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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
Name 5 pro-inflammatory cytokines whose levels are reduced by methotrexate
- IFN gamma - IL-4 - IL-3 - TNF - GMCSF
26
What 2 compounds form Sulfasalazine? (SSZ)
sulfapyridine 5-aminosalicylic acid (mesalazine/mesalamine)
27
How is SSZ split into 5-ASA and sulfapyridine
hydrolysed by colonic bacteria
28
What is the MOA of SSZ
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
29
Side effects of SSZ
- gastric distress - headache - nausea - vomiting and diarrhea - photosensitivity - Leukopenia - Rash
30
Safety information for SSZ
- avoid the sun - discolouration of skin/urine to orange/yellow - diabetes - may cause hypoglycaemia
31
Side effects of gold compounds
- Nephrotoxicity - Pruritis (eczematous reactions) - Ulceration of the mouth, tongue & pharynx - Leucopenia - Thrombocytopenia - Proteinuria
32
Name 2 gold compounds and their ROA
- aurothioglucose (parenteral) - auranofin (oral)
33
Name 2 anti-malarial drugs used as DMARDs
- chloroquine - hydroxychloroquine
34
MOA of anti-malarials as DMARDs
- Inhibit lymphocytes proliferation - Inhibits leukocyte chemotaxis - Inhibits IL-1 production
35
Name 3 immunomodulator drugs used as DMARDs
Azathioprine (purine antagonist) Cyclosporin A (T-cell selective immunosuppressent) Leflunomide
36
How does Leflunomide act as a DMARD?
- Increase in IL-10 - Decrease in IL-11 and IL-6 - Decrease in PGE2 synthesis (it is an immunomodulator)
37
MOA of penicillamine for RA
Decreases the immune response and IL-1 generation, prevents maturation of newly synthesised collagen
38
What is the evolution of monoclonal antibodies?
murine - chimeric - humanized - fully human
39
What is the general suffix for murine (0% human) Mab?
-omab
40
What is the general suffix for chimeric (65% human) Mab?
- ximab
41
What is the general suffix for humanized (>90% human) Mab?
-zumab
42
What is the general suffix for fully human (100% human) Mab?
- umab
43
Name 3 anti-TNF agents
- Etanercept - Infliximab - Adalimumab
44
Name 1 IL-1 receptor antagonist
Anakinra
45
Name 1 IL-6 receptor antagonist
Tocilizumab
46
Name 1 T cell co-stimulatory inhibitor
Abatacept
47
Name 1 anti-CD20 mAb
Rituximab
48
How is TNF-alpha produced?
- 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
What effect does TNF-alpha have?
Stimulates the release of additional inflammatory mediators - chemokines, prostaglandins, proteases, growth factors - active neutrophiles, b cells, endothelial cells
50
What are the two forms of TNF α?
Membrane bound Soluble
51
What 2 receptors does TNF bind to?
TNF receptor type 1/ TNFR1/ p55 TNF receptor type 1/ TNFR2/ p75
52
Where is p55 expressed?
Nearly all cells of the body, including the entire lymphoid system
53
Where is p75 expressed?
has more restricted expression - found on certain subpopulations of immune cells and a few other cell types
54
What is the function of TNFR1 (p55) and TNFR2 (p75)
p55 - apoptosis p75 - any function relating to T-cell survival
55
How are the TNF-α mAb administered?
Etanercept - SC Infliximab - IV Adalimumab - SC
56
Describe the structure of etanercept (Enbrel)
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
MOA of etanercept
- binds to TNF-α and prevents it from interacting with its receptor - also inhibits TNF- beta (lymphotoxin)
58
Describe the structure of infliximab (Remicade)
chimeric IgG1 anti-TNF-α antibody
59
MOA of infliximab
- binds with high affinity to membrane and soluble TNF-α - blocks TNF-α receptor interaction - also cytotoxic for TNF-expressing cells
60
describe the structure of adalimumab (Humira)
Recombinant humanized monoclonal anti-TNF-α antibody
61
MOA of adalimumab
binds to human TNF-α and prevents it interacting with receptor
62
List 7 side effects of TNF inhibitors
- 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
Describe the structure of Anakinra (Kineret)
Recombinant non-glycosylated form of the human IL-1 receptor antagonist (IL-1RA)
64
Patient info for anakinra
- 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
MOA of Tocilizumab (RoActemra)
- competitively inhibits the binding of IL-6 to IL-6R - Prevents IL-6 signal transduction to inflammatory mediators
66
Which forms of IL-6 does Tocilizumab inhibit
membrane bound and soluble
67
Which drug is Tocilizumab used with?
Methotrexate
68
Describe the structure of Abatacept
recombinant fusion protein consisting of - extracellular domain of human cytotoxic lymphocyte antigen 4 - a fragment of the Fc domain of human IgG1
69
MOA of Abatacept
competes with CD28 for binding to CD80/CD86, modulating the second co-stimulatory signal required for full T-cell activation
70
Which cells is CD20 found on?
B cells
71
Who is Rituximab (MabThera) licensed to treat
- 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
Describe the structure of Rituximab
Anti-B cell (cd20) chimeric IgG1 mAb
73
MOA of Rituximab
- Targets and destroys only B cells - Flags B cells for destruction by body's own immune system
74
Name another anti-CD20 for RA
Ocrelizumab
75
What is basilixumab used for?
acute rejection of kidney transplants (anti-inflammatory)
76
What is daclizumab used for?
acute rejection of kidney transplants (anti-inflammatory)W
77
What is omalizumab used for?
moderate to severe asthma (anti-inflammatory)
78
What gene makes you susceptible to RA?
HLA-DRB1

PF3012 (10 decks)

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