Pharm-RA-DMARDs-Biologics Flashcards
What are the 9 biological DMARDs?
- Adalimumab
- Certolizumab Pegol
- Etanercept
- Golimumab
- Infliximab
- Abatacept
- Anakinra
- Rituximab
- Tocilizumab
Cytokines and Cytokine Receptors are expressed in what two forms?
Both membrane-bound and soluble forms
What two ways are soluble cytokines produced?
a. Secreted via vesicular fusion
b. Cleavage of transmembrane cytokines
T/F: once transmembrane cytokines bind their receptors, signaling can be bidirectional?
True
What are the 3 types of cytokine targeted therapies?
- mAbs (next question)
- Therapeutic soluble receptors: primarily target soluble cytokines (Etanercept)
- Receptor antagonists (Anakinra)
What are the three mechanisms thru which monoclonal Abs (mAbs) inhibit cytokine activity?
- Neutralization of soluble and transmembrane cytokines
- Can induce reverse signaling and cell-/complement-mediated cytotoxicity
(1 and 2 are done by Adalimumab, Certolizumab Pegol, Infliximab, Gomilumab) - Can block cytokine receptors (Tocilizumab)
What is the advantage of cytokine receptor-targeted therapy?
It can selectively silence individual receptor subtypes when multiple receptor subtypes ligate a single cytokine.
The cellular basis of the RA cytokine profile may center on what type of cell?
Th17 cells
What cytokines promote differentiation of naive T cells to the Th17 phenotype?
TGF-B, IL-1B, IL-6, IL-21, IL-23 promote differentiations.
IL’s-15 and 23 reinforce this phenotype.
What is the defining cytokine produced by Th17 cells, and what does this cytokine induce?
IL-17; it induces production of IL-1, IL-6, and TNF from macrophages/monocytes
What 5 biologic DMARDs block TNF-a?
4 mAbs and 1 soluble receptor (SR):
- Adalimumab
- Certolizumab pegol
- Golimumab
- Infliximab
- Etanercept (SR)
Route, Structure, and MoA of Abatacept?
Route: IV/SC
Structure: Fusion protein of human CTLA4 + IgG1 fragment
MoA: Blocks the T cell co-stimulatory signal by binding CD80/86 and preventing engagement with CD28.
Route, Structure, and MoA of Adalimumab?
Route: SC
Structure: TNF-a mAb
MoA: Binds TNF-a, blocking its interaction with p55/p75 cell-surface receptors
Route, Structure, and MoA of Anakinra?
Route: SC
Structure: Recombinant human IL-1 receptor antagonist (IL-1Ra)
MoA: Competitively inhibits IL-1alpha and IL-1beta binding to IL-1 type 1 Receptor (IL-1R1)
Route, Structure, and MoA of Certolizumab pegol?
Route: SC
Structure: Fab fragment of humanized TNF-a Ab
MoA: neutralizes both membrane associated and soluble TNF-a
Route, Structure, and MoA of Etanercept?
Route: SC
Structure: Extracellular ligand-binding portion of p75 TNF-R linked to part of human IgG Fc
MoA: binds and inactivates TNF but does not affect TNF production or serum levels
Route, Structure, and MoA of Golimumab?
Route: SC
Structure: Human-derived TNF-a Ab (variable and constant regions)
MoA: binds and neutralizes both soluble and transmembrane TNF-a
Route, Structure, and MoA of Infliximab?
Route: IV
Structure: Chimeric (mouse-human) IgG1k mAb against TNF-a
MoA: binds and neutralizes both soluble and transmembrane TNF-a.
Route, Structure, and MoA of Rituximab?
Route: IV
Structure: Chimeric (mouse-human) IgG1k mAb against B-cell CD20 receptor
MoA: Fab domain binds CD20 & Fc domain recruits immune effector functions to mediate B-cell lysis (3 mechs: complement-dependent or Ab-dependent cellular cytotoxicity, or induction of apoptosis);
It sensitizes drug-resistant B-cell lymphoma lines to cytotoxic chemotherapy.
Route, Structure, and MoA of Tocilizumab?
Route: IV
Structure: Humanized IL-6 receptor-inhibiting mAb
MoA: Binds to both soluble (serum and synovial fluid) and membrane bound IL-6 receptors and inhibits signaling.
What is a common adverse effect of all 9 biological DMARDs? Complications/cautions that result from this effect? (5)
All of them produce IMMUNOSUPPRESSION:
a. ↑’d susceptibility to bacterial, TB, fungal, parasitic infections; some have BBW for this.
b. DO NOT initiate treatment in pt w/ an active infection
c. AVOID LIVE VACCINES
d. URT infections could be especially problematic or could occur more frequently in asthmatics/COPD
e. Pt’s should report s/s of an infection or a recurrent infection during therapy or within several months after discontinuation.
Which of these drugs increases the likelihood of lymphoma/other malignancies? (5)
Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab
What are the ADE/complications associated with these drugs in general?
- Immunosuppression
- Malignancy/Lymphoma
- CHF or hypotension/angina/dysrhythmia
- Blood Dyscrasias
- Lupus-like syndrome
- SJS/Toxic Epidermal Necrosis (TEN)
- Hepatotoxicity
- Counseling proper injection techniques for self-administered SC agents
a. Which agents have been reported to cause CHF or hypotension/angina/dysrhythmia? (4)
b. Which drug is absolutely contraindicated for pt’s with moderate-severe heart failure?
a. Adalimumab, Golimumab, Infliximab, Rituximab
b. Infliximab
