Pharmacology/Anti-cytokine Drugs - Walworth 4/7/16

Question 1

effects of GPCR stimulation

Answer 1

Gs - increase adenylate cyclase

Gi - decrease adenylate cyclase

Gq - increase PLC

Question 2

chemical mediators of inflammation

Answer 2

• vasoactive amines (histamine, 5HT)
• neuropeptides (substance P)
• plasma proteases (Factor XII)
• lipid-derived arachidonic metabolites
• platelet-activating factor
• cytokines: IL1, TNF-alpha

Question 3

examples of diseases resulting from chronic inflammation for which anti-cytokine therapy is useful!

Answer 3

• rheumatoid arthritis
• inflammatory bowel disease
  
  • Crohn’s disease
  • ulcerative colitis
• lupus
• psoriasis

Question 4

major effects of IL1 and TNFalpha

Answer 4

acute-phase rxns

• fever
• incr sleep
• decr appetite
• incr acute-phase proteins
• hemodynamic effects (shock)
• neutrophilia

endothelial effects

• leukocyte adherence
• PGI synthesis
• incr procoag activity
• decr anticoag activity
• incr IL1, IL6, ILB PDGF

fibroblast effects (prolif, collagen synth, PGE, etc)

cytokine effects (incr cytokine secretion)

Question 5

rheumatoid arthritis

• pathophys
• basic drugs: mech

Answer 5

pathophysiology

antigen drives lymphocyte proliferation → production of autoantibody → complement fixation, attraction of infl cells, cytokine production

• activation of innate immune system → DCs migrate to lymph nodes, activate T cells → T cells migrate to joint → produce pro-infl cytokines
• activated macrophages and fibroblasts → produce TNFalpha
• more immune cells recruited to joint

drugs

DMARDs (ex. leflunomide, methotrexate)

• prevent prolif of lymphocytes
• reduce infl process

Question 6

RA drugs

“cepts”

Answer 6

“TNF sponges”

etancercept: contains extracellular domain of TNFalpha-R

• high affinity for TNFalpha → neutralization
• indication: rheumatoid arthritis, other types of arthritis
• admin: subcutaneous, weekly
  
  • often taken in combo with methotrexate

Question 7

RA drubs

“mabs”

Answer 7

“TNF sponges” - antibody to TNFalpha

infliximab: chimeric antibody (part mouse, part human)

• high affinity for TNFalpha → neutralization
• admin: IV

adalimumab: humanized antibody

• admin: subcutaneous

Question 8

RA drugs:

anakinra

Answer 8

IL1 receptor antagonist - endogenous protein

anakinra: chimeric antibody (part mouse, part human)

• admin: daily subcutaneous injection
  
  • can be given with MTX, but not TNF agents

Question 9

RA drugs:

abatacept

Answer 9

CTLA-4-Ig

binds to B7 (aka CD80, CD86) on APC, prevents signal2 in T cell activation (B7/CD28 binding)

• lowers serum concentration of infl mediators
• admin: IV, 2wk, 4wk, monthly followup (shouldn’t be admin with other biologics)
  *

Question 10

IBD

Answer 10

chronic inflammation can affect permeability of epithelial layer (make it more permeable than healthy) → amplifying loop of infl

• Crohn’s disease (entire GI tract)
• ulcerative colitis (colon)

Question 11

IBD drugs

mabs

Answer 11

infliximab: chimeric antibody to TNFalpha

• admin: IV infusion for 2 hr every 2 weeks, then every 8 weeks

certolizumab: PEGylated Fab fragment of humanized TNFalpha antibody

• admin: subcutaneous

Question 12

BAFF

link to disease

Answer 12

B cell Activation Factor

BlyS - B lymphocyte stimulator

member of TNFalpha family

key determinant of whether B cells will survive/die during tolerance processes!

diease link: excess BAFF in lupus →

• excess production of monoclonal antibodies
• kidney deposition
• complement activation

collectively, infl + tissue destruction

Question 13

adverse effects of anti-cytokine therapy

Answer 13

• injection site rxns
• infusion rxns
• cytopenia with anti-TNF therapy : need to monitor CBC
• serious infections (sepsis, TB)
• malignancies reported
• hepatotox (infliximab)

Question 14

contraindications to anti-cytokine therapy

Answer 14

active infections

• TB+? treat latent TB first
• pre existing demyelinating diseases

Question 15

secukinumab

Answer 15

IL17 inhibitor → controls psoriasis