Immunosuppression

What are the classes of medications that are selective immunosuppressive agents?

Calcineurin inhibitors

Inhibition of Lymphocyte Proliferation

m-TOR Inhibitors

Co-stimulation blockade

What medications are calcineurin inhibitors?

cyclosporine, tacrolimus

What medications inhibit lymphocyte proliferation?

azathioprine, mycophenolate mofetil (MMF), mycophenolic acid (MPS)

What medications are m-TOR inhibitors?

sirolimus, everolimus

What medications are co-stimulation blockaders?

belatacept

What type of medications are non-specific immunosuppressive agents?

glucocorticoids (prednisone, methylprednisolone)

What are the three categories of medications that make up maintenance immunosuppression?

calcineurin inhibitors + mycophenolic acid + corticosteroids

What is induction immunosuppression?

early suppression of the immune system post-transplantation; prevents the organ rejection process from initiating at transplant (or pre-op) and immediately on organ placement

What is the purpose of maintenance immunosuppression?

prophylaxis against acute rejection

What is rejection therapy?

management of the immunologic rejection process which can be acute or chronic in order to preserve the organ function

What are some examples of causes of secondary (acquired) immunodeficiencies?

HIV, chemotherapy treatments, immunosuppression for grafts and inflammatory diseases, bone marrow cancers, malnutrition, and spleen removal

How does HIV cause secondary (acquired) immunodeficiency?

depletion of CD4+ helper T cells

How does irradiation and chemotherapy treatments for cancer cause secondary (acquired immunodeficiency?

decreased bone marrow precursors for all leukocytes

How does immunosuppression for graft rejection and inflammatory diseases cause secondary (acquired) immunodeficiency?

depletion or functional impairment of lymphocytes

How does involvement of bone marrow by cancers cause secondary (acquired) immunodeficiency?

reduced site of leukocyte development

How does malnutrition cause secondary (acquired) immunodeficiency?

metabolic derangements inhibit lymphocyte malnutrition and function

How does removal of the spleen cause secondary (acquired) immunodeficiency?

decreased phagocytosis of microbes

What is secondary (acquired) immunodeficiency?

immune system deficiencies acquired through life that are not due to genetic immune disorders

Why do many of these immunosuppression drugs require therapeutic drug monitoring?

they have a narrow therapeutic index

True or False: you can substitute generic for branded immunosuppression drug

FALSE

What is an important note to give the pharmacy in regards to immunosupressive drugs?

NO switching between manufacturers

What could potentially be different between two generic medications?

oral bioavailability

Which calcineurin inhibitor is available through IV?

cyclosporine

What are adverse effects of cyclosporine?

hyperlipidemia, nephrotoxicity, tremor, headache, hypertension, hyperglycemia, gingival hyperplasia, hirsutism, diarrhea, vomiting

What are adverse effects of tacrolimus?

diarrhea, nausea, nephrotoxicity, tremor, headache, insomnia, hyperglycemia, hyperlipidemia, hypertension

What are some examples of medications that INHIBIT CYP3A4 and/or P-gp?

verapamil, nicardipine, -conazole, clarithromycin, erythromycin, indinavir, ritonavir, omeprazole, grapefruit juice

What are some examples of medications that INDUCE CYP3A4 and P-gp?

rifampin, rifabutin, caspofungin, terbinafine, carbamazepine, phenytoin, st. john’s wart, echinacea

What type of kinetics does cyclosporine and tacrolimus have?

linear

what do you monitor while patients are taking calcineurin inhibitors?

trough concentrations

What is a key point about mycophenolic acid pharmacokinetics?

it undergoes enterohepatic circulation

What drugs interact with mycophenolic acid’s enterohepatic circulation?

cyclosporine, tacrolimus, cholestyramine & bile acid resins, certain antibiotics (ciprofloxacin, augmenting, rifampin, etc.)

What drugs interact with mycophenolic acid? (not through enterohepatic circulation)

acyclovir, co-trimoxazole, combined oral contraceptives, phenytoin, aspirin, glucocorticoids

What are adverse effects of mycophenolic acid?

gastrointestinal (N/V, diarrhea), hematologic (leukopenia, neutropenia, anemia, thrombocytopenia), opportunistic infections, CNS (dizziness, insomnia, headache), cardiovascular

What should you do as renal function declines in terms of mycophenolic acid?

adjust the MPA regimen to lower dose with longer interval based upon patient’s response

What is the HPA axis?

hypothalamic pituitary adrenal axis

Where is cortisol secreted from?

the pituitary gland

What regulates cortisol secretion?

ACTH (from anterior pituitary in response from CRH (hypothalamus))

What kind of feedback does cortisol have?

negative

Which glucocorticoids have anti-inflammatory properties?

intermediate and long acting (prednisone, prednisolone, triamcinolone

What glucocorticoids do NOT have anti-inflammatory properties?

cortisone, hydrocortisone

What are some glucocorticoid drug-drug interactions that inhibit steroids?

oral contraceptives, ketoconazole, cyclosporine

What are some glucocorticoid drug-drug interactions that induce glucocorticoids?

phenytoin, phenobarbital, rifampin

What medications gets induced by glucocorticoids?

tacrolimus, cyclosporine, mycophenolic acid

What are side effects of maintenance immunosuppression with glucocorticoid?

dyslipidemia, hyperglycemia, adrenal atrophy, peptic ulcers, changes in behavior, infections, bone necrosis, cataracts, increased sodium retention

What is the glucocorticoid equivalent doses?

cortisone = 25

hydrocortisone = 20

prednisone = 5

methylprednisolone = 4

What are the post-transplant complications?

hypertension

infections

diabetes

hyperlipidemia

osteoporosis

lymphoproliferative disorders

What is allotransplantation?

transplantation of cells, tissues or organs from a donor that is not genetically identical to the recipient (host) but of the same species

What are other terms for the transplanted organ?

allograft, allogenic transplant, or homograft

What is transplant rejection?

the immune attack of recipient to the allograft of donor after transplant

Who oversees/organizes transplantations?

UNOS !

Who can be an organ donor?

living or deceased in good overall physical health

What is sensitization in terms of immune repose to a transplant WITHOUT immunosuppression medications?

in the recipient’s lymph node, alloantigen-specific T cells (CD8+ and CD4+ cells ) are activated

What is acute transplant rejection?

can occur days to years after transplant with fast clinical manifestation; generally reversible but can impact overall organ function; occurs due to the development of cell-mediated immune response against Class II HLA on graft

What is the most common form of clinical transplant rejection?

acute rejection

What is priming of alloreactive T cells assuming no medications have been taken in the transplant recipient?

initial site of encounter of foreign MHC molecules occurs shortly after engraftment, donor dendritic cells that reside in the transplanted organs migrate to regional lymph nodes, where they activate host T cells

What mediates the priming of alloreactive T cells?

direct recognition of intact donor MHC molecules on the surface of dendritic cells by recipient T cells

What is late phase post-transplant assuming no medications in transplant recipient?

during late phase post-transplantation, indirect allorecognition predominates

What is hyperacute rejection?

Preformed antibodies react with alloantigena on vascular endothelium of graft, activate complement and trigger immediate intravascular thrombosis and necrosis of the vessel wall and allograft dysfunction

What is an acute rejection?

CD8+ lymphocytes react with alloantigens on graft endothelial cells and parenchymal cells or antibodies react with endothelial cells ( humoral) and result in damage to these cells and the allograft

What is chronic rejection?

with allograft arteriosclerosis, T cells react with graft alloantigen and may produce cytokines that induce inflammation and proliferate intimal smooth muscle cells resulting in luminal occlusion and gradual allograft dysfunction.