Rang and Dale - Chapter 25

Overview and Classification of Anti-Inflammatory and Immunosuppressive Drugs

• The inflammatory response is essentially a manifestation of the immune system in action. While protective, it can be activated inappropriately or outlast its usefulness, requiring anti-inflammatory and immunosuppressive drugs for remedial action.

• Inflammation forms a significant component of most diseases encountered clinically, making anti-inflammatory drugs widely used across virtually all branches of medicine.

• In the UK alone, $1.4\text{ billion}$ items of this type were dispensed in $2020/21$; because several drugs in this category are available over the counter (OTC) from pharmacy counters, the true usage figure is substantially higher.

• Anti-inflammatory drugs are divided into five major groups:

  • Cyclo-Oxygenase (COX) Inhibitors: Traditional non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs.

  • Antirheumatoid Drugs (DMARDs): Disease-modifying antirheumatic drugs comprising synthetic DMARDs ($\text{sDMARDs}$) and biopharmaceutical/anticytokine agents referred to as biologic DMARDs ($\text{bDMARDs}$).

  • Glucocorticoids.

  • Drugs Used Specifically to Control Gout.

  • Antihistamines: Histamine $H_1$ receptor antagonists used for the treatment of acute allergic conditions and allergic inflammation.

Cyclo-Oxygenase Inhibitors and NSAID Spectrum

• NSAIDs, also termed aspirin-like drugs or antipyretic analgesics, comprise more than $50$ different examples on the global market.

• NSAIDs constitute $5\%-10\%$ of all prescriptions worldwide and are taken daily by more than $30\text{ million}$ people globally (McEvoy et al., 2021).

• Classification, Indications, and COX Selectivity of Common Cyclo-Oxygenase Inhibitors:

  • Propionates:

  • Dexibuprofen: Indications for Osteoarthritis (OA), Musculoskeletal injuries and pain (MS), Dysmenorrhoea (D), Headache & Migraine (H&M). Active enantiomer of ibuprofen.

  • Dexketoprofen: Indications for Postoperative pain (PO), D, H&M. Isomer of ketoprofen.

  • Fenoprofen: Indications for Rheumatoid Arthritis (RA), OA, MS, PO. Non-selective; prodrug activated in the liver (not available in the UK).

  • Felbinac: Indications for MS, OA. Active metabolite of fenbufen.

  • Flurbiprofen: Indications for RA, OA, MS, PO, D, H&M. Very COX-1 selective.

  • Ibuprofen: Indications for RA, OA, MS, PO, D, H&M. Weakly COX-1 selective; available in many formulations and OTC in pharmacies; suitable for children.

  • Ketoprofen: Indications for RA, OA, Acute Gout (G), MS, PO, D. Weakly COX-1 selective; suitable for mild disease.

  • Naproxen: Indications for RA, OA, G, MS, PO, D. Weakly COX-1 selective; potentially cardiovascular (CV) safe.

  • Tiaprofenic acid: Indications for RA, OA, MS.

  • Indoles and Derivatives:

  • Acemetacin: Indications for RA, OA, MS, PO. Ester prodrug of indometacin.

  • Indometacin: Indications for RA, OA, G, MS, PO, D. Weakly COX-1 selective; suitable for moderate to severe disease.

  • Sulindac: Indications for RA, OA, G, MS. Weakly COX-2 selective prodrug.

  • Oxicams:

  • Meloxicam: Indications for RA, OA, Ankylosing Spondylitis (AS). Moderately COX-2 selective; displays fewer gastrointestinal (GI) effects.

  • Piroxicam: Indications for RA, OA, AS. Weakly COX-2 selective.

  • Tenoxicam: Indications for RA, OA, MS.

  • Sulfonyl and Sulfonamide Coxibs:

  • Celecoxib: Indications for RA, OA, AS. Moderately COX-2 selective; produces fewer GI effects.

  • Etoricoxib: Indications for RA, OA, G, AS. Very COX-2 selective.

  • Parecoxib: Indications for PO. Prodrug activated in the liver.

  • Phenylacetates:

  • Aceclofenac: Indications for RA, OA, AS.

  • Diclofenac: Indications for RA, OA, G, MS, PO, H&M. Weakly COX-2 selective; moderate potency; available in various salts.

  • Fenamates:

  • Mefenamic acid: Indications for RA, OA, PO, D. Moderate activity.

  • Tolfenamic acid: Indications for H&M.

  • Miscellaneous:

  • Ketorolac: Indications for PO. Highly COX-1 selective; mainly used ocularly.

  • Nabumetone: Indications for RA, OA. Prodrug activated in the liver.

  • Etodolac: Indications for RA, OA. Moderately COX-2 selective; displays fewer GI effects.

  • Salicylates:

  • Aspirin: Indications primarily for CV usage. Weakly COX-1 selective; component of many OTC preparations; unsuitable for children.

• Structural Features of Selected NSAIDs and Coxibs:

  • Aspirin contains an acetyl group responsible for COX inactivation. De-acetylation yields salicylic acid, which maintains anti-inflammatory activity in its own right.

  • Paracetamol has a simple structure acting as a widely used analgesic agent.

  • Classic NSAIDs are mostly carboxylic acids (e.g., ibuprofen).

  • Coxibs (e.g., celecoxib) contain sulfonamide or sulfone groups. These bulky groups impede access to the hydrophobic channel of the COX-1 enzyme.

Cyclo-Oxygenase Isoforms: Expression and Physiological Roles

• Primary pharmacology across NSAIDs stems from inhibiting fatty acid COX enzymes, thereby blocking biosynthesis of prostaglandins and thromboxanes.

• Two common isoforms exist: COX-1 and COX-2 (sharing $>60\%$ sequence identity and catalysing identical reactions).

• COX-1 Isoform:

  • Constitutively expressed in most tissues, including blood platelets.

  • Fulfills a "housekeeping" role involved in tissue homeostasis.

  • Responsible for producing prostaglandins involved in gastric cytoprotection, renal blood flow autoregulation, and initiation of parturition.

• COX-2 Isoform:

  • Induced in inflammatory cells when activated by inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor-alpha ($\text{TNF-}\alpha$).

  • Considered mainly responsible for producing prostanoid mediators of inflammation (Vane and Botting, 2001).

  • Key physiological exceptions to inducible expression: Constitutively expressed in the kidney to generate prostacyclin ($PGI_2$) for renal homeostasis, and in the central nervous system (CNS) with undetermined functional roles.

Molecular Mechanism of Action and Enzyme Kinetics

• Vane and colleagues (1971) demonstrated direct COX inhibition by NSAIDs, establishing that this single action explains their therapeutic actions and side effects.

• COX enzymes are bifunctional, haem-containing homodimers attached to intracellular membranes. A dioxygenase step is followed by a peroxidase reaction.

• Dimeric Function: Only one monomer is catalytically active at a time. Binding of an NSAID to one COX monomer can inhibit the catalytic activity of the entire dimeric complex.

• Kinetics of Inhibition:

  • Most NSAIDs inhibit the initial dioxygenation reaction.

  • COX-1 inhibition: Rapid "competitive reversible" kinetics.

  • COX-2 inhibition: Time-dependent and frequently irreversible.

• Hydrophobic Channel Architecture and Binding Mechanisms:

  • Both isoforms contain a hydrophobic channel into which arachidonic acid or other substrate fatty acids dock.

  • NSAIDs enter this channel and form hydrogen bonds with an arginine residue at position 120 ($\text{Arg-120}$), preventing substrate access to the catalytic domain.

  • Selectivity Determinant: A single amino acid substitution occurs at the channel entrance—isoleucine in COX-1 versus valine at position 523 ($\text{Val-523}$) in COX-2. This substitution produces a "side pocket" or "bulge" in COX-2 that is absent in COX-1.

  • Large sulfur-containing side groups (such as the sulfonamide moiety in celecoxib) fit into the COX-2 side pocket, but encounter steric hindrance blocking access to COX-1. Non-selective agents like flurbiprofen enter the active site of either enzyme.

• Aspirin Mechanism:

  • Irreversibly inactivates COX by entering the active site and acetylating a serine residue at position 530 ($\text{Ser-530}$).

  • Aspirin-inactivated COX-2 can still generate some hydroxyacids, but cannot produce the endoperoxide intermediate required for prostanoid synthesis.

Pharmacological Actions of NSAIDs

• Anti-Inflammatory Effects:

  • Reduces COX-2-derived prostaglandins ($PGE_2$, $PGI_2$), diminishing inflammatory vasodilatation and secondary postcapillary venule permeability/oedema driven by mediators like histamine.

  • Reactive oxygen radical scavenging (e.g., sulindac) decreases tissue damage mediated by neutrophils and macrophages.

  • Aspirin inhibits nuclear factor kappa B ($NF\kappa B$), suppressing transcription of inflammatory mediator genes.

  • NSAIDs possess a binding site on sulfotransferase enzymes (Wang et al., 2017).

  • Limitations: NSAIDs suppress symptoms of inflammation without altering underlying chronic disease progression, chemokine/cytokine release, leukocyte migration, or lysosomal enzyme release.

• Antipyretic Effects:

  • Resets the hypothalamic thermostat during fever without altering normal body temperature in healthy individuals.

  • Bacterial endotoxins stimulate macrophage release of IL-1 $\rightarrow$ IL-1 induces COX-2 in hypothalamic vascular endothelium $\rightarrow$ E-type prostaglandins ($PGE_2$) activate $EP3$ receptors to elevate temperature set-point (Lee and Simmons, 2018).

• Analgesic Effects:

  • Peripheral action: Decreases COX-2-driven prostaglandin synthesis that sensitises nociceptors to inflammatory mediators like bradykinin and 5-HT. Effective in arthritis, bursitis, muscular/vascular pain, toothache, dysmenorrhoea, and bone metastasis pain. Reduces postoperative opioid requirements by up to one-third (Thybo et al., 2019).

  • Central action: Peripheral inflammatory lesions induce COX-2 expression and prostaglandin release in the spinal cord dorsal horn, facilitating pain transmission to relay neurons (Vuilleumier et al., 2018).

Class-Wide Unwanted Effects and Safety Profile

• Prescribing Golden Rule: Use the lowest dose for the shortest possible duration.

• Gastrointestinal Disturbances:

  • Commonest unwanted effects; $34\%-46\%$ of NSAID users sustain GI damage, causing 400–1000 deaths annually in the UK (McEvoy et al., 2021).

  • Result from gastric COX-1 inhibition, suppressing cytoprotective prostaglandins that normally inhibit acid secretion. Symptoms range from dyspepsia and nausea to mucosal bleeding, ulceration, and perforation.

  • Direct local mucosal irritation (e.g., aspirin) compounds systemic COX inhibition (Henry et al., 1996; Castellsague et al., 2012).

  • Prevention strategies: Co-prescription of proton-pump inhibitors (PPIs), $H_2$-receptor antagonists, or oral misoprostol (Bakhriansyah et al., 2017).

  • Measure of Selectivity: COX-1 inhibition achieved at the concentration required to inhibit COX-2 by $80\%$ (Warner and Mitchell, 2008).

  • Novel Amelioration Strategies: Nitric oxide-donating NSAIDs (NO-NSAIDs / CINODs) and hydrogen sulfide ($H_2S$)-releasing NSAID derivatives (Wallace et al., 2020).

  • NSAID Enteropathy: Small intestine and colon damage, carrying high morbidity/mortality, especially when co-administered with anticoagulants (Lanas et al., 2015).

• Hypersensitivity Reactions:

  • Affects $5\%-15\%$ of patients; NSAIDs represent the leading cause of drug-induced hypersensitivity reactions, surpassing $\beta$-lactam antibiotics (Blanca-Lopez et al., 2019).

  • NSAID-Exacerbated Respiratory Disease (NERD): Characterised by moderate-to-severe asthma, chronic rhinosinusitis, and nasal polyps due to COX inhibition and cysteinyl leukotriene overproduction (Woo et al., 2020).

  • Skin rashes: Common with mefenamic acid ($10\%-15\%$ incidence) and sulindac ($5\%-10\%$ incidence). Severe forms include Stevens-Johnson syndrome and toxic epidermal necrolysis (Laidlaw and Cahill, 2017).

• Adverse Renal Effects:

  • Acute reversible renal insufficiency caused by suppression of $PGE_2$ and $PGI_2$ compensatory vasodilatation against noradrenaline and angiotensin II. High risk in neonates, elderly, heart/liver/kidney disease, hypovolemia, or concurrent use of ACE inhibitors, diuretics, or calcineurin inhibitors.

  • Analgesic Nephropathy: Long-term high-dose consumption/abuse causes interstitial nephritis and renal papillary necrosis (phenacetin main historic cause; paracetamol less toxic).

  • Electrolyte and Acid-Base Disorders: Hyperkalaemia, Type 4 renal tubular acidosis, and nephrotic syndrome (Horl, 2010; Baker and Perazella, 2020).

• Cardiovascular Side Effects:

  • Non-aspirin NSAIDs increase thrombotic risks (myocardial infarction, stroke). Higher COX-2 selectivity correlates with greater risk due to imbalance between endothelial anti-thrombotic $PGI_2$ (generated via COX-1/COX-2) and platelet pro-thrombotic $TXA_2$ (generated via COX-1 alone) (Mitchell et al., 2019).

  • Dose- and time-dependent hypertension occurs via prostacyclin suppression, macula densa renin modulation, sodium/water retention, and heart failure exacerbation.

  • Inhibition of renal COX-2 modulates the methylarginine system, suppressing cardiotoxic asymmetrical dimethylarginine (ADMA) release via NOS (Kirby et al., 2016).

  • Naproxen displays superior CV tolerance relative to diclofenac (Schjerning et al., 2020).

• Other Unwanted Effects:

  • CNS effects, bone marrow depression, elevated liver enzymes, and prolonged bleeding time.

Characteristics of Key Specific Agents

• Aspirin (Acetylsalicylic Acid):

  • Weak acid absorbed in stomach and microvilli of the ileum.

  • Irreversibly inactivates COX-1 and COX-2 by acetylating $\text{Ser-530}$.

  • Anucleate platelets cannot synthesize new enzyme, remaining inhibited for their entire $10\text{-day}$ lifespan. A daily low dose ($75\,mg/day$) maintains platelet COX-1 suppression for secondary CV prevention (Baigent et al., 2009).

  • Non-cardiovascular indications: Reduced incidence of colorectal cancer (Wong, 2019) and reduced cognitive decline in Alzheimer's disease (Weng et al., 2021).

  • Pharmacokinetics: Rapidly hydrolysed ($<30\,min$) by plasma/tissue esterases to salicylate (which inhibits $NF\kappa B$). $25\%$ oxidised, conjugated to glucuronide/sulfate, and $25\%$ excreted unchanged (excretion increases in alkaline urine). First-order elimination kinetics at low doses (half-life $4\,h$); zero-order/saturation kinetics at high doses (half-life $>15\,h$).

  • Toxicity Profile: Reye's syndrome in children (hepatic encephalopathy following post-viral illness, carrying $20\%-40\%$ mortality). Salicylism (tinnitus, vertigo, hearing loss, vomiting).

  • Acute Poisoning Mechanism: Uncouples oxidative phosphorylation in skeletal muscle $\rightarrow$ hyperthermia, increased $CO_2$ $\rightarrow$ respiratory center stimulation $\rightarrow$ hyperventilation $\rightarrow$ respiratory alkalosis. Toxic doses depress respiratory center $\rightarrow$ uncompensated respiratory acidosis combined with metabolic acidosis (accumulation of pyruvic, lactic, acetoacetic acids), dehydration, CNS excitement leading to coma, and bleeding.

  • Drug Interactions: Hazardous increase in warfarin action (displaces warfarin from plasma proteins and impairs haemostasis). Antagonises antihypertensives, probenecid, and sulfinpyrazone. Contraindicated in gout due to reduced urate excretion.

• Paracetamol (Acetaminophen):

  • Analgesic and antipyretic with minimal anti-inflammatory action; free of gastric mucosal and platelet side effects (Hyllested et al., 2002).

  • Mechanism: Inhibits CNS COX (acts as a reducing agent in low-peroxide environments), activates descending serotonergic pathways, and increases cannabinoid receptor activation (Anderson, 2008).

  • Pharmacokinetics: Rapid oral absorption (peak plasma in $30-60\,min$). Half-life $2-4\,h$ (extended to $4-8\,h$ in overdose). Conjugated in liver to glucuronide and sulfate. IV preparations available. Dose adjustment required if weight <50\,kg$.\n * Overdose Toxicity: Doses >150\,mg/kg$saturate normal conjugation. Metabolised by mixed function oxidases to toxic reactive metabolite N-acetyl-p-benzoquinone imine ($\text{NAPQI}$). Depleted glutathione causes$\text{NAPQI}$accumulation, binding liver and renal tubule cell proteins, leading to necrosis. Delayed hepatotoxicity manifests$24-72\,h post-ingestion (Prescott, 2000).\n * Antidote: Intravenous N-acetylcysteine (\text{NAC}$) increases glutathione synthesis; effective within$8\,h$of ingestion ($\text{NAC}$causes anaphylactoid reactions in$10\%-50\% of cases).\n* **Ibuprofen:**\n * Founder of propionic acid class (1969). Racemic mixture; active S(+)$enantiomer,$R(-)$enantiomer converted to$S(+) in vivo. Non-selective COX inhibitor.\n * Pharmacokinetics: Peak serum concentrations at 1-2\,h$, half-life$1.8-2.0\,h$. Liver metabolism via hydroxylation and carboxylation; complete excretion within$24\,h (Bushra and Aslam, 2010).\n * High plasma protein binding (99\%), but does not displace warfarin.\n* **Coxibs (Celecoxib, Etoricoxib, Parecoxib):**\n * Designed to reduce GI toxicity; contraindicated in active ulceration due to COX-2 requirement for mucosal ulcer healing. Pre-treatment CV risk assessment mandatory.\n * *Celecoxib & Etoricoxib:* Used in OA, RA, AS. Oral absorption with peak levels in 1-3\,h$. Extensive hepatic metabolism ($>99\%$), high protein binding ($>90\%). Side effects: headache, dizziness, rash, fluid retention/peripheral oedema.\n * *Parecoxib:* Prodrug of valdecoxib licensed for short-term postoperative pain (IV/IM). Enzymatically hydrolysed in liver (>95\%$) to active valdecoxib (peak levels in$30-60\,min$, half-life$\approx 8\,h$$). Adverse effects: severe skin reactions, renal impairment/failure, postoperative anaemia.