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S4 Pharma CPT > Immunosuppressants > Flashcards

Immunosuppressants Flashcards

1
Q

Lost the 3 main autoimmune diseases rheumatologist deal with

A

Inflammatory arthritis - rheumatoid arthritis

Systemic lupus erythematous

Systemic vasculitis

(Bones, joints, immune system)

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2
Q

What is rheumatoid arthritis?

A

1% UK

Autoimmune multisystem
Initially localised synovium
Inflammatory change and proliferation of synovium -> inflammatory pannus -> leading dissolution of cartilage and bone

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3
Q

Pathogenesis of rheumatoid arthritis

A

Dendritic cells present self antigens to autoreactive T cells -> cytokines* -> activate autoreactive B cells -> autoantibodies (rheumatoid factor/ anti-CCP antibodies) + immune complexes + immune cells (macrophages) deposition in joints

Metalloproteinases + other proteinases break down the extracellular matrix

  • imbalance between pro-inflammatory (IL-1/IL-6/TNF-alpha) & anti-inflammatory (IL-4/ TGF- beta) cytokines
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4
Q

How do we diagnose RA?

A 
Clinical criteria:
Morning stiffness >_1hr 
Arthritis of _>3 joints 
Arthritis of hand joints 
Symmetrical arthritis 
Rheumatoid nodules

Non-clinical criteria:
Serum rheumatoid factor/ anti-CPP antibodies
X-ray changes (periarticular osteopenia, joint space narrowing, juxta-articular bony erosions, subluxation and gross deformity)

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5
Q

What’s the treatment strategy for rheumatoid arthritis?

A

Early use of disease modifying drugs

Aim to achieve good disease control

Use of adequate dosages

Use of combination of drugs

Avoidance of long term corticosteroids

Remission with drugs ideal

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6
Q

Systemic lupus erythematous effects

A

Systemic

Ulcers, seizures, psychosis, depression, pericarditis, endocarditis, myalgia, oedema, hypertension, renal failure, miscarriages, menstruated cycle irregularities, butterfly rash, vasculitis, anaemia, thrombocytopenia. Leukopenia, thrombosis, circulating autoantibodies/ immune complexes

90% women, develop between 15-45yrs
African

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7
Q

What is vasculitis?

A

Inflammation of blood vessels

Thickening/ weakening/ narrowing/ scarring can restrict blood flow -> organ/ tissue damage

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8
Q

Treatment goals in SLE and vasculitis

A

Symptomatic relief
Reduction in mortality
Prevention organ damage
Reduction long term morbidity caused disease and drugs

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9
Q

Give some examples of immunosuppressants

A

Corticosteroids
Methotrexate
Ciclosporin
Cyclophosphamide

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10
Q

How do corticosteroids work?

A

Binds to GRh receptor -> triggers intracellular cascade Prevent IL-1/ IL-6 production by macrophages

Inhibit all stages of T cell activation

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11
Q

Side effects of steroid use

A 
Weight gain 
Thrush
Immunosuppression 
Cataracts
Bruising
Glaucoma 
Osteoporosis
Decreased muscle girth

‘Accelerated old age’

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12
Q

When are corticosteroids prescribed for autoimmune conditions?

A

RA: severe/ flare ups

Lupus: reduce swelling/ tenderness/ pain, once reduced lower dose slowly

Vasculitis: control inflammation, if needed for maintenance therapy lowest dose possible

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13
Q

Why is it important to slowly withdraw from corticosteroid therapy?

A

Causes: Adrenal cortex -> cortisol
Long term use: side effects + reduced feedback HPAA on adrenal gland (adrenal insufficiency) -> reduced appetite, fatigue, weight loss, nausea, V&D, abdo pain, life threatening

Need time for adrenal glands to return to normal secretion

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14
Q

List some disease modifying anti-rheumatic drugs (DMARDSs)

A

Non- biological:
Sulphasalazine
Hydroxychloroquine

Biologics:
Anti-TNF agents
Rituximab
IL-6 inhibitors, JAK inhibitors

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15
Q

Azathioprine mechanism of action and use

A

Anti-proliferation agent
Azathiprine cleaved to 6-MP (TPMT) -> 6-MeMP inactive + 6-TU inactive + TIMP (TPMT) -> 6-MeMPN (inhibits de novo purine synthesis) + 6-TGN (incorporation into DNA)
Overall stops DNA/ RNA synthesis & so immune cell synthesis

Slide 20

Use:
SLE/ vasculitis - maintenance therapy 
RA - weak evidence 
IBD 
Bulbous skin disease
Atopic dermatitis 
Steroid sparing drug
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16
Q

Why is it important to test TPMT activity before prescribing azathioprine?

A

Azathioprine cleaved to 6-MP which is metabolised by TPMT

TPMT is highly polymorphic - individuals have varying amounts of the enzyme

Low/ absent levels = risk of myelosupression

17
Q

Adverse effects of azathioprine

A

Bone marrow suppression (monitor FBC)

Increased risk of malignancy (esp transplant patients) - same as all immunosuppressants

Increased risk infection

Hepatitis (monitor LFTs)

18
Q

Mycophenolate use and mechanism of action

A
  • primarily transplantation
  • good efficacy as induction and maintenance therapy for lupus nephritis/ vasculitis maintenance

MOA:
Prodrug derived from fungus penicillium stolomiferum
Inhibits inosine monophosphate dehydrogenase (needed for guanosine synthesis)
Impairs B and T cell proliferation
Spares other rapidly dividing cells (guanosine salvage alternative pathway in other cells)

19
Q

Mycophenolate mofetil adverse effects

A 
Nausea
Vomiting
Diarrhoea 
Myelosuppression
Increased risk cancer (esp skin)

Less immunosuppression than azathiprine

20
Q

Uses of calcineurin inhibitors, examples, adverse effects

A

Widely used in transplantation
Atopic dermatitis
Psoriasis
Not often used in rheumatology - renal toxicity, check BP and eGFR regularly

Ciclosporin - gums to swell

and tacrolimus

Multiple drug reactions as metabolised by cytochrome P-450 e.g. inducers (decrease levels) rifampicin, omeprazole and inhibitors (increase) antifungals, HIV antivirals

21
Q

Calcinuerin inhibitors mechanism of action

A

Active against helper T cells, prevents production of IL-2 via calcineurin inhibition

Ciclosporin binds to cyclophilin protein

Tacrolimus binds to tacrolimus binding protein

Drug/ protein complexes bind calcineurin -> exerts phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription

22
Q

Cyclophosphamide mechanism of action, uses

A

Cytotoxic agent - alkylation gets agent - cross links DNA so it can’t replicate
Suppresses T/ B cell activity

Uses:
Lymphoma, leukaemia, solid cancers, lupus nephritis, wegner’s granulomatosis (ANCA- vasculitis)

23
Q

Cyclophosphamide adverse effects

A

Excreted by the kidney, acrolein another metabolite is toxic to the bladder epithelium -> haemorrhage cystitis (bleed form bladder)

Prevented through aggressive hydration &/or mesna

Increased risk: bladder cancer, lymphoma, leukaemia
Infertility
Monitor FBC
Adjust dose in renal impairment

24
Q

Methotrexate uses

A 
Gold standard treatment for RA
Malignancy
Psoriasis
Crohn’s disease 
Ectopic pregnancies (obliterates folic acid) 
Vasculitis
Steroid sparing agent asthma
25
Q

Methotrexate mechanism of action

A

Competively & reversibly inhibits dihydrofolate reductase (affinity 1000X higher than folate)

Dihydrofolate reductase catalyses conversion dihydrofolate -> active tertrahydrofolate (carrier of one carbon units in purine & thymidine synthesis)

So inhibits DNA/ RNA synthesis - greater toxic effects on rapidly dividing cells

Mechanism in non malignant disease unclear, possible inhibition T cell activation

26
Q

Methotrexate adverse effects

A

Weekly not daily dosing or can affect kidney/ liver

NSAIDS displace methotrexate (50% protein bound)

Combine with folic acid
Well tolerated

Mucositis
Marrow suppression
Hepatitis
Cirrhosis
Pneumonitis
Infection risk 
Highly teratogenic - abortifacient
27
Q

Sulfasalazine uses

A

Fights infection, relieves pain/ stiffness, anti- inflammatory

Less effective than methotrexate

28
Q

Sulfasalazine adverse effects

A

Similar structure to aspirin - allergy

Myelosuppression
Hepatitis
Rash 
Nausea
Abdo pain
Vomiting

Long term blood monitoring - not always needed
Safe in pregnancy
Few drug interactions
No carcinogenic potential

29
Q

Sulfasalazine mechanism of action

A

Inhibition proliferation T cells, possible T cell apoptosis and inhibition IL-1 production

Reduces chemotaxis and degranulation by neutrophils

30
Q

What are biopharmaceuticals/ biologicals?

A

Exctracted from living systems e.g. whole blood + blood components, stem cell therapy

Recombinant DnA technology -> nearly identical substances to body’s own key signalling proteins e.g. erythropoietin

Monoclonal antibodies - block any given substance or target specific cell type

Receptor constructs

31
Q

How does anti-TNF therapy work?

A

Reduces inflammation - blocks cytokines cascade/ recruitment leukocytes/ production chemokines

Reduced angiogenesis - lowering VeGF levels

Reduced joint destruction by reducing MMPs and other destructive enzymes, bone resorption and erosion, cartilage breakdown

32
Q

What’s a risk with anti-TNF therapy?

A

TB reactivation

TNFalpha is released by macrophages in response to M TB infection - essential for development + maintenance of granulomata (releases TB)

Screen for latent TB before

33
Q

Hats an example of a biological antibody used to treat RA? How does it work?

A

Rituximab

Binds specifically to a unique cell surface marker (CD20) found on a subset of B cells but not on stem cells/ pro-B cells/ plasma cells or any other cell type -> apoptosis B cells

Given every 6 months
Can give to cancer patients

S4 Pharma CPT (22 decks)

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