Rheumatic Disorders (Med Chem) - Block 1 Flashcards
1
Q
What is the gold standard for DMARDs?
A
Methotrexate
2
Q
What are examples of conventional syntheitic DMARDs?
A
- Methotrexate (MTX)
- Leflunomide (LEF)
- Sulfasalazine (SSZ)
- Hydroxycholorquine (HCQ)
3
Q
What are examples of targeted synthetic DMARDs?
A
- Tofacitinib
- Upadacitinib
- Baricitinib
4
Q
How components are inhibited by methotrexate?
A
Disrupts cell division and increases anti-inflammatory effects by adenosine by inhibiting:
1. Dihydrofolic acid reductase (DHFR)
2. Thymidylate synthetase (TYMS)
3. Amino-imidazolecarboxamide ribonecleotide transformylase (AICART)
5
Q
Describe the MOA of methotrexate?
A
- Inhibits TYMS blocking thymine production
- Inhibits DHFR that disrupts DNA methylation and methionine stores
- Inhibits AICART increasing adenosine
* Increased AICAR inhibits ADA (adenine deaminase) and AMP deaminase) blocking the production of guanine (i.e. purine synthesis)
Processes cause disruption in purine and S phase
6
Q
How is Methotrexate eliminated? And how does it affect concomitant therapies
A
OAT1, OAT3, MRP2/4
NSAIDs reduce glomerular filtration and inhibit OAT1/3 and MRP2/4 reducing MTX clearance
7
Q
Methotrexate
CI, ADR
A
CI: teratogenic, hepatic and renal impairment
ADR: GI toxicity (ulcerative stomatits and diarrhea), hepatotoxicity (fibrosis and cirrhosis), malignant lymphoma
8
Q
Describe the MOA of Leflunomide?
A
Teriflunomide (active) inhibits dihyrooradate dehydrogenase (DHODH)
9
Q
What is the importance for DHODH?
A
Rate limiting step of pyrimidine synthesis arresting B cell and T cell proliferation
10
Q
Describe the difference between leflunomide and methotrexate?
A
11
Q
Leflunomide
ADR, CI, BBW
A
ADR: D/N/V, rashes, alopecia, HTN
CI: liver impairment, pregnancy
BBW: fetal toxicity, hepatotoxicity
12
Q
MOA of sulfasalazine? What are the metabolites?
A
Prodrug that is metabolized by colonic bacteria and produce active metabolites:
1. Sulfapyridine: bacterial DNA synthesis inhibitor
2. 5-ASA: NSAID concnetrated in the synovial fluid
13
Q
Sulfasalazine
Brand, CI, ADR
A
Azulfidine
CI: Hemolysis in G6PD def (hemolytic anemia), sulfa allergy, salicylate allergy, different types of anemia
ADR: GI distress, photosensitivity, oligospermia, alopecia, orange-yellow urine or skin, reduces absorption of folic acid and digoxin
14
Q
MOA of Hydroxychloroquine
A
- Blocks the activation of antigen presenting cells
- Prevents acidification of the lysosome and antigen processing -> blocking antigen presentation
- Prevents endosomal TLR signaling (7,8,9) and subsequent cytokine production
15
Q
Hydroxychloroquine
Brand, DI, ADR
A
Plaquenil
DI: Digoxin, antacids
ADR: Ocular toxicity, cardiac, ear disorders, GI and skin effects
16
Q
Describe the components of the JAK stat signaling pathway?
A
- Tyrosine kinase receptor that acts as a cytokine and GFR on immune cells
- Cytokine binds to JAK-R
- JAK phosphorylates STAT which serves as a transcription factor
- STAT activates transcription and production of cytokines
17
Q
Tofacitinib
Brand, MOA, BBW, ADR, CI
A
Xeljanz
MOA: 1st generation Pan Janus kinase (JAK) inhibitor (JAKi) that blocks JAKs 1-3
* Inhibits cytokine and growth factor induced JAK-STAT pathway signaling
BBW: TB, infection, malignancies, MACE, thrombosis
ADR: Increase in TC, bone marrow suppression, GI perforations, Infection
CI: Should not be combined with potent immunosuppressive agents or bDMARDs
* Avoid live vaccines
18
Q
Baricitinib
Brand, MOA, BBW, ADR, CI
A
Oluminant
MOA: Inhibits cytokine and growth factor induced by JAK1 and JAK2 signaling
BBW: TB, infection, malignancies, MACE, thrombosis
ADR: Increase in TC, bone marrow suppression, GI perforations, Infection
CI: Should not be combined with potent immunosuppressive agents or bDMARDs
* Avoid live vaccines
19
Q
Upadacitinib
Brand, MOA, BBW, ADR, CI
A
Rinvoq
MOA: JAK1 selective inhibitor
* Inhibits cytokine induced JAK1 signaling by blocking IL6 and IFN
BBW: TB, infection, malignancies, MACE, thrombosis
ADR: Increase in TC, bone marrow suppression, GI perforations, Infection
CI: Should not be combined with potent immunosuppressive agents or bDMARDs
* Avoid live vaccines
20
Q
What is a chimeric mAb?
A
4/12 domains are murine (2-VL and 2VH)
21
Q
What is humanized mAb?
A
murine CDRs grafted into human mAb (IgG)
22
Q
What is fully human?
A
the protein sequence is fully human
23
Q
What is pegylated fab fragment?
A
polyethylene glycol is attached to the Fab portion of an IgG antibody
24
Q
What are receptor Fc fusion?
A
functional receptor protein joined to the Fc portion of IgG
25
What more humanized the **more/less** immunogenic the mAb
Less
26
What are the disadvantages of having more immunogenicity?
Can lead to hypersensitivity producing antibodies against the therapeutic antibody
27
Prefix for chimeric?
Ximab
28
Prefix for human?
Umab
29
Prefix for humanized?
zumab
30
Prefix for mouse?
omab
31
Prefix for cept?
Fab protion has been replaced with receptor protein sequence
32
What are biosimilars?
same aa sequence as original mAb but produced from a different clone and can have different glycosylations
33
What are the functions of monoclonal antibodies?
mAbs are able to bind to their specific target and induce an effector function:
1. Neutralization/Blocking
1. Complement-Mediated Cytotoxicity (CDC)
1. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
1. Antibody-Dependent Cell-Mediated Phagocytosis (ADCP)
34
What occurs during Antibody Dependent Cell-Mediated Cytotoxicity (ADCC)?
1. Antibodies bind to membrane-surface antigens on the target cell
2. Cells expressing Fc receptors recognize bound antibodies
3. Crosslinking of Fc receptors triggers degranulation into lytic synapse
4. Target cell dies by apoptosis requiring Fc region
35
What occurs during complement dependent cytotoxicity (CDC)?
1. Antibodies bind to membrane surface antigecns on the target cell
2. Multiple pathways elicit a complement cascade, where complement binds to the antibodies
3. Binding of complement leads to the induction of a membrane attack complex
4. Target cell dies of cell lysis requiring Fc region
36
What are examples of anti-tnf-a?
1. Infliximab
1. Entanercept
1. Adalimumab
1. Golimumab
1. Certolizumab pegol
37
What are the non-TNF-a?
1. Abatacept
1. Rituximab
1. Belimumab
1. Tocilizumab
1. Sarilumab
1. Anakinra
38
Infliximab
| Brand, MOA
Remicade
Mouse-human chimeric IgG1 monoclonal antibody
**MOA:** Targets monomer and trimer forms and membrane bound TNF-a
* Neutralizes TNF-a and prevents TNF-a from binding TNF receptor
* Induces ADCC and CDC of cells expressing surface forms of TNF-a
39
Etanercept
| Brand, MOA
Enbrel
Recombinant fusion protein that functions as a decoy receptor
**MOA:** Targets and neutralizes trimer and membrane bound forms of TNF-a and lymphotoxin-a (TNF-b)
* Induces ADCC (apoptosis) of TNF-expressing cells
40
Adalimumab
| Brand, MOA
Humira
Fully human monoclonal IgG1 antibody
**MOA:** Induces CDC of TNF-expressing cells
* Targets soluble and membrane bound TNF-a
41
Golimumab
| Brand, MOA
Simponi (SC), Simponi Aria (IV)
Human IgG1 monoclonal antibody
**MOA:** Targets and neutralizes TNF-a (soluble and membrane bound)
42
Certolizumab pegol
| Brand, MOA
Cimzia
PEGylated humanized Fab’ fragment
**MOA:** Targets and neutralizes soluble and membrane bound TNF-a
* PEGylation delays metabolism and elimination, increases circulation retention, decreases kidney clearance, and reduces immunogenicity of the drug
* Fab fragment is the region of antibody that binds antigen
43
TNF-a inhibitors
| BBW, CI, ADR
**BBW:** serious infections, malignancy
**CI:** acute or active infections, worsening CHF, Live vaccines, bDMARDs, tsDMARDs
**ADR:** Infection, N/HA/R/F, myelosuppression
44
Abatacept
| Brand, MOA, CI, ADR
Orencia
**MOA:** Abatacept binds to CD80/86 on APC
* Inhibits APC’s co-stimulation of T cells and thereby T cell activation
**CI:** Do not combine with bDMARDs or tsDMARDs
**ADR:** Drug maltose may affect blood glucose monitors
* Malignancy risk
* Serious infection risk
* Inj site reaction
45
Rituximab
| Brand, MOA, BBW, ADR, CI
Rituxan
**Biosimilars:** Truxima, Ruxience, Riabni
**MOA:** Chimeric mouse-human IgG1 monoclonal antibody
* Targets CD20 (only on B cells)
* Induces CDC, ADCC, and ADCP
**BBW:** Fatal infusion rx, severe mucocutaneous rx, progressive multifocal leukoencephalopathy, Hep B reactivation
**ADR:** Hypersensitivity, Neutropenia, pancytopenia, lymphopenia, Gi perforation, fever, stomatis, fatigue
**CI:** Infection risk, arrhythmias, pregnancy, Live vaccines, b and tsDMARD
46
Tocilizumab
| Brand, MOA, BBW, Caution, ADR, CI, Interactions
Actemra
**Biosimilars:** Tofidence
**MOA:** Humanized IgG1 mAb antibody against IL-6R
* Prevents IL-6 from binding IL-6R (receptor antagonist)
**BBW:** Serious infection risk
**Cautions:** GI perforation risk, Active infection, malignancy
**ADR:** Inj site rx, Neutropenia, thrombocytopenia, Elevated ALT and AST, Elevated total cholesterol, triglycerides, LDL, and HDL levels
**CI:** Live vaccines, b- and tsDMARD
**Interactions:** CYP450 substrates
47
How does Tocilizumab interact with CYP450 substrates?
Leads to increased metabolism of CYP450 substrates decreasing efectiveness of oral contraceptives and statins
48
Sarilumab
| Brand, MOA, BBW, Caution, ADR, CI, Interactions
Kevzara
**MOA:** Fully human IgG1 monoclonal antibody
* Membrane bound and soluble IL-6 receptor antagonist
**BBW:** Serious infection risk
**Cautions:** GI perforation risk, Active infection, malignancy
**ADR:** Inj site rx, Neutropenia, thrombocytopenia, Elevated ALT and AST, Elevated total cholesterol, triglycerides, LDL, and HDL levels
**CI:** Live vaccines, b- and tsDMARD
**Interactions:** CYP450 substrates (OC, statins)
49
Anakinra
| Brand, MOA
Kineret
**MOA:** Recombinant human IL-1 receptor antagonist
* Binds to and prevents IL-1 from binding IL-1R
* Decreases inflammation, synovial pannus formation, cartilage breakdown, bone resorption
50
Examples of SLE tx?
1. Aspirin
2. CS (methylprednisolone, prednisone)
3. NSAIDs (ibuprofen, nazproxen, diclofenac)
4. Syntheitc DMARDs (methotrexate, hydroxychloroquine)
5. Immunosuppresive agents (Azathioprine, Cyclosporine, Mycophenolate mofetil, Cyclophosphamide)
6. Biologic DMARDs (Belimumab, Rituximab)
51
Azathioprine
| Brand, MOA, Warning, ADR, DDI
Imuran
**MOA:** Purine antimetabolite
* Converted to active form in liver (6-MP)
* Potent mitotic inhibitor
* Inhibits DNA, RNA and protein synthesis
* Decreases T-cell proliferation
* Decreases B cell proliferation
**Warning:** Malignancy risk
**ADR:** Mutagenic, Leukopenia, Pancytopenia, Bone marrow suppression, Hepatotoxicitiy, Infection risk
**DDI:** Xanthine oxidase inhibitors, Furosemide
52
Cyclosporine
| Brand, MOA, Warning, ADR
Sandimmune/Neoral/Gengraf
**MOA:** Inhibits Helper T cells (TH cells) by inbihiting calcineurin, blocking trascription of IL2 and 2R genes, suppressing T and B cells
* Calcineurin is activated as part of signaling through the TCR.
* Cyclophilin blocks calcineurin from dephosphorylating NFAT.
* Blocking NFAT dephosphorylation prevents the production of IL-2.
**Warning:** Neoplasm risk with immunosuppresants, Malignancy risk
**ADR:** Nephrotoxicity, Hepatotoxicity, Anemia, Pain in lower extremities
53
What transporter is cyclosporine a substrate of?
P-gp
54
Describe the Pharmacogenomics of cyclosporine?
Genetic variant in CYP3A4 containing an A- to G- mutation (called CYP3A4-V or CYP3A4*1B) is associated with impaired enzyme activity
* most common in AA populations
55
Diffeerentiate the brands of cyclosporine?
**Sandimmune:** Oil-based suspension of CsA, Variable absorption, non linear
**Neoral and Gengraf:** Microemulsion, less variability in absorption, more predictable dose response
56
Mycophenolate mofetil
| Brand, MOA, BBW, ADR
CellCept
**MOA:** Prodrug
* Inhibits inosine monophosphate dehydrogenase (IMPDH)
* Purine synthesis inhibitor (depletes guanosine nucleotides)
* Suppresses T and B cell proliferation
* Inhibits leukocyte adhesion to endothelium by inhibitng E-selectin, P-selection, and ICAM-1
**BBW:** Infection risk, Malignancy risk, teratogenic
**ADR:** GI disturbances, hyperglycemia, hypercholesterolemia, myelosuppresion
57
What is the function of Inosine monophosphate dehydrogenase (IMPDH)?
Catalyzes the conversion of IMP to GMP along with the reduction of NAD to NADH
**Catalyzes the rate limiting step for guanine nucleotide biosynthesis**
58
Cyclophosphomide
| Brand, MOA, CI,
Cytoxan
**MOA:** Activated into phosporamide mustard
* Cross links DNA to prevent cell replication
* Suppressess T and B cell function
* Acrolein is another toxic metabolite generated and is associated with bladder toxicity
**CI:** Pregnacy and contraception, urinary obstruction
**ADR:** Myelosuppression, renal impariment, hemorrhagic cystitis, cadiotoxicity, HF, **sterility**
59
Belimumab
| Brand, MOA, Caution, ADR
Benlysta
**MOA:** Human monoclonal IgG1 antibody against B-lymphocyte stimulator BLyS
* Inhibits BAFF (B cell activating factor) from binding its receptors (BAFFR, TACI, and BCMA)
* Neutralizes BLyS
* **Targets immature B cells through plasma cells**
* BLyS is produced by all immune cells but its receptors are only present on B cells.
**Caution:** active infection, pregnancy, depression, and suicide risk
**ADR:** Infection, PML, infusion/ inj site rx, malignancy, depression and suicide, migraines, insomnia
60
What is the function of BLyS? What happens when you block it?
1. GF required for B cell survival, maturation, and activation
2. involved in GC reaction, B cell differentiation into plasma cells and antibody production
**Blocking BLys causes apoptosis of B cells**
61
Examples of PsA tx?
**Synthetic DMARDs:** Methotrexate, Leflunomide, Sulphasalazine, Cyclosporine
**PDE4 Inhibitor:** Apremilast
**JAK inhibitor:** Tofacitinib
**Biologic DMARDs:** Anti-TNF inhibitors, Non-TNF inhibitors, Abatacept, Ustekinumab, Ixekizumab, Brodalumab, Secukinumab
62
Apremilast
| Brand, MOA, Caution
Otezla
**MOA:** PDE4 inhibitor that increases cAMP and inhibits NF-kb
* Decreases inflammatory cytokines from macrophages
**Caution:** Depression risk, D/N/V, CYP inducers decrease efficacy
63
Ustekinumab
| Brand, Indication, Caution
Stelara
**Biosimilar:** Wezlana
**MOA:** Human IgG1 monoclonal antibody
* Blocks the actions of IL-12 and IL-23 (by p-40 inhibition)
**Indication:** Plaque psoriasis and psoriatic arthritis
**Caution:** Infection risk, Live vaccines, Malignancy risk, Latex hypersensitivity
64
Secukinumab
| Brand, MOA, Caution
Cosentyx
**MOA:** Human IgG1 monoclonal antibody
* Selectively binds and neutralizes IL-17A
**Caution:** Infection risk, Live vaccines, Latex hypersensitivity
65
Ixekizumab
| Brand, MOA, Caution
Taltz
**MOA:** Humanized IgG4 monoclonal antibody
* Selectively binds and neutralizes IL-17A
**Caution:** Infection risk, Live vaccines, Latex hypersensitivity
66
Brodalumab
| Brand, MOA, BBW, Caution
Siliq
**MOA:** Human monoclonal IgG2 antibody to IL-17R
* IL-17R antagonist
* Inhibits IL-17 from binding to IL-17R
* Blocks the secretion of proinflammatory cytokines
**BBW:** Suicidal behaviors
**Caution:** Infection risk, depression, suicide, Live vaccines
**ADR:** Sore throat, neutropenia, fatigue
67
Summarize therapeutics for psoriatic arthritis?
68
Colchicine
| Brand, MOA, ADR,
Colcyrs, Mitigare
**MOA:** Inhibits polymerization of tubulin into microtubles (cell proliferation)
* Inhibits lysosomal enzymes and phagocytosis
* Inhibits chemotactic factors and mobility of neutrophils (leukotrienes)
* Inhibits inflammasome and IL-1 production
* Inhibits histamine release from mast cells
* **Does NOT reduce serum urate levels only inflammation**
**ADR:** GI disturbances (**D/N/V**), bone marrow depression, thrombocytopenia and aplastic anemia, reversible neuromyopathy
69
How is colchicine distributed in body?
Enterohepatic recirculation (cyclosporine, tacrolimus, verapamil)
70
What medication lower uric acid levels?
**First line:** Allopurinol or Febuxostat
**ALternative:** Probenecid
* Want to keep serum urate levels at 6mg/dL which is below limit of solubility of urate (6.8mg/dL)
* Does not control inflammation
71
What is the function of xanthine oxidase inhibitors?
Prevents the convertion of xanthine to urate
72
Allopurinol
| Brand, MOA, ADR, DDI
Zyloprim
**MOA:** Inhibits purine degradation, XO inhibitor
**ADR:** Skin rashes (exfoliatative dermatitis), Diarhea, Allopurinol hypersensitivity syndrome (deterioration of renal function), SjS/TEN, anemia
**DDI:** XO substrates (AZA, Theophylline, 6-MP)
73
What is the active metabolite of allopurinol?
Oxypurinol: oxidized and noncompetivie inhibitor of XO
74
What are the benefits of inhibitng XO?
1. Plasma urate levels decrease
2. Hypoxanthine and Xanthine levels increase (more soluble than urate and filtered by kidneys)
3. Synovial urate crystals dissolve
75
How does febuxostat differ from allopurinol?
Not purine based and more potent
76
Febuxostat
| Brand, MOA, BBW, ADR, CI, DDI
Uloric
**MOA:** XO inhibitor
**BBW:** CV death with CVD hx
**ADR:** DZ/HA/N/D, elevated LFT, SJS/TEN
**CI:** Hepatic impairment
**DDI:** XO substrates (AZA, Theophylline, 6-MP)
77
What are examples of uricosurics?
1. Probenecid
2. Fenofibrate (off-label)
3. Losartan (off-label)
78
Probenecid
| Brand, MOA, Pharmacology, CI
Benemid
**MOA:** Uricosuric by promoting excretion of urate), N-dialkylsulfamylbenzoates
**Pharm:** URAT1 and OAT inhibitor
**CI:** CKD, Kidney stone hx, G^PD, rash/pruritus
79
What are uricosurics?
Induces uric acid elimination through urination
80
Fenofibrate
| Brand, MOA, Caution, ADR
Tricor
**MOA:** Fenofibric acid inhibits URAT1 used to treat HLD
* Increases renal urate excretion
**Caution:** Rena/hepatic impairment, gallbladder dx, px on anticoags and cyclosporine
**ADR:** Rhabdomyolysis, hepatitis
81
Losartan
| Brand, MOA, Caution, ADR
Cozaar
**MOA:** ARB, Increases urate secretion in PCT by inhibiting **URAT1**
**Caution:** Renal/hepatic impairment, severe CHF, hyperkalemia risk, avoid in pregnancy
**ADR:** **rhabdomylysis, hepatitis**
82
What are the uricase tx?
1. Pegloticase
2. Rasburicase
83
Pegloticase
| Brand, MOA, Indication, BBW, Caution
Krystexxa
**MOA:** PEGylated urate oxidase to reduce immunogenicity
* Oxidizes urate to allantoin (highly soluble)
**Indication:** Severem refractory gout
**BBW:** Anaphylasis, infusion rx, G6PD hemolysis, methemoglobinemia
**Caution:** CHF exacerbations
84
Rasburicase
| Brand, MOA, Indication, BBW
Elitek
**MOA:** r urate-oxidase from yeast
* Converts uric acid to allantoin (more soluble)
**Indication** Urate management in leukemia, lymphoma, and tumor malignancies (TLS)
**BBW:** G6PD hemolysis, methemoglobinemia, severe/fatal hypersensitivity rx
85
What are criteria for recieving uricase tx?
1. Stage 3 CKD (eGFR 50ml/min)
2. Alcoholic
3. 3wk history of discharging masses on fingers
4. Urate level 9mg/dl
5. Received single dose of IV Rasburicase
6. Post infusion urate <1.69 mg/dl
