Immune-Mediated Dz Tx Flashcards
Necessary adjunctive therapies for IMD?
- diet
- topical tx and gastrointestinal barrier protection for steroid (only if indicated w/ concurrent liver/spleen dz etc. or thrombocytopenia d/t ^ risk of bleeding from ulcer)
- blood products (esp anaemia) Darbopoietin (erythropoetin substitute)
- ? Danazol (androgen, not used much now, min evidence)
- ? Plasmapheresis (high level establishments, emergency only with intractable haemolysis etc)
What should be cautioned with steroids and nutrition?
- PEG tube risks
- v fibrous tissue formation so when removed septic peritonitis will ensue
Outline nursing care needed for IMD. LOOK UP
> recumbency - UD, hygeine, excercie > physical signs of deterioration - analgesia, comfort > nutrition - naso-oesophageal, oeseophageal, PEG > water > IV catheter care and fluid tx > diagnostic samples > client comms
How do corticosteroids function on a cellular level?
- associate with binding proteins (transcortin and albumin)
- dissociate, passively diffuse into cell
- bind to cytoplasmic receptors (>3)
- conformational change of R unmasks DNA binding domains
- associates with GREs following nuclear translocation
CEellular targets of corticosteroids?
> inflam cells - eosinophils - T cells - mast cells - macrophages - denritic cells > structural cells - epithelium - endothelium - airway smooth muscle - mucous glands
How do different corticosteroids differ?
- GC and MC activity
> dexamethasone NO MC activity, potent GC
> prednisone/prednisolone GC and MC
How do seroids in US and UK differ?
- Prednisolone used for everything UK
- PrednisONE USA
How does potency, duration or action and dose of the 3 main corticosteroids differ? LOOK UP
> prednisolone - potency 1 - dose 2-4mg/kg/d - DOA 12-36 > methylpred - 1.25 - 2-4 - 12-36 > dex - 7-10 - -
Potential adverse effects of immunosuppressive doses of steroids?
> worse in dogs, WARN OWNERS!!!
- sarcopenia (muscle melt away)
- GIT (esp ulceration)
- MC activity -> fluid retention etc. (pred and methyl pred) contraindicated for CHF
- metabolic effects (bone density)
- Cushingoid appearance after 2-3weeks
- immune vulnerability
What other immunosuppressive drugs (other than steroids) can be used for IMD? What stages of the cell cycle do they act at?
> Mitosis phase - Vinca alkaloids (eg. vinblastine) > GI - calcinuerin inhibitors (eg. cyclosporine) - leflunomide ~ G1-S rapamycin (not used vet) > S - steroids - antimetabolites - mycophenolate mofetil
How do alkylating agents work? LOOK UP
- cross-links twin strands
- inhibits protein synthesis in resting cells, prevents mitosis, kills dividing cells
Egs of alkylating agents?
> cyclophosphamide
- now no longer advocated, only for CHOP lymphoma
ifosphamide
chlorambucil
- minimally toxic, min side effects (myelosuppression)
melhalen, mechlorethamine, nitrosoureas
procarbazine, decarbazine
Outline cyclophospmahde
- dont use
Overview of chlorambucil
- rapidly metabolised (mustard thing)
- slowest acting and least toxic of all alkylating agents
- myelosupression only when admin >1 month
- urinary and feacal excretion
- administer without food
Which immunosuppressive drug is contraindicated in cats?
Azathioprene (irreversiple BM suppression)
Overview of azathioprene
- greater effeect on cellular than humoral immunity
- hepatic metabolism
- competes with endogenous A and G nucleotides -> non-fucntional nucleic aid strands
- slow immunosuppressive effect
- haaem, GIT, hepatic +- neuromuscular toxicity (can exacerbate MG)
What can azathioprene be used alongside?
Steroids
Where are vinca alkyloids derived from? Whih are the 2 most common?
> common periwinkle plant!
- vincristine and vinblastine (though blastine not used for IMD)
How do vinca alkaloids work? ROA?
- bind tubulin, block polymerisation
- breakdown preformed microtubules and ^ rate of PLT release from megakaryocytes
> esp good for IM thrombocytopenia (^no. platlets) - bolus IV, or to preload PLTs
- severe extra-vascular vesicants (get it in the vein!!)
How must vinca- alkaloids be given? Side effects?
- IV
- severe extra-vascualr irritation and sloughing
> warm compress and flush saline if injected wrong
> side effects: - haem
- GIT
- neurological tox (megacolon/megaoesophagus w/ repeated dosing)
Vincristine and vinblastine. ALternative drug that is not used d/t severe neutropenia?
> Vinorelbine
- Semi-synthetic derivative of vinblastine, neutropenia
Lic calcineurin inhibitiros?
- Atopica for atopic derm (Ciclosporin)
- Tacrolimus (Anal furunculosis topically)
Cilosporin and dosing
- IV and oral forms
- large volume of distribution and 1* hepatic metabolism
- should probably monitor drug conc (peak @ 2hrs post administration, acute and chronic)
How can dose of ciclosporin be decresed? Side effects?
> Give ketoconazole to inhibit hepatic metabolism
SIde effects
- renal, GI, heptic
- hirsuitism, gingival hyperplasia, paillomatosis
+- diabetogenic (CI in diabetic patients)
How can GIT side effecs of ciclosporin be reduced?
Feed with some food
What is IVIG? Side effects?
- intravenous immunoglobulin (human) Minimal evidence
- polyspecific IgI derived from healthy donor plasma
- 1* use in human medicine tx of immunodeficiency
- blockade of Fc receptors on mononuclear phagocytic cells (rapid repsonse)
- inhibits phagocytosis of Ab-coated canine RBCs (involved in extravascular breakdown)
- possible role in tx IMHA, IM non-regenerative anaemia, pure red cell aplasia, ITP, EM, TEN, SARDS
> thromboembolism and hypersensitivity and hypertension possible (blood product, so give slowly) - high cost, limited availability
Mechanism of action IVIG
- IgG from healthy donors
Mycophenolate mofetil overview
- fast
- IV
- more GI effects
~= azothioprene - purine synth antagonist
Initial tx for IMD?
> prednisone/prednisolone
- @3-4mg/kgPO (cats tolerate better)
- Max dose dogs >30kg (50-60mg/m^2)
What concurrent tx should be considered for initial tx IMD? In what situations?
> potential for occult rickettsial/protozoal infection
- doxycline + water flush (stricture formation possible)
if IMHA or aggressive IMD
- adjunctive from outset (azathioprene in dogs, chlorambucil in cats)
MG (myasthenia gravis)
- cholinesterase inhibitors instead and titrate low dose upwards (rather than starting high dose)
always consider comorbidities
How long is clinical response assessed over?
7d
If response poor after 7d, what do you do? LOOK UP
- add adjunctive immunosuppressant
- if combo used from start, consider vincrsinte, hIVIG etc.
> beware occult infection, neoplasia and iatrogenic causes that you may have missed!! - always consider supportive measures eg. fresh whole blood, PLT-rich plasma
How often should CBC and UA be repeated? What else should/could be monitored depending on case?
- q7-14d
- look at urine sediment)
- synovial fluid
DOsing regime and reductino rate of corticoseroids?
- 20-25% decerase in dose q4-6weeks as long as clinical remission maintained
- do nto alter adjunctive tx at the same time as steroids UNLESS ESSENTIAL (eg. fulminant infection)
- if signs recurr, return to previous dose and attemt reintroduction of remission more slowly
Stopping corticosteroids…
- can be stopped altogether if clinical remission persists
- cautious tapering of any additional agents atetmpted over following 2-3months
> if several immunosuppressants ued at once only do one at a time
Which antiepileptic drug has potential immune-mediated reactions assocate with it?
- phenobarb
When is prognosis worsened for immunemediated dz patients?
- 2* infection
General tx principles of IMD?
- halt ongoing damage, satisfy nutritional and nursing needs
- non-sepcific immunosuppression mainstay
- corticosteroids form mainstay of tx, various adjuncts helpful
- novel agents potential for more potent and targetted immunosuppression
