Immunosuppressants & Immunomodulators

Question 1

What are eicosanoids?

Answer 1

Signaling molecules derived from FA (plasma membrane lipids –> Arachidonic Acid (AA) –> eicosanoids

Question 2

What enzymes are involved in eicosanoids production?

Answer 2

1. Phospholipases (PLA2): plasma membrane lipids –>AA

2. Cyclooxygenase (Cox 1/2): AA –> eicosanoids

Question 3

What are eicosanoids/prostanoids we have to know?

Answer 3

Prostaglandins (PGE2) & Thromboxanes (TXA2)

Question 4

What is the MoA of Cox Inhibitors?

Answer 4

Inhibit the synthesis of prostanoids

Question 5

What is the main role of COX 1 & 2?

Answer 5

Cox 1 is constitutive (maintains homeostatic function)

• Renal, GI, Platelet formation
• Usually produce toxic effects when inhibited

Cox 2 is inducible (promote inflammatory response)

• Pain, fever, inflammation
• Usually produce therapeutic effects when inhibited

Question 6

What are main COX inhibitors and their toxicities?

Answer 6

NSAIDS

• Gastic Damage (bleeding, ulcers)
• Nephron/kidney damage
• Inhibits platelet activation & clotting

Question 7

What is the MoA of NSAID for Gastic Damage?

Answer 7

NSAIDs inhibit PGE2 (important mucosal component) which leads to weakened mucous layer in the stomach (bleeding, ulcers).

Question 8

What is the MoA of NSAID for Nephron Damage?

Answer 8

NSAIDs inhibit PGE2 (vasodilator) acting on glomerulus of kidney which leads to nephron damage.

Question 9

What is the MoA of NSAID for Platelet Inactivation?

Answer 9

NSAIDs inhibit TXA2 (promotes platelet activation) which leads to clotting inability.

• NSAIDs can provide therapeutic effect for type II MI/stroke in older patients.

Question 10

How is Asprin used off-label as a treatment?

Answer 10

Aspirin is used in conjunction with IVIG to treat kawasaki

Question 11

What are examples of Aspirin toxicity?

Answer 11

1. Reye’s Syndrome (when given asprin during viral infections)
2. Bronchoconstriction (causes aspirin-sensitive asthma by promoting production of brochoconstricting products)
3. Acute & Chronic Aspirin Poisoning

Question 12

What asprin-related drugs can cause chronic aspirin poisoning?

Answer 12

subsalicylate

Question 13

What NSAIDs are non-selective (affect COX 1/2)?

Answer 13

1. Ibuprofen
2. Naproxen
3. Aspirin

Question 14

What NSAIDs are selective COX-2 inhibitors?

Answer 14

1. Celecoxib

2. Rofecoxib

Question 15

What is the advantage of selective COX-2 inhibitors?

Answer 15

fewer GI toxicities

Question 16

What is the disadvantage of selective COX-2 inhibitors?

Answer 16

more CV toxicities like heart attack because COX-2 inhibitors also inhibit the prostacyclin (PGI2) synthesis which are anti-clotting.

Question 17

What are coticosteroid drugs we have to know?

Answer 17

1. Hydrocortisone
2. Prednisone
3. Methylprednisolone
4. Dexamethasone

Question 18

What are 2 therapeutic mechanisms of Corticosteroids?

Answer 18

1. Inhibit pro-inflammatory cytokines
2. Increase anti-inflammatory lipocortin/annexin 1 (inhibits PLA2)
   * Both mechanisms alter the gene transcription in target cells

Question 19

What are examples of corticosteroid toxicities?

Answer 19

1. Oral inhalation (like inhaler for asthma) can cause thrush and penumonia.
2. Cushing Syndrome (aka. hypercortisolim) including affected skin and bones.

Question 20

Corticosteroids can weaken bone in cushing syndrome by decreasing production of

Answer 20

osteocalcin

Question 21

Corticosteroids can weaken skin in cushing syndrome by decreasing production of

Answer 21

keratin

Question 22

What drugs are calcineurin inhibitors?

Answer 22

1. Cyclosporin

2. Tacrolimus

Question 23

What is the mechanism of calcineurin inhibitors?

Answer 23

They inhibit T cell activation by binding to calcineurin to prevent TCR signaling to produce more IL-2.

Question 24

What is the most common calcineurin toxicity?

Answer 24

Non-Hodgkin’s lymphoma

Question 25

What drug is an mTOR inhibitor?

Answer 25

Sirolimus

Question 26

What is the mechanism of Sirolimus?

Answer 26

Sirolismus binds to mTOR (in T cell) and inhibits IL-2 synthesis.

Question 27

What drug is a Jak/stat inhibitor?

Answer 27

Tofacitinib

Question 28

What is the mechanism of Tofacitinib?

Answer 28

Tofacitinib inhibits dimerization of Jak and Stat proteins to prevent IL-2 and IFN-y synthesis in T cells.

Question 29

What drugs are cytokine antibodies?

Answer 29

1. Adalimumab 2. Infliximab 3. Ethanercept * ends in _mab * large so must be given IV or IM

Question 30

What is the mechanism of cytokine antibodies?

Answer 30

They bind to TNF-a to prevent it from binding to TNF receptor.

Question 31

What drugs are DNA synthesis inhibitors?

Answer 31

1. Azathioprine (AZA) 2. Methotrexate 3. Mycophenolate

Question 32

What is the mechanism of Azathioprine?

Answer 32

AZA has 2 products: both leading to cell death 1. inhibit purine synthesis 2. aberrant nucleotide incorporated into DNA (this product can act like mutation and lead to leukemia and carcinoma)

Question 33

What is the mechanism of Methotrexate?

Answer 33

Methotrexate inhibits DHFR enzyme necessary for making folic acid, therefore DNA synthesis is inhibited.

Question 34

What drugs are in pregnancy category D/X

Answer 34

AZA & Mycophenolate (D) | Methotrexate (X)

Question 35

What drugs are cytokine receptor antibodies?

Answer 35

1. Anakinra 2. Rituximab 3. Tocilizumab

Question 36

What is them mechanism of cytokine receptor antibodies?

Answer 36

Anakinra binds to IL-1 receptor (in many cells). Rituximab binds to CD20 (in B cells). Tocilizumab binds to IL-6 receptor.

Question 37

What drugs are immunosuppressants/immunomodulators of transplantation?

Answer 37

1. Calcineurin Inhibitors 2. mTOR inhibitor 3. Azathioprine & mycophenolate 4. Rituximab

Question 38

What drug is analgesic, anti-pyretic, and NOT anti-inflammatory?

Answer 38

Acetaminophen

Question 39

What is the MoA of acetaminophen

Answer 39

Cox 1/2 inhibitor in the CNS only.