Pharmacology of Anti-inflammatory Agents

Course Information

• Course: BMF (Biomedical Sciences)
• Year: 1
• Title: Immunopharmacology of anti-inflammatory agents
• Lecturer: Prof Will Ford, 337
• Date: November 2024
• Location: RCSI Royal College of Surgeons in Ireland

Learning Outcomes

• Appreciate drug treatment approaches for acute vs chronic inflammation
• Differentiate between steroidal and non-steroidal anti-inflammatory approaches
• Outline anti-inflammatory steroid actions and their patient populations
• Compare COX1 and COX2 actions
• Detail selective vs non-selective COX inhibitor uses and limitations

Recap: Acute Inflammation

• Triggered by bacteria, cytokines, chemokines
• Leads to vascular response (vasodilation, increased permeability) causing redness, heat, and swelling
• Inflammatory cells migrate into tissue, releasing mediators causing pain
• Key immune cells are neutrophils (PMNs)
• Many pro-inflammatory mediators are involved

Local and Acute Systemic Effects of Acute Inflammation

• Heat ("calor"): Increased blood flow
• Redness ("rubor"): Leakage of fluid
• Swelling ("tumor"): Leakage of fluid, proteins, increased blood flow, mediators
• Pain ("dolor"): Chemical mediators, exudates pressing on pain receptors
• Loss of function ("function laesa"): Disrupted tissue structure
• Systemic effects also include fever caused by IL-1, TNFα, IL-6 release locally (often by macrophages), which act on the hypothalamus (esp. IL-1) and the liver (esp. IL-6), leading to synthesis of acute phase proteins (e.g., C-reactive protein).

Inflammation, Pain, and Local Mediators

• Local mediators
  • Prostaglandins and leukotrienes
  • Platelet-activating factor (PAF)
  • Histamine
  • 5-hydroxytryptamine
  • Neuropeptides
  • Nitric oxide
  • Bradykinin
  • Adenosine and purines
  • Complement
  • Cytokines
• Pain & Inflammation: These mediators are secreted by immune cells and responsible for inflammation symptoms (e.g., vasodilation). Pain occurs when inflammation is near a nerve fiber.

Recap: Inflammatory Pain

• Inflammatory mediators (PGs, 5-HT, bradykinin) sensitize pain fibers
• Sensitization rather than causing pain itself makes fibers more responsive to stimuli

Recap: Chronic Inflammation

• Triggered by persistent or unresolved conditions (infections, chemicals, autoantigens)
• Key players include macrophages, lymphocytes, and plasma cells
• Active inflammation, tissue response, and tissue repair (including fibrosis) can all be part of chronic inflammation
• Examples include rheumatoid arthritis, atherosclerosis, heart disease, COPD, Crohn's disease, asthma, lupus, psoriasis, cancer, and type II diabetes

Acute vs Chronic Inflammation

• Acute: Inflammation is usually a response to an insult (infection, damage, etc.)
• Chronic: Inflammation itself becomes the problem

The Good, the Bad, and the Ugly

• Acute inflammation: response to infection or trauma, allows immune cell access, initiates healing
• Termination is crucial, achieved by resolvins
• Failure to terminate leads to chronic inflammation

Anti-inflammatory Drugs

• Provide symptomatic relief (reduce inflammation causing pain and fever)
• Best used temporarily while underlying issue is corrected
• Acute: typically treated with NSAIDs or steroids
• Chronic: often treated with combinations of NSAIDs and steroids.

Steroids vs Non-Steroidals

• Steroids are immunosuppressive
• NSAIDs are anti-inflammatory
• Steroid examples include cortisol, cortisone, prednisone, prednisolone, and dexamethasone
• Steroids are indicated for lupus, asthma, COPD, inflammatory bowel disease, and other chronic inflammatory conditions, however, they are contraindicated in active infection, depression, alcohol dependence, high blood pressure, diabetes, and heart failure.

Steroid Hormones

• Glucocorticoids (e.g., cortisol): Affect carbohydrate and protein metabolism
• Mineralocorticoids (e.g., aldosterone): Regulate salt retension
• Androgens: Male sex hormones
• Estrogens: Female sex hormones

Corticosteroids and the HPA Axis

• Axis involves: hypothalamus, pituitary, adrenal glands
• Cortisol is a product of this cascade
• Receptors for corticosteroids are located in multiple cells and tissues

Corticosteroid Mechanism of Action

• Affect gene expression (upregulate or downregulate production of inflammatory or anti-inflammatory mediators like COX-2, iNOS, and IL-10)
• Act on the nucleus by regulating gene expression

Glucocorticoids

• Inhibit phospholipase A2, increase annexin A-1 production
• Reduce IL-1, IL-2, interferon, prostaglandins, leukotriene production
• Decrease basophils, eosinophils, monocytes but increase neutrophils
• Reduce circulating lymphocyte number (T > B lymphocytes, CD4+ > CD8+)
• Adverse effects on carbohydrate metabolism

Use of Glucocorticoids

• Replacement therapy for Addison's disease
• Anti-inflammatory treatment (allergies, eczema, psoriasis, asthma, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease)
  • Inhaled
  • Topical
  • Oral
• Adverse effects include Cushing syndrome, osteoporosis, and poor wound healing

Non-steroidal anti-inflammatory drugs (NSAIDs)

• Used to treat inflammation
• Inhibit cyclooxygenases, thus reducing prostaglandin production
• Are anti-inflammatory, analgesic and anti-pyretic
• Examples: aspirin (irreversible), ibuprofen, indomethacin, diclofenac

NSAIDs and the Arachidonic Pathway

• NSAIDs disrupt the arachidonic pathway, impacting prostaglandin synthesis
• Affect the conversion/synthesis of prostaglandins and thromboxane A2

Cyclooxygenases (COX)

• COX-1: Constitutively expressed
• COX-2: Induced by factors (shear stress, growth factors, cytokines)
• COX enzymes are homodimers, and inhibition of one site in the dimer can render it inactive

NSAID Range of Selectivity

• Initial expectations that selective COX-2 inhibitors would have fewer side effects than non-selective inhibitors were not entirely borne out. For example, rofecoxib was withdrawn from the market in 2004 due to increased risk of cardiovascular events.

Manipulating Aspirin Dosage

• Low-dose aspirin (75mg): Inhibits prostaglandin synthesis by 10-20%, platelets are affected longer than other cells (inhibited for their lifespan) and cumulative effect leads to a lasting block on platelet COX.
• High dose (325mg): Inhibits total prostaglandin synthesis in the body, most cells recover their COX synthesis within 4-8 hours. Administration must be repeated for persistent inhibition of non-platelet COX.

Effectiveness of Aspirin

• Reduces death following myocardial infarction (MI) by 25%
• Has additive effects with heparin, thrombolytic drugs (tPA or streptokinase)
• Primary prevention in those at high risk of future vascular events.

Side Effects of Aspirin

• Excessive bleeding (reduced platelet function)
• Gastrointestinal (GI) damage (increased acid production)
• Reye's syndrome in children (liver protein acetylation)
• Aspirin is the only potent, irreversible antiplatelet NSAID, other options are reversibly inhibited.

Two COX Iso-enzymes

• COX-1 and COX-2 are quite similar at the molecular level. There is also a splice variant COX-3
• COX-1: Constitutively expressed
• COX-2: Induced
• Small difference in amino acid sequence allows for selective drug targeting of COX-2 (e.g., coxibs or COX-2 inhibitors).

Coxibs

• COX-2 selective inhibitors (e.g., celecoxib, rofecoxib)
• Initially designed to reduce side effects like gastric ulcers.
• Subsequent studies show coxibs to be associated with increased cardiovascular events (MI, stroke).

VIGOR - Clinical Trial

• Clinical trial assessing the cardiovascular effects of rofecoxib vs naproxen.
• Rofecoxib showed increased risk of cardiovascular events in comparison to naproxen

COX-2 and Cardiovascular Disease

• Selective COX-2 inhibition reduces prostaglandin I2 (PGI2/prostacyclin) production by vascular endothelium.
• Little to no effect on platelet thromboxane A2 production, which can lead to prothrombotic effects.

NSAIDs and Cardiovascular Disease

• All NSAIDs increase cardiovascular risk (Naproxen the least risk).
• Increased risk depends on dosage
• Avoid NSAIDs in patients at high risk of cardiovascular events
• Limited exposure is best approach when using NSAIDs.

Paracetamol/Acetaminophen

• Not an NSAID—used for fever and pain, not inflammation.
• Mechanism unclear but may involve COX-3 or AM404 activation of TRPA1.
• Still has some cardiovascular, GI, and renal risks.

NSAIDs - What Happens to AA

• NSAIDs block the conversion of arachidonic acid to prostaglandins
• This excess arachidonic acid is diverted to lipoxygenase pathway
• Lipoxygenase produces leukotrienes, leading to bronchoconstriction.

Leukotrienes

• Released by leukocytes (such as mast cells).
• Proinflammatory molecules
• Contribute to various processes like vasodilation, mucus production, and bronchoconstriction

Anti-leukotrienes

• Inhibit leukotriene synthesis or receptors (e.g., zileuton, zafirlukast, montelukast)
• Used for asthma (less effective than inhaled steroids)
• Veliflapon (FLAP inhibitor) in clinical trials.

Anti-leukotriene Drugs

• Zileuton and zafirlukast are used in asthma treatment.
• Not first-line treatment for asthma.
• Don't reverse bronchoconstriction.
• Often used as 'preventers' not 'relievers'.

Targeting Cytokine Signaling

• Inhibitors target signalling molecules for certain cytokines, such as targeting cytokine IL-2 signalling with basiliximab (Simulect)

Perspectives

• Immune responses are complex
• Protective inflammation can become destructive
• No single perfect approach to managing inflammation pharmacologically

What We Have Learned

• Drug approaches for acute vs chronic inflammation
• Steroidal vs non-steroidal anti-inflammatory approaches
• Anti-inflammatory steroid actions, indicated populations
• Comparison of COX1 and COX2
• Uses and limitations of selective vs non-selective COX inhibitors

This quiz explores essential concepts in pharmacology related to anti-inflammatory agents, including the differences between COX-1 and COX-2 enzymes, risks of non-selective NSAIDs, and the mechanism of action of paracetamol. It also addresses appropriate treatments for asthma and indications for steroidal anti-inflammatory agents.