Pharm: Rheumatoid arthritis Flashcards
What is the radiological manifestation of rheumatoid arthritis?
Severe inflammation in proximal metacarpophalangeal joints with relatively little inflammation of distal interphalangeal joints.
What are the therapeutic goals in rheumatoid arthritis?
Preserve function
Prevent pain
What happens in rheumatoid arthritis?
Inflammation of synovial membrane takes place and infiltration of the membrane with macrophages, T and B lymphocytes, fibroblasts, and other inflammatory cells.
This disorder is autoimmune and is caused by T-cells reacting to normal tissue being presented by APC and proliferating/being activated and activating some B lymphocytes and macrophages.
What drugs are used for rheumatoid arthritis and what is their mechanism of action?
To cancel the effect of T-cell proliferation and function:
Methotrexate
Leflunomide
Glucocorticoids
To counter macrophage function:
TNF-alpha inhibitors
Glucocorticoids
Mode of action uncertain:
Sulfasalazine
Hydroxychloroquine
What is the function of TNF-Alpha?
Aggregates as trimers and acts on:
Endothelial cells: Adhesion receptors for leukocytes
Lymphocytes: Activation, proliferation
Macrophages themselves: activation
Antigen presenting cells: Maturation and migration
Some tumour cells: Apoptosis
What is the evidence of TNF-alpha inhibitors working to protect from progression of rheumatoid arthritis?
Women who were given TNF-alpha inhibitors had a lower sharps store after 2 years.
What types of molecules are used to inhibit action of TNF-alpha?
anti-TNFalpha antibodies
Soluble TNF-receptors
What are the anti-TNFalpha antibodies called?
Infliximab (human and mouse sequences are modified to minimise human antigenicity)
Adalimumab (Completely humanised Fab sequence)
Why is minimising human antigenicity of antibodies so important?
Prevents the immune system from clearing out the antibodies before they can carry out their function.
How are antibody drugs named?
Adalimumab
(Ada) - no origin
(lim) - refers to system it is working on (Immune system)
(u) - Human derived
(mab) - monoclonal antibodies
What are the limitations/adverse effects of TNF-alpha use for RA?
Immune suppression:
Increased infection rate, including some infections only seen in immunosuppression.
Particular risk in people with dormant tuberculosis
Increased rate of some malignancies
Another limitation is the cost TNFalpha inhibition can cost 24617$ per year per person!
How do glucocorticoids work in protecting against RA?
They suppress lymphocyte and macrophage function.
How is dexamethasone different to prednisolone and why is that useful?
Dexamethasone has a Fluoride group which makes it much more potent due to extended half life.
How do glucocorticoids work?
They bind to circulating corticosteroid binding globulin in the blood to be transported before entering the cell.
Steroid then binds to a cytosolic receptor which translocates to the nucleus
Steroid-receptor complex binds recognition sequences on promoter of responsive genes stimulating transcription.
What do glucocorticoids do?
Suppress inflammation by suppressing the action of:
Macrophages and cytokines including TNFalpha and other proinflammatory functions.
T-lymphocyte recruitment and proliferation
B-lymphocytes from producing antibodies
What conditions are glucocorticoids administered for?
Autoimmune diseases
Allograft tolerance
Asthma
Dermatitis
Ulcerative colitis
Inflammatory arthritis and other
How are glucocorticoids used?
Sparingly due to the adverse metabolic and mineralocorticoid effects.
Commonly used systemically early in treatment
They are typically injected into joints
What does methotrexate do?
It resembles folic acid and inhibits nucleic acid synthesis by inhibiting dihydrofolate reductase (DHFR).
It acts as an antiproliferative drug.
What are the risks with using methotrexate?
It’s antiproliferative actions impact bone marrow (neutropaenia, thrombocytopaenia) and gut.(Mouth ulcers and GI upset)
Teratogenic risk (high doses embryotoxic)
Hepatotoxicity and pulmonary fibrosis
MTX is mostly renally excreted so ensure renal function is good.
What does leflunomide do?
Blocks dihydroorotate dehydrogenase which is in the pathway of pyrimidine synthesis. This drug is antiproliferative and is presumed to act on T cells.
What are the limitations to using leflunomide?
It is a teratogen with long half life. Takes long time before it is harmless in childbearing aged women.
Should be avoided in young women or reliable contraception
It is hepatotoxic
How can pain be controlled in RA?
By controlling the prostaglandins being released by macrophages in inflamed tissue.
NSAIDs can do this by blocking prostaglandin synthase/cyclo-oxygenase inhibitors
Does inhibiting prostaglandin production reduce progression of the disease?
No it suppresses signs of inflammation and pain but disease still progresses unless treated another way
How are the different forms of treatment combined together for treating RA?
MTX or leflunomide
Add hydroxychloroquine, sulfasalazine
Add biological agent like anti-TNF-alpha
Low-dose systemic glucocorticoids commonly used in early phase when pursuing remission
Cyclooxygenase inhibitors (NSAIDs) for analgesia and acute anti-inflammatory action
How is RA managed non-pharmacologically?
Protection of joints (splints)
Management of CV risk
General functional support to compensate for disability
Psychological support
