1 – Immune Drugs Flashcards
Why use immunosuppressive drugs?
- Treat immune-mediated disease
o GOAL: reduce clinical signs
o *can’t cure them - GOOD EXAMPLE OF RISK MANAGEMENT
o Balance risk of adverse effects with risk of disease itself
What are immune-mediated disease examples?
- IMHA or IMT
- Inflammatory bowel disease
- Immune-mediated polyarthritis
- *immune-mediated derm diseases
- *don’t worry about them now
Immunosuppressive effects
- CONTINUUM OF EFFECTS (know the difference b/w high vs low dose)
- Favors one immune response, while minimizing another
- High dose, prolonged duration leads to severe immunosuppression
- Effects don’t occur immediately
Immunosuppressive effects do NOT occur immediately
- Typically a few weeks before clinical efficacy is observed
- Steroid-induced immunosuppression occurs faster (5-10 days)
What are the basic immunosuppressive drugs: 1st line ?
- Glucocorticoids
- Cyclosporine
Glucocorticoids
- Non-specific response (VERY BROAD)
- Anti-inflammatory vs. immunosuppressive effect: DEPENDS ON DOSE USED
o Higher=more likely it will be immunosuppressive (ex. >2mg/kg/day prednisolone) - Altered leukocyte migration and function
- Decreased lymphocyte function
- *back bone of immunosuppressive therapy in vet med (work well for many conditions)
Altered leukocyte migration and function of glucocorticoids
- Decrease function of monocytes and macrophages
o Decrease Ig receptors, impaired phagocytosis
Decreased lymphocyte function of glucocorticoids
- Cell-mediate immunity decreased most
- *decreased antibody production at HIGH dose
What are the vet formulations of glucocorticoids available?
- Prednisone, prednisolone (horses and cats)
- Dexamethasone
- *probably interchangeable in most patients
Short vs. long acting injectable formulations of glucocorticoids
- Long: acetate (prednisolone or methylprednisolone)
- Short: succinate (dexamethasone)
- *usually start with short acting formulation
- *often just going ORAL
Glucocorticoids therapy
- Start parenteral (in-clinic) and continue orally at home
- *immunosuppressive treatment: start aggressively and taper slowly
o 2-4mg/kg/day prednisone
o *takes time to have an effect so try to ‘hit them hard’ and then wind down (some are life threatening)
Cyclosporine (Atopica): 1st OR 2nd line systemic immunosuppressive drug
- *most reach for glucocorticoids first, some might use this first
- Inhibits enzyme (calcineurin phosphatase)
o Prevents induction of genes coding for cytokines and their receptors
o END RESULT: decrease IL-2 production - *used for atopic dermatitis
*still broad but more specific than glucocorticoids
What does decreased cytokines (IL-2) with cyclosporine (Atopica) lead to inhibition of?
- T-lymphocyte activation, chemotaxis
- Antigen-presenting cells (Langerhans in skin)
- Mast cell and eosinophil infiltration
What are the vet licensed oral forms of Cyclosporine (Atopica) (3)?
- Capsules (dogs): atopic dermatitis
- Solution (cats): various dermatitis conditions
- Used extra-label for other SYSTEMIC immune-mediated diseases
What is the bioavailability of cyclosporin (Atopica)?
- Highly variable
- *formulation-dependent
- Plasma concentration does NOT correlate well with efficacy/safety
o Therapeutic drug monitoring (TDM) NOT helpful - *PD monitoring is important (IL-2 assay at Mississippi St. Lab) (in states, not Canada)
o Overall effect of the drug and not an assay!
Cyclosporine topical (ophthalmic): Optimmune
- DRY EYE: Keratoconjunctivitis sicca (KCS)
- Choric superficial keratitis (CSK) in dogs
- *sandimmune in humans
Compounded cyclosporine CAPSULE potency vs. SOLUTION potency examples
- Capsules: dose was close
- Solution: way outside target zone (lots way too low and way too high)
What are the adverse effects of cyclosporine (Atopica)?
- Vomiting
- GI disorder/diarrhea (very few had to stop b/c of it)
- Gingival hyperplasia
- *Immunosuppression: secondary infections are uncommon, but do occur
- *Drug interactions: P-gp/CYP substrates
- *’safer’ than glucocorticoids (but can mitigate effects with monitoring, and likely MORE EFFECTIVE)
Atopica oral solution for cats: indication and what is it used for?
- Indication: control of feline allergic dermatitis
- Used for other feline immune-mediate dermatoses
o Eosinophilic granuloma/indolent ulcer
o Plasmacytic stomatitis
What are the 2nd line SYSTEMIC immunosuppressive?
- Azathioprine (Imuran)
- Chlorambuvil (Leukeran)
Azathioprine (Imuran)
- Oral or injectable (all human, NO VET)
- Mechanism: purine anti-metabolite=interferes with DNA synthesis
- Metabolized in liver to a variety of active metabolites and inactive metabolites (variability b/w animals)
- *variety of immunosuppressive uses in dogs (NOT USED IN CATS) (Ex. IMHA)
Lymphocytes and purines
- Have to make their own purines
- *more susceptible to azathioprine than other cell types
Azathioprine (Imuran) adverse effects
- **Myelosuppression
- Increased liver enzymes (dose-dependent)
- Pancreatitis
- Rebound ‘hyper-immune’ response possible if drug rapidly discontinued=so TAPER SLOWLY
Myelosuppression of azathioprine (Imurane)
- Especially in cats (decreased hepatic clearance=increased drug exposure)
- Anemia (common, but NOT severe)
Chlorambucil (Leukeran)
- Alkylating agents which cross-links DNA (humans, NO VET)
- Less potent/toxic version of chemotherapy drug cyclophosphamide
- *myelosuppression/vomiting common
o Fanconi’s syndrome and neurological signs: RARE - *expensive, so used for cats and small dogs (considered ‘steroid-sparing)
Chlorambucil (Leukeran) uses
- Lymphocytic/plasmacytic infiltrative disease (Ex. inflammatory bowel disease)
- Indolent ulcers
- Pemphigus
- Atopy
What are some Derm-specific immunosuppressive drugs?
- Apoquel (oclacitinib)
- Cytopoint
Apoquel (oclacitinib): how does it work
- Janus kinase (JAK) inhibitors
o Block intra-cellular communication
o Inhibits pruritic and pro-inflammatory cytokines (**ex. IL-31) that are dependent on JAK1 or JAK3 enzyme activity
o Minimal effect on cytokines involved in hematopoiesis (JAK2-dependent)
What is the indication of Apoquel?
- Control of PRURITUS associated with allergic dermatitis
- Control of ATOPIC DERMATITIS in dogs at least 12 months of age
- *does NOT fix it
Apoquel efficacy
- Rapid effect is typical (faster than cyclosporine)
o Should see effects within a few days - *Drug does work and has an impact
- ORAL twice a day (BID) for 14 days
What are the adverse events of Apoquel?
- Immunosuppression (secondary infection, demodicosis)
- Low incidence of vomit/diarrhea
Cytopoint (canonized monoclonal Ab)
- NOT a drug
- Canine monoclonal Ab against IL-31
- Administered as SC injection: long duration of effect (>30d)
o Can’t be oral=broken down
o Can train clients to do them at home (STORAGE, refrigerator)
o Does decrease over time - Can be used CONCURRENTLY with other atopic derm therapy: ‘trail and error’ approach
What is the indication of Cytopoint?
- Aids in REDUCTION of clinical signs associated with atopic dermatitis in dogs
- *doesn’t solve the underlying allergy problem
Apoquel vs. Cytopoint
- No real differences in efficacy or safety
