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ESA 5 - Pharmacology > Immunosuppression and Rheumatic Disease > Flashcards

Immunosuppression and Rheumatic Disease Flashcards

1
Q

Give 4 examples of diseases that rheumatologists manage

A
  • Inflammatory arthritis, i.e. rheumatoid arthritis
  • Systemic lupud erythematosus
  • Systemic vasculitis
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2
Q

What kind of disease is rheumatoid arthritis?

A

An autoimmune multi-system disease

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3
Q

How common is rheumatoid arthritis?

A

Fairly common - 1% of UK population

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4
Q

Where is RA initially localised to?

A

The synovium

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5
Q

What is the synovium?

A

The tissue covering joints and lining articular surfaces

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6
Q

What happens to the synovium in RA?

A

There is inflammatory change and proliferation of the synvoium, leading to dissolution of cartilage and bone

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7
Q

What causes RA?

A

An imbalance between pro-inflammatory and anti-inflammatory cytokines

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8
Q

Give 3 pro-inflammatory cytokines

A
  • IL-1
  • IL-6
  • TNF-alpha
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9
Q

Give 2 anti-inflammatory cytokines?

A
  • IL-4
  • TGF-beta
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10
Q

Other than cytokines, what molecules are involved in the pathogenesis of RA?

A
  • T cells
  • B cells
  • Macrophages
  • Rheumatoid factor
  • Metalloproteinases
  • Neuropeptides
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11
Q

What kind of diagnosis is RA?

A

Clinical diagnosis

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12
Q

What are the diagnostic criteria for RA?

A
  • Morning stiffness for >1 hour
  • Arthritis of 3 or more joints
  • Symmetrical arthritis
  • Rheumatoid arthritis
  • Rheumatoid arthritis
  • Serum rheumatoid factor
  • X-ray changes
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13
Q

Why are we moving away from rheumatic nodules, serum rheumatoid factor, and x-ray changes as diagnostic criteria for RA?

A

We want to try and treat earlier, and these are later changes

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14
Q

What are the treatment goals in RA?

A
  • Symptomatic relief
  • Prevention of joint destruction
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15
Q

What is the treatment strategy in RA?

A
  • Early use of disease-modifying drugs
  • Use of adequate doses
  • Use of combinations of drugs
  • Avoidance of use of long-term corticosteroids
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16
Q

When should disease modifying drugs be used in RA?

A

Start on the day of diagnosis

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17
Q

What is meant by ‘adequate doses’ in RA treatment?

A

Doses that are adequate in achieving good disease control - aim for remission

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18
Q

Why should you avoid the use of long-term corticosteroids in RA treatment?

A

Steroids have lots of side effects/complications

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19
Q

What systems of the body can lupus affect?

A
  • Central and peripheral nervous system, e.g. seizures, headaches
  • Heart and lungs, e.g. pericarditis, pneumonitis
  • Kidneys, e.g. oedema, hypertension
  • Reproductive system, e.g. miscarriages, menstrual cycle irregularities
  • Blood, e.g. anaemia, thrombocytopenia
  • Eyes and mucous membranes, e.g. ulcers in eyes, nose, mouth, or vagina
  • Gastrointestinal, e.g. nausea, vomiting
  • Musculoskeletal, e.g. extreme fatigue, myalgia
  • Skin, e.g. butterfly rash, vasculitis
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20
Q

What organs are affected in vasculitis?

A
  • Lungs
  • Skin
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21
Q

What are the treatment goals in SLE and vasculitis?

A
  • Symptomatic relief
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and by drugs
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22
Q

Give 5 examples of immunosuppressant drugs

A
  • Corticosteroids
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
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23
Q

What is the mechanism of action of corticosteroids?

A
  • Prevent interleukin 1 and 6 (IL-1 and IL-6) production by macrophages
  • Inhibits all stages of T cell activation
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24
Q

Give 5 disease-modifying anti-rheumatic drugs (DMARD)

A
  • Methotrexate
  • Sulphasalazine
  • Anti-TNF agents
  • Rituixmab
  • Cyclophosphamide
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25
Q

Broadly, what is the advantage of DMARDs over immunosuppressants?

A

Tend to have a more focused action

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26
Q

How long do DMARDs take to have an effect?

A

Cyclophosphamide takes about 10 days to have an effect, whereas the others take 4-6 weeks

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27
Q

What are the clinical uses of azathioprine?

A
  • Used as a maintenance therapy in SLE and vasculitis
  • RA, although weak evidence
  • Inflammatory bowel disease
  • Atopic dermatitis
  • Bullous skin disease
  • Many other uses as a steroid sparing drug
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28
Q

What is meant by a steroid sparing drug?

A

Allows you to drop steroids early, so you’re not exposed to the side effects of steroids

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29
Q

How is azathioprine metabolised?

A
  1. Azathioprine is metabolised to 6-MP
  2. 6-MP is converted either to;
    • 6-MeMP by action of thiopurine methyltransferase (TPMT)
    • TIMP
    • 6-TI inactive
  3. TIMP is then converted to;
    • 6-MeMPN by action of TPMT
    • 6-TGN
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30
Q

What does 6-MeMPN do?

A

Inhibits de novo purine synthesis

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31
Q

What does 6-TGN do?

A

Incorporates into DNA

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32
Q

What is the clinical relevance of TPMT?

A

The TPMT gene is highly polymorphic, and so individuals vary markedly in TPMT activity. When there is low or absent levels of TMPT, there is a risk of myelosuppression, therefore TMPT activity must be tested before prescribing

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33
Q

What are the adverse effects of azathioprine?

A
  • Bone marrow suppression
  • Increased risk of malignancy
  • Increased risk of infection
  • Hepatitis
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34
Q

What should be done due to the risk of bone marrow suppression with azathioprine treatment?

A

Monitor FBC

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35
Q

Who is especially at risk of malignancy due to azathioprine treatment?

A

Transplant patients

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36
Q

What should be done due to the increased risk of hepatitis with azathioprine treatment?

A

Monitor LFTs

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37
Q

Give two examples of calcineurin inhibitors

A
  • Ciclosporin
  • Tacrolimus
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38
Q

Where are calcineurin inhibitors used?

A
  • Transplantation
  • Atopic dermatitis
  • Psoriasis
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39
Q

Why are calcineurin inhibitors not often used in rheumatology?

A

Due to renal toxicity

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40
Q

What must be done due to the risk of renal toxicity with the use of calcineurin inhibitors?

A

Check BP and eGFR regularly

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41
Q

Why are multiple drug interatctions possible with calcineurin inhibitors?

A

Because its action involves the cytochrome P450

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42
Q

Give 4 examples of CYP P450 inducers

A
  • Rifampicin
  • Carbamazepine
  • Phenytoin
  • Omeprazole
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43
Q

Give 5 examples of CYP P450 inducers

A
  • Ciprofloxacin
  • Many anti-fungals
  • Fluoxetine
  • Paroxetine
  • HIV anti-virals
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44
Q

What is the mechanism of action of the calcineurin inhibitors?

A
  • They are active against helper T-cells, preventing the production of IL-2 via calcineurin inhibition
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45
Q

What does calcineurin normally do?

A

Exerts a phosphtase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription.

46
Q

How does ciclosporin inhibit calcineurin?

A

It binds cyclophilin protein, and the drug/protein complexes bind calcineurin

47
Q

How does tacrolimus inhibit calcineurin?

A

It binds tacrolimus-binding protein, and the drug/protein complex bind calcineurin

48
Q

What is mycophenolate mofetil used for in clinical practice?

A

Primarily in transplantation, but also used in treatment of new cases of lupus

49
Q

How good is mycophenolate mofetil as a treatment for lupus?

A

It has a good efficacy as induction and maintenance therapy for lupus nephritis

50
Q

What is the active metabolite of mycophenolate mofetil?

A

Mycophenolic acid

51
Q

Why do blood levels of mycophenolic acid need to be monitored?

A

There is a risk of myelosuppression

52
Q

What are the adverse effects of mycophenolate mofetil?

A
  • Nausea
  • Vomiting
  • Diarrhoea
  • GI ulceration
  • Myelosuppression
53
Q

What is mycophenolate mofetil derived from?

A

The fungus Penicillin stoloniferum

54
Q

What is the mechanism of action of mycophenolate mofetil?

A
  1. It is a prodrug, and so is metabolised to mycophenolic acid
  2. Mycophenolic acid inhibits inosine monophosphate dehydrogenase, which is required for guanine synthesis
  3. This impairs B and T cell proliferation, but spares other rapidly dividing cells

​

55
Q

Why does mycophenolate mofetil spare other rapidly dividing cells?

A

Due to guanosine salvage pathways in other cells

56
Q

What is the mechanism of action of cyclophosphamide?

A

It is an alkylating agent cross links DNA so that it cannot replicate

It is cytotoxic

57
Q

WWhat are the immunological effects of cyclophosphamide?

A

Suppresses B and T cell activity

58
Q

What are the indications for cyclophosphamide treatment?

A
  • Lymphoma
  • Leukaemia
  • Solid cancers
  • Lupus nephritis
  • Wegener’s granulomatosis
59
Q

How is cyclophosphamide metabolised?

A

It is converted to its active form by cytochrome P450 enzymes in the liver. It’s main active metabolite is 4-hydroxycyclophosphamide (4-HC)​

60
Q

What does 4-HC exist in equilibrium with?

A

It’s tautomer, aldophosphamide

61
Q

What happens to aldophosphamide in the body?

A

Most of it is oxidised to make carboxyphosphamide, but a small proportion is converted into phosphoromide mustard

62
Q

What is cyclophosphamide excreted by?

A

The kidney

63
Q

What are the adverse effects of cyclophosphamide?

A
  • Haemorrhagic cystitis
  • Increased risk of bladder cancer, lymphoma, and leukaemia
  • Infertility
64
Q

How can cyclophosphamide cause haemorrhagic cystitis?

A

Acrolein (a metabolite of cyclophosphamide) is toxic to the bladder epithelium

65
Q

How does haemorrhagic cystitis present?

A

Visible or invisible haematuria

66
Q

How can haemorrhagic cystitis caused by cyclophosphamide be prevented?

A

The use of aggressive hydration, and/or Mesna

67
Q

How does Mesna inhibit haemorrhagic cystitis?

A

It binds acrolein (the metabolite that causes this side effect)

68
Q

What are the risks of cyclophosphamide related to?

A

The cumulative dose and patient age

69
Q

How can infertility caused by cyclophosphamide be prevented?

A
  • Oocyte preservation
  • GnRH analogue
70
Q

What should be monitored with cyclophosphamide treatment?

A

FBC

71
Q

When should the dose of cyclophosphamide be adjusted?

A

In renal impairment

72
Q

What is a good alternative for cyclophosphamide in lupus nephritis, and why?

A

It is safer, and as effective

73
Q

What is the gold standard treatment for RA?

A

Methotrexate

74
Q

Other than RA, what are the indications for the use of methotrexate?

A
  • Malignancy
  • Psoriasis
  • Crohn’s disease
75
Q

What is the mechanism of action of methotrexate in malignant disease?

A

It competitively and reversibly inhibits dihydrofolate reductase (DHFR), and therefore inhibits synthesis of DNA, RNA, and proteins

76
Q

How does the affinity of methotrexate for DHFR compare to that of folate for DHFR?

A

The affinity of methotrexate is 1000x that of folate

77
Q

What does dihydrofolate reductase do?

A

It catalyses the conversion of dihydrofolate to the active tetrahydrofolate, the key carrier of one-carbon units in purine and thymidine synthesis

78
Q

In what stage does methotrexate act specifically?

A

In DNA and RNA synthesis, therefore it is cytotoxic in the S phase of the cell cycle

79
Q

What is the result of methotrexate acting specifically in the S-phase of the cell cycle?

A

It has greater toxic effect on rapidly dividing cells, such as malignant and myeloid cells, and GI and oral mucosa), which replicate their DNA more frequently

80
Q

What is the mechanism of action of methotrexate in non-malignant disease?

A

Not clear - not via anti-folate action, but could be;

  • Inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine
  • Inhibition of T cell activation
  • Suppression of intercellular adhesion molecule expression by T cell
81
Q

What is adenosine?

A

A purine nucleoside that is elaborated at injured and inflamed sites. It is a regulatory autocoid

82
Q

How does adenosine act as a regulatory autocoid?

A

It is generated as a result of cellular injury or stress, and interacts with specific G-protein coupled receptors on inflammatory and immune cells to regulate their function

83
Q

What is the mean oral bioavailability of methotrexate?

A

33% - ranges between 13-76%

84
Q

What is the mean intramuscular bioavailability of methotrexate?

A

76%

85
Q

How can methotrexate be administered?

A

PO, IM, or SC

86
Q

What should be done in a patient on PO administration of methotrexate with partial response, or nausea?

A

Swap to SC

87
Q

How often is methotrexate given?

A

Weekly, not daily

88
Q

Why can methotrexate only be given weekly?

A

Because it is metabolised to polyglutamates with long half lives

89
Q

What is the maximum dose of methotrexate in RA?

A

20-25mg/week, any more and you get increased side effects with no increase in effect

90
Q

What % of methotrexate in the blood is protein bound?

A

50%

91
Q

What can displace methotrexate from the proteins its bound to in the blood?

A

NSAIDs

92
Q

How is methotrexate excreted?

A

Renally

93
Q

What are the advantages of using methotrexate in practice?

A
  • Well tolerated
  • Improved QoL
  • Retardation of joint damage
  • Anchor drug for DMARD combinations
94
Q

What is the result of methotrexate being generally well tolerated?

A

50% of patients continue the drug for >5 years, longer than any other DMARD

95
Q

What are the adverse effects of methotrexate?

A
  • Mucositis
  • Marrow suppression
  • Hepatitis
  • Cirrhosis
  • Pneumonitis
  • Infection risk
  • Highly teratogenic and abortifactient
96
Q

How can the methotrexate adverse effects of mucositis and marrow suppression be treated?

A

Folic acid supplementation

97
Q

What is sulfasalazine?

A

A conjugate of a salicylate (5-ASA) and a sulfapyridine molecule

98
Q

What is sulfasalazine designed to do?

A

Relieve pain and stiffness, and fight infection

99
Q

What are the immunological effects of sulfasalazine?

A
  • Inhibition of T cell proliferation
  • Possible T cell apoptosis
  • Inhibition of IL-2 production
  • Reduced neutrophil chemotaxis
  • Reduced neutrophil degranulation
100
Q

Where in the body is the main activity of sulfasalazine?

A

Within the intestine, as it is poorly absorbed

101
Q

What is the result of the main activity of sulfasalazine being in the large bowel?

A

It is effective in IBD

102
Q

What are the adverse effects of sulfasalazine?

A
  • Myelosuppression
  • Hepatitis
  • Rash
  • Nausea
  • Abdominal pain and vomiting
103
Q

What are the adverse effects of sulfasalazine mainly due to?

A

The sulfapyridine moiety

104
Q

When do the adverse effects of sulfasalazine usually occur?

A

Within the first 2 weeks, and then are fine after

105
Q

What are the advantages of suldasalazine in practice?

A
  • Effective
  • Favourable toxicity
  • Long term blood monitoring not always needed
  • Very few drug interactions
  • No carcinogen potential
  • Safe in pregnancy
106
Q

How are biopharmaceuticals obtained?

A

Recombinant DNA technology produces substances that are nearly identical to the bodys own key signalling proteins

107
Q

What kind of molecule are the majority of biopharmaceuticals?

A

Monoclonal antibodies

108
Q

How do monoclonal antibodies work as biopharmaceuticals?

A

They are ‘custom-designed’ to specifically block any given substance in the body, or target any specific type

109
Q

What are fusion proteins?

A

They are biopharmaceuticals based on a naturally occuring receptor, acting to block it

110
Q

What are the effects of blocking TNF-alpha?

A
  • Decreased inflammation
  • Decreased angiogenesis
  • Decreased joint destruction
111
Q
A

ESA 5 - Pharmacology (28 decks)

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