Autoimmune Treatment Flashcards
(37 cards)
What are the main drug classes used to treat autoimmune disease?
- Non-steroidal anti-inflammatory drugs (NSAIDs).
- Immunosuppressant drugs.
What are the main clinical effects of NSAIDs?
- Anti-inflammatory.
- Analgesic (reduce pain).
- Antipyretic (reduce body temperature)
What is the main mechanism of NSAIDs?
- Inhibit the enzyme cyclooxygenase (COX)
- This leads to reduced production of prostaglandins
What are the physiological effects of prostaglandins?
- Powerful vasodilation
- Decreased blood flow
What are common adverse effects of NSAIDs?
- Gastric irritation
- Reduced renal blood flow
- Prolonged bleeding due to inhibition of platelet function
- Increased risk of thrombotic events including myocardial infarction, especially with COX-2 selective drugs
Why were several COX-2 selective NSAIDs removed from the market?
• They increased the risk of thrombotic events by inhibiting prostaglandin I₂
What are the two types of cyclooxygenase?
- COX-1: expressed in most tissues, involved in homeostasis
- COX-2: upregulated in activated immune and inflammatory cells, induced by cytokines IL-1 and TNF-alpha
Why is COX-2 inhibition considered the anti-inflammatory mechanism of NSAIDs?
• Because COX-2 is induced during inflammation and contributes to inflammatory prostaglandin production
Which older NSAIDs are non-selective?
- Aspirin
- Ibuprofen
- Paracetamol
What do COX-2 selective NSAIDs treat, and what don’t they affect?
- Treat symptoms such as vasodilation, oedema, and pain
- Do not inhibit T-cell activation
- Do not inhibit cytokine or ROS release
- Do not reduce inflammatory cell accumulation
Why can autoimmune disease progress even with NSAID treatment?
• Because NSAIDs reduce symptoms but not the underlying immune processes
What is the problem with COX-1 inhibition in older NSAIDs?
• GI disruption is caused by inhibition of COX-1, which normally maintains gastrointestinal homeostasis
How do COX-2 selective drugs compare to COX-1?
- Less GI disruption
- More selective for inflammatory processes
- Used for treatment of inflammatory disorders
How does arachidonic acid interact with COX?
- Travels down a long channel in COX
- Binds to the catalytic centre
- Is metabolised into prostaglandin E2
- Prostaglandin E2 is released into cells
How do traditional NSAIDs block COX activity?
- Bind to a site in the COX channel
- Prevent arachidonic acid from reaching the catalytic site
- Block conversion to prostaglandins
What makes COX-2 selective NSAIDs specific?
- COX-2 has a larger channel and an extra binding site
- COX-2 selective drugs are larger and don’t fit into COX-1
- They bind both sites in COX-2, increasing potency and selectivity
How do immunosuppressants affect the immune system?
- Act directly on immune processes
- Mostly inhibit the induction phase of immune responses
- Inhibit T-cell proliferation
What mechanisms do immunosuppressants use?
- Inhibit IL-2 production (e.g. cyclosporin)
- Inhibit cytokine gene expression and protein synthesis (e.g. corticosteroids)
- Inhibit purine or pyrimidine synthesis, interfering with DNA replication (e.g. azathioprine)
What are clinical uses of immunosuppressants?
- Prevent organ transplant rejection
- Treat various autoimmune diseases
- Can suppress protective immune responses to infection
What is cyclosporin and how does it work?
- A cyclic peptide of 11 amino acids
- Inhibits IL-2 production
- Reduces proliferation of T-cells
- Binds cyclophilin in T-cells
- Inhibits transcription factor activation for IL-2
- Reduces effector T-cell function and cytokine secretion
What are glucocorticoids and how are they used?
- Endogenous adrenal steroids with natural anti-inflammatory effects
- Used as drugs: hydrocortisone, prednisolone, dexamethasone
- Suppress gene transcription and protein synthesis
- Broad immunosuppressive and anti-inflammatory effects
What are the actions of glucocorticoids on inflammatory cells?
- Reduce macrophage activity by suppressing cytokine gene transcription (e.g. IL-2, TNF-alpha, IFN-gamma)
- Reduce helper T-cell proliferation
- Decrease inflammatory cytokine production
- Inhibit nitric oxide, histamine, and prostaglandin production
What is the overall effect of glucocorticoids?
- Reduce chronic inflammation
- Suppress autoimmune responses
What is the mechanism of action of glucocorticoids?
- Bind to intracellular nuclear receptors
- When activated, receptors dimerize and undergo a conformational change that exposes a DNA binding domain
- Receptor migrates to nucleus
- Modify DNA transcription via glucocorticoid response elements and/or Fos/Jun and NF-kappaB
- Suppress protein synthesis
