Immunosuppressive Drugs - Zheng 4/14/16 Flashcards
breakdown of immunity: 2 types: subdivisions
1. innate immunity
- physical (skin, mucosa)
- humoral (complement)
- cellular (macrophages, NK cells)
2. adaptive immunity
- humoral (antibodies)
- cellular (T cells)
cytokines: effects on T cells
IL2: stimulates proliferation of T cells, B cells
some situations in which we might need/want to suppress the immune system
- solid organ/tissue transplantation
- bone marrow transplantation
- autoimmune diseases
5 rules of transplantation therapy
- get best ABO and HLA match possible organ donor
- intensive induction
- low-dose maintenance therapy (goal: combinatorial therapy using drugs with distinct mechs of action)
- investigate each episode of transplant dysfunction (graft rejection, drug tox, infection)
- modify tx as appropriate - withdraw drug if adverse rxn > benefit
induction therapy
two main groups of antibodies used:
1. depleting agents: kill activating lymphocytes
- antithymocyte globulin
- Muromonab-CD3 mAb
2. immune modulators
- Daclizumab (anti-IL2R) mAb
- Muromonab-CD3 mAb
intensifies initial immunosuppressive therapy in high-risk patients (repeat transplant patients, pediatric patients, pre-sensitized patients, AfAms)
*also allows you to delay use of nephrotoxic calcineurin inhibitors
maintenance therapy
usually combinatorial therapy: diff drugs with diff mechs of action → synergistic effects and minimal toxicities
avoid steroids or build in steroid withdrawal
reduce calcineurin inhibitors and/or incorporate calcineurin inhibitor withdrawal in favor of serolimus
therapy for established rejection
use of agents against activated T cells
- high dose glucocorticoids
- antithymocyte abs
- Muromonab-CD3 mAb
calcineurin inhibitors
- cyclosporine
- tacrolimus (FK506) - new drug, approx 100x more potent
indication: prevention and tx of transplant rejection for organ transplants
- useful for autoimmunes (rheumatoid arthritis, psoriasis)
- typically used at maintenance doses bc of nephrotoxicity
calcineurin inhibitors:
mechanism of action
NFAT is a transcritpion factor that can bind to promoter of IL2 → trigger immune response
- typically phosphorylated, hanging out in cytoplasm
when MHC/antigen-TCR recognition happens, T cell activation → increase in intracellular Ca
- Ca binds to calmodulin → Ca-calmodulin bind to phosphatase calcineurin → de’Ps the NFAT → NFAT upregs transcription of IL2 and other infl cytokines
**calcineurin inhibitors (cyclosporine, tacrolimus) inhibit action of calcineurin → prevent upreg of IL2
calcineurin inhibitors:
PK
toxicity
drug interactions
pharmacokinetics
- administered either IV or oral
- primarily metabolized by hepatic P450s
toxicity
- renal tox is major adverse effect (up to 70% of pts)
- other adverse effects: HTN, diabetes (esp in conjunction with glucocorticoids), tremor, hirsutism
- increased risk of malignancies, infections
drug interactions
- interacts with drugs that affect P450 enzymes
- avoid grapefruits/grapefruit juice
- serolimus reduces metabolism → enhances calcineurin tox!!!
- separate use of these two drugs by time
cytotoxic drugs x2
indications
side effects
drug ints
azathioprine : pro-drug → activated via reductive rxn with glutathione
- used as adjunt to prevent kidney rejection, severe rheumatoid arthritis, some autoimmune indications
- side effects: bone marrow suppression; increased risk of neoplasia and infection
- drug interactions: metabolized by xanthine oxidase (blocked by allopurinol)
mycophenolate mofetil
- mech of action: inhibitor of IMP DH (req for de novo purine synth) → B and T cells lack purine salvage pathways!!! → selectively suppresses lymphocyte proliferation!
- approved for use in renal/liver/heart transplants to be used with calcineurin inhibitors and corticosteroids
- toxicity: GI disturbance, myelosuppression, headache, HTN
mTOR inhibitors
- sirolimus (Rapamycin) : bacterially produced macrolide - structurally related to tacrolimus
- everolimus: ester-derivative of sirolimus
used in transplant patients, for some autoimmune conds, for some cancer conditions
mechanism of action: IL2 causes a signaling cascade that ultimate hits mTOR pathway → transcription and translation of stuff that leads to growth and metabolism
- sirolimus and everolimus inhibit mTOR pathway
mTOR inhibitors:
PK
toxicity
drug interactions
pharmacokinetics
- oral admin: peaks after 1h, absorption affected by high fat diet
- mainly metabolized by CYP3A4, transported by P-glycoprotein
- verolimus half-life is shorter
toxicity
- dose-dep increase in serum chol and TGs
- not nephrotoxic in and of itself, but can decrease drug metab of calcineurin inhibitors and extend their half life → renal tox
- other effects: anemia, leukopenia, infections
drug interactions
- pay attn to admin with drugs that affect CYP3A4 and/or P-glycoprotein
- pay attn to admin with calcineurin inhibitors (separate by time) to avoid renal tox
biologics (antibodies)
can interrupt MHC/antigen-TCR interaction
can interrupt IL2-IL2R interation
very specific!
1. antilymphocyte/antithymocyte antibodies
- act mainly on circulating lymphocytes, also can deplete thymus-dep lymphocytes when adminstered continuously
- used for induction therapy in organ/bone marrow transplant
2. Daclizumab antibody
- specific for alpha subunit (CD25) of IL2R on activated T cells
- treats acute rejection in renal transplant by acting as competitive antagonism of IL2-induced T cell prolif
- side effects: mostly immunosuppression
3. Muromonab-CD3 antibody
- causes destruction of CD3-bearing T cells
- used to prevent rejection of liver/kidney/heart transplants and knock out T cells prior to bone marrow transplant
-
adverse effects: “cytokine release syndrome” → engagement of TCR leads to cytokine storm
- admin glucocorticoids before Muromonab-CD3
- potential acute hypersensitivity
- increased infection
glucocorticoids
natural and synthetic steroid hormones
glucose+cortex+steroid
mech of action: binding of steroid to GR leads to 2 GR monomer forming a GR dimer → translocation into nucleus, binding to GRE → inhibit expression of cytokine genes (IL1, IL2, IL6, INF, TNFalpha) → inhibit T cell prolif, T cell dependent immunity
therapeutic use: organ transplant rejection, autoimmune diseases, allergic rxns, leukemia/hematopoeitic malignancies, shock, adrenocortical dysfx
adverse effects:
- growth retardation (kids), muscle wasting, osteoporosis/bone loss
- obesity, hyperglycemia, HTN
- skin ulcers, increased infection
