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3921 > 2 Overview of DMARDs > Flashcards

2 Overview of DMARDs Flashcards

1
Q

What is an auto-immune disease?

A

Immune system produces inappropriate response against own cells resulting in
inflammation and damage

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2
Q

What is a potential cause of auto-immune diseases

A

Environmental trigger in genetically susceptible individuals (SNPs in important
immune regulating process genes)

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3
Q

What are main drug targets to INHIBIT for treatment of RA

A 
Cytokines
Pro-inflammatory signalling
COX-2
Antigen presentation
T-cell activation
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4
Q

What is a drug target to STIMULATE for the treatment of RA

A

CTLA4

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5
Q

What are drug targets to destroy for RA treatment (2)

A 
Rapidly proliferating cells (T)
Adaptive cells (T and B)
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6
Q

What are some symptomatic treatments of RA (3)

A

Non-pharmacological
Analgesics
Anti-inflammatory drugs (non-steroidal, corticosteroids)

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7
Q

When are DMARDs started

A

Early in combination with NSAIDs or GC

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8
Q

What is the effect of DMARDs

A

Delayed efficacy on symptoms

Long term outcome improvement by slowing disease progression

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9
Q

What are some synthetic DMARDs (4)

A

Methotrexate and Leflunomide (anti-metabolites)
Hydroxychloroquine
Sulfasalazine

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10
Q

What are some biological DMARDs (4)

A

TNF-a inhibitors
IL-6 inhibigots
Rituximab
Abatacept

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11
Q

What is methotrexate

A

Analogue of folic acid (Vitamin B9)

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12
Q

What is the drug target of methotrexate

A

DIhydrofolate reductase)

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13
Q

What are the pharmacokinetics of methotrexate (4)

A

Given orally
Lower doses compared to cancer
Long half life in RBC
Renally eliminated

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14
Q

What does methotrexate form in RBC and WBCs

A

Polyglutamate derivatives

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15
Q

What is the MOA for methotrexate (3)

A

Inhibits the synthesis of thymidylate and purine nucleotides
Essential for DNA synthesis and cell proliferation
Lymphocytes are highly susceptible

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16
Q

What is the toxicity of methotrexate (5)

A

1) Bone marrow suppression = higher risk of infections
2) Liver accumulation -= hepatotoxicity
3) Mouth Ulcers
4) Nausea
5) Pneumonitis (particularly year 1, elderly and diabetic high risk)

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17
Q

What is the drug target of leflunomide

A

Dihydroorotate dehydrogenase

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18
Q

What is the MOA of leflunomide (2)

A

Inhibits de novo pyrimidine synthesis

Essential for DNA/RNA synthesis, cellular proliferation

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19
Q

What are the pharmacokinetics of leflunomide (3)

A

Converted to teriflunomide
Protein binding > 99%
Metabolism by gut/liver 14 day half-life

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20
Q

Is leflunomide a pro-drug

A

Yes

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21
Q

What are some toxicities for leflunomide (6)

A 
Gastro-intestinal 
Skin rash, alopecia
Minor infections
Liver function abnormality
Peripheral neuropathy
Pneumonitis
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22
Q

What is the drug target of sulfasalazine?

A

Unknown

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23
Q

What is the in vivo MOA of sulfasalazine

A

Unkonwn

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24
Q

What are some in vitro MOAs of sulfasalazine

A

Inhibit various inflammatory mediators
Inhibit nuclear factor kappa B activation
Reduce synthesis of inflammatory mediators (IL-2, IL-1, chemookine)

25
Q

What are the pharmacokinetics of sulfasalazine (2)

A

Converted to 5-aminosalicylic acid

Poor bioavailability, surprisingly works in joints

26
Q

Is sulfasalazine a pro-drug

A

Yes

27
Q

What are some toxicities of sulfasalazine (7)

A 
GI
rash
headache
dizziness
depression
reversible infertility in males
thrombocytopenia
28
Q

What is the drug target of hydroxychloroquine

A

Lysosomes

29
Q

What is the MOA of hydroxychloroquine

A

Increased intracellular lysosome pH
Diminished lysosome enzyme processing of immune signalling proteins
Inhibits TLR9 signalling in dendritic cells, peptide loading for MHC
Prevents activation of innate immune cells, stops presentation to lymphocytes

30
Q

What are the pharmacokinetics of hydroxychloroquine (3)

A

Orally administered
Long half life > 40 d
Renal excretion

31
Q

What are the toxicities of hydroxychloroquine

A

Corneal deposits
Retinal toxicity (dose and time dependent)
GIT

32
Q

2 main MOA of conventional DMARTs

A

Inhibition of RNA synthesis and cellular proliferation

Inhibition of intracellular signalling in immune cells

33
Q

What is a missing target for effective RA treatment

A

Signalling mediators

34
Q

What are some biological DMARDs

A

Infliximab
Tocilizumab
Rituximab
Abatacept

35
Q

What are antibodies

A

Large MW proteins

36
Q

How are antibodies delivered

A

SC injection into interstitial space of hypodermis

37
Q

What are the pharmacokinetics of antibodies

A

Slow absorption into the systemic circulation
Transport via lymphatics
Long half-life of days

38
Q

How are antibodies broken down

A 
Degradation by proteolysis
Fcy receptor-mediated clearance
Target-mediated clearance
Non-specific endocytosis
Formulation of immune-complexes (ICs) 
Complement- or Fc receptor-mediated clearance mechanisms
39
Q

How are antibodies eliminated

A

Smaller peptides excreted in urine <30kDa

40
Q

What are some TNF-a inhibitors

A 
› Etanercept (Enbrel)
› Infliximab (Remicade)
› Adalimumab (Humira)
› Certolizumab (Cimzia)
› Golimumab (Simponi)
41
Q

What is the MOA of TNF-a inhibitors

A

Reduced NKFB signalling

Diagram

42
Q

What is the drug target of TNF inhibitors

A

Extracellular TNF or TNFR or membrane-bound TNF

43
Q

What are the pharmacokinetics of TNF inhibitors

A

Large molecules, not orally bioavailable

Infliximab given via IV injection, all others via SC

44
Q

What are toxicities of TNF inhibitors

A

Injection site reactions common
Infections - especially opportunistic bacteria and fungi
Recurrence of latent infections (TB and HBV)
Increased risk of malignancy
Demylinating disease and Congestive heart failure

45
Q

Drug target of tocilizumab (IL-6)

A

IL-6 receptor

46
Q

What is the MOA of tocilizumab (4)

A

Binds to IL-6 receptor
Blocks IL-6 from binding at the cell surface receptor
Prevents JAK-STAT3 intracellular signalling
Reduces cellular survival and proliferation

47
Q

What are the pharmacokinetics of tocilizumab

A

IV administration

Long half-life

48
Q

What are some toxicities of tocilizumab (4)

A

Abnormal liver function
Neutropenia (increased risk of infection, including cellulitis)
Increased cholesterol (both HDL and LDL)
Increased risk of GI perforation

49
Q

What is the drug target of rituximab

A

CD20 on B-cells

50
Q

What is the MOA of rituximab

A

Binds to CD20 on B-cells

ADCC - cell death

51
Q

What are the pharmacokinetics of rituximab

A

IV, stat, fortnightly then 6 monthly

Long half-life

52
Q

What are some toxicities of rituximab (6)

A 
Headache
Fever
Chills
Stomach pain
Nausea
Diarrhoea
53
Q

What happens at the end of immune response

A

CTLA4 upregulation on T-cells

54
Q

What happens after CTLA4 upregulation

A

CTLA4 binds to CD80/CD86

55
Q

What does abatacept bind to as a CTLA4 agonistic antibody

A

CD80/CD86

56
Q

What is the MOA of abatacept

A

Inhibits CD80/86 on APC preventing activation and proliferation of T-cells
Inhibits T-cell mediated cytokine release

57
Q

What are the pharmacokinetics of CTLA4 inhibitors

A

SC (weekly)
IV (monthly)
13d half-life

58
Q

What are some toxicities or abatacept

A

Hypersensitivity

Respiratory function worsening in COPD and headache

59
Q

What are the 3 main MOA for biological DMARDs

A

Ligand blockade
Receptor blockade
Depletion

3921 (22 decks)

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