Immunosuppressants Flashcards
(60 cards)
1
Q
Allergic Disease
A
- Hypersensitivity
- Use an anti-inflammatory NOT an immunosuppressant dose
- Common antigens that most individuals do not respond to lead to inflammation and tissue damage
2
Q
Immune-mediated disease
A
- Self antigens
- Foreign antigens
- Failure of tolerance
- Host tissues become 1° or 2° target –> inflammation, tissue damage
3
Q
Autoimmune disease
A
- A type of immune-mediated disease
- Self-antigens lead to inflammation and tissue damage
4
Q
Molecular mimicry
A
- Similarity between foreign and self peptides results in cross-activation of T or B cells
5
Q
Hemolytic anemia example of molecular mimicry
A
- Myocplasma pneumonia
6
Q
Rheumatic fever after Streptococcus pyogenes infection example of molecular mimicry
A
- M protein (virulence factor) of Streptococcus pyogenes cross-react with glycoproteins
- Heart, joints, kidney
7
Q
Immune stimulation and molecular mimicry
A
- Immunization
- Infection (e.g. Anaplasma, Rickettsia, etc.)
- Neoplasia
- Goal of treatment is to identify and eliminate underlying cause
8
Q
What is the goal of treatment if you can’t determine the underlying cause?
A
- Treat clinical signs
- Adverse effects
- Have to use immunosuppressants
9
Q
Allergic diseases and immunosuppressants
A
- USE ANTI-INFLAMMATORY DOSES**
e. g. Reactive airway disease, atopy, mild IBD, mild CNS noninfectious inflammatory diseases
10
Q
Immune-mediated and autoimmune Immunosuppressant philsophy
A
- Use Immunosuppressive > anti-inflammatory doses
- e.g. IMHA, ITP, Severe IBD, Pemphigus, SLE, Severe CNS non-infectious inflammatory diseases
- These are usually life threatening, and we have to be very agressive
11
Q
Glucocorticoids Overview
A
- 1° medication used clinically
- Best, fastest, and cheapest drug
- Mis-used regularly
12
Q
Relative potencies of glucocorticoids
A
- Budesonide > Dexamethasone > Prednisone/nisolone > Hydrocortisone
From most potent to least potent
13
Q
Which steroid (prednisone/prednisolone) do you use in cats and why?
A
- Cats you use prednisolone because they have decreased conversion from prednisone to prednisolone
- Some subpopulations of dogs that also don’t make this conversion
14
Q
Mechanism of action of Glucocorticoids in Immunosuppression
A
- Decreased capillary permeability (decreases extravasation)
- Decreases lymphocyte production
- Decreases cytokine release
- Stabilizes lysosomes (recycling center)
15
Q
Where are glucocorticoid receptors located?
A
- EVERY vertebrate animal cell
- However, every individual may have different expression of glucocorticoid receptors
- Because they are merely in every cell, does not mean that they will all react the same
- If we start an an appropriate dose
- Receptors expressed a little differently in every individual
- Other options too
16
Q
Physiologic dose for Prednisolone/Prednisone
A
- e.g. dog with Addison’s
- 0.25-0.5 mg/kg SID
- with Dr. Haines we said 0.15-0.3 mg/kg
17
Q
Anti-inflammatory dose for Prednisone/prednisolone
A
- 0.5-1 mg/kg SID
18
Q
Immunosuppressive dose for prednisolone/prednisone
A
- 2 mg/kg SID
19
Q
Half life of prednisone/nisolone
A
- 24 hours approximately
- Therefore we can usually do SID instead of BID
20
Q
Dexamethasone relative potency to prednisone and half life
A
- 7 times as potent as pred (divide pred dose by 7)
- Half life ~48 hours
21
Q
Maximum dose of Prednisone/Prednisolone per day
A
- 60-80 mg per DAY
- Sensitivity of larger animals tends to be increased with glucocorticoids
- Metered squared dosing
22
Q
Adverse effects of glucocorticoids
A
- Muscle catabolism
- PU/PD
- Panting
- Weakness
- SUppression of HPA axis
- Immune suppression
- Dysregulation of glucose
- Basically start looking like a Cushingoid dog
23
Q
Calcineurin Inhibitors Examples
A
- Cyclosporine (Atopica)
- FDA approved for allergic dermatitis in dogs and cats
- Tacrolimus used for perianal fistulas as a topical in veterinary medicine
24
Q
Mechanism of action of Calcineurin inhibitors
A
- Inhibits enzyme critical for T cell activation
- Calcineurin enzyme helps to import/induce nuclear factor of activated T cells (NFAT) –> this stimulates IL2 which helps to regulate WBC, especially T lymphocytes
25
Indications of calcineurin
- Modified (micro-emulsion form): no generic availability
- Allergic dermatitis
- Perianal fistula
- KCS (ophthalmic drops)
- IMHA, ITP, IMPA
26
Unmodified formulations and generic cyclosporine bioavailability
- Pretty poor
27
Cyclosporine or atopica cost-cutting
- Combined with ketoconazole
- Increases oral bioavailability of cyclosporine to cut cost
- Extra label drug use
- Basically inhibiting P-glycoprotein efflux to elevate it in the bloodstream
28
Adverse effects of Cyclosporine
- Gingival Hyperplasia***
- Immunosuppression
- Hepatoxicity
- Thromboembolism
29
Drug interactions of cyclosporine
- Inhibits Cytochrome P450 enzymes
- Inhibits P-glycoprotein
- Do NOT use with chemotherapy drugs taht are P-glp substrates; extralabel doses of ivermectin (Collie-morphism)
30
Purine interferants examples
- Azathioprine
31
MOA of Purine Interferents
- Anti-metabolite
- Metabolites of the drug interferes with incorporation of purines into DNA (guanine)
- Inhibits Proliferation of lymphocytes
32
Azathioprine use
- FDA approved for humans and ELDU for vet patients
- Frequently used in dogs
- Toxic in cats!!! DO NOT USE IN CATS
- Rare to use in horses
33
Clinical use of Azathioprine
- Dogs only
- IBD, IMHA, ITP
- Used in combination with glucocorticoids to enable dose reduction of glucocorticoid
34
How long does azathioprine take to work?
- Several days to weeks for full effects
| - Therefore it is NOT a good choice for monotherapy, especially in acute crisis
35
Oral bioavailability of azathioprine
- Good
36
Adverse effects of azathioprine
- bone marrow suppression!! Delayed and reversible
- Hepatotoxicity! (monitor liver enzymes)
- GI: vomit, diarrhea
- Immune suppression
37
Purine Interferants MOA
- Enzyme inhibition
- Non-competitive, reversible inhibitor of Inosine-5-monophosphate dehydrogenase (IMPDH)
- I think it works like azathioprine by inhibiting proliferation of lymphocytes
38
Purine interferant example
- Mycophenolate mofetil
| - FDA human approved; ELDU for vet patients
39
Clinical use of mycophenolate mofetil
- Dogs for sure; possibly cats
- IMHA, ITP, dermatologic conditions, IBD (?), SRMA
- Available oral and IV
40
Adverse effects of mycophenolate mofetil
- GI - diarrhea, anorexia, vomiting***
- Bone marrow suppression
- 30-40% of cats!!
41
Mycophenolate
- do NOT use Mycophenolate mofitil concurrently with azathioprine as they both inhibit purine synthesis
42
Pyrimidine interferant MOA
- Metabolite interference with pyrimidine synthesis enzyme
- Inhibits de novo pyrimidine synthesis
- Targets T and B cells that lack a salvage pathway
- uracil part of RNA
e. g. Leflunomide
43
Example of a pyrimidine interferant
- Leflunomide
44
Pharmacokinetics of Leflunomide
- Prodrug
| - Active metabolite is highly protein bound
45
Oral bioavailability of Leflunomide
- Good oral bioavailability
| - Cmax of active metabolite varied greatly in 4 dogs after single oral dose
46
Clinical use of leflunomide
- IMPA, ITP, IMHA, colorectal polyps
47
Adverse effects of leflunomide
- bone marrow suppression (potential necrosis)
- Make sure that you're doing CBCs!
- GI: vomiting, diarrhea
- Severe idiosyncratic reactions: hepatotoxicity, toxic epidermal necrolysis
48
Alkylating agent example
- Chlorambucil
| - Cyclophosphamide
49
MOA of ALkylating agents
- Causes cross-linking of DNA resulting in altered protein production
- Cytotoxic to proliferatin leukocytes
50
Pharmacokinetics of Chlorambucil and Cyclophosphamide
- Orally bioavailable
| - Compounded drug stability unknown
51
Clinical use of Chlorambucil
- Feline IBD/GI lymphoma
- K9IBD
- K9 Oncology patients
- Can be cost prohibitive for dogs
52
Cyclophosphamide indications
- Oncology patients
| - Dogs/cats
53
Adverse effects of alkylating agents (e.g. chlorambucil and cyclophosphamide)
- Cytotoxic myelosuppression
- Neurotoxicity (rare)
- GI: vomit, diarrhea, inappetence
54
Janus kinase inhibitor (JAK1-3) drug example
- Oclacitinib
55
Oclacitinib MOA
- Janus kinase (JAK)-1 and 3 inhibitor
- Inhibits activity of activity of pro-inflammatory cytokines (particularly IL-31)
- IL31 is a key mediator of pruritus in dogs
56
Oclacitinib trade name
- Apoquel
- FDA approved cutaneosu pruritus in dogs >12 months a day
- Oral twice a day
57
Cytopoint
- New once per month anti-IL31 caninized monoclonal antibody for SC injection has conditional license
58
Clinical use of oclacitinib or apoquel
- oral medication
- Atopic dermatitis (JAK1 > JAK2 and JAK3)
- IBD???
59
Adverse effects
- Can develop serious infections
- Concurrent use with other immunosuppressives hasn't been tested
- GI: vomiting and diarrhea
60
Which patients do you want to be cautious using corticosteroids with?
- NSAIDs, diabetics, pancreatitis, or Cushing's animals
