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Drug Action III > Rheumatic Disorders (Med Chem) - Block 1 > Flashcards

Rheumatic Disorders (Med Chem) - Block 1 Flashcards

1
Q

What is the gold standard for DMARDs?

A

Methotrexate

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2
Q

What are examples of conventional syntheitic DMARDs?

A
  1. Methotrexate (MTX)
  2. Leflunomide (LEF)
  3. Sulfasalazine (SSZ)
  4. Hydroxycholorquine (HCQ)
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3
Q

What are examples of targeted synthetic DMARDs?

A
  1. Tofacitinib
  2. Upadacitinib
  3. Baricitinib
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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)

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5
Q

Describe the MOA of methotrexate?

A
  1. Inhibits TYMS blocking thymine production
  2. Inhibits DHFR that disrupts DNA methylation and methionine stores
  3. 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

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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

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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

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8
Q

Describe the MOA of Leflunomide?

A

Teriflunomide (active) inhibits dihyrooradate dehydrogenase (DHODH)

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9
Q

What is the importance for DHODH?

A

Rate limiting step of pyrimidine synthesis arresting B cell and T cell proliferation

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10
Q

Describe the difference between leflunomide and methotrexate?

A
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11
Q

Leflunomide

ADR, CI, BBW

A

ADR: D/N/V, rashes, alopecia, HTN
CI: liver impairment, pregnancy
BBW: fetal toxicity, hepatotoxicity

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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

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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

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14
Q

MOA of Hydroxychloroquine

A
  1. Blocks the activation of antigen presenting cells
  2. Prevents acidification of the lysosome and antigen processing -> blocking antigen presentation
  3. Prevents endosomal TLR signaling (7,8,9) and subsequent cytokine production
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15
Q

Hydroxychloroquine

Brand, DI, ADR

A

Plaquenil
DI: Digoxin, antacids
ADR: Ocular toxicity, cardiac, ear disorders, GI and skin effects

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16
Q

Describe the components of the JAK stat signaling pathway?

A
  1. Tyrosine kinase receptor that acts as a cytokine and GFR on immune cells
  2. Cytokine binds to JAK-R
  3. JAK phosphorylates STAT which serves as a transcription factor
  4. STAT activates transcription and production of cytokines
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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

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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

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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

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20
Q

What is a chimeric mAb?

A

4/12 domains are murine (2-VL and 2VH)

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21
Q

What is humanized mAb?

A

murine CDRs grafted into human mAb (IgG)

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22
Q

What is fully human?

A

the protein sequence is fully human

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23
Q

What is pegylated fab fragment?

A

polyethylene glycol is attached to the Fab portion of an IgG antibody

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24
Q

What are receptor Fc fusion?

A

functional receptor protein joined to the Fc portion of IgG

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25
Q

What more humanized the more/less immunogenic the mAb

A

Less

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26
Q

What are the disadvantages of having more immunogenicity?

A

Can lead to hypersensitivity producing antibodies against the therapeutic antibody

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27
Q

Prefix for chimeric?

A

Ximab

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28
Q

Prefix for human?

A

Umab

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29
Q

Prefix for humanized?

A

zumab

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30
Q

Prefix for mouse?

A

omab

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31
Q

Prefix for cept?

A

Fab protion has been replaced with receptor protein sequence

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32
Q

What are biosimilars?

A

same aa sequence as original mAb but produced from a different clone and can have different glycosylations

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33
Q

What are the functions of monoclonal antibodies?

A

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)

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34
Q

What occurs during Antibody Dependent Cell-Mediated Cytotoxicity (ADCC)?

A
  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
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35
Q

What occurs during complement dependent cytotoxicity (CDC)?

A
  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
Q

What are examples of anti-tnf-a?

A
  1. Infliximab
  2. Entanercept
  3. Adalimumab
  4. Golimumab
  5. Certolizumab pegol
37
Q

What are the non-TNF-a?

A
  1. Abatacept
  2. Rituximab
  3. Belimumab
  4. Tocilizumab
  5. Sarilumab
  6. Anakinra
38
Q

Infliximab

Brand, MOA

A

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
Q

Etanercept

Brand, MOA

A

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
Q

Adalimumab

Brand, MOA

A

Humira
Fully human monoclonal IgG1 antibody

MOA: Induces CDC of TNF-expressing cells
* Targets soluble and membrane bound TNF-a

41
Q

Golimumab

Brand, MOA

A

Simponi (SC), Simponi Aria (IV)
Human IgG1 monoclonal antibody

MOA: Targets and neutralizes TNF-a (soluble and membrane bound)

42
Q

Certolizumab pegol

Brand, MOA

A

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
Q

TNF-a inhibitors

BBW, CI, ADR

A

BBW: serious infections, malignancy
CI: acute or active infections, worsening CHF, Live vaccines, bDMARDs, tsDMARDs
ADR: Infection, N/HA/R/F, myelosuppression

44
Q

Abatacept

Brand, MOA, CI, ADR

A

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
Q

Rituximab

Brand, MOA, BBW, ADR, CI

A

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
Q

Tocilizumab

Brand, MOA, BBW, Caution, ADR, CI, Interactions

A

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
Q

How does Tocilizumab interact with CYP450 substrates?

A

Leads to increased metabolism of CYP450 substrates decreasing efectiveness of oral contraceptives and statins

48
Q

Sarilumab

Brand, MOA, BBW, Caution, ADR, CI, Interactions

A

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
Q

Anakinra

Brand, MOA

A

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
Q

Examples of SLE tx?

A
  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
Q

Azathioprine

Brand, MOA, Warning, ADR, DDI

A

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
Q

Cyclosporine

Brand, MOA, Warning, ADR

A

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
Q

What transporter is cyclosporine a substrate of?

54
Q

Describe the Pharmacogenomics of cyclosporine?

A

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
Q

Diffeerentiate the brands of cyclosporine?

A

Sandimmune: Oil-based suspension of CsA, Variable absorption, non linear
Neoral and Gengraf: Microemulsion, less variability in absorption, more predictable dose response

56
Q

Mycophenolate mofetil

Brand, MOA, BBW, ADR

A

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
Q

What is the function of Inosine monophosphate dehydrogenase (IMPDH)?

A

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
Q

Cyclophosphomide

Brand, MOA, CI,

A

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
Q

Belimumab

Brand, MOA, Caution, ADR

A

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
Q

What is the function of BLyS? What happens when you block it?

A
  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
Q

Examples of PsA tx?

A

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
Q

Apremilast

Brand, MOA, Caution

A

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
Q

Ustekinumab

Brand, Indication, Caution

A

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
Q

Secukinumab

Brand, MOA, Caution

A

Cosentyx
MOA: Human IgG1 monoclonal antibody
* Selectively binds and neutralizes IL-17A

Caution: Infection risk, Live vaccines, Latex hypersensitivity

65
Q

Ixekizumab

Brand, MOA, Caution

A

Taltz
MOA: Humanized IgG4 monoclonal antibody
* Selectively binds and neutralizes IL-17A

Caution: Infection risk, Live vaccines, Latex hypersensitivity

66
Q

Brodalumab

Brand, MOA, BBW, Caution

A

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
Q

Summarize therapeutics for psoriatic arthritis?

68
Q

Colchicine

Brand, MOA, ADR,

A

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
Q

How is colchicine distributed in body?

A

Enterohepatic recirculation (cyclosporine, tacrolimus, verapamil)

70
Q

What medication lower uric acid levels?

A

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
Q

What is the function of xanthine oxidase inhibitors?

A

Prevents the convertion of xanthine to urate

72
Q

Allopurinol

Brand, MOA, ADR, DDI

A

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
Q

What is the active metabolite of allopurinol?

A

Oxypurinol: oxidized and noncompetivie inhibitor of XO

74
Q

What are the benefits of inhibitng XO?

A
  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
Q

How does febuxostat differ from allopurinol?

A

Not purine based and more potent

76
Q

Febuxostat

Brand, MOA, BBW, ADR, CI, DDI

A

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
Q

What are examples of uricosurics?

A
  1. Probenecid
  2. Fenofibrate (off-label)
  3. Losartan (off-label)
78
Q

Probenecid

Brand, MOA, Pharmacology, CI

A

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
Q

What are uricosurics?

A

Induces uric acid elimination through urination

80
Q

Fenofibrate

Brand, MOA, Caution, ADR

A

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
Q

Losartan

Brand, MOA, Caution, ADR

A

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
Q

What are the uricase tx?

A
  1. Pegloticase
  2. Rasburicase
83
Q

Pegloticase

Brand, MOA, Indication, BBW, Caution

A

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
Q

Rasburicase

Brand, MOA, Indication, BBW

A

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
Q

What are criteria for recieving uricase tx?

A
  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

Drug Action III (23 decks)

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