Immunomodulatory treatment Flashcards
List tx options
- corticosteroids (mainstay, various adjunctive tx may be helpful)
- other immunosuppressive drugs (alkylating agents, antimetabolites, mitotic inhibitors - vinca alkaloids, calcineurine inhibitors, others)
- novel agents offer more potent and targeted immunosuppression
Aim - tx
- halting ongoing damage
- satisfy nutrional and nursing requirements
- non-specific immunosuppression is key
What are possible adjunctive therapies to corticosteroids?
- diet
- topical therapy and GIT barrier protection
- splenectomy?
- blood products and darbepoietin (synthetic erythropoeitin)
- danazol? plasmapherisis?
What is danazol?
drug which suppresses gonadotrophin production and has some weak androgenic effects
Indications - splenectomy
- IMTP
- intractable haemolysis
Indications - topical therapy and GIT barrier protection
- Topical: only if concurrent dz which increases tendency for ulcers to form - look out for GIT bleeding
- GIT protection: usually for IMTP as ramifications bad if bleeding d/t ulcers occur
What is plasmapheresis?
- filtering plasma using external filter
- for temporary/emergency control of intractable haemolysis
What are the important aspects of nursing care?
- recumbency: urination, defecation, hygiene, gentle exercise
- CS of clinical deterioration?
- analgesia and general comfort
- nutrition (naso-oesophageal, oesophageal, PEG tubes)
- water access and ability to drink
- IV catheter care, IVFT
- procurement of diagnostic samples
- client communication
- TLC
Action - corticosteroids
- associate with binding proteins (transcortin and albumin)
- following dissociation from binding proteins, passively diffuse into cell
- bind to a cytoplasmic receptor (>/3)
- conformational change of receptor unmasks DNA binding domain; associates with GREs following nuclear translocation
What are GREs associated with?
= Growth Response Element
- associated with pro- and anti-inflammatory genes
What does fluorination of prednisone do?
increases GC and MC activity
What does addition of CH3 to prednisone to make it dexamethasone do?
abolishes MC activity so only left with GC activity
Is dexamethasone or prednisone most potent?
dexamethasone is 7-8 times more potent vs prednisone thus lower dose can last > 48 hours
Potential averse effects of corticosteroids
- CNS
- MSK
- GIT
- fluid, electrolyte balance
- metabolic
- endocrine
- immune system
What stage of the cell cycle do vinca alkaloids target?
M phase
Which drugs target G1 of cell cycle?
- calcineurin inhibitors
- leflunomide
Which drug targets cells b/w G1 and S phases?
rapamycin (but typically not used clinically)
Which drugs target the ‘S’ phase of the cell cycle?
- corticosteroids
- antimetabolites
- Mycophenolate mofetil
Action - alkylating agents
- alkylate DNA causing breaks in molecule and cross-linking of twin strands
- inhibit protein synthesis in resting cells, prevent mitosis and kill dividing cells
Examples - alkylating agents
- cyclophosphamide, ifosfamide, chlorambucil
- melphalan, mechlorethamine, nitrosoureas
- procarbazine, dacarbazine
Is cyclophosphamide or chlorambucil more frequently used as an alkylating agent in I-M dz?
- CHLORAMBUCIL most commonly
- (cyclophosphaide not used for I-M dz but for shock chemo tx of lymphoma)
Action - chlorambucil
- rapidly metabolised to phenylacetic acid mustand
- site of biotransformation poorly define
- slowest acting, least toxic of all alkylating agents
- myelosuppression (main side effect) generally not observed until administered for > 1mo
- urinary and faecal excretion
- administered without food
Name 2 antimetabolites
- AZATHIOPRINE
- (methotrexate)
Action - azathioprine
- greater decrease of cellular than humoral immunity
- hepatic metabolism to active 6-mercaptopurine, then to 6-thioinosinic, 6-thioguanylic, thiouric acids
- compete with endogenous adenine and guanine to form non-function nucleic acid strands
- slow immunosuppressive effect? (at least 2 weeks, may be faster with steroids)
- these side effects are relatively uncommon: haematological, GIT, hepatic +/- neuromuscular toxicity
- CI in cats because narrow therapeutic window because cuases irreversible immunosuppression
What are vinca alkaloids? Examples?
- originally extracted from common periwinkle plant
- vincristine and (vinblastine) are the most commobly used
- difference is presence of a methyl (vinblastine) or formyl group (vincristine)
Action - vinca alkaloids
- bind to tubulin, block polymerisation, also break down pre-formed microtubules - increased release of PLTs from megakaryocytes
- both vincristine and viblastine used in the tx of ITP (usually vincristine)
- can be bolus IV or to pre-load PLTs
- severe extra-vascular vesicants!
- toxicity: haematological, GIT, neurologicall
Potential averse effects of corticosteroids
- CNS
- MSK
- GIT
- fluid, electrolyte balance
- metabolic
- endocrine
- immune system
Name 2 calcineurin inhibitors
- ciclosporin
- tacrolimus
- ACTION: target calcineurin which is a phosphatase enzyme
Which drugs target G1 of cell cycle?
- calcineurin inhibitors
- leflunomide
Action and use - ciclosporin
- IV and oral forms
- large volume of distribution
- primary hepatic metabolism
- therapeutic drug monitoring
- acute and chronic
- ketoxonazole may be used to reduce costs
- GIT, renal, hepatic toxicity, also hirsutism, gingival hyperplasia, papillomatosis, +/- diabetogenic (thus CI if DM).
Which drugs target the ‘S’ phase of the cell cycle?
- corticosteroids
- antimetabolites
- Mycophenolate mofetil
Action - alkylating agents
- alkylate DNA causing breaks in molecule and cross-linking of twin strands
- inhibit protein synthesis in resting cells, prevent mitosis and kill dividing cells
Examples - alkylating agents
- cyclophosphamide, ifosfamide, chlorambucil
- melphalan, mechlorethamine, nitrosoureas
- procarbazine, dacarbazine
Is cyclophosphamide or chlorambucil more frequently used as an alkylating agent in I-M dz?
- CHLORAMBUCIL most commonly
- (cyclophosphaide not used for I-M dz but for shock chemo tx of lymphoma)
Action - chlorambucil
- rapidly metabolised to phenylacetic acid mustand
- site of biotransformation poorly define
- slowest acting, least toxic of all alkylating agents
- myelosuppression (main side effect) generally not observed until administered for > 1mo
- urinary and faecal excretion
- administered without food
Name 2 antimetabolites
- AZATHIOPRINE
- (methotrexate)
Action - azathioprine
- greater decrease of cellular than humoral immunity
- hepatic metabolism to active 6-mercaptopurine, then to 6-thioinosinic, 6-thioguanylic, thiouric acids
- compete with endogenous adenine and guanine to form non-function nucleic acid strands
- slow immunosuppressive effect? (at least 2 weeks, may be faster with steroids)
- these side effects are relatively uncommon: haematological, GIT, hepatic +/- neuromuscular toxicity
- CI in cats because narrow therapeutic window because cuases irreversible immunosuppression
What are vinca alkaloids? Examples?
- originally extracted from common periwinkle plant
- vincristine and (vinblastine) are the most commobly used
- difference is presence of a methyl (vinblastine) or formyl group (vincristine)
What is vinorelbine?
- semi-synthetic derivative of vinblastine
- can cause neutropaenia
Name 2 calcineurin inhibitors
- ciclosporin
- tacrolimus
What is ciclosporin isolated from?
2 different fungal organisms
Action and use - ciclosporin
- IV and oral forms
- large volume of distribution
- primary hepatic metabolism
- therapeutic drug monitoring
- acute and chronic
- ketoxonazole may be used to reduce costs
- GIT, renal, hepatic toxicity, also hirsutism, gingival hyperplasia, papillomatosis, +/- diabetogenic (thus CI if DM).
What is human IVIG?
- polyspecific IgG derived from healthy donor plasma
- primary use in human medicine is in tx of immunodeficiency
- blockade of Fc R on mononuclear phagocytic cells accounts for rapid response
- inhibits phagocytosis of Ab-coated RBCs
- possible role in acute rx IMHA, immune-mediated non-regen anaemia, pure red cell aplasia, ITP, EM, TEN and SARDS
- SIDE EFFECTS: thromboembolism, hypersensitivity possible
- high cost, limited availability
What is Mycophenolate mofetil?
- increasingly common immunosuppressive drug
- antagonises the enzyme needed for BC and TC growth
List guidelines for immunosuppressive tx
- start with prednisone or prednisolone
- cats tolerate better
- max dose in dogs >30kg is 60-80mg/dog
- caution if used in parallel with doxycyline for ricekettsial or protozoal infection.
- caution if IMHA or aggressive I-M dz, consider adjunctive tx from outset: azathioprine in dogs or chlorambucil in cats
- caution as rx of acquired MG represents special case
- always consider co-morbidities
What is response to immunosuppressive therapy is porr?
- add adjunctive immuno-suppressants if not already being administered
- caution if combination rx used from outset and still no response, consider additional measures (vincristine, hIVIG)
- beware of occult infsn, neoplasia, iatrogenic cause
- always consider supportive measures (FWB, PLT-rick plasma)
How often should the CBC and UA be monitored?
- q7-14 days
- also examine urine sediment
(+/- monitor synovial fluid with sterile technique)
How should corticosteroid dose be tapered?
- over 3-4mo following initial remission
- 20-25% decrease in dose every 4-6 wks so long as clinical remission maintained
- don’t alter adjunctive rx at same time unless essential (e.g. fulminant infxn)
- if signs recur, return to previous dose: attempt reinduction of remission, taper more slowly next time
- corticosteroid rx may be stopped completely if clinical remission persists
- cautious tapering of additional agents over following 2-3 months
- caution if several immunosuppressant used, taper one at a time and slowly
- all rx may be stopped if long-term remission
- TLC essential
T/F: phenobarbital has a known I-M reaction sometimes
True
