Immunosuppressives Flashcards
Arachidonic Acid Cascade
Membrane Phospholipids
becomes Arachidonic acid via phospholipase A2 (which is increased by thrombin, bradykinin, AG 2, and epinephrine)
- becomes leukotrienes involving WBCs (neutrophil chemotaxis and bronchoconstriction) via lipooxygenase
- becomes prostaglandins (E2, F2) (vasodilation, inflammatory mediators and proteases; increases renal function and GI protection, bronchodilation, increases pain, temperature and uterine tone) via cyclooxygenase 2
- becomes prostacyclins (decrease platelet aggregation, uterine tone, and cause vasodilation) via cyclooxygenase 2
- becomes thromboxane A2 (causes platelet aggregation and vasoconstriction) via cyclooxygenase 1
COX1 is constitutive (pre-existing) in many tissues where it converts arachidonic acid to prostanoids (thromboxanes, rpostaglandin, prostacyclines) and is involved in hemostasis, and vascular and bronchial smooth muscle tone. It can also be induced, though, at sites of inflammation and injury by 2-3 fold. GI mucosa, coagulopathy,
COX2 is induced and synthesized by macrophages and inflammatory cells 20 fold and really amplifies pain and inflammation. Constitutive in GI integrity and healing, help with resolution of inflammation,
Corticosteroids block phospholipase A2 and protein synthesis of COX enzymes
LOX - anti-inflammatory
Corticosteroids
Derivatives of endogenously produced cortisol.
Enter the cellular cytosol through passive diffusion and bind to cytosolic receptors that bring them into the nucleus where they inhibit transcription of certain genes- namely pro-inflammatory mediators (cytokines and chemokines (IL 1,2, 6, 8, TNFa), endothelial cellular adhesion molecules (ICAM-1, E-selectin), inflammatory peptides, etc.), suppress T Cell proliferation, inhibit phagocytosis and chemotaxis, impaired macrophage activity through the Fc receptor, decreased antibody production and binding, apoptosis of activated lymphocytes, induce anti-inflammatory cytokies like IL-10 and transforming growth factor beta TGFb). They also inhibit fibroblast and leukocyte movement and activity and inhibit expression of COX-2, phospholipase A2adhesion, complement, and histamine. This also affects cell mediate immunity and inhibits wound healing.
Side effects: iatrogenic hyperadrenocorticism (PU, PD, PP, panting, weight gain, pendulous abdomen, hair thinning), suppress HPA (ACTH) as well as TSH And T4, antagonize insulin and causes hyperglycemia, changes cardiac muscle function and cause water retention- risk of CHF esp in cats, inhibit ADH response in renal tubules, proteinuria, retention of water sodium and chloride and increased excretion of potassium and calcium. immunosuppression, steroid hepatopathy, pacnreatitis, weakens muscle, cartilage, and ligaments, delays wound healing
cortisol has 1:1 glucocorticoid and mineralocorticoid effects and lasts <12hrs.
- hydrocortisone is basically the same (0.8-1 mineralocorticoid)
- prednisolone/prednisone is 3.5-5x more potentin glucocorticoid and 0.3-0.8 mineralo. lasts 12-36hrs
- DexSP is 25-30x more potent gluco with 0 mineralocorticoid activity and lasts > 48hrs
Cyclosporine
derived from the soil fungus Tolypocladium inflatum
human transplants
inhibition of calcineurin which inhibits activation of nuclear facotr of activated T cells (NFAT) which is required for the nuclear transcription of genes coding for inflammatory cytokines. IL-2 is suppressed and therefore so are T cells (cell mediated immunity CD4, Thelper)
lipophilic- vegetable oil based (not recommended b/c highly variable PK) and ultramicronized formulation Atopica
Dogs food affects its absorption in the small intestine - can freeze or go ahead and give in food
OK in cats
Liver cytochrome p450 metabolism - ketoconazole drastically reduces the dose. then excreted in the bile
Monitoring: High doses within one week
- 1. TDM: Need whole blood as concentrate in rbcs and proteins. trough just before next dose or 2 hours after to get the peak and AUC. HPLC gold standard. parent vs metabolites- which may also confer action
- 2. Newer pharmacodynamic monitoring whereby IL2 and IFN-gamma levels are measured
experimentally increases thromboxane production but hasn’t caused detectable hypercoagulability and is usually negated by thromboprophylaxis in IMHA
Side effects: mainly but not that bad GI, gingival hyperplasia, skin things. Rarely liver and kidney toxicity. No significant myleosuppression yay!!
Associated with emergence of cancer! especially lymphoma
Atopica is expensive and no good other formulations
IV and oral
Azathioprine
Purine analog prodrug that the liver breaks down into 6MP and affects humoral and cell mediated immunity (suppresses B and T lymphocyte activation and proliferation as well as macrophage function)
targets lymphocytes because of their requirement for purine in DNA synthesis.
It is metabolized to 6MP which looks very similar to adenine and guanine and is inserted in the s phase of cell division.
drug interaction with allopurinol can lead to toxicity
CATS (safer to use cyclosporine and chlorambucil) and Giant schnauzers have low concentrations of TPMT (thiopurine methyltransferase) and can lead to myelosuppression!
Side effects: mild self-limiting GI, myleosuppression, hepatotoxicity (15% of dogs hae high ALT) (both are idiosyncratic, nondose dependent, reversible), pancreatitis
Monitor CBCs and Chems!
Takes 1-2 weeks to begin inhibiting lymphocyte proliferation although some reports in humans takes months
Cheap, good for big dogs
Mycophenolate mofetil
fermentation product of the penicillum fungus
prodrug of mycophenolic acid (MPA)
inhibits inosine monophosphate dehydrogenase (IMPDH) which is an enzyme responsible for the de novo synthesis of purine (which lymphocytes require), in a selective, reversible, noncompetitive manner (isoform 2 > 1). Since the MOA is similar to azathioprine, don’t use together (Also dont use cyclo and aza together because of risk of side effects increases)
affects both humoral and cellular immunity by affecting B and T cells, also down regulates adhesion expression and inhibits lymphocytes in the S phase of the cell cycle.
Primary side effects is GI- takes 2 weeks to see and can be marked** although prudent to monitor CBCs as myelosuppression has been documented in people
Extensive protein binding and thus variable effects in people. Also variable oral bioavailability in dogs
Excreted conjugated to glucuronide but cats seem to use glucosidation and so can tolerate it
IV and Oral
Leflunomide
Historically did well in canine renal transplants but was cost prohibitive. Now side effects are coming out
isoxazol derivative prodrug that is metabolized by intestines and liver to A77 1726 (teriflunomide)
main MOA is reversible inhibition of dihydro-orotate dehydrogenase which is an enzyme needed in the de novo synthesis of pyrimidines, which targets lymphocytes as they need to de novo synthesis like mycophenolate. causes G1 cell cycle arrest
so thus it decreases B and T cell production and proliferation, impaired leukocyte adhesion, and may have some anti-inflammatory effects via inhibition of tyrosine kinases for cytokines and IL-2
inhibits herpes virus
Side effects include GI upset, myelosuppression, hepatopathy
Monitor CBCs, chems, and blood trough levels through Auburn
Vincristine
Vinca alkaloid derived from the madagascar rosy periwinkle plant catharanthus roseus
cause disruption of microtubules which are necessary for cellular functions
they bind to tubulin causing inhibition of microtubule synthesis and disruption of intact microtubules especially of dividing cells arresting chromosomal separation in metaphase, neurons and platelets!!!
May also inhibit RNA, DNA and protein synthesis and modify prostaglandin production
Cell cycle specific cytotoxic agent
Minimally myelosuppressive, used in cancer and ITP
Must be given IV- causes severe tissue necrosis SQ and IM and has poor oral bio-availability.
Biphasic elimination- very fast initial plasma clearance due to its extensive distribution to intarcellular tubulin and biliary excretion but then very long terminal half life due to its gradual relase of it bound to circulating plasma proteins and tubulin.
Platelets are the principal carrier of it and concentrate it heavily. It is a much weaker immunosuppressive than other drugs therefore it’s use is really limited to cancer and ITP. Thought behind ITP is that it presents vincristine to the mononuclear macrophage system. It does increase megakaryocytopoiesis and thrombopoiesis but these are already maximal in ITP. causes a transient remission of ITP within one week and shortens hospitalization time. also inexpensive!
Major potential side effect is neurotoxicity although GI is also possible
Minimal myelosuppression unless ABCB1-1delta (MDR1) and the dose reduced by 50-25%. sometimes abnormal cell shapes seen cytologically but of no clinical significance.
Cyclophosphamide
cell cycle nonspecific nitrogen mustard derivative alkylating agent that inhibits DNA division during cellular division. inhibits cellular and humoral immunity
pro-drug metabolized by the liver cytochrome p450 to two metabolites 4-hydroxycyclophosphamide (basically phosphoramide mustard that replaces a hydrogen atom with an alkyl group ont he guanine base of DNA that interefes with DNA replication and RNA transcription) and acrolein. the former is what exerts anti-neoplastic and immunosuppressive effects while the latter, acrolein is what causes hemorrhagic cystitis
NOT RECOMMENDED IN EITHER SPECIES. humans can receive concurrent lasixs or mesna a sulfhydryl donor that inds to acrolein. may predispose to permanent fibrosis and even TCC
Side effects: GI, myelosuppression (esp neutropenia) and hair loss (poodles and old English sheepdogs)- same for all alkylating agents. can be long lasting side effects. cant crush, hard in smaller patients, monitor CBCs
Chlorambucil
nitogen mustard derivative noncel cycle specific alkylating agent used in chemotherapy protocols and immunosuppression
causes inappropriate cross-linking of DNA via insertion of a alkyl group on the guanine base thus interfering with DNA replication and RNA transcription and affect humoral and cell mediated immunity
high oral bio-availabiity and is highly protein bound
metabolized by the liver to the active metabolite phenylacetic acid mustard
Occassionally GI side effects, DOSE DEPENDENT myelosuppression and skin
safe in cats although neuro side effects have been reported as well as acquired fanconi’s syndrome
Monitor CBC’s
NSAIDs
also have spinal and supraspinal COX 1 and 2 enzymes that are transmitters of nociceptive pain
Regulators of gene expression
Glucocorticoids
Cause inappropriate DNA crosslinking and thus affect resting and dividing cells (Esp lymphocytes)
alkylating agents cyclophosphamide and chlorambucil
Inhibit de novo purine synthesis which targets dividing cells (lymphocytes)
mycophenolate and azathioprine
Inhibitor of de novo pyrimidine synthesis (thus targeting lymphocytes)
leflunomide
Kinase and phosphatase inhibitors thus affecting transcription of cytokines vital for proliferation and maturation of T cells
cyclosporine (and tacrolimus)
