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Clinical Pharmacology & Intro to Prescribing > Session 10: Immunosuppression > Flashcards

Session 10: Immunosuppression Flashcards

1
Q

What is rheumatoid arthritis?

A

Auto-immune multi-system disease that is fairly common.

It is initially localised to the synovium of the joins. There is proliferation of the synovium called a pannus which leads to dissolution of cartilage and bone.

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2
Q

Rheumatoid arthritis pathogenesis.

A

Three phases:

Initiation phase with non-specific inflammation.

Amplification phase with plasma cells producing rheumatoid factors and T cell activation.

Chronic inflammatory with imbalance of pro-inflammatory factors such as IL-1, IL-6, TNFalpha and anti-inflammatory.

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3
Q

Clinical criteria to diagnose RA.

A

Morning stiffness lasting more than 1 hour

Arthritis of 3 or more joints

Arthritis of hand joints

Symmetrical arthritis

Rheumatoid nodules

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4
Q

Non-clinical criteria of (Ix) of RA.

A

Serum rheumatoid factor or Anti-CCP antibodies.

X-ray changes

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5
Q

X-ray changes of RA.

A

Soft tissue swelling

Loss of joint space

Marginal erosion

Periarticular Osteopenia

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6
Q

Treatment strategy of RA.

A

Early use of disease-modifying drugs.

Good disease control and get the RA into remission state with drugs.

Adequate dosages

Combinations of drugs

Avoidance of long-term corticosteroids.

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7
Q

Other common auto-immune disorders.

A

Systemic Lupus Erythematous

Vasculitis (SLE can cause vasculitis)

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8
Q

Common pathophysiology of vasculitis.

A

Inflammation of blood vessels.

This will cause problems in many organs supplied with vessels.

Kidneys, pulmonary haemorrhage, skin purpuric rashes.

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9
Q

Treatment goals in SLE and vasculitis.

A

Symptomatic relief

Reduction in mortality

Prevention of organ damage

Reduction in long term morbidity

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10
Q

Give examples of immunosuppressants.

A

Corticosteroids

Methotrexate

Azathioprine

Ciclosporin

Tacrolimus

Mycophenolate mofetil

Leflunomide

Cyclophosphamide

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11
Q

Explain the mechanism of action of corticosteroids.

A

Prevention of IL-1 and IL-6 production by macrophages (pro-inflammatory)

Inhibit all stages of T-cell activation

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12
Q

Give examples of non-biologics

A

Sulphasalazine

Hydroxychloroquine

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13
Q

Give examples of biologics.

A

Anti-TNF agents

Rituximab

IL-6 inhibitors

JAK inhibitors

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14
Q

When is Azathioprine used?

A

SLE

Vasculitis (maintenance therapy for the two)

Inflammatory bowel disease

Atopic dermatitis

Bullous skin disease

Also used as a steroid sparing drug

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15
Q

Pharmacokinetics of azathioprine.

A

A prodrug converted into 6-MP which is the active metabolite.

This will then further be deactivated by TPMT and then excreted renally.

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16
Q

What is special about TPMT?

A

Highly polymorphic

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17
Q

What is important to test for before prescribing azathioprine?

A

TPMT activity

This is because the levels of TPMT will vary a lot in people.

If TPMT is low then there will be more adverse drug effects.

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18
Q

ADRs of Azathioprine.

A

Bone marrow suppression

Increased risk of malignancy

Increased risk of infection

Increased risk of liver toxicity

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19
Q

Give examples of calcineurin inhibitors.

A

Ciclosporin

Tacrolimus

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20
Q

Give use of ciclosporin and tacrolimus.

A

Transplantation

Atopic dermatitis

Psoriasis

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21
Q

Why is ciclosporin and tacrolimus not often used in rheumatology.

A

Because it can renally toxic.

That’s why you need to check BP and eGFR regularly.

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22
Q

What drugs will interact with ciclosporin and tacrolimus?

A

CYP P450 inducers and CYP P450 inhibitors

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23
Q

Mechanism of action of ciclosporin.

A

Active against helper T-cell and prevent production of IL-2 via calcineurin inhibition.

This is by ciclosporin binding to cyclophilin protein to form a complex.

This complex will bind to calcineurin. Calcineurin usually is supposed to cause IL-2 transcription, but ciclosporin inhibits this.

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24
Q

Mechanism of action of tacrolimus.

A

Binds to tacrolimus-binding protein.

This complex will then bind to calcineurin and inhibit IL-2 transcription.

25
Q

When is mycophenolate mofetil used?

A

Transplantation

Induction and maintenance therapy for lupus nephritis and vasculitis maintenance.

26
Q

Prior to surgery in transplantation medicine something is monitored, related to mycophenolate mofetil.

What and why?

A

Mycophenolic acid to see if they have been taking the drug or not.

27
Q

Mechanism of action of mycophenolate mofetil.

A

Prodrug from Penicillium stoloniferum

It inhibits inosine monophosphate dehydrogenase that is required for guanosine synthesis.

Impairs B and T cell proliferation.

It also spares other rapidly dividing cells

28
Q

ADRs of mycophenolate mofetil.

A

Nausea

Vomiting

Myelosuppression (however less so than Azathioprine)

Mucusitis

Skin cancer

29
Q

Mechanism of action of cyclophosphamide.

A

Cytotoxic agent that cross links DNA so it cannot replicate.

It suppresses T cell activity as well as B cell activity.

30
Q

Uses of cyclophosphamide.

A

Lymphoma, Leukaemia, Solid cancers

Lupus nephritis

Wegener’s granulomatosis

ANCA-vasculitis

31
Q

Pharmacokinetics of cyclophosphamide.

A

Prodrug that is converted in the liver by cytochrome P450 to its active form.

The main active metabolite is 4-hydrocyclophosphamide and it exists in equilibrium with its tautomer aldophosphamide.

It is then excreted by kidneys.

32
Q

What is another metabolite of cyclophosphamide?

A

Acrolein

33
Q

What is the danger with acrolein?

A

Toxic to the bladder epithelium and can lead to haemorrhagic cystitis.

34
Q

How can the effects of acrolein be managed?

A

By aggressive hydration and/or Mesna

35
Q

ADRs of cyclophosphamide.

A

Increased risk of bladder cancer, lymphoma and leukaemia.

Infertility

Anaemia

This means dose needs to be adjusted in case of renal impairment.

36
Q

What would you give in lupus nephritis; mycophenolate mofetil or cyclophosphamide?

A

Mycophenolate mofetil because it has more or less the same outcome but with less ADRs.

37
Q

What is the golden standard for rheumatoid arthritis?

A

Methotrexate

38
Q

When else is methotrexate used?

A

Crohn’s

Psoriasis

Malignancy

Ectopic pregnancy

39
Q

Explain the mechanism of action of Methotrexate in malignancy.

A

It works as an anti-folate by competetively and reversibly inhibiting dihydrofolate reductase meaning that dihydrofolate can’t be converted into the active form tetrahydrofolate.

Tetrahydrofolate is needed for purine and thymidine synthesis and if this doesn’t work DNA, RNA and protein synthesis stops working.

This is a cytotoxic drug leading to destruction of cells, especially those which rapidly divide = malignancy.

40
Q

Explain the mechanism of action of methotrexate in non-malignancy.

A

Not via an anti-folate action.

The action is not clearly understood but it might be T-cell deactivation.

41
Q

In RA, what is given alongside of methotrexate?

A

Folic acid

42
Q

Pharmacokinetics of methotrexate.

A

Oral bioavailability around 33%.

Where as the intramuscular injection bioavailability is around 76%.

Metabolised into polyglutamates with long half-lives.

Protein bound

Renal excretion

43
Q

Administration of methotrexate.

A

PO

IM

S/C

44
Q

What is the frequency of dosing regiment of methotrexate?

A

Weekly

Not daily!

This is due to the long half-life

45
Q

Why would you not want to give NSAIDs to someone taking Methotrexate?

A

Because around 50% of methotrexate is protein bound.

NSAIDs will displace the methotrexate and increase the free drug concentration of methotrexate.

This leads to more of an effect and higher risk of ADRs.

46
Q

ADRs of methotrexate.

A

Mucositis

Bone marrow suppression

Hepatitis

Cirrhosis

Pneumonitis

Infection in general

It is also highly teratogenic and should not be used in pregnancy.

47
Q

What is sulfasalazine used for?

A

Rheumatoid arthritis

Crohn’s

Ulcerative colitis

It is designed to relieve pain and stiffness as well as to fight infection.

48
Q

Mechanism of action of sulfasalazine.

A

Inhibition of proliferation, and apoptosis of T-cells.

Also inhibition of IL-2 production.

Inhibition of chemotaxis and degranulation of neutrophils as well.

49
Q

ADRs of sulfasalazine.

A

Myelosuppression

Hepatitis

Rash

Nausea

Vomiting

Abdo pain

50
Q

Why is sulfasalazine often used instead of some other medications?

A

Very few drugs interactions

No carcinogenic potential

Safe in pregnancy

Less ADRs

51
Q

What are biologicals?

A

Medication extracted from the living system such as whole blood, blood components or stem cells.

Recombinant DNA such as growth hormone or EPO.

Monoclonal antibodies

52
Q

Give examples of biologicals.

A

Anti-TNF agents

Rituximab

IL-6 inhibitors

JAK inhibitors

53
Q

Effects of blocking TNF-alpha

A

Anti-inflammatory action by blocking cytokine cascade.

Reduced angiogenesis by reduced VEGF levels.

Reduced joint destruction by blocking of MMPs and other destructive enzymes. Reduction of bone resorption and erosion. Reduction of cartilage breakdown.

54
Q

What is a risk with anti-TNF therapy?

A

TB reactivation.

55
Q

Why can TB be reactivated in anti-TNF therapy?

A

Because TNF-alpha is essential for development + maintenance of granulomas.

If TNF-alpha is blocked then the granuloma encasing the TB infection will break down and secondary TB activation will ensue.

56
Q

What is important to do before giving anti-TNF treatment?

A

Screen for a latent TB infection

57
Q

Explain the mechanism of action of rituximab.

A

Binds specifically to a unique cell-surface marker CD20 which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type.

Since B cells usually present antigens to T cells, produce cytokines and produce antibodies, all of these will be inhibited.

All in all rituximab induced B cell apoptosis.

58
Q

ADRs of corticosteroids.

A

Cataracts

Ulcers

Skin/striae

Hypertension/glycaemia

Infection

Necrosis of femoral head

Glycosuria

Osteoporosis/obesity (central)

Immunosuppression

Diabetes

Clinical Pharmacology & Intro to Prescribing (24 decks)

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