Drugs used for the treatment of autoimmune disease Flashcards
(29 cards)
Non-steroidal anti-inflammatory drugs
Cyclooxygenase inhibitors
leads to inhibition of prostaglandin synthesis
- anti-inflammatory effects
- analgesic effects (reduction in pain)
- antipyretic effects (reduction of body temperature)
Effects of prostaglandins
- powerful vasodilation
- decrease in blood flow
Cyclooxygenase
Two isoforms:
COX-1
COX-2
COX-1
expressed in most tissues
house keeping role involved in tissue homeostasis
COX-2
expression induced in activated inflammatory cells
expression induced by cytokines IL-1 and TNF-alpha (pro-inflammatory signals)
Anti-inflammatory action of NSAIDs is due to
inhibition of COX-2
Non-selective NSAIDs
Aspirin
Ibuprofen
Paracetamol
COX-2 inhibitors
NO DIRECT EFFECT on immune processes that contribute towards tissue damage (ie accumulation of inflammatory cells is not reduced) → do not inhibit T cell activation, release of cytokines or ROS, they relieve symptoms of autoimmune disease so the disease will still progress
Reduce vasodilation, oedema and pain
COX enzyme
long channel and circular catalytic centre
arachidonic acid travels down channel, enters active site and binds to enzyme
catalyses conversion of arachidonic acid to prostaglandin E2
prostaglandin E2 has a lower affinity for the enzyme, travels back down channel and released into body cells
Non-selective NSAIDs - mechanism
NSAIDs interact with binding site in channel of cyclooxygenase - found in both COX-1 and 2
binding blocks substrate from travelling down channel
prevents substrate activating enzyme
stops production of mediator of prostaglandins
Mechanism of COX-2 selectivity
COX-2 has wider channel and additional binding site for drugs
- made drug bigger so it no longer fit in COX-1 channel → induced COX-2 selectivity
- created drugs with side chain that interacts with second binding site in COX-2 → increased potency of drug as drug now has two binding sites to react with
Common adverse effects of NSAIDs
- Gastric irritation
- Effect on renal blood flow
- A tendency to prolong bleeding through inhibiting platelet function
- Increased likelihood of thrombotic events including myocardial infarction (especially COX-2 selective drugs – through inhibiting
prostaglandin I2) → several of the drugs were removed from market due to this reason
Immunosuppressant drugs
Interact directly with immune system, blocking activation and proliferation of T-cells and release of mediators from macrophages
Cyclosporin
Inhibits IL-2 production
Corcitosteroids
inhibit cytokine gene expression
Azathioprine
inhibit purine or pyrimidine synthesis, interfering with DNA replication
Cyclosporin mechanism of action
Deceased proliferation of T-cells by inhibiting IL-2 release
Reduces function of effector T-cells that secrete cytokines, which mediate autoimmune reactions
Cyclosporin binds to a cytosolic protein in T-cells called CYCLOPHILIN
Inhibits transcription factor activation and synthesis of IL-2
Glucocorticoids
Adrenal steroids – endogenous substances that maintain a low level of anti-inflammatory action
Main drugs include: hydrocortisone, prednisolone and dexamethasone
Powerful anti-inflammatory and immunosuppressive agents
Through the suppression of many genes → suppressing gene transcription and protein synthesis
Actions of glucocorticoids on inflammatory cells
Reduced activity of macrophages by decreasing gene transcription
of cytokines (Il-2, TNFalpha, IFN-gamma)
Deceased action of helper T-cell by decreased proliferation → need protein synthesis, stops T cells dividing
Decreased production of cytokines involved in inflammation
Decreased production of nitric oxide, histamine and prostanoids → these mediators are synthesised by enzymes, glucocorticoids block production of the enzymes and hence block production of mediators
OVERALL, this leads to a reduction in chronic inflammation and
Autoimmune reactions
Glucocorticoids - mechanism of action
Bind intracellular cytoplasmic glucocorticoid receptors that then dimerize
Activates receptor to undergo conformational change
Exposes DNA binding domain
Steroid-receptor complex translocates to nucleus
Interacts with glucocorticoid response elements, Fos/Jun or NFkappaB to modify gene transcription
Azathioprine
Interferes with purine synthesis and is cytotoxic
Widely used for immunosuppression for control of tissue rejection in transplant surgery
Azothioprine (pro-drug) is metabolised: → mercaptopurine
Mercaptopurine - Purine analogue that inhibits DNA synthesis → interferes with natural DNA synthesis
SINCE, DNA synthesis is required for T-cell proliferation, azothioprine can also be used to inhibit cell-mediated immune reactions
Antirheumatoid drugs
Immunosuppressants
Glucocorticoids
NSAIDS – reduce symptoms but do not retard the progress of the disease
Disease modifying anti-rheumatoid drugs
Effects of disease-modifying anti-rheumatoid drugs
- Improve symptoms and reduce disease activity
- swollen and tender joints
- pain
- disability
Often used as second line treatment since they are slow in onset - sometimes takes months before seeing clinical benefit
Initially taken alongside immunosuppressants and NSAIDs
Sulfasalazine
Produces remission in rheumatoid arthritis
Thought to work via reducing activity of phagocytes (macrophages / neutrophils) by scavenging ROS and / or nitric oxide → exact mechanism not fully defined
-reducing amount of mediators circulating around joints is beneficial for autoimmune disease
