Immunosuppressants Flashcards
what is autograft?
cells from the same person are put back on them in another location
what is allograft?
cells or tissue from a donor and giving them to another person to use
what is xenograft?
taking human tumour cells and putting them in mice (or another species)
what are the 3 stages of graft (organ) rejection?
hyperacute - in minutes
aute - 7-21 days
chronic - 3 months
what can cause organ rejection?
tissue have certain memories, and when they are placed in another individual and the tissues mesh but are not completely compatible, a reaction can occur
what is the major target for anti-rejection drugs?
T cell and B cell activation/clonal expansion, cytokine production, antibody action
what is the process that leads to organ rejection?
foreign organ proteins bind to antigens on macrophages
stimulate T cell response
T cells help mediate B cell response by releasing cytokines(make antibodies)
antibodies mediate antibody response (neutralization, opsonization, phagocytosis), leading to organ rejection
describe the process of antibody formation
1) antigen binds to antigen receptor on activated B cell
2) proliferation occurs
3) further proliferation and differentiation into two types of cells
4) plasma cells mediate antibody response
5) memory cells contain antibody memory aspect and knows if youve been exposed to the allergen before
what are anti-rejection drugs
drugs that act on the induction phase (B cell activation via T cells and proliferation) of immune response or that target the effector phase of immune response (differentiation/synthesis of B cells leading to tissue injury)
what are two categories of anti-rejection drugs targeting induction phase? give examples for each
inhibitors of interleukin-2 production (cyclosporine, tacrolimus)
inhibitor of cytokine gene expression (glucocorticoids)
both IL and cytokines are major factors that help activate B and T cells
what is cyclosporine?
a fat soluble cyclic peptide with 11 amino acids derived from fungus Tolypocladium inflatum and is used in the treatment of organ transplant (kidney, heart, bone marrow)
what is a benefit of cyclosporine?
low doses can be used in autoimmune diseases such as RA
What is the moa for cyclosporine?
cyclosporine binds to cytosolic protein cyclophilin (immunophilin) and form a complex which inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription - decr. T cell activation
briefly describe the PK for cyclosporine
Oral or IV admin oral admin has slow and incomplete absorption metabolism occurs in both GI and liver t1/2 = 24h concentrated in peripheral tissue
what are some side effects of cyclosporine?
nephrotoxicity** hypertension increased risk of infection liver dysfunction others: hyperglycemia, anorexia, lethargy, hirsutism, tremor, paraesthesia, gum hypertrophy, GI upset
what are some drug interactions with cyclosporine? which inhibits its metabolism and which induce it?
inhibit: CCBs antifungals - ketoconazole, fluconazole antibacterial agents - erythromycin, clarithromycin grapefruit juice induce: anticonvulsants - phenytoin antituberculosis agents - isoniazid, rifampin
what is tacrolimus?
a macrolide antibiotic produced by Streptomyces tsukubaenis with an moa similar to cyclosporine and used to prevent organ transplant rejection
how does the moa of tacrolimus differ from cyclosporine?
it binds to immunophilin FK binding protien (FKBP) which inhibits calcineurin phosphatase - leading to decreased activation of transcription factor NF-AT and decreased IL-2 gene transcription
briefly describe the PK for tacrolimus
oral or IV admin
t1/2 = 9-12h
metabolized by the liver
toxic effects similar to cyclosporine
what are 5 categories of anti-rejection drugs targeting effector phase? give examples of each
1) inhibit action of IL-2 (sirolimus)
2) inhibitors of purine synthesis (myclophenolate mofetil, azathioprine)
3) alkylating cytotoxic agents (cyclophosphamide)
4) suppressor of immune response (glucocorticoids)
5) immunosuppressive antibodies (polyclonal or monoclonal antibodies)
what is sirolimus?
a new macrolide antibiotic derived from Streptomyces hygroscopicus
what is the moa for sirolimus?
binds to intracellular immunophilins but does NOT block IL-2 gene transcription
interferes with IL-2 signal transduction pathway in activated T cells resulting in deceased clonal proliferation of T cells and B cells
what is mycophenolate mofetil?
an agent that is converted to mycophenolic acid
selectively inhibits proliferation of both T and B lymphocytes and cytotoxic T cells
what is the moa for mycophenolate mofetil?
potent inhibitor of inosine 5’-monophosphate dehydrogenase, a crucial enzyme in purine synthesis
T cells and B cells are particularly dependent on this pathway for proliferation
briefly describe the PK for mycophenolate mofetil
oral admin (well absorbed)
Mg and Al impair absorption
metabolite mycophenolic acid and glucoronide conjugate undergo enterohepatic circulation
eliminated by kidney as inactive glucoronide
what does azathioprine do?
it is metabolized to 6-mercaptopurine which is a purine antimetabolite
interferes with purine synthesis (inhibits HGPRT enzyme, which catalyzes conversion of purine base to purine ribosyl monophosphate) and is cytotoxic in dividing cells
results in inhibition of clonal T and B cell proliferation
inhibits both cell mediated and antibody mediated immune reactions
what is a major side effect for azathioprine?
bone marrow depression
what is cyclophosphamide? how does it work?
a nitrogen mustard (alkylating agent)
inactive until metabolized by liver into active phosphoramide mustard
alkyl groups cross react with two DNA nucleophilic sites (intra/inter guanine) and inhibit DNA replication, leading to cell death
what are some SE’s of cyclophosphamide?
bone marrow depression
affects more WBCs than platelets
GI disturbance
give some examples of glucocorticoids
prednisone
methylprednisolone
dexamethasone
how do glucocorticoids work?
high doses induce lymphocyte migration to extravascular space - subsequently reduce lymphocyte proliferation
leads to size reduction of lymphoid tissues
affect more T cells than B cells
what is the MoA for glucocorticoids?
suppression of the induction and effector phases of immune response:
inhibit macrophage activation (antigen presenting cells) and release of IL-1beta
decrease clonal expansion of T and B cells and IL-2 secreting T cells
decrease production and action of cytokines (interleukins, TNFgamma)
decrease generation of IgG
what different conditions can glucocorticoids be used for?
anti-inflammatory and immunosuppressive therapy (ex: asthma, allergic rhinitis, eczema, RA, organ transplant)
neoplastic diseases
addison’s syndrome
what are some SE’s of glucocorticoids?
insomnia, mood changes
increased appetite, weight gain
suppress response to injury or infection
metabolic effects (fluid retention, osteoporosis, GI bleeding, hyperglycemia)
what is the difference between polyclonal and monoclonal antibodies?
poly - anti-lymphocyte immunoglobulin which inhibits T cells, lysis
mono - antibodies against IL-2 receptor which prevents T and B cell activation and proliferation
what do polyclonal antibodies do?
bind to proteins on the surface of lymphocytes triggering the complement response and cause lysis of lymphocytes
what are some adverse effects of polyclonal antibodies?
anaphylaxis
what do monoclonal antibodies do?
directly against a specific surface component of T cells and affects the induction and effector phases of immune response to allograft
targets CD3 proteins with antigen receptors, CD4 co-receptors, IL-2 receptors
what types of meds can be used to prevent acute rejection of an organ transplant?
high dose glucocorticoids
purine synthesis inhibitors
immunosuppressive antibodies
what types of meds can be used to prevent chronic rejection of an organ transplant?
1) triple drug therapy (low dose):
calcineurin inhibitor (tacrolimus)
purine synthesis inhibitors (mycophenolate, azathioprine)
glucocorticoid
2) for breakthrough episodes of chronic rejection: alkylating agents (cyclophosphamide) or immunosuppressive antibodies (poly or monoclonal antibodies)
what is an autoimmune disease?
occurs when the adaptive immune system loses self-tolerance rendering the system unable to distinguish between self and non-self antigens
what happens when the two self-tolerance mechanisms fail?
adaptive immune system responds as it would to non-self antigens and mounts an immune response. the body’s inability to eliminate the self-antigen results in a sustained response that leads to chronic inflammation
what are 3 classes of drugs used to treat rheumatoid arthritis?
NSAIDs
glucocorticoids
disease-modifying antirheumatic drugs (DMARDs)
name some examples of DMARDs
methotrexate sulfasalazine leflunomide anti-TNFalpha therapies Anti-IL therapies
what is RA?
it is a chronic autoimmune disorder involving inflammation within the joint
what are the 3 phases in RA and what do each of them do?
1) intiation phase - inflammation within joint
2) amplification phase - T cell activation
3) chronic inflammatory phase - tissue injury due to destruction of bone and remodelling of joint
why are Anti-TNF and Anti-IL effective DMARDs?
because they are released within the joint during the chronic inflammatory phase and are early participatns in the inflammatory cascade
name 5 anti-TNF based drugs
entanercept infliximab adalimumab certolizumab golimumab
what is etanercept?
the only soluble receptor TNF antagonist
it is fully human protein that functions like an antibody and binds to TNF (note: does not bind complement or cause cell lysis)
name 3 Anti-IL based drugs
anakinra
canakinumab
tocilizumab
what is ulcerative colitis?
inflammation of the submocosa and ulcerations that may cover the entire surface of the colon
what are some symptoms of ulcerative colitis?
diarrhea bleeding severe pain loss of nutrition anemia-starvation (risk)
what is a complication that could arise from UC?
colon can become stiff from scarring and burst, leading to peritonitis
what is Crohn’s disease
inflammatory disease which may cover the entire digestive system
what are some differences between UC and crohn’s?
crohns tends to be separate, isolated regions of inflammation
fistulas may form
intestinal wall may be breached
crohn’s may also be associated with severe skin inflammation
what is the curative treatment option for UC?
surgical removal of colon
what are 3 goals of treatment for IBD?
treat the acute outbreak
induce and retain remission
treat complications
what is first line treatment for mild-mod UC?
5-amino salicylic acid
what is 5-ASA?
works only in the large intestine in sulfasalzine by bacteria
does not work by COX inhibition
unknown MoA
what are the 3 responses patients could have to glucocorticoid use? describe each
1) steroid responsive (40%) - symptoms improve over 1-2 weeks and the disease remains in remission as the steroids are tapered off
2) steroid dependent (30-40%) patients respond well to steroids, but experience relapse of the disease with tapering off of steroids
3) steroid unresponsive (15-20%) do not respond to steroid treatment
when are glucocorticoids used?
acute treatment of mod-severe IBD
not useful in maintaining remission
what are some side effects to glucocorticoids?
weight gain moon-face stress emotional responses steroid-dependent diabetes increased risk of infection
when would thiopurines be used for IBD patients?
when they are steroid-resistant or dependent
useful for remission and reduction of relapse
not useful for acute attacks due to long onset time
when would methotrexate be used in IBD treatment?
steroid-resistant or dependent patients
when is cyclosporine used for IBD patients?
for most serious cases of UC and CD
used right before surgery
what are TNFalpha inhibitors?
TNFalpha is a major pro-inflammatory ligand
inhibition of this is used to treatment conditions such as eczema and RA
which TNFalpha inhibitor is not effective in UC treatment?
etanercept
what are some disadvantages to using TNFalpha inhibitors for IBD treatment?
repopulation of submucosa is required if drug kills immune cells
very expensive
increases changes of serious lung infections, esp. tuberculosis
what is thalidomide?
inhibitor of NF-kB (transcription factor involved in inflammation)
not used do to serious birth defects when used by pregnant mothers
why may anti- or pro-biotics be used in UC and CD treatment?
these diseases may be due to changes in intestinal flora
anti- or probiotics could change proportions of different bacteria
