RCSI BMF Immunopharmacology of Anti-inflammatory Agents PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Class Year 1 Course BMF Title Immunopharmacology of anti-inflammatory agents Lecturer Prof Will Ford 337 Da...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Class Year 1 Course BMF Title Immunopharmacology of anti-inflammatory agents Lecturer Prof Will Ford 337 Date November 2024  Learning outcomes 1. Appreciate drug treatment approaches for acute versus chronic inflammation 2. Discriminate between steroidal and non-steroidal anti-inflammatory approaches 3. Outline the actions of anti-inflammatory steroids and their indicated populations 4. Compare the actions of COX1 and COX2 5. Describe the uses and limitations of selective versus non-selective COX inhibitors RECAP: Acute inflammation…causes and LO: 1 process? TRIGGER VASCULAR RESPONSECELLULAR RESPONSE Neutrophils (PMNs)  the key immune cells in acute   inflammation Lots of pro- inflammatory x mediators are involved!  LO: 1 RECAP: Local and acute systemic effects of acute Symptom Cause inflammation Heat (“calor”) Increased blood flow Redness Leakage of fluid IL-1, TNFa, IL-6 produced locally (“rubor”) (esp. by macrophages) Swelling Leakage of fluid and proteins; (“tumor”) Increased blood flow; Release of inflamm. mediators Pain (“dolor”) Chemical mediators; Exudates press on pain Act on hypothalamus Act on liver receptors (esp. IL-1) (esp. IL-6) Loss of function Pain; (“function Swelling; laesa”) Disrupted tissue structure Fever Synthesis of acute phase proteins (eg. C-reactive protein) 25 BCE-50CE  LO: 1 Inflammation, pain and local mediators Local mediators Pain & inflammation Prostaglandins and These local mediators are secreted by leukotrienes immune cells Platelet activating factor (PAF) They are responsible for the symptoms of Histamine inflammation (eg. vasodilation) 5-hydroxytryptamine Pain occurs when inflammation occurs Neuropeptides near a nerve fibre Nitric oxide Bradykinin Adenosine and purines Complement Cytokines RECAP: Inflammatory pain Inflammatory mediators such as PGs, 5HT and bradykinin sensitise pain fibres Rather than cause pain they sensitise pain fibres making them more likely to respond to  RECAP: Chronic inflammation Active inflammation Trigger (eg. persistent or unresolved Response  tissue All occurring infections, chemicals, damage autoantigens… etc) together! Tissue repair (incl. fibrosis) Examples: Key players in Rheumatoid arthritis chronic Atherosclerosis & heart disease x inflammation MACROPHAGES, Chronic obstructive pulmonary disease (CO Crohn’s disease lymphocytes, Asthma plasma cells Lupus  Psoriasis Cancer Type II diabetes  LO: 1 Acute versus chronic inflammation – simplified! e: inflammation is usually a solution to an insult (infection, damage etc) Chronic: inflammation itself is the problem  LO: 1 The good, the bad and the ugly Acute inflammation is the response to infection or trauma Vasodilation allows immune cells access the site of infection *Inflammation also triggers healing* Acute inflammation must be terminated which is achieved by the production of resolvins Failure to terminate inflammation leads to chronic inflammation  LO: 2 Anti-inflammatory drugs Anti-inflammatory drugs provide symptomatic relief (eg. reduce pain and fever) Ideally used as temporary measure until underlying disease is brought under control Acute inflammation can be treated with non-steroidal anti-inflammatory drugs (NSAIDs) or steroids….but may not always need treatment Chronic inflammation can be treated with combinations of NSAIDs, steroids, biologic agents to target individual cytokines or immune cells The longer any anti-inflammatory agent is used (e.g. during chronic inflammatory conditions like rheumatoid arthritis or gout), the higher the risk of developing side effects  LO: 3 Steroids versus non-steroidals? Steroids are immunosuppressive, NSAIDs are anti-inflammatory Steroid examples: cortisol (endogenous), cortisone, prednisone, prednisolone, dexamethasone Indicated in patients with lupus, asthma, COPD, inflammatory bowel disease and other chronic inflammatory conditions Contra-indicated in patients with active infection, depression or alcohol dependence, highWhy?? blood pressure, diabetes, heart failure  LO: 3 Steroid hormones Glucocorticoids – cortisol affects carbohydrate and protein metabolism Mineralocorticoids – aldosterone salt retaining activity, synthesized by Zona glomerulosa Androgens – male sex hormones Oestrogens – female sex hormones  LO: 3 Corticosteroids and the HPA axis Hypothalamus CRH (CRF) Pituitary - ACTH Adrenal glands Cortisol Glucocorticoid receptors in multiple downstream cells and tissues Eg. immune cells, bone, liver, fat tissue  LO: 3 Corticosteroid mechanism of action  LO: 3 Glucocorticoids Inhibit phospholipase A₂ – Increase annexin A-1 production Reduce the production of IL-1 and 2, interferon, prostaglandins and leukotrienes Decrease in basophils, eosinophils and monocytes but increase in neutrophils Circulating lymphocyte number is also reduced – (reduction in T > B; CD4+ > CD8+) Adverse effects on carbohydrate metabolism*  LO: 3 Use of glucocorticoids Replacement therapy – Addison’s disease Anti-inflammatory treatment (Allergies, eczema, psoriasis, asthma, rheumatoid arthritis, ulcerative colitis, IB) – Inhaled – beclomet(h)asone, fluticasone – Topical – hydrocortisone, clobetasol – Oral - prednisone ADVERSE EFFECTS  Cushingoid syndrome – Having the appearance of making too much cortisol - facial puffiness and weight gain  Osteoporosis  Poor wound healing From Damjanov, 1996.  LO: 4 Non-steroidal anti- inflammatory drugs NSAIDs are used to treat inflammation Act to inhibit cyclooxygenases and, hence, prostaglandin production Are anti-inflammatory, analgesic and anti-pyretic Include aspirin (irreversible), ibuprofen, indomethacin, diclofenac NSAIDs and the arachidonic pathway LO: 4 NSAIDs NSAIDs TxA2 Vasoconstriction Vasodilation Bronchoconstriction Eur J Immunol, 51 (10) 2399-2416, DOI: (10.1002/eji.202048909) Cyclooxygenases act on LO: 4 AA Two COX (PGH synthase) enzymes exist COX-1 expressed constitutively “housekeepeing” COX-2 induced by shear stress, growth factors, tumour promoters, and cytokines  No …as do lipoxygenases ta n AL O One 5-LOX gene Requires FLAP Present in leukocytes, hence “leukotrienes” Involved in asthma, anaphylactic shock, and cardiovascular disease  LO: 4 Each eicosanoid has many functions  LO: 4 functions and creating several drug targets  LO: 4 Termination of inflammation omega-three Eicosapentaenoic acid (EPA) E type resolvins polyunsaturated fatty acids Docosahexaenoic acid (DHA) D type resolvins  LO: 4 Mechanism of COX inhibition COX enzymes are homodimers Inhibition of one site makes the dimer inactive* Aspirin covalently modifies COX COX can be protected by co- administration of a reversible inhibitor  LO: 5 NSAID range of selectivity It was thought that selective COX-2 inhibitors would remove the adverse effects Rofecoxib was withdrawn from the market in 2004 Stroke Myocardial infarction  Manipulating aspirin LO: 5 dosage to achieve platelet specificity 75mg Aspirin 325mg Aspirin Inhibits all Inhibits prostaglandin prostaglandin synthesis by 10-20% formation in body Most cells will recover Most cells, except within 4-8 hours platelets, will recover Platelets will remain within 4-8 hours by inhibited for their lifespan de novo synthesis of Daily dosage will cumulatively COX inhibit all platelet COX but non- platelet COX will only be Repeated minimally affected administration is Gastric ulceration (and other likely to cause side effects) is less likely to Manipulating aspirin LO: 5 dosage to achieve platelet specificity 120 Platelets Other cells 100 80 % COX activity 60 40 20 0 0 10 20 30 40 50 Days  LO: 5 Effectiveness of aspirin Decreases incidence of death following MI by ~ 25% Has additive effect with heparin (not shown) Has additive effect with thrombolytic agents such as tPA or streptokinase (see later) Primary prevention in patients for whom the risk of future vascular events is ≥ 0.6% per year and who are not at increased risk of gastrointestinal bleeding (≥ 0.1% per year).  LO: 5 Side-effects of aspirin Excessive bleeding ‒ due to reduced platelet function Gastrointestinal (GI) haemorrhage ‒ increase acid production Reye’s syndrome in children* ‒ acetylation of liver proteins Aspirin is the only NSAID with potent and specific antiplatelet effects - other NSAIDs are reversible  LO: 5 Two COX iso-enzymes are known In terms of their molecular biology, COX-1 and COX-2 are very similar (also a “COX-3” which is a splice variant of COX-1) 65% amino acid homology and near-identical catalytic sites The replacement of isoleucine at position 523 in COX-1 with the smaller valine in COX-2 allows access to a hydrophobic pocket, and selective drugs - coxibs  LO: 5 Coxibs COX-2 selective inhibitors: celecoxib, rofecoxib Developed to protect against gastric ulceration – Have similar efficacies to that of the non- selective inhibitors, but the GIT side effects are decreased by ~50% Significant increase in myocardial infarction (MI), stroke, and death from a vascular event Rofecoxib (trade name, Vioxx) was taken off  LO: 5 VIGOR – clinical trial (CV results) COX selectivity COX-2 COX-1 Rofecoxib Naproxen Relative Risk Event Category N=4047 N=4029 (95% CI) Confirmed CV events 45 (1.7) 19 (0.7) 0.42 (0.25 - 0.72) Cardiac events 28 (1.0) 10 (0.4) 0.36 (0.17 - 0.74) Cerebrovascular events 11 (0.4) 8 (0.3) 0.73 (0.29 - 1.80) Peripheral vascular events 6 (0.2) 1 (0.04) 0.17 (0.00 - 1.37) Patients with Events (Rates per 100 Patient- Source: Data on file, MSD Years)  LO: 5 COX-2 and cardiovascular disease Selective COX-2 inhibition is associated with reduced prostaglandin I₂ (PGI₂ / prostacyclin) production by vascular endothelium Little or no inhibition of potentially prothrombotic platelet thromboxane A₂ production Therefore, an exaggerated prothrombotic effect will be observed in patients treated chronically with coxibs! Fitzgerald GA Coxibs and cardiovascular disease. N Engl J Med. 2004 Oct 21;351(17):1709-11. PMID:15470192  NSAIDS and LO: 5 cardiovascular disease All NSAIDS increase cardiovascular risk – Naproxen the least The increased risk is dose-dependent Avoid NSAID use in patients at high risk of cardiovascular event When using – use lowest dose for shortest period  LO: 5 Paracetamol / acetaminophen Not an NSAID as it is only used for fever and pain and not inflammation MOA is unclear with multiple theories – COX-3 (COX-1 splice variant)? – Its metabolite AM404 activates TRPA1 in the spinal cord producing anti-nociceptive response Still has CV, GI and renal risks  LO: 5 NSAIDs – what happens to AA? NSAIDs block conversion of arachidonic acid to prostaglandins Excess arachidonic acid is diverted to lipoxygenase (LOX or 5-LO) pathway LOX produces leukotrienes which cause bronchoconstriction  No ta Leukotrienes n AL O Released by leukocytes, leukotrienes are proinflammatory  No ta Anti-leukotrienes n AL O Inhibition of leukotriene synthesis – Zileuton Inhibition of leukotriene receptor – Zafirlukast – Montelukast Used for asthma – Not as effective as inhaled steroids Veliflapon (FLAP inhibitor) in clinical trials to prevent CV events Anti-leukotriene drugs No ta n AL O Both zileuton and zafirlukast are used in the treatment of asthma Not first-line treatment Do not reverse bronchoconstriction “Preventers” rather than “relievers”  Targeting cytokine LO: 5 signalling Basiliximab TNF inhibitors – target (Simulect®) the signalling molecule mAb acts as an IL-2 R – Infliximab – Crohn’s, antagonist ulcerative colitis – Used following organ – Etanercept, Adalimumab transplants to prevent – RA rejection  Perspectives Immune responses are a double-edged sword…. protective inflammation can turn into destructive inflammation There is no single perfect approach for pharmacological management of inflammation Eliminating inflammation carries its own risks!  What we have learned 1. Appreciate drug treatment approaches for acute versus chronic inflammation 2. Discriminate between steroidal and non-steroidal anti-inflammatory approaches 3. Outline the actions of anti-inflammatory steroids and their indicated populations 4. Compare the actions of COX1 and COX2 5. Describe the uses and limitations of selective versus non-selective COX inhibitors