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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
Q

CYP P450 inhibitors

A

Ciprofloxacin
Fluoxetine - SSRI
Paroxetine - SSRI
Idinavir - HIV antivirals

26
Q

Use of mycophenolate mofetil

A

Primarily used for transplantation - monitor mycophenolic acid (active ingredient)

Induction and maintenance therapy for Lupus nephritis and vasculitis

27
Q

Mycophenolate mofetil mechanism of action

A

Prodrug from fungus - penicillium stoloniferum

Inhibits inosine monophosphate dehydrogenase which impairs B and T cell proliferation but spares other rapidly deciding cells

28
Q

ADRs of mycophenolate mofetil

A 
Nausea and vomiting
Diarrhoea 
Severe myelosuppression 
Increased risk of cancer 
Mucositis - sores and ulcers in mouth
29
Q

Cyclophosphamide uses

A

Small dose:

  • lupus nephritis
  • ANCA vasculitis
  • wegener’s granulomatosis

High dose:

  • lymphoma
  • leukaemia
30
Q

Mechanism of action of cyclophosphamide

A

Alkylating agent - cross links DNA so that it can not replicate therefore suppresses:

  • B cell activity
  • T cell activity
  • inflammatory cells
31
Q

Pharmacokinetics of cyclophosphamide

A

Prodrug activated by CYP450 in the liver to 4-hydroxycyclophosphamide

Excretion:
- renal

32
Q

Acrolein

A

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
Q

ADRs and indications of cyclophosphamide

A
  • 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
Q

Methotrexate uses

A 
Gold standard for rheumatoid arthritis 
Malignancy 
Psoriasis 
Crohn’s disease 
Ectopic pregnancy 
Inflammatory myopathies 
Steroid sparing drug in asthma 
Vasculitis
35
Q

Methotrexate mechanism of action for malignancy

A

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
Q

DHFR

A

Catalyses the conversion of dihydrofolate to the active tetrahydrofolate which aids purine and thymidine synthesis

37
Q

Methotrexate pharmacokinetics

A
  • 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
Q

Dose of methotrexate

A

WEEKLY

  • has a long half life so not given every day
39
Q

Methotrexate protein binding

A

50% protein bound
Displaced by NSAIDs

  • take with folic acid
40
Q

ADRs of methotrexate

A

Normally well tolerated

Mucositis
Marrow suppression
( respond to folic acid supplementation)

Hepatitis
Cirrhosis
Pneumonitis
Infection

TERATOGENIC and ABORTIFACIENT

41
Q

Sulfasalazine

A

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
Q

Effects of sulfasalazine

A

T cells:

  • inhibit proliferation
  • apoptosis
  • inhibibition of IL2 production

Neutrophils:

  • reduced chemotaxis
  • reduced degranulation
43
Q

ADRs of sulfasalazine

A

Due to sulfapyridine moiety

  • myelosuppression
  • hepatitis
  • rash
  • nausea and vomiting
  • abdominal pain
44
Q

Sulfasalazine advantages

A 
Effective 
Long term blood monitoring not needed 
Very few drug interactions 
Not carcinogenic 
Can be given in pregnancy
45
Q

Biologics

A
  • extracted from living systems
  • recombinant DNA
  • monoclonal antibodies
  • receptor constructs - fusion protein s
46
Q

Anti TNF - alpha

A

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
Q

TNF - alpha

A

Essential for the development and maintenance of granulomata
Released by macrophages in response to mycobacterium tuberculosis

48
Q

Before giving anti-TNF treatment what should happen?

A

Screen for latent TB as therapy could cause TB reactivation

49
Q

Rituximab

A

Binds to CD20 found on a subset of B cells causing B cell apoptosis

Very specific and effective in rheumatoid arthritis

50
Q

Role of B cells

A

Present antigens to T cells
Produce cytokines
Produce antibodies

CPT (23 decks)

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