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Clinical Pharmacology > 8.1 Immunosuppression > Flashcards

8.1 Immunosuppression Flashcards

1
Q

What is rheumatoid arthritis?

A

Multi-system disease localised to the synovium

Antibodies attack the snyovial membrane which leads to:
- Inflammatory change and proliferation of the the synovium (pannus)
- Pannus formation
- Erosion of cartilage and bone

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2
Q

What is the pathogenesis of rheumatoid arthritis?

A

Imbalance between pro-inflammatory and anti-inflammatory mediators

Pro-inflammatory
IL-1
IL-6
TNF-alpha
T and B cells
Rheumatoid factor
Anti-CCP antibodies

Anti-inflammatory
IL-4
TGF-beta

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3
Q

What are the clinical features of rheumatoid arthritis?

A

Morning stiffness for more than an hour
Arthritis of more than 3 joints
Arthritis of MCPJ/PIPJ
Symmetrical arthritis
Rheumatoid nodules

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4
Q

What are the non-clinical features of rheumatoid arthritis?

A
  • Serum rheumatoid factor/ Anti-CCP antibodies
  • X-ray changes- SPADES
  • Soft-tissue swelling
  • Peri-articular osteoporosis
  • Absent osteophytes
  • Deformity
  • Erosions (later feature)
  • Subluxation (later feature)
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5
Q

What are the treatment goals of rheumatoid arthritis?

A

Symptomatic relief
Prevention of join destruction

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6
Q

What is the treatment strategy for rheumatoid arthritis?

A
  • Early use of disease-modifying drugs
  • Good disease control
  • Adequate dosages
  • Combinations of drugs
  • Avoidance of long-term corticosteroids
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7
Q

What is systemic lupus erythematosus?

A

Auto-immune condition affecting the entire body

Systemic LUPUS Erythamotsus

Sleepy (extreme fatigue) and myalgia
Leukopenia, thrombocytopenia,anaemia
proteinUria, renal failure
Psychosis,seizures and cognitive dysfunction
Ulcers in eyes,nose, mouth
Skin rash over face and cheeks
Emesis, nausea and diarrhoea

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8
Q

What is vasculitis?

A

Inflammation of the vessels

Affects large, medium or small vessels

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9
Q

How does vasculitis present?

A

Purpura rash
Lung consolidation on X-ray due to blood
Glomerulonephritis- coke coloured urine

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10
Q

What are the treatment goals in SLE & vasculitis?

A
  • Symptomatic relief e.g. arthralgia, Raynauds
  • Reduction in mortality
  • Prevent organ damage
  • Reduction in long term morbidity caused by disease and drugs
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11
Q

What are some examples of immunosuppressants?

A

Corticosteroids
Methotrexate
Ciclosporin
Cyclophosphamide

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12
Q

How do corticosteroids work?

A

Prevent IL-1 and IL-6 production by macrophages

Inhibits all stages of T-cell activation

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13
Q

How are other disease-modifying anti-rheumatic drugs (DMARDs) classified?

A

Non-biologics
- Methotrexate, sulphasalazine
- Hydoxycholorquin, Leflunomide
- Azathioprine

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

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14
Q

What is Azathioprine used for?

A

SLE & Vasculitis
Rheumatoid arthritis
IBD
Atopic dermatitis
Bullous skin disease
Many other uses as ‘steroid sparing’ drug

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15
Q

What are the pharmacodynamics of azathioprine?

A

6-MP is metabolised by thiopurine methyltransferase (TPMT)

TPMT gene is highly polymorphic

Low/absent TPMT levels- risk of myelosuppression

Test TPMT activity before prescribing

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16
Q

What are the adverse of azathioprine?

A

Bone marrow suppression
-Monitor FBC

Increased risk of malignancy
-Especially in transplanted patients

Increased risk of infection

Hepatitis
-Monitor LFT

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17
Q

Give two examples of calcineurin inhibitors

A

Ciclosporin
Tacrolimus

Widely used in transplantation

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18
Q

What are calcineurin inhibitors used for?

A

Atopic dermatitis
Psoriasis
Transplantation

Many possible drug interactions due to CYP450

19
Q

What are the adverse drug reactions of calcineurin inhibitors?

A

Renal toxicity

20
Q

What important drug to drug interactions need to be considered for ciclosporin and tacrolimus?

A

CYP inducers
CYP inhibitors

21
Q

Give some examples of CYP450 inducers and inhibitors

A

Inducers
Rifampicin
Carbemazepine
Phenytoin
Omeprazole

Inhibitors
Ciprofloxacin
Antifungals
HIV antivirals

22
Q

How do ciclosporin and tacrolimus work?

A

Prevents production of IL-2 via calcineurin inhibition

Active against helper T-cells

23
Q

What does ciclosporin bind to?

A

Cyclophilin protein

24
Q

What does tacrolimus bind to?

A

Tacrolimus- binding protein

25
Q

How do cyclophosphamides and mycophenolate mofetil work?

A

Prevent proliferation of B and T cells

26
Q

What are adverse drug reactions can happen with cyclophosphamide and mycophenolate mofetil?

A

Toxic to bladder epithelium- can cause haemorrhagic cystitis/ cancer
Nausea, vomiting
Myelosuppression
Infertility

27
Q

What are some important drug to drug interactions for cyclophosphamide and mycophenolate mofetil?

A

Many vaccinations

28
Q

What is methotrexate the gold standard treatment of?

A

Rheumatoid arthritis

Also used in malignancy, psoriasis and Crohn’s

29
Q

How does methotrexate work in malignancy?

A

Competitively and reversibly inhibits dihydrofolate reductase

Affinity of methotrexate for dihydrofolate reductase is 1000x that of folate

Dihydrofolate reductase catalyses conversion of dihydrofolate to active tetrahydrofolate, key carrier in purine and thymidine synthesis

Methotrexate therefore inhibits synthesis of DNA, RNA and proteins

30
Q

What part of the cell cycle is methotrexate cytotoxic?

A

Acts during DNA and RNA synthesis therefore S-phase

Greater toxic effect on rapidly dividing cells which replicate DNA more frequently

31
Q

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

e.g. RA and psoriasis

A

Not clear

Mechanism is not via anti-folate action

Possibly by
- Inhibition of accumulation of adenosine
- Inhibition of T cell activation

32
Q

What is the bioavailability of methotrexate via different methods?

A

Oral-13%
Intramuscular- 76%

Administered PO, IM or SC

33
Q

Why do you need to be careful with taking NSAIDs with methotrexate?

A

50% of methotrexate is protein bound

NSAIDs displace

34
Q

What are the adverse drug reactions of methotrexate?

A

Mucositis
Marrow suppression
Hepatitis, cirrhosis
Pneumonitis
Infection risk

Highly teratogenic

35
Q

What is sulfasalazine used for?

A

Rheumatoid arthritis

36
Q

What immunological effects does sulfasalazine have?

A

T cell
- Inhibition of proliferation
- Possible T-cell apoptosis
- Inhibition of IL-2 production

Neutrophil
- Reduced chemotaxis
- Reduced degranulation

37
Q

What are the adverse drug reactions of sulfasalazine?

A

Myelosuppression
Hepatitis
Hypersensitivity

38
Q

What are the important drug to drug reactions for sulfasalazine?

A

Very few
Caution with some PPIs

39
Q

What are some examples of biological therapies?

A

Infliximab
Rituximab

40
Q

How do biological disease modifying anti-rheumatic drugs work? (DMARDs)

A

Monoclonal antibodies inhibit TNF-alpha

41
Q

What effect does blocking TNF alpha have?

A

Decreased inflammation as reduced cytokine cascade
Decreased angiogenesis
Decreased joint destruction

42
Q

What are the ADRs for biological DMARDs?

A

Teste for latent TB may reactivate latent disease due to the inhibition of TNF alpha

43
Q

What are some important drug to drug interactions for biological therapies?

A

Other immunosupressants

Clinical Pharmacology (45 decks)

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