What are the three strategies for maintenance therapy in organ transplants?
- Inhibit gene expression of proinflammatory mediators (glucocorticoids)
- Inhibit clonal expansion of lymphocytes (cytotoxic metabolites)
- Inhibit intracellular signaling in lymphocytes to prevent activation and expansion (Calcineurin/IL2 inhibitors and MTOR inhibitors)
What are the indications for glucocorticoids?
Graft vs host re bone marrow transplants
Autoimmune disease Tx (RA, SLE, MS)
Limit allergic reactions to Ab-immune Tx
Block 1st dose cytokine storm reaction of transplant drugs
What is the MOA of glucocorticoids?
- Bind GRE (glucocorticoid response element) to suppress T and B cell transcription of proinflammatory mediator genes and cytokine genes (TNF alpha, ILs)
- Suppress inflammatory immune cell (macrophages etc) production of prostaglandins by
- upregulating lipocortin to inhibit arachidonic acid
- down-regulating COX-2
What are the side effects of glucocorticoids (prednisone, cortisol)?
- Growth suppression re kids
- Decreased wound healing
- Hyperglycemia (and diabetogenic with calcineurin inhibitors)
What are the indications for Azathioprine?
Organ transplants (hi dose)
Autoimmune disease like RA (low dose)
What is the MOA of azathioprine?
- Prodrug converted to 6-mercaptopurine (6-MP)
- The de novo purine synthesis pathway converts it to Thio-dGTP
Thio-dGTP (instead of regular dGTP) is then incorporated into the DNA causing DNA lesions -> apoptosis
- Decreased T cells and B cells
What are the side effects of azathioprine?
It affects all rapidly dividing cells so it can cause:
GI toxicity, alopecia, hepatotoxicity, pancreatitis
Myelosuppression (WBC, RBC, platelets)
What three factors make the myelosuppression from azathioprine (AZA) worse?
Allopurinol inhibits xanthine oxidase, an enzyme that metabolizes AZA so reduce dose re gout patients
ACE inhibitors because they suppress EPO
- Some patients do not make TPMT, an enzyme that metabolizes AZA, so FDA recommends genotyping and decreasing the dose in these patients.
What are the indications for use of mycophenolate mofetil?
Why does mycophenolate mofetil have fewer side effects than AZA?
It selectively targets lymphcytes and has less effect on rapidly dividing cells.
What is the MOA of mycophenolate mofetil?
Prodrug hydrolyzed to mycophenolic acid -> inhibits IMP dehydrogenase in the de novo purine synthesis pathway
This blocks conversion of IMP to GTP and dGTP ( building blocks for DNA)
Specific to T cells and B cells because they prefer the de novo pathway, while other cells can use the salvage pathway
What are the side effects of mycophenolate mofetil?
Congenital abnormalities and miscarriage!
Can you combine mycophenolate mofetil with tacrolimus (a calcineurin inhibitor)?
Yes, but you must decresae the dosage of MM because Tacrolimus inhibits its metabolism
What are the two calcineurin inhibitors?
Cyclosporine and TaCrolimus
are the Calcineurin inhibitors
What are the indications for calcineurin inhibitors?
Immunosuppression re organ transplant
Cyclosporine used off label at lower dose for MANY autoimmune diseases (RA, IBD, psoriasis, etc)
What is the MOA of calcineurin inhibitors?
They decrease gene transcription of IL-2 which is critical for T-cell clonal expansion, differentiation and maturation
(and also activation of B-cells)
- Cyclosporine binds to cyclophilin
- Tacrolimus binds to FKBP-12
What is the ADME for the calcineurin inhibitors?
IV or oral
Oral dose has variable bioavailability so must monitor blood
Dosed by signs of rejection not by toxicity
Metabolized by CYP3A so adjust dose re other CYP3A drugs
Excreted in feces
What are the side effects of calcineurin inhibitors?
Renal dysfunction (dose-limiting and cause for D/C)
HTN re kidney and cardiac transplant patients
Diabetogenic (especially combined with glucocorticoids)
Infections and malignancies (esp nonmelanoma skin CA)
What should you consider when deciding to prescribe Cyclosporine or Tacrolimus?
Cyclosporine is worse re kidneys, HTN, diabetogenesis
Tacrolimus has neurotoxic effects: HA, tremor, seizures, motor disturbances
You have a heart transplant patient who is taking a calcineurin inhibitor and gets HTN. What can you use to treat the HTN?
CCBs, BBs, diuretics
Careful re ACE inhibitors if also on AZA
What are the indications for Sirolimus (aka Rapamycin)?
Immunosuppression re organ transplant
What is the MOA of sirolimus?
It is an mTOR inhibitor
It binds to FKBP-12 and inhibits mTOR (a key enzyme for T-cell activation and proliferation through translation of mRNA)
What is the ADME for Sirolimus?
Metabolized by CYP3A so dose adjust
Bioavailability varies widely so follow blood levels
What are the side effects of Sirolimus?
Hyperlipidemia (dose dependent)
Myelosuppression (less with calcineurin inhibitors)
Hypertension (dose dependent)
Lymphocoele (lymphatic fluid around kidney transplant)
Renal toxicity if pre-existing nephropathy
Which two transplant drugs should NOT be combined?
Sirolimus and Cyclosporine
Combination increases the renal toxicity of cyclosporine
and the hyperlipidemia and myelosuppression of sirolimus
These two do not play well together!