Immunosuppressive Therapy Flashcards
Immunosuppressive Drug
A drug used to prevent the production of antibodies
One primary use is in the field of organ transplants
Immunosupprissive drugs prevent transplanted organs from being rejected by the recipient
Also used to treat graft-versus-host-disease
The other area where these drugs are used is to treat autoimmune disorders
Calcineurin Inhibitors
Cyclosporine
Lipophylic cyclic peptide of 11 AA
Isolated from a fungi
Tacrolimus
Macrolide antibiotic
isolated from fungus
MOA similar to cyclosporine
Calcineurin Inhibitors MOA
both bind with cytoplasmic proteins
drug protein complex specifically inhibits calcineurin (calcium &calmodulin dependent phosphate)
causes reduced transcriptional activity for IL-2, TNF alpha and granulocyte macrophage colony-stimulating factor
# of T lymphocytes is reduced!!!
T cell dependent B cell responses are inhibited
Immune response decreased
Cyclosporine administration
IV
Oral
Opthalmic formulations available
Initially given IV because it is variably & incompletely absorbed orally
Opthalamic preperation used for keratoconjunctivitis sicca
Cyclosporine use
For solid organ transplant, GVHD and several autoimmune diseases (RA)
Toxic!–generally not used as 1st line agent
Cyclosporine SE
Nephrotoxicity: most common/concerning
HTN-use Ca2+ channel blockers fro treatment
Neurotoxicity: mild tremor, HA/seizures, blindness
Infection: viral (CMV) and fungal common
Benign and malignant lymphoproliferative disease
Others: hyperkalemia, hypomagnesemia, glucose intolerance, hyperuricemia
Cyclosporine Monitoring Parameters
renal function
BP
Serum electrolytes and magnesium
LFT (may elevate bilirubin)
Tacrolimus
IV, oral and topical prep
Use: for prevention of organ rejection (with availability for newer agents w/ less toxicity use has declined)
Used w/ methotrexate for prevention of acute GVHD
Topical preparations used for severe, plaque, psoriasis and severe atopic dermatitis
Tacrolimus SE
Nephrotoxicity:
Neurotoxicity-HA, tremors, paresthesias, coma
HTN
Pulmonary–dyspnea
GI–N/V diarrhea, abd discomfort
Fatigue
Other: hyperkalemia, hypomagnesemia, hyperglycemia
Tacrolimus Monitoring Parameters
Renal function Electrolytes and magnesium BP Fasting blood glucose Tacrolimus levels
Sirolimus
Macrolide antibiotic struct similar to tacrolimus but not an inhibitor of calcineurin
Sirolimus binds to intracellular proteins and Inhibits Growth of Hematopoietic and lymphoid cells
2nd line Agent for use in combination with other immunosuppressive agents for phrophylactic organ rejection
Sirolimus SE
GI: N/V, diarrhea, elevation of LFTs Hypertriglyceridemia Throbocytopenia Leucopenia BP changes HA, mucous membrane irritation, infx, epistaxis Nephrotoxicity (not often encountered) THROMBOCYTOPENIA & NEUTROPENIA dose limiting toxicity
Prednisolione MOA
Glucocorticoids: diffuse across cell membrane
bind to specific receptors then enter the nucleus and interacts w/ DNA
Prednisolone MOA cont
antiinflammatory effectsL inhibts production of most cytokines and proinflamm mediators
Inhibits innate immunity by suppressing phagocytic function of neutrophils and macrophages
causes neutrophilic leukocytosis
decreases number of circulating T cells
w/ chronic admin decreases IgG and IgA
Prednisolone uses
undesirable immunological Prophylaxis for prevention of rejection of a transplanted organ in a recipient Autoimmune diseases Inflammatory disorders Allergic conditions Malignancies
Prednisolone SE
related to dosage and more common for long term therapy
Skin and thinning and purpura (bleeding underskin)
Cushingoid appearance/ wt gain
Cataracts and glaucoma
HTN 7 Hyperlipidemia leading to atherosclerosis
GI: gastritus, ulcers, may initially increase appetite
Prednisolone
Osteoporosis
Neuropsychiatric
Initailly may cause euphoria/insomnia
May lead to depression and mania or psychosis
Hyperglycemia leading to development of DM
Hypothalamic pituitary adrenal insufficiency
Heightened risk of typical and opportunistic infection
Prednisolone Monitoring Parameters
BP
CMP
Lupids
Long Term
Opthalamic exam
DEXA scanAzathioprine (Imuran)
Class: antimetabolite MOA: acts as a purine antagonist and inhibits the sythesis of proteins, RNA and DNA Clinical uses Immunosupression in renal homografts Autoimmune disease (SLE, RA)
Azathioprine SE
Fever Nausea Bone marrow supression Hepatotoxicity (diagnosis of exclusion) Skin cancer
Azathioprine Monitoring Parameters
CBC w/ platelet counts initially weekly
- If significant neutropenia occurs the drug is held until the WBC count has risen
- Rare, persistant or recurrent neutropenia then azithioprine has to be discontinued
LFTs total bilirubin and alkaline phosphatase
Cyclophosphamide MOA
alkylating agent
MOA: one of the most potent immunosuppressive therapies
Inhibits DNA sythesis by binding and damaging DNA itself
Able to damage DNA in any phase of the cycle although preferes highly dividing cells
Cyclophosphamide uses
Treating leukemias and lymphomas
Others: severe glomerulonephritis
Rheumatoid vasculitis and other types of systemic vasculitis
Given intermittently or as a daily dose
Cyclophosphamide SE
Severe N/V Myelosuppression Hemorrhagic cystitis Hepatitis Cardiac Damage Pulmonary fibrosis Development of opportunistic infx Development of later malignancies
Cyclophosphamide Monitoring parameters
Frequent CBCs with a differential (lymphopenia more concerned w/ neutropenia)
Renal function including a UA to check for
LFTs
After off CYC annual UA and if hematuria either gross or microscopic occurs need to have cystoscopy
Cyclophosphamide (CYC) and the Bladder
One of the metabolites of CYC is acrolein
Acrolein is toxic to the human bladder it can cause:
Hemorrhagic cystitis
Bladder cancer (even long after treatment)
Risk of acrolein toxicity can be reduced by:
Adequate hydration
Concordant administration of MESNA (sodium 2-mercaptoethane sulfonate
