Exam Notes

Analgesics, Anti-inflammatories, and Immunosuppressants

Overview

• Analgesics treat pain, anti-inflammatories reduce inflammation, and immunosuppressants suppress the immune system.
• Glucocorticoids (GCs) have anti-inflammatory effects but also adverse effects.
• Disease-modifying anti-rheumatoid drugs (DMARDs) include methotrexate and sulfasalazine.
• Immunosuppressants include anti-IL2 drugs and inhibitors of DNA synthesis.
• Treatments for gout are also addressed.

Pain, Inflammation, and the Immune System

• Pain types: nociceptive, inflammatory, neuropathic.
• Inflammatory pain: normal response to injury, becomes chronic if unresolved.
• Chronic inflammation: often autoimmune, involves cytokines.
• Overlap: analgesics ↔ anti-inflammatories ↔ immunosuppressants.

Glucocorticoids

• Powerful anti-inflammatory drugs (corticosteroids).
• Mimic endogenous glucocorticoid hormones.
• Examples: hydrocortisone, prednisolone, dexamethasone, betamethasone.
• Suppress both innate and adaptive immune systems.
• Effective against all inflammatory reactions, irrespective of cause.

Glucocorticoid Mechanisms of Action

• Main mechanism: alter gene expression in the nucleus (slow).
• Bind to glucocorticoid receptor, dimerization, translocation to the nucleus, binds to GRE.
• Modify expression of many genes.
• Cytosolic effects (rapid): interaction with NF-kB, release of annexin 1.

Anti-inflammatory Effects of GCs

• Decreased extravasation of neutrophils.
• Decreased generation of cytokines (IL-1 to IL-8, TNF-{\alpha}).
• Decreased production of prostanoids via COX2 inhibition.
• Decreased clonal expansion of T-cells.
• Decreased expression of cell adhesion molecules.
• Increased synthesis of anti-inflammatory factors (e.g., IL-10).

Adverse Effects of GCs

• Not suitable for long-term use.
• Suppression of response to injury/infection.
• Cushing’s syndrome.
• Osteoporosis, Hyperglycaemia.
• Redistribution of body fat and muscle wasting.
• Sudden withdrawal → rebound adrenal insufficiency.

Rheumatoid Arthritis

• Common chronic inflammatory condition.
• Joints become swollen, painful, deformed.
• Autoimmune reaction involving cytokines (TNF-{\alpha} and IL-1).
• Treated with NSAIDs, DMARDs, and anti-cytokine agents.

Range of DMARDs

• NSAIDs relieve symptoms, DMARDs halt/reverse the disease.
• Slow onset of effect.
• Examples: methotrexate, sulfasalazine, gold complexes, antimalarials.

DMARD Mechanisms of Action

• Methotrexate: folate antagonist, inhibits purine metabolism, reduces cytokine production.
• Sulfasalazine: blocks superoxide generation, inhibits prostanoid synthesis, reduces IL-8 release.

Effects of other DMARDs

• Penicillamine: decreases immune response and IL-1 generation.
• Gold complexes: accumulates in synovial cells, mechanism unknown.
• Anti-malarials: chloroquine and hydroxychloroquine, mechanism of action unknown.

Anti-cytokine Agents

• Anti-IL2 agents: suppress T-cell activation.
• Anti-TNFs: monoclonal antibodies against TNF-{\alpha}.
• Anti-IL1{\beta}: anakinra (recombinant IL-1Ra).

Biologicals used in inflammatory disorders

• A table adapted from Rang & Dale’s Pharmacology, 9th edition, 2020, listing biologicals used in inflammatory disorders such as ankylosing spondylitis (AS), Crohn’s disease (CD), severe gout (G), psoriatic arthritis (PA), plaque psoriasis (PP), psoriasis (PS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE)

Mechanisms and treatment of RA

• Diagram illustrating the mechanisms and treatments of rheumatoid arthritis, highlighting the roles of T cells, macrophages, cytokines (IL-1, TNF-{\alpha}), and various drugs (anti-IL-2 agents, immunosuppressants, methotrexate, glucocorticoids, anti-TNF and IL-1 agents, DMARDs).

Immunosuppressants

• Used in autoimmune disease and to prevent transplant rejection.
• Impair immune system; risk of infection and malignancy.
• Act in the induction phase of immune response.
• Three main classes: inhibit IL-2 action, inhibit cytokine gene expression, inhibit DNA synthesis.

Anti-IL2 Immunosuppressants

• Ciclosporin: binds to cyclophilin, inhibits calcineurin, reduces IL-2 expression.
• Tacrolimus: similar effect but more potent, binds to FK-binding protein.

Other Immunosuppressants

• Azathioprine: interferes with purine synthesis, inhibits DNA/RNA synthesis.

Treatment of Gout

• Metabolic disorder; deposition of urate crystals in joints.
• Treated with NSAIDs & glucocorticoids.
• Selective drugs: allopurinol, probenecid, colchicine.

Summary

• Continuum of drugs for pain, chronic inflammation, and immune disorders.
• Glucocorticoids are major anti-inflammatory drugs.
• DMARDs used in rheumatoid arthritis.
• Immunosuppressants used in rheumatoid arthritis, cancer, and organ transplant.
• Treatments for gout reduce uric acid synthesis.