Immunosuppressive Therapy Flashcards
What is the primary immunosuppressive? What are 5 other secondary ones that can be added on?
glucocorticoids - Prednisolone, Dexamethasone
- Azathioprine
- Cyclosporine
- Chlorambucil
- Leflunomide
- Mycophenolate mofetil
What adjunctive and supportive therapies can be added for immunosuppressive therapy?
ADJUVANT = human IVIg, Vincristine, Melatonin
SUPPORTIVE = blood products, antiplatelet therapy
How are immunosuppressive therapies picked?
- expected course and prognosis of disease
- concurrent diseases
- safety and efficacy
- ease of administration and monitoring
- cost
Why are glucocorticoids a first-line therapy for immunosuppression?
- effective
- relatively rapid onset
- cheap
What are 4 immunosuppressive mechanisms of action of glucocorticoids?
- decreased inflammatory cytokines
- decrease antigen presenting
- down-regulate Fc receptor expression on macrophages
- suppression of T-cell function
What are 7 side effects associated with glucocorticoids?
- PU/PD, panting, polyphagia
- muscle atrophy and weakness
- iatrogenic hyperadrenocorticism
- vacuolar hepatopathy
- infections, sepsis
- GI ulceration
- hypercoagulability
What are 4 contraindications for the use of glucocorticoids for immunosuppression?
- diabetes mellitus
- infections
- hyperadrenocorticism
- NSAID therapy —> needs a washout period
How do the doses of Prednisolone and Dexamethasone compare?
PREDNISOLONE - 2 mg/kg/day, 50 mg/m^2, dose cap at 50-80 mg/day
DEXAMETHASONE - 7-10x more potent than Prednisone, 0.2-0.3 mg/kg/day (SP = 3 mg/mL)
How are glucocorticoid doses altered once remission is reached? What is done is a patient relapses?
decrease 25% every 2-4 weeks for 4-6 months with the goal of discontinuing or getting to the lowest effective dose
return to the original effective dose
What is avoided when decreasing glucocorticoid doses?
decreasing other medications
In what 4 situations should other therapies be considered when using glucocorticoids?
- no or poor response
- excessive side effects
- long duration of therapy anticipated
- corticosteroids contraindiccated
(consider drug availability, patient size, cost, adverse effects, and efficacy —> little to no evidence to support one over the other)
What are 3 mechanisms of actions of Azathioprine?
- inhibits purine synthesis, which disrupts lymphocyte proliferation
- blocks T-cell activation and promotes T-cell apoptosis
- decreases antibody synthesis
Is Azathioprine used in cats?
not usually —> metabolism relies on thiopurine methyltransferase, which is low in cats
What are the 4 most common side effects associated with Azathioprine? What is commoly monitored?
- cytopenias - 2-3 months
- hepatotoxicity - 1-4 weeks
- GI signs - mild and self-limiting
- CHRONIC - subclinical anemia (PCV >25-30%)
CBC/Chem
When is Azathioprine hepatotoxicity seen? What. isthe most common sign? How is it solved?
concurrent prednisone administration
discordant ALT > ALP, increased BILI
- dose reduction by 50% —> discontinuing can cause hyperbilirubinemia
- SAMe can prevent and/or reverse
Why is Azathioprine commonly used? What is it the proposed second-line agent of choice for?
has glucocorticoid-sparing effects
IMHA
What onset of Azathioprine have? How is it tapered?
slow, takes around 3 weeks
after prednisone, over 2-3 months - 2 mg/kg/day q 48 hr —> 1 mg/kg/day q 48 —> 1 mg/kg twice weekly
What are the 2 mechanisms of action of Cyclosporine? How is it unique?
- calcineurin inhibitor that decreases IL-2 synthesis
- impairs function of T-cells and blunts immune response specific for lymphocytes
NOT CYTOTOXIC = no bone marrow suppression
Cyclosporine drug interactions:
What is the most common side effect of Cyclosporine? What else is seen? What is not seen?
GI signs
- hepato/nephrotoxicity
- gingival hyperplasia
- hypertrichosis, excessive shedding, papillomatosis
- opportunistic infections (significant fungal infections)
- platelet activation - avoid with IMHA?
myelosuppression
What onset does Cyclosporine have?
days
How is therapeutic drug monitoring used for Cyclosporine?
- measurement of blood drug levels - measures build-up
- pharmacodynamic assays - drug effect on target cells assesses T-cell function and immune response (IL-2)
What administrations of Cyclosporine are available? What is not recommended?
- oral microemulsion improves bioavailability - Atopica —> expensive for large dogs
- injectable, IV - Sandimmune
oil-based, caution with generics
What is the mechanism of action of Cyclophosphamide? What is it used for?
alkylating agent
IMHA —> fallen out of fever for immunosuppression, mostly used for chemotherapy
What is the most common adverse effect of Cyclophosphamide?
hemorrhagic cystitis
What are the 2 mechanisms of action of Chlorambucil? What onset does it have? What species does it work particularly well in?
- alkylating agent
- targets B-cells
slow - takes 2 weeks
cats
What is the most common clinical sign associated with Chlorambucil? What are 3 other signs?
GI signs
- myelosuppression - dose-dependent, monitor CBC
- alopecia and poor hair growth in Poodles
- neurologic signs in cats
What is Chlorambucil used to treat?
- IBD
- PLE
- glomerulonephritis
cats
($$$, no generics available)
What are the 3 mechanisms of action of Leflunomide?
- inhibits de novo pyrimidine synthesis
- inhibits B and T-cell function and proliferation
- suppresses antibody production
myelosuppression!
What 4 side effects are associated with Leflunomide?
- GI - inappetence, vomiting
- myelosuppression
- cutaneous drug reactions
- hepatotoxicity
generally well-tolerated
What should be monitored in patients on Leflunomide? What is it used to treat?
CBC/Chem (ALT)
- IMA, ITP, MUE
- histiocytosis
- IMPA, pemphigus
- refractory colorectal polyps
What are the 3 mechanisms of action of Mycophenolate mofetil?
- reversible inhibitor of inosine monophosphate dehydrogenase
- inhibits de novo purine synthesis
- inhibits lymphocyte proliferation and antibody production
What is the most common side effect seen with Mycophenolate mofetil? What else is seen? What needs to be monitored?
GI - diarrhea, vomiting, poor appetite, large bowel diarrhea —> common in high doses, can add Metro
- myelosuppression
- lymphoma
CBC/Chem
What 5 drugs decrease the bioavailability of Mycophenolate mofetil? What drug is avoided?
- Fluoroquinolones
- Metronidazole
- PPI, uncoated tablets
- glucocorticoids increase metabolism
- Cyclosporine
Azathioprine - has similar MOA = more side effects
How can Mycophenolate mofetil be used that is different compared to the other second-line drugs?
can be used alone in satable disease
What are 3 pros and a con to using Mycophenolate?
- low toxicity
- tablet size makes dosing easier for medium to larger dogs (where Cyclosporine would be very expensive)
- can be used as a stand alone treatment or in refractory/relapsing disease
can take 2-3 weeks to start working
What is the monitoring timeline like for patients in remission?
- improvement in clinical signs and clinicopathologic abnormalities
- initiate prednisone taper by 25% q 2-4 weeks
- acceptable maintenance dose or discontinue
- continue treatment for 3 months
- taper second line drug in a similar manner
How is immunosuppressive relapse approached?
- prednisone + second line drug
- long-term therapy of low-dose glucocorticoid or second line drug
What is human IVIg? What is its mechanism of action?
purified IgG pooled from human plasma
blocks Fc receptors, eliminated pathogenic antibodies, inhibits complement, and modulates cytokine synthesis
How is human IVIg used for IMHA and ITP?
IMHA = short-term stabilization, refractory
- does not reduce transfusion requirements or length of hospitalization
ITP = reduces platelet recovery time and length of hospitalization
- does not increase expense compared to Prednisone alone
What are the 4 most common adverse effects associated with human IVIg?
- hypersensitivity reactions
- anaphylaxis
- hypercoagulation
- renal failure
What is Vincristine? What are 2 mechanisms of action? What is it most commonly used for?
vinca alkaloid chemotherapy
- disruption of intracellular microtubules
- cell cycle specific cytotoxicity
adjunctive treatment for ITP
How are platelets affected by Vincristine? What does this result in?
- platelets carry vincristine
- increases megakaryocytopoiesis and thrombosis
- reduces platelet destruction by intoxicated macrophages
increases platelets within 3-5 days and shortens hospitalization
What are the 4 most common side effects associated with Vincristine?
- perivascular extravasation
- neurotoxicity
- GI signs
- minimally myelotoxic
What supportive therapy is preferred in patients undergoing immunosuppressive therapy?
transfusions
- pRBCs**
- fresh whole blood*
- plasma, platelets
What gastroprotectants are commonly added for patients undergoing immunosuppressive therapy?
- H2 blockers - Famotidine
- PPIs - Omeprazole
- Sucralfate
What are the 2 most common causes of poor response to therapy?
- misdiagnosis - underlying etiology not detected, normal variations common in CKCS and Greyhounds
- not enough time for a response
What medication side effects and disease processes can look like a patient is not responding to therapy?
- failure of PCV to increase
- recent decrease in PCV
- non-regenerative anemia (Azathioprine!)
