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CPT > L15 - Immunosuppressants > Flashcards

L15 - Immunosuppressants Flashcards

1
Q

Rheumatoid arthritis

A

Autoimmune multi systemic diseases initially causing inflammation localised to the synovium (joints) leading to dissolution of cartilage and bone

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2
Q

Pannus

A

Tissues and inflammatory cells involved in inflammation and proliferation of the synovium

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3
Q

Juvenile idiopathic arthritis

A

Rheumatoid arthritis that occurs in children aged 3+

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4
Q

Diagnostic criteria for rheumatoid arthritis

A

Morning stiffness - for more than 1 hour
Arthritis of 3+ joints including hands and wrist
Symmetrical arthritis
Rheumatoid nodules

Investigations:

  • serum rheumatoid factor/ anti -CCP antibodies
  • X - ray changes due to joint damage
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5
Q

Pathogenesis

A

Antibodies (anti-CCP) against self antigens cause more pro-inflammatory mediators to be produced than anti-inflammatory mediators

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6
Q

Pro inflammatory mediators

A

IL-1 and 6
TNF - alpha
Metalloproteinases - causes joint damage and inflammation

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7
Q

Anti- inflammatory mediators

A

IL-4

TGF- beta

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8
Q

SLE

A

Prevalent in African Caribbean ladies
Multi systemic
Treat with steroids (anabolic)
Characteristic face rash

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9
Q

Vasculitis

A 
Vessel inflammation 
Can causes:
- nephritic syndrome 
- purpuric ulcers 
- pulmonary haemorrhage
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10
Q

Immunosuppressant examples

A 
Corticosteroids 
Methotrexate 
Azathioprine 
Cyclosporin
Tacrolimus 
Mycophenolate mofetil 
Leflunomide 
Cyclophosphamide 
Monoclonal antibodies - biologics
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11
Q

Corticosteroid mechanism of action

A
  1. Lipophilic so passes through the plasma membrane
  2. Binds to a glucocorticoid receptor in the cytoplasm and forms a complex
  3. Translocates into the nucleus forming a homodimer
  4. Prevents gene transcription of interleukin 1 and 6 (inflammatory mediators) therefore not produced by macrophages
  5. Inhibits all stages of T cell activation
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12
Q

Side effects of corticosteroids

A
  1. Weight gain
  2. Thrush ( candidiasis)
  3. Immunosuppression if used for 3+ months
  4. Glaucoma
  5. Cataracts
  6. Causes accelerated old age - osteoporosis, muscle weakness and bruising
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13
Q

DMARDs - disease modifying anti rheumatic drugs

A

Non biologics:

  • hydroxychloroquine
  • sulphasalazine

Biologics:

  • anti TNF agents
  • rituximab
  • IL-6 inhibitors
  • JAK inhibitors
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14
Q

Azathioprine use

A

Steroid sparing drug

SLE and vasculitis - maintenance therapy 
RA - not as effective 
Inflammatory bowel disease 
Atopic dermatitis - rarely used  
Bulbous skin disease
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15
Q

Azathioprine pharmacodynamics

A

Is a prodrug of 6MP given orally

  • TPMT (thiopurine methyltransferase) metabolises (cleaves) azathioprine into 6-MP
  • 6-MP is converted to 6MeMP via TPMT
  • decreases DNA and RNA synthesis by inhibiting de novo purine synthesis
  • apoptosis of activated lymphocytes
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16
Q

What should be done before prescribing azathioprine?

A

Test TPMT activity before prescribing as the TPMT gene is highly polymorphic therefore there is varied activity in individual

  • low or absent TPMT increases the risk of myelosupression
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17
Q

Azathioprine ADRs

A
  • Bone marrow suppression - suppresses RBCs, WBCs and platelets - therefore monitor FBC
  • Increased risk of malignancy especially in transplanted patients
  • increased risk of infection
  • drug induced hepatitis - monitor LFTs
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18
Q

Calcineurin

A

Calcium and calmodulin

  • exerts phosphates activity of activated T cells
  • nucleus factor migrates
  • IL-2 is transcribed
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19
Q

Calcineurin inhibitors examples

A

Cyclosporin

Tacrolimus

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20
Q

Uses of calcineurin inhibitors

A

Used in:

  • transplantation
  • atopic dermatitis and psoriasis
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21
Q

How do calcineurin inhibitors work?

A

Distorts the cell membrane cytoskeleton

Cyclosporin and tacrolimus are active against T helper cells - prevent the production of IL-2

  • cyclosporin binds to the cyclophilin protein
  • tacrolimus binds to the tacrolimus binding protein
  • the drug-proetin complexes bind to calcineurin
22
Q

ADRs of calcineurin inhibitors

A
  • gum hypertrophy

- nephrotoxic - check BP and eGFR

23
Q

Pharmacokinetics of calcineurin inhibitors

A

Metabolised by CYP450

24
Q

CYP P450 inducers

A

Rifampicin - used in TB
Carbemazepine - antipsychotic
Phenytoin - antipsychotic
Omeprazole - PPI

25
CYP P450 inhibitors
Ciprofloxacin Fluoxetine - SSRI Paroxetine - SSRI Idinavir - HIV antivirals
26
Use of mycophenolate mofetil
Primarily used for transplantation - monitor mycophenolic acid (active ingredient) Induction and maintenance therapy for Lupus nephritis and vasculitis
27
Mycophenolate mofetil mechanism of action
Prodrug from fungus - penicillium stoloniferum Inhibits inosine monophosphate dehydrogenase which impairs B and T cell proliferation but spares other rapidly deciding cells
28
ADRs of mycophenolate mofetil
``` Nausea and vomiting Diarrhoea Severe myelosuppression Increased risk of cancer Mucositis - sores and ulcers in mouth ```
29
Cyclophosphamide uses
Small dose: - lupus nephritis - ANCA vasculitis - wegener’s granulomatosis High dose: - lymphoma - leukaemia
30
Mechanism of action of cyclophosphamide
Alkylating agent - cross links DNA so that it can not replicate therefore suppresses: - B cell activity - T cell activity - inflammatory cells
31
Pharmacokinetics of cyclophosphamide
Prodrug activated by CYP450 in the liver to 4-hydroxycyclophosphamide Excretion: - renal
32
Acrolein
A toxic metabolite of cyclophosphamide that can cause haemorrhagic cystitis in the bladder epithelium Therefore: - give small dose of cyclophosphamide - use aggressive hydration - use Mesna
33
ADRs and indications of cyclophosphamide
- increased risk of bladder cancer, lymphoma and leukaemia - infertility - adjust dose in renal impairment (Mycophenolate mofetil is safer and as effective in lupus nephritis)
34
Methotrexate uses
``` Gold standard for rheumatoid arthritis Malignancy Psoriasis Crohn’s disease Ectopic pregnancy Inflammatory myopathies Steroid sparing drug in asthma Vasculitis ```
35
Methotrexate mechanism of action for malignancy
Competitively and reversibly inhibits dihydrofolate reductase (DHFR) - inhibits synthesis of DNA,RNA and proteins - cytotoxic during the S phase of the cell cycle - greater toxicity on rapidly dividing cells as they replicate DNA more frequently - has a higher affinity (1000x) for DHFR than folate
36
DHFR
Catalyses the conversion of dihydrofolate to the active tetrahydrofolate which aids purine and thymidine synthesis
37
Methotrexate pharmacokinetics
- oral bioavailability is 33% - IM bioavailability 76% Administered: orally, IM or SC injection If patient has a partial response or has nausea with oral methotrexate, swap to SC injection Excretion: - renal
38
Dose of methotrexate
WEEKLY - has a long half life so not given every day
39
Methotrexate protein binding
50% protein bound Displaced by NSAIDs - take with folic acid
40
ADRs of methotrexate
Normally well tolerated Mucositis Marrow suppression ( respond to folic acid supplementation) Hepatitis Cirrhosis Pneumonitis Infection TERATOGENIC and ABORTIFACIENT
41
Sulfasalazine
Conjugate of salicylate and sulfapyridine- do not give if aspirin allergy Not as effective as methotrexate Poorly absorbed therefore main activity is within the intestine for IBD
42
Effects of sulfasalazine
T cells: - inhibit proliferation - apoptosis - inhibibition of IL2 production Neutrophils: - reduced chemotaxis - reduced degranulation
43
ADRs of sulfasalazine
Due to sulfapyridine moiety - myelosuppression - hepatitis - rash - nausea and vomiting - abdominal pain
44
Sulfasalazine advantages
``` Effective Long term blood monitoring not needed Very few drug interactions Not carcinogenic Can be given in pregnancy ```
45
Biologics
- extracted from living systems - recombinant DNA - monoclonal antibodies - receptor constructs - fusion protein s
46
Anti TNF - alpha
Decreases inflammation - decreased cytokines cascade - less leukotrienes recruited to joint Decreased angiogenesis as inhibits VEGF Less joint destruction - inhibits destructive enzymes - less cartilage breakdown - less bone resorption and erosion
47
TNF - alpha
Essential for the development and maintenance of granulomata Released by macrophages in response to mycobacterium tuberculosis
48
Before giving anti-TNF treatment what should happen?
Screen for latent TB as therapy could cause TB reactivation
49
Rituximab
Binds to CD20 found on a subset of B cells causing B cell apoptosis Very specific and effective in rheumatoid arthritis
50
Role of B cells
Present antigens to T cells Produce cytokines Produce antibodies

CPT (23 decks)

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