Term
Function
Immune Suppression Drugs |
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Definition
| suppress the immune system to Tx rejection or organ transplants/tissue grafts, graft-vs-host hisease, autoimmune idseases, & certain allergic rxns. |
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Term
| What has traditionally been the major problem of immunosuppressive agents? |
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Definition
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Term
| What are the 4 classes of immune system drugs? |
|
Definition
1) glucocorticoids
2) immunophilin ligands
3) cytotoxic agents
4) Ab/biologics |
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Term
| What are the 2 types on immunophilin ligands? |
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Definition
1) calcineurin inhibitors
2) mammalian target of rapamycin inhibitor |
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Term
| What are the 2 types of cytotoxic agents? |
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Definition
1) anti-metabolites
2) alkylating agent |
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Term
| What are the 2 types of Ab/biologics? |
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Definition
1) Polyclonal
2) Monoclonal |
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Term
| What powerful immunosuppresive agents also have broad anti-inflammatory effects? |
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Definition
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Term
| Why is it easy to assume there should be SE with glucocorticoid immuno suppressive therapy? |
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Definition
| glucocorticoid receptors are on virtually all mammalian cells |
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Term
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Definition
| Steroids bound to CBG (corticosteroid-binding globulin) => enterance of soluble sterois into cell (w/o CBG) => cytosolic steroid receptor complexes 2 molecules of hsp90 & a number of other "stabilizers" => release of molecules upon binding => active receptor dimer enters nucleus => receptor binds to GRE (glucose response elements) in promoter enhancer regoins => modulation of transcription |
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Term
| What does the glucocorticoid ligand receptor also modulates the activity of? |
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Definition
| pro-inflammatory transcription factors AP1 & NF-ϰB |
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Term
Overall Effect
glucocorticoids |
|
Definition
anti-growth
anti-inflammation
immunosuppression |
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Term
| What 5 actions do glucocorticoids use to exert their effects? |
|
Definition
1) reduce cytokine-induced inflammation
2) inhibit T cell proliferative response to Ag, induce lymphocyte/eosinophil apoptosis
3) inhibito monocyte/macrophage activation, chemotaxis, & ability to recognize/respond to Ag & mitogens
4) decreased emigration of leukocytes from vessels
5) suppressed production of pro-inflammatory PGs, LTs, TXAs, & PAF |
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|
Term
| How do glucocorticoids reduce cytokine-induced inflammation? |
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Definition
| inhibit production of IL-1, IL-2, IL-4 & TNFα |
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Term
| How does glucocorticoids decrease emigration of leukocytes from vessels? |
|
Definition
| inhibit neutrophil chemotaxis & adhesion to endothelium |
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Term
| How do glucocorticoids suppress production of pro-inflammatory PGs, LTs, TXAs, & PAF? |
|
Definition
| inhibit phospholipase A2 & COX2 |
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Term
| What is the most widely perscribed steroid? |
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Definition
|
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Term
|
Definition
| liver to active form: prednisolone |
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Term
| When might prednisone & prednisolone NOT be considered equivalent? |
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Definition
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Term
|
Definition
idopathic throbocytopenic purpura
RA
asthma
inflammatory bowel disease
allergic rxns (inc. allergic rhinitis)
inflammatory skin disease
*initial Tx to induce requisite immunosuppression assoiciated with solid organ & hematopoieticc stem cell transplants
*graft-vs-host disease
(* relavent to this lecture) |
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Term
| When can glucocorticoid toxicity be seen? |
|
Definition
| chronic use (average & cumulative dose, low dose) |
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Term
| What is the problem with glucocorticoid toxicity effects? |
|
Definition
| many of them are asymptomatic until they are advanced s.a. cataracts, osteoporosis & atherosclerotic disease |
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Term
Sx
glucocorticoid toxicity |
|
Definition
1) skin/soft tissue: thining, purpura, Cushing's, alopecia, acne, hirsutism, poor wound healing
2) Ocular: cataracts, increased ocular pressure/glaucoma
3) Vascular: accelerated atherosclerosis, hyperlipidemia, HTN
4) GI: gastritis, peptic ulcer disease, GI bleeding
5) Musculoskeletal: osteoporosis, osteonecrosis, myopathy
6) Neurological: psychosis, euphoria, memory impairment (esp. elderly), pesudo-tremor cerebri, increased ICP (insomnia > euphoria > depression)
7) Opportunistic Infections
8) Endocrine: DM/hyperglycemia, hyperlipidemia, increased appetite/wt. gain, growth inhibition/delay onset of puberty
9) GU: amenorrhea/anovulation/infertility |
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|
Term
| Why do glucocorticoids cause osteoporosis? |
|
Definition
1) osteoblast function is inhibited => impaired bone formation
2) decreased calcium absorption from gut
3) increased excretion of calcium in urine |
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Term
| Why are there usually no warnings of an opportunistic infection in glucocorticoid use? |
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Definition
| reduction in inflammatory & febrile responses can mask the warning signs |
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Term
MOA
immunophilin binding agents |
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Definition
| binding to innumophilins (intracellular proteins) => selectively block production of IL-2 & other sytokines in CD4 T cells |
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Term
| What have innumophilin binding agents dramatically improved? |
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Definition
| long-term survival of transplanted organs |
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Term
SOA
immunophilin binding agents |
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Definition
transplants
hematopoietic stemm cell transplant
RA
psoriasis
atopic dermatitis
exzema
chronic dry eyes (secondary to ocular inflammation) |
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Term
| What are the 2 calcineurin-inhibiting agents? |
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Definition
| cyclosporine & tacrolimus |
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Term
|
Definition
| lipophilic cyclic decapeptide |
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Term
|
Definition
| lipophilic non-Abx macrolide |
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Term
| How are both cycosporine & tacrolimus derived? |
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Definition
|
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Term
| What immunophilin do cyclosporines bind? |
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Definition
|
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Term
| What immunophilin does tacrolimus bind? |
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Definition
| FKBPs (FK Binding Proteins) |
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Term
MOA
calcineuriun-inhibiting agents |
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Definition
| immunophilin-drug complex bind to & inhibit calcineurin => recduced transcription of early cytokine genes IL-2 (most important), IL-3, IL-4, TNFα, IFNγ, & GM-CSF => dose-dependent inhibition of lymphocyte production after TcR-CD3 receptors bound |
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Term
|
Definition
| calcium-calmodulin dependent serine/threonine phosphatase |
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Term
| What is the limitation os alcineurin-inhibiting agents? |
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Definition
| not effective in halting amplification of immune response AFTER activation |
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Term
| What cells do cyclosporine & tacrolimus primarily act on? |
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Definition
| T helper cells cytokine production (=> inhibition of T cell dependent B cells, T suppressor & T cytotoxic functions) |
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Term
| Are cyclosporine & tacrolimus cytotoxic or myelotoxic? |
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Definition
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Term
| Why must blood levels be monitored for both cyclosporine & tacrolimus? |
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Definition
| extremely variable bioavailability |
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Term
Elminiation
calcineurin inhibitors |
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Definition
| CYP3A4 (=> DDIs that could alter blood levels) |
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Term
Which calcineurin inhibitor is preferred for liver transplant?
Why? |
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Definition
| tacrolimus b/c cyclosporeine is partially dependent on bile salts for absorption |
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Term
| Can hemodialysis remove cyclosporine or tacrolimus? |
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Definition
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Term
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Definition
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Term
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Definition
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Term
| What can prolong the half life of both tacrolimus & cyclosporine? |
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Definition
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Term
|
Definition
1) nephrotoxicity: (occurs at therapeutic & low doses) renal injury, progressive renal failure, tubular dysfunction (=> hyperkalemia, hypophosphatemia, hyperuricemia, hypeomagnesemia)
2) HTN (due to sodium rentntion & vasoconstriction)
3) neurotoxicity: benign tumor common & improves with dose alteration, headaches, visual disturbances, sleep disorders, seizures, cerebral edema, encephalopathy, coma (more common with tacrolimus)
4) Metabloism: glucose itolerance, DM, bine loss, hyperlipidemia, hyperurcemia, gynecomastemia
5) Malignancy: several, inc. non-Hodgekin's lymphoma, skin cancers
6) Gingival hyperplasia
7) Hirsutism
8) Alopecia |
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Term
| Why is HTN a problem with calcineurin inhibitors? |
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Definition
Difficult to treat:
1) calcium channcel blockers have no effect on chronic toxicity
2) ACEIs can potentiate acotemia & hyperkalemia
3) diuretics can worsen hyperuricemia & predispose gout |
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Term
|
Definition
| non-Abx macrolide produced by fungus & binds to immunophilins (like tacrolimus, but isn't a calcineurin-inhibitor) |
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Term
|
Definition
| intereferes with signal transduction pathways elicited by IL-2
binds FKBPs (like tacrolimus), esp. FKBP12 => mTOR inhibition (mammalian Target of Rapamycin) => T cell arrest in G1 |
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Term
| What is sirolimus commonly combined with? |
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Definition
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Term
| Can sirolimus be combined with tacrolimus? |
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Definition
| yes bc FKBP12 is present in such large amounts that sacrolimus doens't rate-limit tacrolimus |
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Term
|
Definition
wound healing
lymphoceles
dyslipidemia
thrombocytopenia
decreased proliferation of vascular smooth muscle
synergistic nephrotoxicity when combined with calcineurin inhibitor |
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Term
|
Definition
| CYP3A4 => same DDIs as calcineurin inhibitors |
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Term
| What are the 4 anti-metabolite cytotoxic agents? |
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Definition
1) azathioprine
2) methotrexate
3) mycophenolate mofetil
4) leflunomide |
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Term
|
Definition
| nitroimidazole derivative of 6-mercaptopurine (6-MP) |
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Term
|
Definition
serum: 30 min
biological: 24 hr |
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Term
|
Definition
1) coverted to 6-MP by GSH in RBCs
2) in liver by xanthine oxidase & thiopurine methyltransferase |
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Term
|
Definition
| intracellular by hypoxanthine guanine phosphoribosyltransferase (HGPRT) to thioinosinic acid & thioguanylic acid |
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Term
|
Definition
| thioinosinic acid & thioguanylic acid suppress intracellular inosinic acid => suppression of adenine & guanine synthesis => decreased RNA production => decreased B& T cells, Ig production, IL-2 secretion |
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Term
|
Definition
maintenance for organ transplant
autoimmune disorders |
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Term
|
Definition
bone marrow suppression
anemia
alopecia
GI Sx
liver disease (rare) |
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Term
|
Definition
| allopurinal = lethal interaction since allopurinol blocks metabolism of azathioprine by xanthine oxidase |
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Term
|
Definition
RA
psoriasis
tissue vs graft host disease |
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Term
|
Definition
| structural analog of folic acid |
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Term
|
Definition
| competitively & irreversibly binds to DHFR => decreased FH4 => affected purine & pyrimidine metabolism |
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Term
Metabolism/Excretion
methotrexate |
|
Definition
| 80-90% unchanged in urine |
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Term
|
Definition
| other folate depleteing drugs s.a. bactram or probenecid |
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Term
|
Definition
GI upset
stomatitis
alopecia
macrocytosis
CNS: fatigue, headaches, loss of concentration
fevers
opportunistic infections
hematologic malignancies s.s B cell lymphoproliferative disorder
bone marrow toxicity => pancytopenia
interstitial lung disease
hepatotoxicity
(SE can be severe/fatal) |
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Term
|
Definition
| lymphocyte specific agent used to treat refractory renal or other solid organ transplant rejection episodes |
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Term
|
Definition
| inhibits IMPD (inosine monophosphate dehydrogenase) => decrease production of GMP => depletion of guanosine nuclotides & excess of adenosine nucleotides => lymphocyte proliferation & response to antigenic or mutagenic stimulation is depressed |
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Term
Metabolism/Excretion
mycophenolate mofetil |
|
Definition
hydrolyzed to acive form mycophenolic acid in liver & GI.
principle metabolite is glucuronide form that is inactive & excreted in urine/bile |
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Term
| Why are neutrophils spared (i.e. phagocytosis & bacterial killing) with mycophenolic acid? |
|
Definition
| decreased GTP pools in lymphocytes & monocytes only |
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Term
|
Definition
| GI - ileus, diarrhea, gastritis, N/V |
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Term
|
Definition
| inhibits pyrimidine (not purine) synthesis |
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Term
|
Definition
RA
psoriatic arthritis
autoimmune skin disorders
allograft rejection |
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Term
|
Definition
diarrhea
GIliver damage
kidney impairment
teratogenic effects |
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Term
| What is the cytotoxic alkylating agent? |
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Definition
|
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Term
|
Definition
| severe, life-threatening autoimmune diseases & inflammatory diseases s.a SLE, Wegener's granulomatosis, vasculitis, refractory RA |
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Term
Metabolism
cyclophosphamide |
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Definition
| in liver to 4-hydroxyxyxlophosphamide & aldophosphoramine => active metabolite phosphoramide mustard & non-alkylating bladder toxic metabolite acrolein |
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Term
|
Definition
| 2 armed dichlorethyl moieties of phosphoramide mustard metabolite attach to nucleic acid chains or enzyme macromolecules & interfere with functions |
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Term
| Where are the active metabolites of cyclophosphamide found? |
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Definition
| lipophilic, so protein bound & in tissue |
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Term
Excretion
cyclophosphamide |
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Definition
| inactive metabolites excreted in urine (renal failure dose adjustment) |
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Term
|
Definition
1) drugs that alter hepatic microsomal enzyme activity
2) succinylcholine => prolonged neuromuscular blockade thru reduction of PChE
3) TCAs & other anticholinergic agents => decrease bladder emptying => prolonged bladder exposure to acrolein |
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Term
|
Definition
alopecia
N/V
anorexia
diarrhea
atomatitis
mucositis
sterility
gonodal suppression
myelosuppression
anemia
acute hemorrhagic cystitis
congestive heart failure
pulmonary toxicity |
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Term
| What name indicates humanized monoclonal Abs? |
|
Definition
|
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Term
| What name indicated chimeric Abs? |
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Definition
|
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Term
| What are the 6 drug types seen in Ab/biologics? |
|
Definition
| 1) Lymphocyte Immune Globulin
2) Antithymocyte Globulin
3) Muromonab-CD3
4) RH0(D)-Immune Globulin
5) Anti-TNFα Agents
6) Anti-Cytokine Abs |
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Term
SOA
antithymocyte globulin |
|
Definition
organ transplant
transplant rejection |
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Term
def
antithymocyte globulin |
|
Definition
| polyclonal Abs in human lymphoid cells |
|
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Term
|
Definition
infection
fever
headache
lymphoma
malignancies (esp. when combined with other immunosuppressives) |
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Term
|
Definition
| anti-CD3 monoclonal Ab aka OKT3 |
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Term
|
Definition
| organ transplant (esp. kidney & esp. during rejection periods) |
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Term
|
Definition
| inactivate, deplete, & destroy T cells |
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Term
|
Definition
| cytokine release syndrome: fever, headache, HTN |
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Term
| SOA
RhL0(D) immune globin |
|
Definition
| to passively immunize Rh- mothers against Rh Ag on baby's RBCs => prevents erythroblastosis fetalis in subsequent pregnancies if administered within 1-3 days post birth |
|
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Term
|
Definition
| autoimmune dieases s.a. RA, psoriasis, & Crohn's |
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Term
| What are the 3 anti-TNFα drugs? |
|
Definition
1) Adalimumab (humanized monoclonal Ab)
2) infliximab (chimeric monoclonal Ab)
3) Etanercept |
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Term
| What are the 2 anti-cytokine Abs? |
|
Definition
1) Daclizumab (humanized monoclonal Ab)
2) Basiliximab (chimeric monoclonal Ab) |
|
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Term
|
Definition
| bind CD25 (on IL-2 receptor on T cells) |
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Term
|
Definition
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