Imnosuppresants Flashcards
Immune dysregulation signs
Hypersensitivity
Autoimmune disorders
Rejection of transimplanted organs
Immunodeficiency
Immunosuppressants
- Corticosteroids eg prednisone
- Immunophilin ligands: Cyclosporine, tacrolisnus, sirolismus
- Mycophenolate mofetil
- Cytotoxic drugs: Azathioprine
-Antimetabolites: methotrexate, MMF, Azathioprine - Immunoglobulin based agents: Atanercept
Immune potentiators
Aldesleukin
Interferons
MOA of corticosteroids
Decrease synthesis of prostaglandins, Leukotriene, cytokines
Inhibit proliferation T-lymphocytes, cytotoxic to some Tcells
Clinical uses of prednisone
Autoimmune conditions: RA, UC
Asthma/COPD
TB IRIS
Haematological cancers
Organ transplantation
Side effects of prednisone
Adrenal suppression
Cushings
Osteoporosis
Stunting
Cataracts
Muscle wasting
Salt retention
HPT
Glucose intolerance/ DM
Behavioural changes incl Insomnia, psychosis
Immunosuppressants metabolised by CYP450
(Immunophilin ligands)
Cyclosporine
Tacrolimus
Which immunosuppressants are used for psoriasis
Topical tacrolimus and
Pimecrolismus
Side effects of cyclosporine and tacrolimus
Nephrotoxicity – dose related
Neurotoxicity(tacrolimus)
Hypertension
Hyperglycemia (tacrolimus)
Hyperkalemia
Hyperlipidemia
Gingival hyperplasia + hirsutism (ciclosporin)
Alopecia (tacrolimus)
Side effects of Sirolimus
Hyperlipidarmia
Myelosuppresion
Hepatotoxicity
Diarrhoea
Moa of mycophenolate mofetil (MMF)
Basically prevent rejection of organs for transplantation
Most cells have two pathways to synthesize purines. One is the de novo pathway, dependent on the enzyme inosine monophosphate dehydrogenase (IMPDH), and the other is the salvage pathway, dependent on the enzyme hypoxanthine-guanine-phosphoribosyl-transferase (HGPRTase). MMF which is rapidly converted to mycophenolic acid, which is a potent, reversible, non-competitive inhibitor of IMPDH, inhibiting the synthesis of purines (GTP - guanosine-5-triphosphate) required for DNA and RNA synthesis.
Since T and B-cells are highly dependent on this enzyme for DNA synthesis. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway ,because the salvage pathway in these cells is less robust and less active. MMF selectively blocks proliferation of T-cells and suppresses antibody formation by B-cells.
Similar to metabolite, metabolites are drugs that Interfere with DNA synthesis either through folic acid metabolism inhibition or purine or pyramiding synthesis. Cells need purine and pyramiding as building blocks for Nucleic acid synthesis
Other cells rely on the salvage pathway for purine synthesis, are therefore spared by MMF.
Clinical uses of MMF
Liver, kidney and heart transplant
Combined with low-dose ciclosporin in renal transplant to prevent nephrotoxicity
Other autoimmune disorders – lupus nephritis
Side effects of MMF
Toxicity:
Gastrointestinal disturbances (nausea, vomiting, diarrhoea)
Myelosuppression (neutropenia)
Transplant medication combinations
Immunophilin Ligands: Tracrolismus or Cyclosporine or Sirosmus
AND
Mycophenolate Mofetil: Cellcept or Myfortic
AND
Corticosteroids: Prednisons
MOA
Main MOA Is folate antagonism
It binds with a high affinity to the active catalytic site of dihydrofolate reductase (DHFR) and inhibits it. The result is a reduced synthesis of tetrahydrofolate, with a decrease in the synthesis of thymidylate and purine nucleotides interfering with nucleic acid synthesis.
The function, replication and proliferation of T-cells (and other cells!!) is reduced.
Methotrexate is used in high doses for the treatment of malignancies such as acute leukemia, non-Hodgkin’s lymphoma and solid tumors (sarcoma) (via its antiproliferative/cytotoxic action).
It is also used in lower doses in the management of RA, psoriasis and ectopic pregnancy.
Methotrexate is administered orally, intravenously (in high dose regimens) or intrathecally.
There is quite large Interindividual variability in pharmacokinetics, and absorption is saturable (at doses of >25mg po) leading to erratic and reduced oral bioavailability at higher doses.
90% of methotrexate is excreted unchanged in urine, with majority excreted within 12 hours of dose. Requires dose adjustment in renal failure.
MTX clearance can exceed creatinine clearance due to additional tubular secretion (some drug drug interactions due to competition for these transporters).
In high dose regimens, it is very important to mmaintain adequate hydration to prevent crystallization in renal tubules and nephrotoxicity.
Around 10% of methotrexate metabolized by liver to a metabolite that is a less potent inhibitor of DHFR.
