B-31. Immunopharmacology II. (Inhibitors of cytokine gene expression, 5-ASA derivatives)

Question 1

Inhibitors of cytokine expression classes?

Answer 1

a. ) Calcineurin Inhibitors
b. ) mTOR Inhibitors
c. ) JAK Inhibitors

Question 2

Calcineurin inhibitors (3 drugs)

Answer 2

1. ) Cyclosporin A

2. ) Tacrolimus and Pimecrolimus

Question 3

mTOR inhibitors (3 drugs)

Answer 3

1. ) Sirolimus (aka rapamycin)
2. ) Everolimus
3. ) Temsirolimus

Question 4

Jak inhibitors (2 drugs)

Answer 4

1.) Tofacitinib and Baricitinib

Question 5

Cyclosporin A MOA?

Answer 5

Binds cyclophilin, a protein with proline-cis-trans-isomerase activity, forming a drug-protein complex that inhibits calcineurin which blocks the TCR activation cascade and thus NFAT/NF-kB activation and IL-2 secretion.
This results in blockade of cellular immunity.

Question 6

Cyclosporin A, What does it consist of and where is it isolated from?

Answer 6

A hydrophobic cyclic peptide of 11 amino acids; isolated from P. inflatum

Question 7

Kinetics of Cyclosporin A

Answer 7

1.) IV injection (solvent is polyoxyethylated ricinus oil) may cause anaphylaxis
2.) Oral solution
-35% bioavailable (absorption inhibited by glycoprotein P)
High protein binding so you have to monitor whole blood levels; metabolism by CYP3A4
Many different preparations available with different kinetics (including eye drop)

Question 8

Cyclosporin A indications

Answer 8

1. ) Transplants
   - prevention of GVHD; heart + liver transplants
2. ) Psoriasis and RA
3. ) Xerophthalmia
   - as in Sjogren’s; as eye drop

Question 9

Side effects of Cyclosporin A

Answer 9

1. ) Nephrotoxic (highly; vasoconstricts + increased Na reabsorption)/ hepatoxic/ neurotoxic
2. ) Hypertension and hyperglycemia and hyperlipedmia
3. ) Gingival hyperplasia
4. ) Hirsutism

Question 10

Tacrolimus and pimecrolimus structure and isolated from?

Answer 10

Tacrolimus is a macrolide structure, isolated from Streptomyces tsukubaensis

Question 11

Tacrolimus and pimecrolimus MOA

Answer 11

binds FKBP12 (FK506 binding protein) forming a drug protein complex inhibiting calcineurin
(Has stronger inhibition than cyclosporine; pimecrolimus has same MOA)

Question 12

Kinetics and indicaitons of tacrolimus and pimecrolimus

Answer 12

Kinetics: oral (low bioavailability) or IV
Indications:
1.) Transplantation- liver, heart, and kidney
2.) Atopic dermatitis (as a topical cream)
3.) Off-label: AI disease, GVHD and lung transplant

Question 13

Side effects of tacrolimus and pimecrolimus

Answer 13

Similar to cyclosporine with increased diabetes and neurotoxic risk, no gingival hyperplasia/hirutism

Question 14

What is Sirolimus similar to? from?

Answer 14

“Rapamycin”; similar to tacrolimus; from S. hygroscopicus

Question 15

Everolimus and Temsirolimus
What kind of variants?
MOA?

Answer 15

Synthetic variants
MOA: bind FKBP12 which complexes to inhibit mTOR (“mammalian target of rapamycin”)
-mTOR inhibition results in decreased IL-2 induced lymphocyte activation
-in other cells, mTOR is involved in GF response, angiogenesis, fibroblast proliferation, autophagocytosis, and metabolism

Question 16

Everolimus and Temsirolimus kinetics

Answer 16

Sirolimus + everolimus= oral

temsirolimus= IV

Question 17

Everolimus indications

Answer 17

1. ) Kidney cancers (everolimus or temsirolimus)
2. ) Breast, neuroendocrine cancers, and astrocytoma (everolimus)
3. ) Tuberous sclerosis- rare genetic disorder of many benign tumors (everolimus)

Question 18

Sirolimus indications

Answer 18

1. ) Transplantation- kidney/GVHD (sirolimus)

2. ) Coronary grafts/stents (sirolimus coating to prevent re-occlusion)

Question 19

Temsirolimus indication

Answer 19

1. ) Kidney cancers (everolimus or temsirolimus)

2. ) Mantle-cell lymphoma (temsirolimus)

Question 20

Side effects of Everolimus and Temsirolimus

Answer 20

1. ) Myelosuppression (thrombocytopenia/pancytopenia)
2. ) Insulin resistance (with hyperglycemia; via metabolic effects of mTOR inhibition)
3. ) Hyperlipidemia
4. ) Hepatotoxicity, pneumonitis, and GI upset

Question 21

Tofacitinib and Baricitinib MOA

Answer 21

Tofacitinib blocks JAK1 + 3
Baricitinib blocks JAK1 + 2
-Leading to the blocking of IL-2 mediated lymphocyte activation
Also blocks effects of IL-4, 6, 7, 9, 15, and 21
Are considered “non-classical” biologicals- low molecular weight

Question 22

Kinetics of Tofacitinib and Baricitinib

Answer 22

Oral administration, good bioavailability
Tofacitinib
-short T half-life, extended release forms with CYP metabolism
Baricitinib
-longer T half-life with kidney elimination

Question 23

Tofacitinib and Baricitinib indication

Answer 23

RA (alone or in combo with MTX; other indications in research

Question 24

Side effects of Tofacitinib and Baricitinib? Worse in combo with what?

Answer 24

1.) Airway infections
2.) Hyperlipidemia
3.) CK and liver enzyme elevation
4.) Myelosuppression
Worse in combo with MTX

Question 25

5-aminosalicylic acid derivative drugs

Answer 25

Sulfasalazine (SSZ) (also olsalazine + balsalazide)

Question 26

Sulfasalazine MOA

Answer 26

Are cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine
5-ASA is not absorbed and acts in the GI tract to
1.) induce PPARy expression inhibiting NFkB and TLRs
2.) Block cytokines IL-1/2/8 and TNF-alpha as well as COX/LOX enzymes
3.) Has antioxidant effect as well

Question 27

What effect does the metabolite sulphapyridine have?

Answer 27

Sulphapyridine is absorbed from the colon and may be activate for RA patients via unknown mechanism

Question 28

Sulfasalazine kinetics

Answer 28

10-20% uncleaved SSZ is absorbed and eliminated in bile and urine
sulphapyridine is metabolized in liver

Question 29

Indication of sulfasalazine

Answer 29

1. ) IBD
   - better for UC than Crohn’s (both SSZ and the derivatives olsalazine and balsalazide)
2. ) RA-mildly effective
3. ) Ankylosing Spondylitis

Question 30

Sulfasalazine side effects

Answer 30

1. ) Nausea, vomiting, HA, malaise (all drugs)
2. ) Myelosuppresion and oligospermia
   - reversible (only SSZ)
3. ) Rash
   - common (only SSZ)
4. ) Sulfonamide toxicity