Joint Pain Pharmacology Flashcards
(44 cards)
1
Q
Drugs to know for the exam?
A
- Etanercept
- Allopurinol
- Adalimumab
- Belimumab
- Colchicine
- Tocilizumab
- Probenecid
- Tofacitinib
- Pegloticase
- Abatacept
- Rituximab
- Febuxostat
- Steroid
- NSAIDs
- Methotrexate
- Anakinra
- Infliximab
2
Q
Match the following drugs with site of action:
- Colchicine
- Indomethacin
- Allopurinol
- Probenecid
- Glucocorticoid (Steroid)
- Pegloticase
A
- Colchicine - D
- Indomethacin - D
- Allopurinol - A
- Probenecid - C
- Glucocorticoid (Steroid) - D
- Pegloticase - B
3
Q
What are the therapeutic goals of gout medications?
A
- Increase excretion of uric acid
- Inhibit inflammatory cells
- Inhibit uric acid biosynthesis
- Provide symptomatic relief
- NSAIDs or steroids (short term)
4
Q
Identify the risk of NSAID therapy for acute gout:
Male patient (75 YO) w/ renal disease
A
Dependent on vasodilatory PGs to maintain renal blood flow
5
Q
Identify the risk of NSAID therapy for acute gout:
55 YO woman w/ peptic ulcer
A
NSAIDs block cytoprotective PGs in GI
6
Q
Identify the risk of NSAID therapy for acute gout:
68 YO male w/ previous MI & FaHx of heart disease
A
- NSAIDs (not aspirin) may increase risk (or not prevent) of MI
- Blocks PGI2 & TXA2
7
Q
Identify the risk of NSAID therapy for acute gout:
Female patient w/ nasal polyps & previous rxn to aspirin
A
Hypersensitivity rxn due to leukotrienes
8
Q
Identify the risk of NSAID therapy for acute gout:
45 YO male taking warfarin for DVT prophylaxis
A
Increased risk of bleeding
9
Q
Why is aspirin contraindicated in the treatment of gout?
A
- Decreases uric acid secretion
- Increases uric acid
- Makes gout worse
10
Q
A patient that can’t take an NSAID for relief to acute gout symptoms has which of the following options?
- Wait until symptoms subside (few days)
- Take low dose colchicine (w/i 48 hrs)
- Intraarticular glucocorticoid injections
- Celecoxib
- Low dose oral steroids
A
All except Celecoxib
NSAID = hypersensitivity
11
Q
What are the non-biologic DMARDs?
A
- Methotrexate
- Sulfasalazine
- Hydroxychloroquine
- Azathioprine
- N-penicillamine
- Mycophenolate mofetil
- Leflunomide
12
Q
What are the biologic DMARDs?
A
- Etanercept
- Infliximab
- Adalimumab
- Rituximab
- Anakinra
- Abatacept
- Tocilixumab
- Belimumab
- Apremilast
- Tofacitinib
- Secukinamab
- Ustekinumab
13
Q
What is a DMARD?
What are biologics?
A
- Disease Modifying Anti-Rheumatic Drugs
- Drugs that slow or halt the progression of disease
- Biologics
- A class of drugs which includes monoclonal Ab, receptor analogues, & chimeric small molecules designed to bind to or mimic their molecular targets
14
Q
Match the drug to the site of action:
- Methotrexate
- Infliximab
- Abatacept
- Anakinra
- Rituximab
- Tocilizumab
A
- Methotrexate - C
- Infliximab - D
- Abatacept - B
- Anakinra - F
- Rituximab - A
- Tocilizumab - E
15
Q
What is the mechanism of Abatacept?
A
Blocks the co-stimulation of T-cells
16
Q
What is the mechanism of Methotrexate & Leflunomide?
A
Inhibits the proliferation & activity of T-cells & B-cells
17
Q
What is the mechanism of Etanercept, Infliximab, Adalimumab, Golimumab & Certolizumab?
A
Inactivate TNF-α
18
Q
What is the mechanism of Anakinra?
What is the mechanism of Tocilizumab?
A
Anakinra blocks the action of IL-1
Tocilizumab inactivates IL-6
19
Q
What is the mechanism of action of glucocorticoids?
A
Inhibit T-cell activation & IL-2 production by regulation of gene transcription
Inhibit the formation of PGs
20
Q
What is the mechanism of NSAIDs?
A
Inhibit formation of PGs
21
Q
What is the mechanism of Methotrexate?
A
- Irreversibly binds to & inhibits DHFR
- Results in inhibition of purine & thymidylic acid synthesis
- Interfering w/ DNA synthesis, repair & cellular replication
22
Q
What is the mechanism of Sulfasalazine?
A
- Metabolized to sulfapyridine & 5-aminosalicylic acid
- Mechanism not known but IgA & IgM rheumatoid factor production are decreased
- In-vitro suppression of T-cell activation & inhibition of B-cell proliferation
- Inhibits release of inflammatory cytokines
23
Q
What is the mechanism of Hydroxychloroquine?
A
- Mechanism unclear
- Suppression of T-lymphocyte responses to mitogens
- Decreased leukocyte chemotaxis
- Stabilization of lysosomal enzymes
- Inhibition of DNA & RNA synthesis
- Trapping of free radicals
24
Q
What is the mechanism of Azathioprine?
A
- Cleaved to 6-mercaptopurine
- Converted to additional metabolites that inhibit de novo purine synthesis
- Cell proliferation inhibited, impairing a variety of lymphocyte functions
25
What is the mechanism of N-penicillamine?
* Chelates w/ lead, copper, mercury & other heavy metals to form stable, soluble complexes that are excreted in urine
* Depresses circulating IgM rheumatoid factor, depresses T-cell but not B-cell activity
26
What is the mechanism of Mycophenolate mofetil?
* Converted to active metabolite that inhibits inosine monophosphate dehydrogenase
* Leading to suppression of T & B-lymphocyte proliferation
27
What is the mechanism of Leflunomide?
* Undergoes rapid conversion to its active metabolite, A77-1726
* This metabolite inhibits dihydroorotate dehydrogenase
* Leads to a decrease in ribonucleotide synthesis & arrest of stimulated cells in the G1 phase of cell growth
* Consequently, leflunomide inhibits T-cell proliferation & production of autoantibodies by B-cells
28
Which of the following drugs are human monoclonal antibodies?
* Adalimumab
* Belimumab
* Tocilizumab
* Rituximab
* Infliximab
* Adalim**u**mab, Belim**u**mab, Tociliz**u**mab
* Rituximab & Infliximab are chimeric
29
**Pharmacokinetics of MABs**
What is the admin & absorption?
What is the distribution?
* Administration & Absorption
* SubQ = 24-95% bioavailability
* IM = 24-95% bioavailability
* IV = 100% bioavailability
* Distribution
* Extracellular
* Does NOT cross BBB
30
What are the half-lives of MABs?
* **Therapeutic Ab from human source have longer biological half-life than those from mouse source**
* Human = 20-21 days
* Murine = 12-48 hrs
* Varies w/ IgG isotype
* Human IgG1, IgG2, IgG4 = 20-21 days
* Human IgG3 = 7 days
* Long half-life = infrequent admin
31
What is the mechanism for longer biological half-life for human MABs vs. mouse MABs?
* **Concept of neonatal Fc receptor (FcRn) for IgG**
* Transfers passive immunity from mother to fetus
* Role for FcRn to protect IgG from degradation throughout life
* Mouse IgG does not bind FcRn
* Fab or F(ab)2 antibody fragments lack Fc region - do not bind FcRn
32
Which of the following drugs inhibit TNF-α?
* Infliximab
* Adalimumab
* Etanercept
* Only infliximab & adalimumab
* All of the above
**All of the above**
* Infliximab & adalimumab bind to both m-TNF & s-TNF & induce apoptosis of expressing cells
* Etanercept neutralizes s-TNF but not m-TNF
33
What are the mechanisms of action of therapeutic antibodies?
* Antagonism or neutralization
* Antibody binds & inactivates a soluble antigen
* Antibody acts as a competitive inhibitor of ligand binding to cellular receptor
34
What is the action of Belimumab?
* BLSP (BLyS) is the co-stimulator for B-cell survival & function
* **Belimumab is a monoclonal Ab against BLyS**
* Specific binding to BLyS prevents the interaction of BLyS with its receptor & decreases the B-cell survival & production of autoantibodies
35
Which of the following best explains the mechanism of action of rituximab?
* Complement-dependent cytotoxicity (CDC)
* Antibody-dependent cellular cytotoxicity (ADCC)
* Both CDC & ADCC
* None of the above
**Both CDC & ADCC**
36
What is complement-dependent cytotoxicity? (CDC)
* Antibody binds cell surface antigen on target cell
* Fc region binds complement protein & activates complement system resulting in cell lysis
37
What is antibody-dependent cellular cytotoxicity? (ADCC)
* Antibody binds cell surface antigen on target cell
* Fc region binds Fc receptors on NK cell, neutrophil or macrophage
* Results in lysis or phagocytosis of target cell by immune cell
38
What are the adverse effects of therapeutic antibodies?
* Generally safe & well-tolerated
* Immunogenicity: generation of endogenous Ab against the therapeutic Ab
* Concerns:
* Neutralizes the effect of therapeutic Ab
* Hypersensitivity rxn: either localized to injection site or systemic
39
For each pair of drugs, predict which would have greater potential for immunogenicity:
* Infliximab vs. Adalimumab
* Rituximab vs. Belimumab
* Tocilizumab vs. Infliximab
* Ibritumomab vs. Tocilizumab
* **Infliximab** vs. Adalimumab
* **Rituximab** vs. Belimumab
* Tocilizumab vs. **Infliximab**
* **Ibritumomab** vs. Tocilizumab
40
What is Ibritumomab?
* Monoclonal Ab directed against CD20 antigen found on pre-B & mature B lymphocytes (normal & malignant)
* Binding induces apoptosis in B lymphocytes
41
**Abatacept**
* Mechanism of Action
* Administration
* Use
* Fusion protein
* After T-cell has engaged in APC, a 2nd signal is produced by CD28 on the T-cell that interacts w/ CD80 or CD86 on the APC, leading to T-cell activation
* **Abatacept binds to CD80 & 86, thereby inhibiting the binding to CD28 and preventing the activation of T-cells**
* Parenteral admin, IV infusion
* RA w/ inadequate response to other drugs
42
**Anakinra**
* Mechanism of action
* Administration
* Use
* Recombinant protein
* **Competitive antagonist of IL-1 receptor**
* SubQ admin
* Moderate/severe RA in adult patients who have failed _\>_1 DMARDs
* May be used alone or in combination w/ DMARDs (other than TNF-α inhibitors)
43
**Tofacitinib**
* Mechanism of Action
* Metabolism
* Use
* Oral, targeted DMARD
* Synthetic small molecule
* **Inhibition of JAKs prevents cytokine or growth factor mediated gene expression & cellular activity of immune cells**
* CYP450 metabolism (3A4, 2C19)
* Moderate/severe RA in adults intolerant to methotrexate
44
**Apremilast**
* Mechanism of Action
* Metabolism
* Use
* Side Effects
* Oral, small molecule inhibitor of PDE-4
* CYP450 metabolism (3A4)
* Adult patients w/ psoriatic arthritis
* Neuropsych effects
* Depression. suicidal ideation, mood changes
* May cause weight loss
