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Immunosuppressants - Coggle Diagram
Immunosuppressants
Methotrexate
(cytotoxic agents)
Indications
: cancers, autoimmune disorders (e.g. RA), haematopoietic stem cell transplantation
PK
: IV & oral routes have good tissue distribution, oral bioavailability erratic at moderate-high doses, eliminated renally 90% unchanged (dose adjustment require if low eGFR)
MOA
: cytotoxic drug, folate antagonism (inhibits dihydrofolate reductase which reduces synthesis of purines & nucleic acids), suppresses inflammatory responses + cell activity & replication
Contraindications
: preexisting blood dyscrasias (e.g. neurtopaenia), existing renal/hepatic disease, previous/existing herpes/varicella infections, serous effusions (med concentrates in fluids), pregnancy or lactation
Adverse effects
: bone marrow suppression, mucosal ulceration, dermatological (alopecia, rash, pigmentation, urticaria), hepatotoxicity, nephropathy, hyperuricaemia, pulmonary pneumonitis
Other cytotoxic drugs: azathioprine, sulfasalazine, hydroxychloroquine, cyclophosphamide
Immunophilin Ligands
Indications
: prevention of rejection following solid organ transplant, prevention of GVH after allogenic stem cell transplant, autoimmune conditions
e.g. cyclosporine, tacrolimus, sirolimus (binds to FK-binding protein 12 - also anti-proliferative agent)
PK
: ciclosporin & tacrolimus - oral & IV; sirolimus - only oral
Ciclosporin - variable absorption (erratic bioavailability), metabolised by CYP3A4, victim of drug-drug interactions, TDM important
Toxicity
Ciclosporin & tacrolimus: nephrotoxicity (dose-dependent), hypertension, neurotoxicity, hyperglycaemia, hyperkalaemia, hyperlipidaemia, gingival hyperplasia, hirsutism (cyclosporin), alopecia (tacrolimus)
Sirolimus: hyperlipidaemia, hepatotoxicity, diarrhoea, myelosuppresion
Overview
Decrease the body's immune response & reduce ability to fight infection and other disease (e.g. cancer)
Used in organ transplant medicine to prevent rejection of BM or solid organs
Used in treatment of conditions caused by overactive immune response e.g. autoimmune conditions)
DMARDs / disease modifying antirheumatic drugs - they stop/slow the disease process of inflammatory forms of arthritis & other connective tissue diseases
Immune system
Essential for protection against pathogens
Examples of dysregulation: hypersensitivity reactions, autoimmune disorders, rejection of transplanted tissues, immunodeficiency
Innate immunity
: initiates defense against pathogens & antigenic insult, consists of complement, phagocytes, and NK cells + physical barriers (skin, mucous membrane, etc.)
Adaptive immunity
: if innate response is inadequate, adaptive response is mobilised, consists of T & B lymphocytes
Immunoglobulin-based therapies (biologics)
Examples:
IL-2 receptor inhibitors: Basiliximab
Anti-B-cell antibody: Rituximab
TNF-alpha inhibitors: Infliximab, Adalimumab, Etanercept
Adverse reactions
: hypersensitivity, serum sickness, generation of autoantibodies, risk of infections (TNF-alpha inhibitors = TB)
Indications
Anti-B-cell antibodies: RA, lymphoma
IL-2 receptor inhibitors: prevent organ rejection
TNF-alpha inhibitors: RA, psoriasis, Crohn's disease
HIGH COST
Mycophenolate mofetil (MMF)
Toxicity
: GI disturbances (N&V), myelosuppression (neutropaenia)
Indications
: sole agent for suppression in liver, kidney & heart transplant, combined with low-dose ciclosporin in renal transplant to prevent nephrotoxicity, other autoimmune disorders (lupus nephritis)
MOA
: Inhibits synthesis of purines required for DNA synthesis - T & B lymphocytes depend solely on inhibited enzyme for DNA synthesis
Glucocorticoids
(Prednisone)
MOA
: decrease sysnthesis of prostoglandins, leukotrience, cytokines; inhibits proliferation of T-lymphocytes (cytotoxic to some T-cells)
Indications
: immunosuppression after organ transplantation, treatment of haematological cancers, autoimmune disorders (RA, UC), asthma/COPD
Adverse effects
: adrenal suppression, Cushing's disease, osteoporosis, stunting, cataracts, muscle wasting, salt retention, glucose intolerance/diabetes, behavioural changes, insomnia, psychosis
Organ transplant meds
Tacrolimus OR Cyclosporin OR Sirolimus
MMF
Prednisolone (activated form of prednisone, does not require liver activation)