Immunosuppressants Flashcards

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Immune-mediated disease

A
  • Self antigens
  • Foreign antigens
  • Failure of tolerance
  • Host tissues become 1° or 2° target –> inflammation, tissue damage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Autoimmune disease

A
  • A type of immune-mediated disease

- Self-antigens lead to inflammation and tissue damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Molecular mimicry

A
  • Similarity between foreign and self peptides results in cross-activation of T or B cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Hemolytic anemia example of molecular mimicry

A
  • Myocplasma pneumonia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Allergic diseases and immunosuppressants

A
  • USE ANTI-INFLAMMATORY DOSES**

e. g. Reactive airway disease, atopy, mild IBD, mild CNS noninfectious inflammatory diseases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Glucocorticoids Overview

A
  • 1° medication used clinically
  • Best, fastest, and cheapest drug
  • Mis-used regularly
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Relative potencies of glucocorticoids

A
  • Budesonide > Dexamethasone > Prednisone/nisolone > Hydrocortisone

From most potent to least potent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Anti-inflammatory dose for Prednisone/prednisolone

A
  • 0.5-1 mg/kg SID
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Immunosuppressive dose for prednisolone/prednisone

A
  • 2 mg/kg SID
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Half life of prednisone/nisolone

A
  • 24 hours approximately

- Therefore we can usually do SID instead of BID

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Indications of calcineurin

A
  • Modified (micro-emulsion form): no generic availability
  • Allergic dermatitis
  • Perianal fistula
  • KCS (ophthalmic drops)
  • IMHA, ITP, IMPA
26
Q

Unmodified formulations and generic cyclosporine bioavailability

A
  • Pretty poor
27
Q

Cyclosporine or atopica cost-cutting

A
  • 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
Q

Adverse effects of Cyclosporine

A
  • Gingival Hyperplasia***
  • Immunosuppression
  • Hepatoxicity
  • Thromboembolism
29
Q

Drug interactions of cyclosporine

A
  • 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
Q

Purine interferants examples

A
  • Azathioprine
31
Q

MOA of Purine Interferents

A
  • Anti-metabolite
  • Metabolites of the drug interferes with incorporation of purines into DNA (guanine)
  • Inhibits Proliferation of lymphocytes
32
Q

Azathioprine use

A
  • 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
Q

Clinical use of Azathioprine

A
  • Dogs only
  • IBD, IMHA, ITP
  • Used in combination with glucocorticoids to enable dose reduction of glucocorticoid
34
Q

How long does azathioprine take to work?

A
  • Several days to weeks for full effects

- Therefore it is NOT a good choice for monotherapy, especially in acute crisis

35
Q

Oral bioavailability of azathioprine

A
  • Good
36
Q

Adverse effects of azathioprine

A
  • bone marrow suppression!! Delayed and reversible
  • Hepatotoxicity! (monitor liver enzymes)
  • GI: vomit, diarrhea
  • Immune suppression
37
Q

Purine Interferants MOA

A
  • Enzyme inhibition
  • Non-competitive, reversible inhibitor of Inosine-5-monophosphate dehydrogenase (IMPDH)
  • I think it works like azathioprine by inhibiting proliferation of lymphocytes
38
Q

Purine interferant example

A
  • Mycophenolate mofetil

- FDA human approved; ELDU for vet patients

39
Q

Clinical use of mycophenolate mofetil

A
  • Dogs for sure; possibly cats
  • IMHA, ITP, dermatologic conditions, IBD (?), SRMA
  • Available oral and IV
40
Q

Adverse effects of mycophenolate mofetil

A
  • GI - diarrhea, anorexia, vomiting***
  • Bone marrow suppression
  • 30-40% of cats!!
41
Q

Mycophenolate

A
  • do NOT use Mycophenolate mofitil concurrently with azathioprine as they both inhibit purine synthesis
42
Q

Pyrimidine interferant MOA

A
  • 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
Q

Example of a pyrimidine interferant

A
  • Leflunomide
44
Q

Pharmacokinetics of Leflunomide

A
  • Prodrug

- Active metabolite is highly protein bound

45
Q

Oral bioavailability of Leflunomide

A
  • Good oral bioavailability

- Cmax of active metabolite varied greatly in 4 dogs after single oral dose

46
Q

Clinical use of leflunomide

A
  • IMPA, ITP, IMHA, colorectal polyps
47
Q

Adverse effects of leflunomide

A
  • bone marrow suppression (potential necrosis)
  • Make sure that you’re doing CBCs!
  • GI: vomiting, diarrhea
  • Severe idiosyncratic reactions: hepatotoxicity, toxic epidermal necrolysis
48
Q

Alkylating agent example

A
  • Chlorambucil

- Cyclophosphamide

49
Q

MOA of ALkylating agents

A
  • Causes cross-linking of DNA resulting in altered protein production
  • Cytotoxic to proliferatin leukocytes
50
Q

Pharmacokinetics of Chlorambucil and Cyclophosphamide

A
  • Orally bioavailable

- Compounded drug stability unknown

51
Q

Clinical use of Chlorambucil

A
  • Feline IBD/GI lymphoma
  • K9IBD
  • K9 Oncology patients
  • Can be cost prohibitive for dogs
52
Q

Cyclophosphamide indications

A
  • Oncology patients

- Dogs/cats

53
Q

Adverse effects of alkylating agents (e.g. chlorambucil and cyclophosphamide)

A
  • Cytotoxic myelosuppression
  • Neurotoxicity (rare)
  • GI: vomit, diarrhea, inappetence
54
Q

Janus kinase inhibitor (JAK1-3) drug example

A
  • Oclacitinib
55
Q

Oclacitinib MOA

A
  • 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
Q

Oclacitinib trade name

A
  • Apoquel
  • FDA approved cutaneosu pruritus in dogs >12 months a day
  • Oral twice a day
57
Q

Cytopoint

A
  • New once per month anti-IL31 caninized monoclonal antibody for SC injection has conditional license
58
Q

Clinical use of oclacitinib or apoquel

A
  • oral medication
  • Atopic dermatitis (JAK1 > JAK2 and JAK3)
  • IBD???
59
Q

Adverse effects

A
  • Can develop serious infections
  • Concurrent use with other immunosuppressives hasn’t been tested
  • GI: vomiting and diarrhea
60
Q

Which patients do you want to be cautious using corticosteroids with?

A
  • NSAIDs, diabetics, pancreatitis, or Cushing’s animals