Pharm 3 Immuno

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IMMUNOSUPPRESSANTS

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what interleuken released by T cells was said to be an important stimulator of differentiation and proliferation of T and B cells, and what T cells release it?

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IL-2, released by CD4+ T cells

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what leads to the stimulation of calcineurin, and what is calcineurin?

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T-cell receptor activation elevates intracellular Ca++ which stimulates the Ca++ calmodulin dependent phosphatace, calcineurin

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what else does this increase in Ca++ stimulate (2 pathways)?

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MAP kinase and NFkB signaling

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what does calcineurin activate, and what is the result?

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activates NFAT which helps induce expression of cytokines, like IL-2, TNF-alpha, and INF-gamma

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what drug and drug type targets antigen recognition?

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antibody therapy - Muromonab

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what types of drugs (2) and examples target cytokine induction?

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calcineurin inhibitors (cyclosporine, tacromilus) and corticosteroids (prednisone, prednisolone)

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what type of drug and two examples target IL-2 receptor activation on T and B cells?

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antibody therapy - daclizumab and basiliximab

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what drug types (2) and drug examples targets lymphocyte proliferation?

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antiproliferatives (sirolimus) and cytotoxic drugs (azathioprene and mycophenylate), and possibly steroids

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CORTICOSTEROIDS

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how do these work, generally (2 categories of effects)?

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1) interfere with T cell activation at multiple levels - reduce lymphocyte levels, inhibit cytokine gene expression and bind to glucocorticoid response elements; 2) anti-inflammatory effects

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for allograft rejection what are they given in combination with?

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cyclosporine or tacrolimus - permits lower dose of cyclosporine

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what regimens are given if acute rejection is likely (either/or)?

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1) methylprednisone IV pulses; 2) high dose oral prednisone

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CYTOTOXIC DRUGS

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what are the most commonly used cytotoxic drugs for immunosuppression (4)?

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1) azathioprine; 2) mycophenolate mofetil; 3) cyclophosphamide; 4) methotrexate

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how does azathioprine work and what does it inhibit (complete MA)?

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metabolized to 6-mercaptopurine, which inhibits de novo purine synthesis, but also inhibits the salvage pathway, and produces Thio-GMP which is incorporated into DNA backbone and damages DNA - these effects ultimately inhibit gene translation and prevent cell proliferation

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how is it given and what is the regimen for organ transplant?

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injected at time of transplant, then given orally with decreasing dose

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what else was azathioprine said to be used for?

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rheumatoid arthritis

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what is the most limiting adverse reaction to azathiprine, and how many people get it?

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leukopenia - 50% of renal transplant patients - often from bone marrow suppression

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what patients should not receive azathioprine and why?

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pregnant/nursing patients, due to teratogenic effects

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what is the MOA of mycophenolate mofetil (complete)?

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it is metabolized to MPA (mycophenolic acid) which is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase, which is critical for de novo synthesis of purines

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how does this differ from azathiprine?

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lymphocytes almost exclusively use the de novo synthesis pathway rather than the salvage pathway, and as such leucopenia is not nearly as big of a problem

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wha action does MPA dramatically inhibit?

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B cell proliferation

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what should be remembered about the pharmacokinetics of MPA (2)?

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1) highly protein bound (95%); 2) high bioavailability (94%)

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what is mycophenolate mofetil used for, andwhat is it given with?

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prophylaxis for rejection of renal and hepatic transplants - almost always given with cyclosporine or tacromilus and/or corticosteroids - has helped make possible discontinuation/lowering of steroids

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what drug interactions must we know for MPA (3 drugs/problems)?

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1) antacids with magnesium/aluminum hydroxides reduce absorption; 2) acyclovir/MPA can increase each other's levels; 3) cholestyramine reduces MPA levels by binding to MPA glucuronide in the intestine preventing its excretion

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who should not be given mycophenolate mofetil?

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pregnant/nursing patients, due to teratogenic effects

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what is the MOA of cyclophosphamide?

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alkylating agent - alkylates DNA in proliferating cells

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what part of the immune response is it most effective against?

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B cells / humoral immunity

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what is cyclophosphamide used for (2 categories)?

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1) patients receiving bone marrow transplants; 2) autoimmune disorders (RA, SLE, WG, ITP)

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what are adverse reactions of cyclophosphamide (3)?

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1) hemorrhagic cystitis; 2) cardiotoxicity; 3) severe pancytopenia

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what other immunosuppressant is typically used for RA and psoriasis that are intractable to corticosteroids/other immunosuppressant therapies?

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methotrexate

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what can chronic use of low doses of methotrexate result in?

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liver damage, exacerbated by alcohol

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CLASSIC IMMUNOSUPPRESSANTS

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what are the calcineurin inhibitors we must know (3)?

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1) cyclosporine; 2) tacromilus; 3) pimecrolimus

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what other drug is a "classic immunosuppressant" but does not inhibit calcineurin?

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sirolimus

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where do classic immunosuppressants come from (origin) and what are they like chemically?

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highly lipophilic, from microorganisms

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what part of the MOA is shared by all of these drugs?

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they cross the cell membrane unmetabolized and bind endogenous ligands called immunophilins - binding to immunophilins is a MUST for calcineurin inhibition

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what immunophilins are bound by which drugs?

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cyclosporine binds cyclophilin A while the rest bind FKBPs (FK-506 binding proteins)

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what type of activity does calcineurin have that these drugs (except sirolimus) inhibit?

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protein phosphatase activity - blocks the activation/nuclear translocation of NFAT, which in turn blocks the induction of numerous cytokines, especially IL-2

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how can cyclosporine and tacromilus and pimecrolimus share a mechanism, but have different binding targets?

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each immunophilin/immunosuppressant complex shares the same binding site on calcineurin catalytic subunit

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what should be remembered about the disposition/pharmacokinetics of calcineurin inhibitors?

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1) absorbed slowly and incompletely - 6-56% bioavailability; 2) distribute widely outside blood; 3) eliminated/metabolized in liver (earlier drugs in lecture eliminated renally, but metabolized hepatically)

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in what organ transplants are calcineurin inhibitors used, and what are they given with?

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almost all solid organ transplants - often with corticosteroids, also sometimes with cycotoxic drugs as well

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when is IV administration performed and what can result?

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when there are GI complications - IV administration may be accompanied by anaphylactic reactions

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what have recent studies shown is the most effective of these drugs in improving graft survival and preventing rejection?

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tacrolimus - used in 50% of all new renal transplants

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what is its potency compared to cyclosporine?

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100x as potent

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what are emerging as first line treatments for atopic dermatitis, especially in children (2)?

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ointment forms of tacrolimus and pimecrolimus

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what are advantages of calcineurin inhibitors over steroids?

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1) do not impair function/viability of Langerhans and dendritic cells, which are critical to development of mature immune responses in children; 2) topical calcineurin inhibitors are not absorbed into the bloodstream as steroids are (steroids cause problems such as alteration of HP axis this way); 3) lack of absorption into the bloodstream results in very little systemic immunosuppression, resulting in fewer AEs compared to orally administered counterparts

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what are the differences in treatment efficacy like between calcineurin inhibitors and steroids?

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negligibile

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which drug is generally recommended for mild to moderate atopic dermatitis, and which is recommended for moderate to severe cases?

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pimecrolimus for mild-moderate, tacrolimus for moderate-severe

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which of these drugs is absorbed into the blood the very least, and thus causes the least systemic immunosuppression?

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pimecrolimus

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what are calcineurin inhibitors 2nd or 3rd line for (3)?

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1) RA; 2) Crohn's; 3) Behcet's syndrome

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what are main AEs for calcineurin inhibitors (4 besides increased susceptibility to infections)?

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1) lymphoproliferative disease (leading to immunodeficiency); 2) nephrotoxicity (can occur in 75% of patients); 3) hypertension; 4) neurotoxicity; 5) GI; 6) hirsutism; 7) hypoglycemia

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what are the two forms of renal dysfunction, and what is each?

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1) functional - improves when drug is withdrawn; 2) chronic dysfunction - irreversible, with histologic abnormalities and mild proteinuria - seen at 6-12 months post-op

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what is typically the first sign that renal function may be impaired?

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halt in decline of levels of BUN, creatinine (these are generally higher post-operatively, but then return toward baseline)

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what is the leading reason for conversion to tacrolimus therapy?

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failure of reduction in cyclosporine dose to cause response in BUN/creatinine levels

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what should it be noted that renal dysfunction and hypertension can result in?

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negative impact on allograft survival

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how common is hypertension in transplant patients who use calcineurin inhibitors, and what are effects/course like?

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occur in 50% of transplant patients - effects are mild to moderate, and generally improve with time and therapy

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what problem can certain antihypertensives cause in these patients?

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can decrease the metabolism of calcineurin inhibitors

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why shouldn't potassium sparing diuretics be used for hypertension caused by calcineurin inhibitors?

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calcineurin inhibitors can cause hyperkalemia

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what can tacrolimus cause in the heart?

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hypertrophy - effects subside when dosing lowered

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what neurotoxic effects occur (3)?

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1) tremor; 2) headache; 3) convulsions (infrequent)

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what GI effects occur (2) besides N/V and diarrhea?

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1) gum hyperplasia; 2) hepatotoxicity

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what drug is most likely to cause hirsutism, and what race is most likely to get it?

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cyclosporine - commin in dark skinned caucasians

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what drug is most likely to cause hyperglycemia, and what % of liver transplant patients get it with this drug?

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tacrolimus - 33 to 47%

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what % of patients with kidney transplant get post-transplant diabetes melltus?

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20%

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what races are most likely to get PTDM?

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black, hispanic

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what treatment does PTDM often require, and what effect does it have?

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insulin - reverses 15% in one year, 50% by two years

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what adverse reactions can be caused by topical calcineurin inhibitors (4)?

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1) itching; 2) burning; 3) melanoma; 4) lymphoproliferative disease

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what drugs increase levels of cyclosporine (4 classes)?

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1) CCB's (dilatiazem, nicardipine, verapimil); 2) antibiotics (erythromycin, gentamicin, tobramicin, vancomycin); 3) antifungals (amphotericin B, azoles); 4) grapefruit juice

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what drugs reduce immunosuppressive potency (3)?

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1) anticonvulsants (phenytoin); 2) antibiotics (rifampin); 3) St. John's wort - reduction in drug levels can cause rejection

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what classes of drugs exacerbate toxicity (5)?

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1) other immunosuppressants; 2) certain antibiotics; 3) antifungals; 4) certain antiinflammatory; 5) GI agents; 6) azathioprine

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what can azathioprine cause when combined with cyclosporine?

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leukopenia

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what anti-inflammatory drugs exacerbate toxicity (2)?

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1) azapropazon; 2) naproxen

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what GI agents exacerbate toxicity (2)?

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1) ranitidine; 2) cimetidine

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people with what diseases should not be given topical calcineurin inhibitors?

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chicken pox, measles

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what drug in particular should be avoided in diabetics?

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tacrolimus

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what is the most important precaution/contraindication for these drugs?

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pregnancy

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what is it absolutely imperative that the physician should do after transplant?

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monitor plasma cyclosporine levels due to all of the adverse effects and drug interactions, as well as the variable absorbance of orally administered calcineurin inhibitors

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what does sirolimus do once it binds to the FKBP?

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binds to and inhibits the protein kinase mTOR (target of rapamycin - rapamycin is the other name of sirolimus) that is part of a larger protein complex

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what is the result of inhibition of mTOR?

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induces G1 phase and prevents cellular proliferation of T and B cells

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how is sirolimus absorbed/eliminated/metabolized?

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well absorbed, biliary elimination, metabolized by CYP3A4 into many metabolites

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what dramatically slows absorption?

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administration with fatty food

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how do gender and age affect pharmacokinetics of sirolimus?

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cleared more rapidly by women, absorbed more slowly by children (avoid under 13 years of age)

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what drug, when co-administered with sirolimus, causes increase in sirolimus levels?

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cyclosporine

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what is sirolimus mainlu used for, and how is dosing given?

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used for organ transplant - given ASAP post op, with loading dose of triple maintenance dose

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what is the most important reason for considering co-administration of sirolimus with cyclosporine/corticosteroid therapy?

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permits the discontinuation of cyclosporine after only a couple months

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what adverse effect must we know for sirolimus?

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hypercholesterolemia (can be treated by lipid-lowering agents) - take precautions with those with history of hypercholesterolemia/heart disease/obesity

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what drug interactions must we know for sirolimus (2)?

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P450, also cyclosporine (increases renal risks/myelosuppression/lipemia)

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ANTIBODY REAGENTS

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what is Rh0D immune globulin (rhogam) derived from, what is it directed aganst/used for?

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derived from human plasma and against Rh(D) antigen on RBC - prevents sensitization of mothers to Rh(D) antigen - prevents hemolytic disease of newborn

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how are monoclonal antibodies produced?

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immunize mouse with an antigen, and take mature dendritic cells from the mouse and fuse them with immortal cells, creating hybridoma cells that can be maintained in culture and will continue producing a certain antibody

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what monoclonal antibody must we know?

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muromonab-CD3

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what is it used for (2)?

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1) prophylaxis of organ rejection in kidney tranplants; 2) to deplete T cells from donor bone marrow prior to transplants

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what does it bind to, and what is the result?

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binds to CD3 glycoprotein, resulting in preventing antigen from binding to antigen recognition complex on T cell surface, and also causes clearance of CD3 T cells - these actions inhibit T cell immunity

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what is it usually co-administered with?

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cyclosporine/tacrolimus and/or cortocisteroids

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how is it administered?

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IV bolus

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what are the three main adverse effects with muromonab-CD3?

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1) CRS (cytokine release syndrome) where binding causes activation of T cells and a release of cytokines; 2) increased risk of infection compared to corticosteroids; 3) neoplasia

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what is CRS like and what precaution should be taken?

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can be flu-like ranging to shock - patients should be monitored in a facility equipped and staffed for CPR

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what may help prevent CRS?

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pretreatment with steroids before muromonab delivery

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what else limits muromonab use?

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expensive