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PF3012 > Pharmacology of DMARDs > Flashcards

Pharmacology of DMARDs Flashcards

1
Q

How was methotrexate originally designed?

A

Folate pathway antagonist by inhibiting dihydrofolate reductase

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2
Q

List 6 MOA of methotrexate

A
  1. Folate antagonism
  2. Adenosine signalling
  3. Polyamine inhibition
  4. Generation of ROS
  5. Decrease in adhesion molecules
  6. Alteration of cytokine profiles
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3
Q

Side effects of methotrexate

A

nausea
vomiting
diarrhoea
hepatotoxicity
myelosuppression
pneumonitis

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4
Q

Pharmacokinetics of methotrexate

A

Poorly absorbed from GIT, skin, mucous membranes

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5
Q

What is FH4

A

tetrahydrofolate. it is essential for nucleotide synthesis
- methotrexate has a high affinity for TH4

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6
Q

What does dihydrofolate reductase (DHFR) do

A
  • Maintains active FH4
  • Reduces folic acid to FH4
  • regenerates FH4 from FH2
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7
Q

How is methotrexate reversed

A

Leucovorin

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8
Q

What does FH4 do

A
  • Important for conversion DUMP (deoxyuridine monophosphate) to DTMP (deoxythymidine monophosphate)
  • This is the rate limiting step in DNA synthesis - catalysed by thymidylate synthase
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9
Q

What reaction does thymidylate synthetase catalyse?

A

The conversion of DUMP to DTMP (rate limiting step in DNA synthesis)

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10
Q

Is the majority of adenosine formed extracellularly or intracellularly

A
  • extracellularly by the sequential dephosphorylation of ATP to adenosine
  • can also be formed intracellularly from ATP and exported from the cell
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11
Q

What transmembrane enzyme sequentially dephosphorylates ATP and ADP to form ADP (in the synthesis of adenosine)

A

CD39

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12
Q

What transmembrane enzyme converts AMP into adenosine

A

CD73

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13
Q

What happens to adenosine after it is synthesised

A

it can be converted to inosine
it can act via the adenosine receptors to activate various downstream receptors

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14
Q

How does Methotrexate block intracellular adenosine formation

A
  • Inhibits AICAR transformylase
  • Accumulation of AICAR
  • AICAR inhibits adenosine deaminase
  • Increases levels of adenosine
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15
Q

What does AICAR stand for

A

5-aminoimidazole-4-carboxamide ribonucleotide

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16
Q

How is the adenosine which is formed intracellularly transported out of the cell

A

ENT1 - extracellular nucleoside transporter

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17
Q

What does adenosine deaminase do

A

converts adenosine to inosine

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18
Q

What receptor does adenosine primarily act on

A

A2A receptor, although it is a paracrine signalling molecule which can bind to 4 different GPCRs

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19
Q

What inflammatory effects does adenosine binding to A2A have?

A
  • Decrease in superoxide anion
  • Increased neutrophil function
  • Promotes transition from M1 (pro-inflammatory) to M2 (anti-inflammatory) macrophages
  • Inhibits cytokine production
  • Decrease in T cell activation and proliferation by inhibiting TCR
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20
Q

Which polyamines have a high concentration in a variety of diseases

A

Spermine and spermidine

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21
Q

How do spermine and spermidine have a negative effect in diseases

A

Can be converted into lymphotoxins (hydrogen peroxidase and ammonia) by monocytes.
Methotrexate inhibits this

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22
Q

How does methotrexate inhibit polyamine formation

A

Polyamines are formed by the methyl donors SAM and methionine.
These are made from tetrahydrofolate (THF/FH4) and methyltetrahydrofolate (5-CH3-THF)
Methotrexate depletes THF and 5-CH3-THF via inhibition of DHFR

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23
Q

How does methotrexate generating ROS help RA?

A
  • ROS result in increase in apoptosis of transformed T cells
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24
Q

Name 3 adhesion molecules which methotrexate decreases levels of

A
  • ICAM-1
  • VCAM-1
  • E-selectin
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25
Q

Name 5 pro-inflammatory cytokines whose levels are reduced by methotrexate

A
  • IFN gamma
  • IL-4
  • IL-3
  • TNF
  • GMCSF
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26
Q

What 2 compounds form Sulfasalazine? (SSZ)

A

sulfapyridine
5-aminosalicylic acid (mesalazine/mesalamine)

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27
Q

How is SSZ split into 5-ASA and sulfapyridine

A

hydrolysed by colonic bacteria

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28
Q

What is the MOA of SSZ

A

SSZ is hydrolysed by colonic bacteria into sulfapyridine and 5-ASA
- 5-ASA remains in bowel scavenges oxygen radicals and inhibits COX and 5-LO
- sulfapyridine is completely absorbed and undergoes hydroxylation, glucuronidation, acetylation in the liver
- parent molecule inhibits T-cell proliferation and B-cell activation
- inhibits NFKB

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29
Q

Side effects of SSZ

A
  • gastric distress
  • headache
  • nausea
  • vomiting and diarrhea
  • photosensitivity
  • Leukopenia
  • Rash
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30
Q

Safety information for SSZ

A
  • avoid the sun
  • discolouration of skin/urine to orange/yellow
  • diabetes - may cause hypoglycaemia
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31
Q

Side effects of gold compounds

A
  • Nephrotoxicity
  • Pruritis (eczematous reactions)
  • Ulceration of the mouth, tongue & pharynx
  • Leucopenia
  • Thrombocytopenia
  • Proteinuria
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32
Q

Name 2 gold compounds and their ROA

A
  • aurothioglucose (parenteral)
  • auranofin (oral)
33
Q

Name 2 anti-malarial drugs used as DMARDs

A
  • chloroquine
  • hydroxychloroquine
34
Q

MOA of anti-malarials as DMARDs

A
  • Inhibit lymphocytes proliferation
  • Inhibits leukocyte chemotaxis
  • Inhibits IL-1 production
35
Q

Name 3 immunomodulator drugs used as DMARDs

A

Azathioprine (purine antagonist)
Cyclosporin A (T-cell selective immunosuppressent)
Leflunomide

36
Q

How does Leflunomide act as a DMARD?

A
  • Increase in IL-10
  • Decrease in IL-11 and IL-6
  • Decrease in PGE2 synthesis

(it is an immunomodulator)

37
Q

MOA of penicillamine for RA

A

Decreases the immune response and IL-1 generation, prevents maturation of newly synthesised collagen

38
Q

What is the evolution of monoclonal antibodies?

A

murine - chimeric - humanized - fully human

39
Q

What is the general suffix for murine (0% human) Mab?

A

-omab

40
Q

What is the general suffix for chimeric (65% human) Mab?

A
  • ximab
41
Q

What is the general suffix for humanized (>90% human) Mab?

A

-zumab

42
Q

What is the general suffix for fully human (100% human) Mab?

A
  • umab
43
Q

Name 3 anti-TNF agents

A
  • Etanercept
  • Infliximab
  • Adalimumab
44
Q

Name 1 IL-1 receptor antagonist

A

Anakinra

45
Q

Name 1 IL-6 receptor antagonist

A

Tocilizumab

46
Q

Name 1 T cell co-stimulatory inhibitor

A

Abatacept

47
Q

Name 1 anti-CD20 mAb

A

Rituximab

48
Q

How is TNF-alpha produced?

A
  • In the synovial tissue, T cells produce interferon gamma and other proinflammatory cytokines ……….these stimulate macrophages, fibroblasts, chondrocytes, osteoclasts and B cells
  • Activated macrophages and fibroblasts produce tumour necrosis factor alpha, IL-1, IL-6, 1L-15, IL-18 and other proinflammatory cytokines
49
Q

What effect does TNF-alpha have?

A

Stimulates the release of additional inflammatory mediators - chemokines, prostaglandins, proteases, growth factors
- active neutrophiles, b cells, endothelial cells

50
Q

What are the two forms of TNF α?

A

Membrane bound
Soluble

51
Q

What 2 receptors does TNF bind to?

A

TNF receptor type 1/ TNFR1/ p55
TNF receptor type 1/ TNFR2/ p75

52
Q

Where is p55 expressed?

A

Nearly all cells of the body, including the entire lymphoid system

53
Q

Where is p75 expressed?

A

has more restricted expression - found on certain subpopulations of immune cells and a few other cell types

54
Q

What is the function of TNFR1 (p55) and TNFR2 (p75)

A

p55 - apoptosis
p75 - any function relating to T-cell survival

55
Q

How are the TNF-α mAb administered?

A

Etanercept - SC
Infliximab - IV
Adalimumab - SC

56
Q

Describe the structure of etanercept
(Enbrel)

A

dimer of covalently bound receptors of the higher-affinity Type 2 TNF-α receptor (p75) linked to the Fc portion of human IgG1

recombinant soluble p75 TNF receptor: Fc fusion protein

57
Q

MOA of etanercept

A
  • binds to TNF-α and prevents it from interacting with its receptor
  • also inhibits TNF- beta (lymphotoxin)
58
Q

Describe the structure of infliximab (Remicade)

A

chimeric IgG1 anti-TNF-α antibody

59
Q

MOA of infliximab

A
  • binds with high affinity to membrane and soluble TNF-α
  • blocks TNF-α receptor interaction
  • also cytotoxic for TNF-expressing cells
60
Q

describe the structure of adalimumab (Humira)

A

Recombinant humanized monoclonal anti-TNF-α antibody

61
Q

MOA of adalimumab

A

binds to human TNF-α and prevents it interacting with receptor

62
Q

List 7 side effects of TNF inhibitors

A
  • opportunistic infections (impaired host defence, invasive fungal infections, reactivation of M. tuberculosis - infliximab)
  • Malignancy
  • Congestive heart failure
  • Congenital abnormalities
  • Infusion/infection site reactions
  • Demyelination
  • Development of auto-antibodies and Lupus like syndrome
63
Q

Describe the structure of Anakinra (Kineret)

A

Recombinant non-glycosylated form of the human IL-1 receptor antagonist (IL-1RA)

64
Q

Patient info for anakinra

A
  • can be used alone or in combination with anti-TNF-α
  • short t1/2 (4-6 hours)
  • sc injection once a day
  • used in juvenile RA, not adult
65
Q

MOA of Tocilizumab (RoActemra)

A
  • competitively inhibits the binding of IL-6 to IL-6R
  • Prevents IL-6 signal transduction to inflammatory mediators
66
Q

Which forms of IL-6 does Tocilizumab inhibit

A

membrane bound and soluble

67
Q

Which drug is Tocilizumab used with?

A

Methotrexate

68
Q

Describe the structure of Abatacept

A

recombinant fusion protein consisting of
- extracellular domain of human cytotoxic lymphocyte antigen 4
- a fragment of the Fc domain of human IgG1

69
Q

MOA of Abatacept

A

competes with CD28 for binding to CD80/CD86, modulating the second co-stimulatory signal required for full T-cell activation

70
Q

Which cells is CD20 found on?

A

B cells

71
Q

Who is Rituximab (MabThera) licensed to treat

A
  • non-hodgkin’s lymphoma
  • chronic lympocytic-leukemia
  • RA
  • granulomatosis
    in adults
  • rheumatoid arthritis with methotrexate for patients who do not respond to anti-TNF treatments (RA)
  • off label for multiple sclerosis
72
Q

Describe the structure of Rituximab

A

Anti-B cell (cd20) chimeric IgG1 mAb

73
Q

MOA of Rituximab

A
  • Targets and destroys only B cells
  • Flags B cells for destruction by body’s own immune system
74
Q

Name another anti-CD20 for RA

A

Ocrelizumab

75
Q

What is basilixumab used for?

A

acute rejection of kidney transplants (anti-inflammatory)

76
Q

What is daclizumab used for?

A

acute rejection of kidney transplants (anti-inflammatory)W

77
Q

What is omalizumab used for?

A

moderate to severe asthma (anti-inflammatory)

78
Q

What gene makes you susceptible to RA?

A

HLA-DRB1

PF3012 (10 decks)

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