Antiinflammatory Drugs

Front 1

What type of cell is part of both the innate and adaptive immune systems

Back 1

Mast Cell
(Can degranulate due to complement or IgE mediated activation)

Front 2

Acute Transplant rejection is mediated by

Back 2

Preformed Ab

Front 3

An APC must express

Back 3

Peptide/MHC
CD28
B7-1 and B7-2

Front 4

2 types of APCs

Back 4

Dendritic cells and Monocyte

Front 5

TH1 effector T-cell
1) induiced by APC secretion of_____
2) secretes

Back 5

1) IL-12
2) IFN-gama

Front 6

TH17 effector T-cell
1) induced by APC secretion of_____
2) secretes

Back 6

1)IL-23
2)IL-17, IL-22

Front 7

Genertion 1 drugs are generally termed

Back 7

Antiproliferatives

Front 8

Name the 5 Generation 1 drugs we discussed

Back 8

1) Cyclophosphamide
2)Azathiprene
3)Methotrexate
4)Mycophenylate
5) Leflunomide

Front 9

1)What are the negative side effects of most Generation 1 drugs
2) what is the exception to this and what is it's side effect?

Back 9

1)Bone marrow supression
Infection

2) Leflunomide- Diarrhea

Front 10

Cyclophosphamide
1)Generation
2)Mechanism of action
3) elimination/consequence of this
4)Cytotoxic only to:

Back 10

1) First
2)Bifunctional DNA alkylation which cross links DNA. This causes DSBs during repair and shuts down cell division.
3)Elimination not kidney dependant (can use this during renal failure)
4)Cytotoxic only to dividing cells

Front 11

What Generation 1 drug would you give to a pt. in Kidney failure?

Back 11

Cyclophosphamide because is is not renally cleared

Front 12

Describe when it is best to give Cyclophosphamide with respect to Ag exposure and why?

Back 12

Give at same time as Ag because before Ag, T-cells will not be proliferating, and 10-days after, all the proliferating will be done.

Front 13

Azahioprene
1)Generation
2)Mechanism
3) TO what active substance is it metabolized and by what enzyme is this done.
4) What effect does this metabolite have?

Back 13

1) First
2) Starves cell of purines
3) Converted to 6-Mercaptourine and then to T-IMP by HGPRT.
4)T-IMP is a competitive inhibitor that inhibits conversion of IMP to AMP or GMP (purines)

Front 14

Methotrexate
1)Generation
2)Mechanism
3) What is the pathway by which Mtx acts
4)How does its structure explain its mechanism of inhibiton?

Back 14

1) first
2) Starves cells of purines
3) Inhbits DHFR that transforms DHF back to THF. THF is required in several 1-carbon transfers in the synthesis of purines
4)it is a DHF analog

Front 15

Methotrexate, aside from blocking T-cell proliferation, also blocks ___1___.
2) This is exploited to treat what disease?

Back 15

1) B-celll proliferation
2) Rheumatoid Arthritis

Front 16

Mycophenylate
1) Generation
Inhibits production of __2___ from ____3___
4) Why is (2) needed?

Back 16

1) first
2) GMP
3) IMP
4) GMP needed to make iNOS necessary for immune effectors

Front 17

Leflunomide
1) Generation
2) Mechanism
2) Side effect and explanation?

Back 17

1) first
2)Starves Cell of pyrimidine
3) Diarrhea- get caught in enterohepatic cycle and stays in gut for a long time.

Front 18

Cycloporine
1) Generation
2) describe how Cyclosporine blocks immune response.
3) What two downstream factors are reduced because of Cyclosporine action?
4) Why might Cyclopsorine be specific for T-cells?

Back 18

1) Second
2)i. Binds to cyclophilin ( not usually involved in the rxn) Cyclophilin-Cycolsporine complex blocks calcineurin (a phosphatase) activity that is required for signally from T cell receptor. Does this by blocking Ca++/Calcineurin binding to NFAT. NFAT is phosphorylated in the cytoplasm, and cannot go to the nucleus without being de-phosphorylated.
v.N-FAT acts as a transcription factor for genes such as IL-2 and IFN-γ (but not TNF because this action is on lymphocytes and TNF is mainly made by monocytes)
4) Caclineurins is in very limiing concentrations in T-cells

Front 19

1)Name the three Generation 2 anti-inflammatory drugs we talked about.
2) How is Generation 2 distinguished?

Back 19

1)Cyclosporine
FK506
Rapamycin
2) More selective for T-cells

Front 20

FK506:
1)Same mechanism as
2)Binds to
3) Generation

Back 20

1) Cyclosporine
2) FK-506 Binding protein
3) Second

Front 21

FK506 and Cyclosporine
1)Anti-?
2) Do they have activity on established inflammation?
3)Bone marrow toxicity?
4) Kidney Toxicity?

Back 21

1) lymphocytic
2) YEs
3) No bone marrow toxicity
4) No kindey toxicity

Front 22

Rapamycin
1) generation
2) blocks what cellular funtion?
3)target? Function of target?
4) Clinical USe?

Back 22

1) Second and a half
2) Translation
3) mTOR- regulator of cell cycle
4) Drug Coated Stents

Front 23

Toxicity of second generation Immune suppressants?

Back 23

1) Infection

Front 24

Name the 3 Generation three drugs we talked about.

Back 24

Etaneracept
Infliximab
Natalizumab

Front 25

Third Generation Drugs generally are called....

Back 25

BIologicals

Front 26

Infliximab
1) Generation
2)Structure

Back 26

1) third
2) Humanized mouse monoclonal anti-TNF antibody

Front 27

Etaneracept
1) Generation
2) Structure

Back 27

1) Third
2)TNFR2-IgG constant region fusion protein (indicated by “cept” ending)

Front 28

2)Infliximab, Eteneracpt, and Natalizumab are given with a small dose of__________
2) Why?

Back 28

1) Methotrexate
2) To supress immune response to the murine part to th mAb

Front 29

Both infliximab aned Etaneracept block what?

Back 29

TNF

Front 30

Both infliximab and Etaneracept are given by what route? why?

Back 30

IV because they are proteins

Front 31

Both infliximab and Etaneracept were originally given for what disease?

Back 31

Rheumatoid Arthritis?

Front 32

Both infliximab aned Etaneracept have these TWO important side effect. Give both the effect and the reason for it.

Back 32

1)uncovering latent TB, as TNF is important in controlling TB

2)Exacerbate MS---- explained by loss of signaling to TNFR2. There are two TNF receptors
a. TNF1R is pro-inflammatory
b. TNF2R is important in oligodendrocyte regeneration in remyelination

Front 33

What 2 drugs can cause uncovering of latent TB

Back 33

Infliximab and etaneracept

Front 34

What two drugs can cause MS exacerbation?

Back 34

Infliximab and etaneracept

Front 35

Natalizumab
1) MAb that blocks ____1_____ which is a type of ___2______ important for ____3______.
4) toxicity
5) Clinical use of Natalizumab

Back 35

1) VLA4
2)Adhesion Molecule
3) adhesion between inflammatory cells and substrates in vascular endothelium and in inflammatory cells themselves (important in both innate and adaptive immunity)
4) Can unmask neurotropic JC virus
5) MS and Crohn's

Front 36

Which drug can unmask JC virus?

Back 36

Natalizumab

Front 37

Treatment for MS and Crohn's

Back 37

Natalizumab

Front 38

Which MAb drug may soon be replaced by a small molecule inhibitor?

Back 38

Natalizumab

Front 39

Glucocorticoids
1) Pathway

Back 39

Bind a binding protein in the blood, then bind to their receptor HSP90, BP falls off an the receptor/GC gos to the nucleus.

Front 40

Glucocortiocoids exert their effect how?

Back 40

Inihibit transcription of COX-2, cytokines, chemokines, and adhesion molecules

Front 41

Glucocorticoid effects on WBC count

Back 41

Do not change otal WBC count.
Change differential count because they inhibit WBC migration. Neutrophils go up because they are trapped in the blood, monocytes/lymphocytes go down because they are trapped in secondary lymph organs.

Front 42

Does tachyphylaxis happen in response to GCs?

Back 42

No

Front 43

Toxicity of GCs:
1) Endocrine

Back 43

1) Mineraocorticoid cross-over leading to Na+ retetion, water retention, K+ wasting.
LEads to hypokalemic acidosis.

Front 44

Glucocorticoids
1) Pathway

Back 44

Bind a binding protein in the blood, then bind to their receptor HSP90, BP falls off an the receptor/GC gos to the nucleus.

Front 45

Glucocortiocoids exert their effect how?

Back 45

Inihibit transcription of COX-2, cytokines, chemokines, and adhesion molecules

Front 46

Glucocorticoid effects on WBC count

Back 46

Do not change otal WBC count.
Change differential count because they inhibit WBC migration. Neutrophils go up because they are trapped in the blood, monocytes/lymphocytes go down because they are trapped in secondary lymph organs.

Front 47

Does tachyphylaxis happen in response to GCs?

Back 47

No

Front 48

Toxicity of GCs:
1) Endocrine A
2) Endocrine B
3)Bone
4) GI
5) Musculoskeletal
5)

Back 48

1) Mineraocorticoid cross-over leading to Na+ retetion, water retention, K+ wasting.
Leads to hypokalemic acidosis.
2)ACTH Suppression leading to adrenocortical insufficiency
3) Increases bone resorbtion stunting growth
4) Peptic Ulcers
5) muscle catabolism

Front 49

Why is it necessary to taper patients off of GCs?

Back 49

GC supresses ACTH secretion and leads to adrnocortical insufficiency

Front 50

Which GC has the best anti-inflammatory propeties? Why dont we use it more often?

Back 50

Dexamethsone, not used much because it has LONG duration and is difficult to reverse if there is toxicity.

Front 51

How do Prednisone and Triamcinolone compare to cortisol in terms of 1)anti-inflammatory properties?
2) Duration?

Back 51

1) Pred. and Triam. are4-5x more effective
2) Cortisol is short acting, Prednisone ad Triamcinolone are intermediate acting

Front 52

How do prednisone, triamcinolone, and dexamethasone compare to cortisol in terms of Salt retention?

Back 52

Cortsiol= 1
Prednisone= 0.3-0.8
Triamcinolone=0
Dexamethasone= 0

Front 53

Arachidonic Acid is released from?

Back 53

The SN2 positions of Phosphatidylinositol

Front 54

Released Arachidonic acid can go down one of two pathways. The First one is COX. Where does it go from here?

Back 54

1) COX--> to PG, Thromboxanes, or Prostacyclins

Front 55

Released Arachidonic acid can go down one of two pathways. The second one is Lipoxygenase. Where does it go from here?

Back 55

1) Lipoxygenase- to LTA4 or D4 which then form LTB4 or LTC4 which can cause Asthma or be converted to lipoxins LXB4 and LXC4 (requires glutathione) which inhibit IL-4 secretion from Dendritic cells (anit-inflammatory)

Front 56

1)Describe how AA metabolism by lipoxygenase can be both inflammatory and anti-inflammatory.

2)How does this interact with our drugs?.

Back 56

1) Lipoxygenase- to LTA4 or D4 which then form LTB4 or LTC4 which can cause Asthma or be converted to LXB4 and LXC4 (requires glutathione) which inhibit IL-4 secretion from Dendritic cells (anit-inflammatory)

2) if we use NSAIDs to inhibit COX, this can exacerbate an asthma patient by shunting to the Lipoxygenase pathway. But in a pt. w/o asthma, the anti-inflammatory effects of lipoxins LXA4 and LXB4.

Front 57

How do lymphocytes contribute to the AA pathway?

Back 57

The make AA but dont have COX or lipoxygenase so they must release AA to be processed by other local cells.

Front 58

Diet effect on AA metabolism

Back 58

18:3-->20:5 unsaturated fatty acids favor formation of TxA3 which is ANTAGONIZES platelet aggregation. This is why we want fish oils. Also, 18:1--> 20:3 is not a good COX substrate.

Front 59

1)Aspirin does what?

2) why is it an anticoagulant?

Back 59

1)Acetylates COX

2)COX-Ac in platelets cannot be regenerated and is responsible for production of pro-coagulant factors.

Front 60

How is aspirin allergenic?

Back 60

Salicylate haptenates a protein to become immunogenic.

Front 61

Two kinds of COX and their funtions and inhibitors.

Back 61

COX1- constitutive, GI protective by controlling perfusion of the GI mucosa. inhibited by NSAIDS


COX2- Inducible in inflammation inhibited selectively by Celecoxib

Front 62

Acetaminophen action
1) broken down to what active product
2) How does this product work to reduce pain and fever?

Back 62

1) p-amino phenol
2) Enzymatically conjugated to Aracidonate. This conjugate is an agonist for the Endogenous cannabinoid receptor which reduces pain and fever. Also reduces COX to inactive form

Front 63

Aspirin:
1) COX1
2) COX2
3) Anti-inflamm
4) Analgesia
5)Antipyresis
6) Gastric Bleeding

Back 63

1) +
2) +
3) +
4) +
5) +
6)++

Front 64

Acetaminophen
1) COX1
2) COX2
3) Anti-inflamm
4) Analgesia
5)Antipyresis
6) Gastric Bleeding

Back 64

1)-
2)-
3)-
4)+
5)+
6)-

Front 65

Ibuprofen
1) COX1
2) COX2
3) Anti-inflamm
4) Analgesia
5)Antipyresis
6) Gastric Bleeding

Back 65

1)+
2)+
3)+
4)+
5)+
6)+

Front 66

Naproxen:
1) COX1
2) COX2
3) Anti-inflamm
4) Analgesia
5)Antipyresis
6) Gastric Bleeding

Back 66

1)+
2)+
3)+
4)+
5)+
6)+

Front 67

Celebrex
1) COX1
2) COX2
3) Anti-inflamm
4) Analgesia
5)Antipyresis
6) Gastric Bleeding

Back 67

1)-
2)+
3)+
4)+
5)+
6)+/-

Front 68

First level of immunosupressive therapy

Back 68

NSAIDS

Front 69

what cytokine promotes the formation of complement fixing Ab?

Back 69

IFN-gamma

Front 70

what cytokine promotes the formation of IgE non- complement fixing Ab?

Back 70

IL-4

Front 71

What cytokine is important for all t-cell proliferation

Back 71

IL-2

Front 72

When must one discontinue first generation immunosupressives (anti-proliferatives)?

Back 72

first sign of infection

Front 73

Which first-gen immunosupressant must be activated by the liver?

Back 73

Cyclophosphamide

Front 74

What is the selectivity of second generation immunosupressants?

Back 74

lymphocyte selective

Front 75

Major two organ-toxicities of Cyclosporine?

Back 75

heart (atherosclerosis) and kidney

Front 76

What do glucocorticoids do to inhibits immune activity?

Back 76

can inhibit COX II induction

Front 77

1)General danger associated with Glucocorticoid immunosupression

2) When would one not use glucocorticoids?

Back 77

1) general feeling of well-being

2) Liver failure

Front 78

1)Describe glucocorticoid withdrawl

2) IN the case of infection, what do we do with glucocorticoids?

Back 78

1)low ACTH, cant maintain blood glucose or Na+ levels
2) withdraw slowly, even in infection

Front 79

Only two cells that make thromboxanes

Back 79

platelets and macrphages

Front 80

Leukootrienes:
1) bronchial effect?
2)Vascular effect?
3) platelet effect?

Back 80

1) bronchoconstrict
2)increase perm.
3) no platelet effect for LT

Front 81

Prostaglandins:
1) bronchial effect?
2)Vascular effect?
3) platelet effect?

Back 81

1) bronchodilator
2)vasodilator
3) decrease agreggation

Front 82

Thromboxanes:
1) bronchial effect?
2)Vascular effect?
3) platelet effect?

Back 82

1)Bronchoconstrictor
2) vasoconstrictor
3) increase agreggation

Front 83

Mode of action of NSAIDs

Back 83

inhibit COX produciton of PG

Front 84

1) Why is tylenol not a good anti-inflammatory?
2) what does it cause?
3) why do we prefer it to aspirin in kids?

Back 84

1) weak against COX
2)analgesic, antipyretic
3) Reye's syndrome