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SA Clinical Pharmacology & Therapeutics > S8) Rheumatology and Immunosuppressants > Flashcards

S8) Rheumatology and Immunosuppressants Flashcards

1
Q

Identify some diseases rheumatologists treat

A
  • Rheumatoid arthritis (RA)
  • Psoriatic Arthritis (PsA)
  • Systemic lupus erythematosus (SLE)
  • Systemic vasculitis
  • Autoimmune myositis
  • Spondyloarthropathy
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2
Q

Briefly illustrate the pathogenesis of rheumatoid arthritis

A

There is an imbalance between pro-inflammatory chemical mediators and anti-inflammatory chemical mediators,

inflammation around the synovial joints

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3
Q

State 7 different possible ways of diagnosing RA

A
  • Morning stiffness ≥ 1 hour
  • Arthritis of ≥ 3 joints
  • Arthritis of hand joints
  • Symmetrical arthritis
  • Rheumatoid nodules
  • Serum rheumatoid factor
  • X-ray changes
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4
Q

What are the treatment goals for RA?

A
  • Symptomatic relief
  • Prevention of joint destruction
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5
Q

Outline the treatment strategy for RA

A
  • Early use of disease-modifying drugs
  • Aim to achieve good disease control
  • Use of adequate dosages
  • Use of combinations of drugs
  • Avoidance of long-term corticosteroids
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6
Q

What are the treatment goals in SLE & vasculitis?

A
  • Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and by drugs
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7
Q

Identify five immunosuppressant drugs

A
  • Corticosteroids
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
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8
Q

Identify five other disease-modifying anti-rheumatic drugs (DMARDs)

A
  • Methotrexate
  • Sulphasalazine
  • Anti-TNF agents
  • Rituximab
  • Cyclophosphamide (used to treat cancer but can be used to treat autoimmune disease)
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9
Q

Describe the mechanism of action of corticosteroids

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

→ therefore it is not very targeted so wipes out everything

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10
Q

Methotrexate is the gold standard treatment for Rheumatoid Arthritis.

What are its other indications?

A
  • Malignancy
  • Psoriasis/Psoriatic arthritis
  • Crohn’s disease
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11
Q

In three steps, describe the mechanism of action for methotrexate on malignant cells, myeloid cells, GI & oral mucosa

A

⇒ Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)

⇒ This prevents the conversion of dihydrofolate to active tetrahydrofolate in purine and thymidine synthesis

⇒ Thus, inhibits the synthesis of DNA, RNA and proteins (cytotoxic in S phase)

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12
Q

The mechanism of action of methotrexate in non-malignant disease e.g. RA, psoriasis is not clear. The mechanism is not via anti-folate action.

Suggest three possible mechanisms

A
  • Inhibition of T cell activation
  • Suppression of intercellular adhesion molecule expression by T cells
  • Inhibition of enzymes involved in purine metabolism → accumulation of adenosine
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13
Q

What is adenosine and what does it do?

A
  • Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress
  • It interacts with specific GPCRs on inflammatory and immune cells to regulate their function
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14
Q

How is methotrexate administered?

A
  • Oral
  • Intramuscular
  • Subcutaneous
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15
Q

How does the oral/intramuscular bioavailability change for methotrexate?

A
  • Mean oral bioavailability = 33% (13-76%)
  • Mean intramuscular bioavailability = 76%
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16
Q

When are doses given for methotrexate?

A

Weekly, not daily dosing – metabolised to polyglutamates with long half lives

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17
Q

Identify five ADRs of methotrexate

A
  • Mucositis
  • Marrow suppression
  • Hepatitis
  • Cirrhosis
  • Pneumonitis
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18
Q

How can mucositis and marrow suppression as a result of methotrexate be treated?

A

Folic acid supplementation (has an affinity 1000x of folate to DHFR)

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19
Q

Why should a female patient on methotrexate not fall pregnant?

A

Methotrexate is highly teratogenic and abortifacient

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20
Q

Which conditions are treated by sulphasalazine?

A

Sulphasalazine is used to treat inflammatory arthritis:

  • Rheumatoid arthritis
  • Psoriatic Arthritis
  • Spondyloarthritis
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21
Q

What are the immunological effects of sulphazine on T cells?

A

T cell:

  • Inhibition of proliferation
  • Apoptosis (possible)
  • Inhibition of IL-2 production
22
Q

What are the immunological effects of sulphazine on neutrophils?

A

Neutrophil:

  • Reduced chemotaxis
  • Reduced degranulation
23
Q

Where is the site of release for sulphasalazine and what is the significance of this?

A
  • Site of release is the colon (poorly absorbed)
  • Effective in IBD
24
Q

The adverse effects of sulphasalazine are mainly due to sulfapyridine moiety.

What are they?

A
  • Myelosuppression
  • Hepatitis
  • Rash
25
Which clinical conditions are treated by azathioprine in practice?
- SLE - Vasculitis - Atopic dermatitis - Bullous skin disease
26
Describe the mechanism of action of azathioprine
- Cleaved to 6-mercaptopurine (6-MP) → antagonist of purine synthesis - Anti-metabolite decreases DNA and RNA synthesis
27
What are the adverse effects of azathioprine?
- Bone marrow suppression (monitor FBC) - Increased risk of malignancy - Increased risk of infection - Hepatitis (onitor LFT) (these side effects are common in al types of immunosuppressants)
28
When is mycophenolate mofetil used in practice?
- Transplantation (primariliy) - Lupus nephritis (induction and maintenance therapy) * inhibits the proliferation of B and T cell lymphocytes by depleting guanosine nucleotides
29
What are the adverse effects of mycophenolate mofetil?
- Nausea - Vomiting - Diarrhoea - Myelosuppression
30
Describe the mechanism of action of mycophenolate mofetil
- Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis) - Impairs B- and T-cell proliferation - Spares other rapidly dividing cells
31
Cyclophosphamide is a cytotoxic alkylating agent which cross links DNA so that it cannot replicate. What are its immunological effects?
- Suppresses T cell activity - Suppresses B cell activity
32
What are the indications for cyclophosphamide?
- Lymphoma - Leukaemia - Solid cancers - Lupus nephritis - Wegener’s granulomatosis (ANCA vasculitis)
33
Cyclophosphamide has significant toxicity and thus, some important considerations should be made. What are these?
- Increased risk of bladder cancer, lymphoma and leukaemia - Infertility - Monitor FBC - Adjust dose in renal impairment → mycophenolate mofetil is much safer and effective in lupus nephritis
34
What are biopharmaceuticals / "biologicals"?
- **Biologicals** are drugs made from substances extracted from living systems *e.g. blood components, stem cell therapy* - It uses recombinant DNA technology to produce substances nearly identical to the body's own key signalling proteins *e.g. GH, EPO* * →* uses **monoclonal antibodies** so “custom designed” to block something specific in the body → medicine ends in ‘**mabs**’ for monoclonal antibodies
35
What are the three effects of blocking TNF-α?
- ↓ Inflammation - ↓ Angiogenesis - ↓ Joint destruction
36
What are the risks of Anti-TNF therapy?
**TB reactivation** – TNFα is essential for development + maintenance of granulomata (released from macrophages in reponse to M TB infection) so TB reactivation is a risk -> must get a latent TB test to check for no TB before going on the drug
37
The biological, rituximab is very effective in RA. Explain why by describing its mechanism of action
- Binds specifically to a cell-surface marker CD20 found on a subset of B cells - Causes B cell apoptosis
38
Identify two calcineurin inhibitors
- Ciclosporin - Tacrolimus
39
Describe the three uses of ciclosporin and tacrolimus in clinical practice
- Transplantation - Atopic dermatitis - Psoriasis
40
Why are calcineurin inhibitors not used in rheumatology?
Renal toxicity
41
Describe the mechanism of action of calcineurin inhibitors
**Active against helper T cells, preventing production of IL-2 via calcineurin inhibition:** - Ciclosporin binds to cyclophilin protein - Tacrolimus binds to tacrolimus-binding protein - Drug/protein complexes bind calcineurin
42
what is lupus (SLE)
→ autoimmune condition where organs get inflamed It can become life threatening can lose hair, scar
43
what is vasculitis
→ inflammation of vasculature it can co exist with lupus and RA,
44
azathioprine in practice
* treats SLE (lupin) and vasculitis * can also treat IBD * it is a steroid sparing agent (replacement of steroid)
45
azathioprine in practice
* treats SLE (lupin) and vasculitis * can also treat IBD * it is a steroid sparing agent (replacement of steroid)
46
CYP P450 inducers and inhibitors
→ inducers can cause the drug to reduce its own levels as its metabolised faster
47
explain the pharmacodynamics of cyclophosphamide
* prodrug, converted in the liver * active metabolite is 4-hydroxycyclophosphamide (very poisonous) * it exists in equilibrium with Aldophosphamide which is oxidised * it is excreted by the kidney
48
mechanism of action of methotrexate
→ competitively and reversibly inhibits DHFR → DHFR is a key component if purine and thymidine synthesis → methotrexate inhibits DNA,RNA and protein synthesis during the S phase → it has a greater effect on rapidly dividing cells replicating their DNA
49
What is the role of B cells
* present antigens to T cells * produce cytokines * produce antibodies
50
what are some tests you need to take regulary from a patient on azathioprine?
-> Liver function test (can be damaging to the liver) -> FBC (because it can damage bone marrow so reduce the amount of white and red blood cells)
51
what test should be taken by the patient before being prescribed Azathioprine
- TPMT - if these are in low levels this mean there will be more of an active form of azathioprine - it will last longer and so will its effects (reducing RNA, DNA and protein synthesis) -

SA Clinical Pharmacology & Therapeutics (36 decks)

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