Flashcards in Session 6 - Autoimmunity Deck (53)
What is autoimmunity?
the state that is present when an individual has made an immune response to self-antigens.
What can aid in the diagnosis of autoimmunity?
the presence of autoantibodies in serum provides evidence for autoimmunity, and these may be helpful in diagnosing and monitoring autoimmune diseases.
What does autoimmune disease mean?
the term applied to a disease in which autoimmunity is thought to play a significant pathogenic role.
What are two overall categories of autoimmune disease?
Organ specific (target antigen in one specific tissue) vs Non-organ specific (if target antigen in many different tissues)
Give some organ specific autoimmune diseases
Chronic atrophic gastritis
Diabetes mellitus (type 1)
Premature ovarian failure
Give some mixed autoimmune diseases
Primary biliary cirrhosis
Autoimmune haemolytic disease
Give some non-organ specific immunse diseases
Systemic Lupus Erythematosus
Progressive systemic sclerosis
Name some immunosupressant categories of drugs
Cytotoxic alkylating agents
What is the mechanism of action of glucocorticoids
Diffuse into cytoplasm and bind receptor. Complex moves to nucleus and binds Hormone Response Element (HRE). Inducers/Inhibits transcription.
Give three examples of glucocorticoids
Hydrocortisone (Cortisol) (Oral for replacement, IV for status asthmaticus and anaphylactic shock)
What are the indications for glucocorticoids?
Replacement of endogenous corticosteroids
What are the contraindications for glucocorticoids?
Give five adverse drug reactions of glucocorticoids
Suppression of HPA axis
Suppression of growth in children
Mineralocorticoid effects if the glucocorticoid also has those actions
Why should long term therapy with glucocorticoids be withdrawn slowly?
Long term therapy must be withdrawn slowly, due to HPA suppression
What is the mechanism of action of azathioprine?
Azathioprine is a pro-drug, which is converted into 6-Mercaptopurine in the liver
6-Mercaptopurine is a fraudulent purine nucleotide that impairs DNA synthesis and has a cytotoxic action on dividing cells
What are four indications for azathioprine?
Rheumatoid Arthritis, Inflammatory Bowel Disease
Prevention of graft and transplant rejection
Autoimmune conditions where corticosteroid therapy alone inadequate
What is the route of administration for azathioprine?
Oral / IV
What are three adverse drug reactions for azathioprine?
Myelosuppression Leukopenia, thrombocytopenia, anaemia
Increased infection susceptibility
GI disturbances (nausea, vomiting, diarrhoea)
Give a drug interaction with azathioprine
Interacts with Allopurinol (treats gout), necessitates lowering of dose
Give a therapeutic note for the use of azathioprine
6-Mercaptopurine is eliminated by the enzyme TPMT, which is subject to a high rate of genetic polymorphism. High levels of TPMT expression will lead to under-treatment, low levels of TPMT expression gives toxicity.
What is the mechanism of action of cytotoxic alkylating agents
Pro-drug, that is activated by CYP450s.
Alkylating agent, which creates cross-links in DNA so that it cannot replicate. Therefore it selectively acts on cells with a higher mitotic rate.
Give a cytotoxic alkylating agent
Give an indication for cytotoxic alkylating agents
Give a contraindication for cytotoxic alkylating agents
Give an adverse drug reaction for cytotoxic alkylating agents
Induction of bladder cancer (urine concentration of acrolein metabolite)
Lymphoma and Leukaemia
Infertility & Teratogenesis
Give a drug-drug intteraction for cytotoxic alkylating agents
Pro-drug is activated by CYP450s (inducers/inhibitors)
What is the mechanism of action of Calcineurin Inhibitors
Reduction in IL-2 synthesis and release, via Calcineurin inhibition suppressing both cell-mediated and antibody-specific adaptive immune responses. Active against T helper cells.
Ciclosporin binds to Cyclophilin and Tacrolimus binds to Tacrolimus-Binding-Protein
Drug/Protein complexes bind to and inhibit Calcineurin, which normally has a phosphatase activity on the Txn factor for IL-2. Therefore, inhibition of Calcineurin reduces IL-2
What is the indication for Calcineurin Inhibitors
Prevention of graft and transplant rejection
Prevention of graft vs. host disease
Atopic dermatitis, psoriasis
Give two calcineurin inhibitors
Cyclosporin (Binds Cyclophilin)
Tacrolimus (Binds Tacrolimus-Binding-Protein)
Give three adverse drug reactions of calcineurin inhibitor
Nephrotoxic (proximal tubule), renal damage almost always occurs
Hypertension in 50% of people
What is a drug-drug interaction of calcineurin inhibitor ?
Metabolism is by CYP450, so is affected by inducers/inhibitors
Give a therapeutic note for calcineurin inhibitoprs
Unlike most immunosuppression agents, Cyclosporin does not cause myelosuppression
What is an indication for Mycophenolate Mofetil
Transplant immunosuppression (agent of choice)
What is a mechanism of action for Mycophenolate Mofetil
Inhibits the enzyme Inosine Monophosphate Dehydrogenase, which is required for Guanosine synthesis
Impaired B-cell and T-cell proliferation
What is an adverse drug reaction for Mycophenolate Mofetil
Myelosuppression Leukopenia, neutropenia
Increased risk of infection (especially viral)
What is a therapeutic notes for mycophenolate mofetil
Highly selective. Spares other rapidly dividing cells, due to the presence of guanosine salvage pathways
Name a couple disease modifying anti-rheumatic drugs (DMARDS)
Give an indication for methotrexate use
Immunosuppression and Cancer chemotherapy
Give a contraindication for methotrexate
Give four routes by which methotrexate can be administered
Orally, intravenously, intramuscularly, intrathecally
What is the mechanism of action for methotrexate?
Competitively antagonises Dihydrofolate Reductase (DHFR), preventing the regeneration of intermediates (tetrahydrofolate) essential for the synthesis of purines and thymidine, thus inhibiting DNA synthesis.
What is an adverse drug reaction to methotrexate? (5)
Increased infection risk
Give a drug-drug interaction for methotrexate
Adverse DDIs with drugs affecting renal blood flow and renal elimination, e.g. NSAIDs
What clinical monitoring should be carried out while on methotrexate?
Baseline chest X-ray, FBC, LFT, U+E + Creatinine
Monthly FBC, LFT, U+E + Creatinine
What should you be worried about if giving methotrexate with NSAIDs?
Plasma protein binding ~50% - NSAIDs displace, raising plasma concentration
How often is methotrexate given?
What do aminosalicylates treat,and how?
Inflammatory bowel conditions
Sulfasalazine is broken down in the gut to the active component 5-aminosalicylate (5-ASA) and sulfapyridine, which acts as a vehicle to transport the drug to the colon.
Inhibition of T-cell proliferation and IL-2 production. Reduced Neutrophil chemotaxis and degranulation.
What are some contraindications for aminosalicylates?
Give four adverse drug reactions of aminosalicylates
GI disturbances (Nausea, vomiting, abdominal pain)
Name two anti-tnf agents
Infliximab (Monoclonal Antibody)
Etanercept (Fusion protein)
Give a mechanism of action of tnf-a
Blocks the effects of TNF-α
Decreased inflammation, decreased Angiogenesis, decreased joint destruction
Give an adverse drug reaction of anti-tnf (4)