Immunosuppressives Flashcards
Performed the first successful solid organ (kidney) transplant in 1954
Dr. Joseph Murray
There are two groups of biologics (antibodies) used for induction therapy. What are they?
- ) Depletion agents
2. ) Immune modulators
Include antithymocyte globulin and Muromonab CD3 mAb
Depleting agents
Include Daclizumab (anti-IL-2R) and Muromonab (anti-CD3) mAbs
Immune modulators
A typical combination of drugs for maintenance therapy for a patient with a transplant is use of a
Calcineurin inhibitor, glucocorticoids, and mycophenolate mofetil
For maintenance therapy, you want to use protocols without
Steroids
For maintenance therapy, you want to use protocols with the reduction of calcineurin inhibitor or switching to
Sirolimus (Rampmycin)
Treatment of established rejection requires the use of agents against activated
T cells
What are the two calcineurin inhibitors?
Cyclosporine and Tacrolimus (FK 506)
What are two cytotoxic drugs used for transplantation?
Azathioprine and mycophenolate mofetil
What are the two mTOR inhibitors used for transplantation?
Sirolimus (rampamycin) and Everolimus
The most important drug in the history of organ transplantation
Cyclosporine
Used for prevention and treatment of transplant rejection for kidney, liver, heart and other organs
Calcineurin inhibitors
Typically used at the maintenance doses with other immunosuppressants because of the nephrotoxicity
Calcineurin inhibitors
Calcineurin inhibitors are also useful for autoimmune disorders such as
Psoriasis and RA
A newer drug that shares the same mechanism of action as cyclosporine, but is up to 100 times more potent
Tacrolimus
Can be administered in two different ways:
- ) IV in an ethanol-polyoxyethylated castor oil mixture
- ) Orally in gelatin capsule or a microemulsion formulation
Cyclosporine
The peak level of cyclosporine in plasma occurs in
1.5-2 hours after oral administration
Tacrolimus and cyclosporine interact with other drugs that affect the
P450 system
What should be avoided when taking cyclosporine and tarolimus?
Grapefruit and grapefruit juice
Enhanced by sirolimus through reduced drug metabolism by P450
Renal toxicity
Bacterially produced macrolide and is structurally related to tacrolimus
Sirolimus
An ester-derivative of sirolimus
Everolimus
Used in transplants, certain autoimmune conditions, drug-eluting stents, and as an anticancer drug
mTOR inhibitors
The mTOR inhibitors reach peak level within
1 Hour of administration
Absorption of the mTOR inhibitors can be affected by a
High-fat diet
The mTOR inhibitors are mainly metabolized by P450 and transported by
P-glycoprotein
What has a shorter half-life, sirolimus or everolimus?
Everolimus
Causes a dose-dependent increase in serum cholesterol and triglycerides
The mTOR inhibitors
Close attention should be given to drugs that affect the activity of
-such as the mTOR inhibitors
CYP3A4 and P-glycoprotein
Used as an adjunct for preventing kidney rejection and for treatment of severe rheumatoid arthritis and other autoimmune diseases
Azathioprine
The main side effect of azathioprine is
Bone marrow suppression
zathiprine use also possesses risks of
Neoplasia and infections
Azathioprine is mainly metabolied by xanthine oxidase. Meaning it has interactions with
Allopurinol
A potent inhibitor of inosine monophosphate dehydrogenase, an enzyme critical for de novo purine synthesis
Mycophenolate Mofetil
Unlike other cell types, B and T cells lack
Purine salvage pathways
Therefore, mycophenolate selectively suppresses
Lymphocyte proliferation
Approved by FDA for oral or iv use with calcineurin inhibitors and corticosteroid in patients with renal, liver or heart transplants
Mycophenolate
Can cause GI disturbances, myelosuppression, headache and hypertension
Mycophenolate
Antibodies against lymphocyte cell-surface receptors can prevent lymphocyte activation, thereby achieving
Immunosuppression
Both polyclonal and monoclonal antibodies against lymphocyte cell-surface receptors are widely used for prevention and treatment of
Organ transplant rejection
Tend to be more specific than other immunosuppressents
Immunosuppressive antibodies
Obtained by injection of human thymic lymphocytes into a horse or sheep
Anti-lymphocyte/thymocyte antibodies
Primarily act on circulating lymphocytes. They will also deplete thymus dependent lymphocytes when administered continuously
Anti-lymphocyte/thymocyte antibodies
Humanized monoclonal antibody specific for the alpha subunit (CD25) of the IL-2 receptor on activated T cells
Daclizumab monoclonal antibody
Daclizumab monoclonal antibody is used against acute rejection in renal transplant recipients by competitive antagonism of
IL-2 induced T-cell proliferation
A mouse monoclonal antibody raised against the CD3 subunit of the T cell receptor (TCR) complex
Muromonab-CD3 antibody
The muromonab-CD3 antibody causes the destruction of
CD3 bearing T cells
Useful to prevent acute rejection of heart, kidney and liver transplants. It is also used to deplete T-cells from donor bone marrow prior to bone marrow transplantation
Muromonab
An adverse effect of muromonab-CD3 is
Cytokine release syndrome
Engagement of TCR causes lease of cytokines such as TNF-alpha. Glucocorticoids should be administered before injection of Muromonab-CD3
Cytokine Release Syndrome
Infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), and golimumab (Simponi) re all examples of antibodies with
Anti-TNF-a function
Another anti-TNF-a is a soluble receptor fusion protein called
Etanercept (Enbrel)
Anti-PD1 antibodies such as pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) function as
Immune checkpoint inhibitors
A class of natural and synthetic steroid hormones
Glucocorticoids
Inhibit expression of cytokine genes (IL-1, IL-2, IL-6, interferon and TNF-α), and T-cell proliferation and T-cell dependent immunity
Glucocorticoids
