activity. * Decrease ( $\downarrow$ ) antibody formation.

Terminology and Pathologies of Inflammation and Autoimmunity

Rheumatoid Arthritis (RA): * Defined as a chronic destructive inflammatory disease of the joints. * Progresses to include extraarticular autoimmune reactions. * Characterized by the dysregulation of pro-inflammatory cytokines, specifically $TNF ext{-}\alpha$ and $IL ext{-}1$ . * Cytokine release stimulates immune cell activation and proliferation through the Janus kinase (JAK) signal transduction cascade, leading to inflammation and joint damage.
Systemic Lupus Erythematosus (Chronic Lupus Erythematosus): * A chronic autoimmune disease affecting various organs, including the skin, joints, kidneys, circulatory system, and Central Nervous System (CNS).
Inflammatory Bowel Disease (IBD): * Crohn’s Disease: A chronic, often progressive disease affecting any part of the digestive tract (mouth to anus). Inflammation is most common at the end of the small intestine, the beginning of the colon, or near the anus. It affects the entire thickness of the intestinal wall and can spread to adjacent organs. It is characterized by "fragmentary lesions," where healthy mucosa alternates with inflamed sections. * Ulcerative Colitis: A chronic form of IBD usually affecting the colon and rectal mucosa. Unlike Crohn's, it affects only the upper layer of the mucosa.

Adrenal Cortex Disorders

Addison's Disease: * Caused by primary chronic adrenal cortex deficiency (CACD). * Results in total or partial deficiency of cortisol and aldosterone. * Can be caused by autoimmune disease.
Tertiary Chronic Adrenal Cortex Deficiency (CACD): * Occurs at the hypothalamus level. * Commonly caused by rapid discontinuation of Glucocorticoid (GC) therapy following long-term administration. * Note: It is not characterized by significant electrolyte imbalance because aldosterone secretion is primarily regulated by the Renin-Angiotensin-Aldosterone System (RAAS) rather than Adrenocorticotropic hormone (ACTH).
Hypercortisolism (Cushing’s Syndrome): * Condition of elevated cortisol levels caused by pituitary or adrenal tumors or medication. * ACTH-dependent: e.g., Cushing’s disease. * ACTH-independent: e.g., iatrogenic, caused by prolonged GC therapy at supraphysiological doses.

Mechanism of Action of Glucocorticoid Receptor Agonists

Intracellular Genomic Mechanism: * In the steroid-free (unbound) state, glucocorticoid receptors (GR) are located in the cytoplasm bound to stabilizing chaperone proteins, including heat-shock protein 90 ( $Hsp90$ ) and immunophilin. * Steroid binding initiates a conformational change and an exchange of chaperone proteins. * The steroid-GR complex attaches to the dynein protein trafficking pathway for translocation into the nucleus. * In the nucleus, the complex dimerizes and binds to glucocorticoid response elements (GRE) on the regulatory regions of sensitive genes. * Result: Binding either represses or stimulates transcription, changing $mRNA$ and protein synthesis. * Key mediated effects: Reduction in inflammatory cytokines and upregulation of Annexin A1 synthesis.
Non-genomic Mechanism: * Provides more rapid responses by binding to membrane-associated receptors; these mechanisms do not involve changes in gene regulation and are currently poorly understood.

Classification and Pharmacology of Glucocorticoids

Short-acting Agents: * Hydrocortisone: GC activity = $1$ ; Mineralocorticoid (MC) activity = $1$ . Used for hormonal replacement in acute/chronic adrenal cortex insufficiency.
Medium-acting Agents: * Prednisolone: GC activity = $4$ ; MC activity = $0.3$ . * Methylprednisolone: Used for autoimmune diseases (RA), IBD, transplantology, and allergic conditions (anaphylactic shock, bronchial asthma).
Long-acting Agents: * Dexamethasone: GC activity = $30$ ; MC activity = $0$ .
Functional Effects: * Membrane Stabilizing (Fast): Lysosomal and mast cell stabilization; decreases vascular permeability and increases adrenoceptor sensitivity to catecholamines. * Genomic (Slow): Annexin-induced phospholipase A2 ( $PLA2$ ) inhibition; direct/indirect inhibition of $COX ext{-}2$ ; inhibition of activator protein $AP1$ and nuclear factor kappa ( $NF ext{-}kB$ ); inhibition of T-lymphocyte activation.

Glucocorticoid Therapy Principles and Complications

Circadian Rhythm: Therapy should consider the natural cortisol secretion rate (peak at approximately $6 ext{ a.m.}$ ; lowest around midnight).
Iatrogenic Cushing's Syndrome Symptoms: * "Central" obesity (face and torso, sparing limbs). * Osteoporosis and limb muscle atrophy. * Hyperglycemia and hypertension. * Abdominal stretches, hirsutism in women, and depressed immunity. * Ulcerogenic effects and mental disorders (e.g., depression).
Feedback Inhibition: Exogenous GC usage reduces Corticotropin-releasing hormone ( $CRH$ ) effect on the adenohypophysis, leading to decreased $ACTH$ secretion and subsequent adrenocortical atrophy.
Withdrawal Guidelines: * Sudden discontinuation after long-term use can cause acute adrenal insufficiency because of gland atrophy. * Treatment lasting more than $3$ weeks at supra-physiological doses must be stopped gradually.
Dosing Strategies: * Acute: High doses for short periods. * Chronic: Lowest effective maintenance dose. * Alternate-day therapy: Double the GC dose every second day.

Mineralocorticoid Receptor Agonists

Fludrocortisone: * A fluorinated derivative of hydrocortisone. * GC activity = $10$ ; MC activity = $125 ext{--}250$ . Duration: Medium. * Mechanism: Agonist for aldosterone receptors in distal renal tubules and collecting ducts; promotes DNA transcription of epithelial $Na^+$ channels. * Effects: Increases $Na^+$ reabsorption and water retention (leading to increased BP) and increases $K^+$ excretion. * Indications: Replacement therapy for Addison's disease (combined with GC). * Side Effects: Hypertension, oedema, hypokalemia.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Cyclooxygenases (COX): * $COX ext{-}1$ : Constant (constitutive) expression in tissues; mediates gastric protection via prostaglandins. * $COX ext{-}2$ : Mainly inducible; concentration increases $10 ext{--}20$ times during inflammatory stimuli (especially in connective tissue).
Subsets of NSAIDs: * Acetylsalicylic acid (Aspirin): Dose-dependent non-selective inhibition. Irreversibly inhibits $COX ext{-}1$ . At high doses, inhibits $COX ext{-}2$ . Antiplatelet effect is $170$ times more potent for $COX ext{-}1$ than $COX ext{-}2$ . * Diclofenac and Ibuprofen: Reversibly inhibit both $COX ext{-}1$ and $COX ext{-}2$ . * Etoricoxib (Coxibs): Selective and reversible $COX ext{-}2$ inhibition. Designed to avoid GI side effects.
Side Effects and Risks: * GI Toxicity: Associated with $COX ext{-}1$ inhibition. * Cardiovascular (CV) Toxicity: Selective $COX ext{-}2$ inhibitors increase the risk of myocardial infarction and stroke by altering the balance between prostacyclin ( $PGI_2$ ) and thromboxane ( $TXA_2$ ). Contraindicated in coronary heart disease, peripheral artery disease, and severe chronic heart failure. * Renal Risk: Both $COX ext{-}1$ and $COX ext{-}2$ inhibition can interfere with renal blood flow. Increased risk of acute renal failure when combined with ACE-inhibitors ( $ACE ext{-}I$ ) or ARBs and diuretics. * Reye's Syndrome: Risk in children under $12$ using aspirin for fever; presents as rapidly progressive toxic encephalopathy.

Gout and Uric Acid Metabolism

Pathophysiology of Gout: * Chronic disease caused by deposition of urate crystals in joints and tissues (e.g., kidney stones). * Uric acid is the final product of purine metabolism: ext{hypoxanthine} ightarrow ext{xanthine} ightarrow ext{uric acid}. Both steps are catalyzed by xanthine oxidase.
Uricostatic Agents: * Allopurinol: A purine/hypoxanthine analogue and prodrug metabolized to alloxanthine (oxypurinol). Alloxanthine is an irreversible xanthine oxidase inhibitor. Used for chronic hyperuricemia and prevention of chemotherapy complications. * Febuxostat: A selective, reversible xanthine oxidase inhibitor of non-purine origin.
Therapy for Acute Gout Attacks: * NSAIDs, local Glucocorticoids (intra-articular), and systemic Glucocorticoids.
Side Effects of Uricostatic Therapy: Skin rash and potential for acute gout attacks upon initiation.