Rheumatology Flashcards
Corticosteroid ADRs
Cushingoid presentation Growth retardation Cataracts Osteoporosis Avascular necrosis Infection Psychiatric disorders
Corticosteroids mechanism
Prevent IL-1 and IL-6 production by macrophages
Inhibit all stages of T-cell activation
Azothioprine uses
Maintenance therapy in SLE and vasculitis.
IBD
Bullous skin diseases
Atopic dermatitis
Azathioprine mechanism
Cleaved to 6-mercaptopurine (6-MP)
This is an anti metabolite
Reduced DNA and RNA synthesis
Azathioprine metabolism
6-MP metabolised by TMPT
Gene is highly polymorphic
Myelosuppression risk in those with low/no TMPT.
Azathioprine ADRs
Hepatitis
Infection
Increased risk of malignancy
Myelosuppression
Ciclosporin mechanism
Binds to cyclophillin protein
Inhibits calcineurium
Prevents IL-2 production in T-helper cells
Tacrolimus mechanism
Binds to tacrolimus binding protein
Inhibits calcineurium
Prevents IL-2 production in T-helper cells
Uses of ciclosporin and tacrolimus
Transplant mechanism
Atopic dermatitis
Psoriasis
RA and SLE patients with cytopaenias (no effect on bone marrow)
Ciclosporin and tacrolimus ADRs
Hyperuricaemia Hypertrichosis Gingival hyperplasia GI complaints Hyperlipidaemia Nephrotoxicity Hypertension
Mycophenolate mofetil mechanism
Inhibits inosine monophosphate dehydrogenase - required for guanosine synthesis
Impairs B and T cell proliferation
Spares other rapidly dividing cells, as they have guanine salvage pathways
Mycophenolate mofetil uses
Transplantation
Lupus nephritis
Mycophenolate mofetil ADRs
Myelosuppression
GI
Risk of toxicity in hepatic or renal failure
Ciclosporin and tacrolimus DDIs
CYP450 metabolism
Cyclophosphamide mechanism
Alkylating agent
Cross linking prevents DNA replication
Suppresses B and T cell activity
Cyclophosphamide uses
Haematological malignancies
Lupus nephritis
Wegeners granulomatosis
Polyarteritis nodusum
Cyclophosphamide pharmacodynamics
Pro-drug converted by CYP450 to active forms
Active metabolites- 4-hydroxycyclophosphamide, aldophosphamide
Acrolein- toxic to the bladder, causes haemorrhagic cystitis.
Excreted by kidney
Cyclophosphamide ADRs
FBCs
Infertility
Lymphoma, leukaemia
Bladder cancer
Methotrexate mechanism
Inhibits dihydrofolate reductase
Prevents purine and thymidine synthesis-toxic in the S-phase, so worse for rapidly dividing cells
Role unclear in non-malignant disease-not via antifolate action, possibly a build up of adenosine causing GPCR signalling to reduce activity of T cells
Methotrexate uses
Gold standard for RA Malignancy Psoriasis Crohns Unlicensed in inflammatory myopathies, vasculitis, steroid sparing in asthma
Methotrexate pharmacokinetics
Can be administered PO, IM, SC Weekly dosing - active metabolites (polyglutamates) have long half lives (but own T1/2 8 hrs) 50% protein bound - displaced by NSAIDS Renal excretion Oral bioavailability 13-76%
Methotrexate ADRs
Mucositis and myelosuppression - reduced by folic acid supplements Pneumonitis Infection Teratogenic, abortifacient Hepatitis, cirrhosis
Sulphasalazine and mesalazine mechanism
Conjugate of a salicylate and a sulfapyridine molecule
Salicylate is anti inflammatory
Sulphapyridine fights infection
T-cell - inhibit proliferation, promote apoptosis, prevent IL-2 production
Neutrophil - reduced chemotaxis, reduced de granulation
Sulphasalazine and mesalazine metabolism
Cleaved in large bowel, so good for IBD
Sulphapyridine absorbed
Salicylate largely unabsorbed
Sulphasalazine and mesalazine ADRs
Rash
Hepatitis
GI
Myelosuppression
Anti TNF therapy uses
Clinically active RA
Withdrawn if no improvement/adverse effect within 6 months
Anti TNF therapy effects
Reduced inflammation
Reduced angiogenesis
Reduced joint destruction
Adolimumab
Etanercept
Ifliximab
Anti TNF
Rituximab
Monoclonal antibody against CD20
