Immunosuppressants

Question 1

What are some examples of immunosuppressants?

Answer 1

Corticosteroids 
Methotrexate 
Azathioprine 
Ciclosporin
Tacrolimus 
Cyclophosphamide

Question 2

What is the method of action for corticosteroids?

Answer 2

Prevent IL-1 and IL-6 production by macrophages
Inhibit all stages of T cell activation

Not targeted, so produce many side effects

Question 3

What is azathioprine used for?

Answer 3

SLE and vasculitis maintenance therapy

IBD

Question 4

Describe the pharmacodynamics of azathioprine

Answer 4

6-MP is metabolised by TPMT
TPMT gene is highly polymorphic

Low/absent TPMT => risk of myelosupression

Question 5

What is the mechanism of action of azathioprine?

Answer 5

Cleaved to 6-MP which decreases DNA and RNA synthesis

Question 6

What are some adverse effects of azathioprine?

Answer 6

Bone marrow suppression - need to monitor FBC
Inc risk of malignancy - esp in transplant pts
Inc risk of infection
Hepatitis - monitor LFTs

Question 7

What are some examples of calcineurin inhibitors?

Answer 7

Ciclosporin

Tacrolimus

Question 8

What are calcineurin inhibitors used for?

Answer 8

Transplantation
Atopic dermatitis
Psoriasis

Question 9

What are some adverse effects of calcineurin inhibitors?

Answer 9

Renal toxicity - check BP and eGFR

Inhibits cytochrome P-450

Question 10

What is the mechanism of action of calcineurin inhibitors?

Answer 10

Active against helper T cells => prevent IL-2 production
Drug-protein complexes bind to calcineurin

Ciclosporin - binds to cyclophilin protein
Tacrolimus - binds to tacrolimus binding protein

Question 11

What is mycophenolate mofetil used for in practice?

Answer 11

Primarily in transplantation

Also good for induction and maintenance therapy in lupus nephritis/vasculitis

Question 12

What is the mechanism of action of mycophenolate mofetil?

Answer 12

Inhibits inosine monophosphate dehydrogenase => reduced guanosine synthesis

Impairs B and T cell proliferation
Spares other rapidly dividing cells

Question 13

What are some adverse effects of mycophenolate mofetil?

Answer 13

Nausea, vomiting and diarrhoea

Myelosuppression

Question 14

What is the method of action of cyclophosphamide?

Answer 14

Alkylating agent - cross links DNA
Unable to replicate

Suppress T and B cell activity

Question 15

What are some indications for cyclophosphamide?

Answer 15

Lymphoma, leukaemia
Lupus nephritis
Wegener’s granulomatosis; ANCA-vasculitis

Lower dose used for non-cancer

Question 16

Describe pharmacodynamics of cyclophosphamide

Answer 16

Converted in liver - CYP P450

Question 17

Describe pharmacokinetics of cyclophosphamide

Answer 17

Excretion - kidney

Produces a metabolite which is toxic to the bladder => haemorrhagic cystitis

Question 18

What are some important considerations for cyclophosphamide?

Answer 18

Significant toxicity =>
Inc risk of bladder cancer, lymphoma and leukaemia
Risk of infertility
Adjust dose with renal impairment

Question 19

What are some indications for methotrexate use?

Answer 19

Good standard treatment for RA

Malignancy
Psoriasis
Crohn’s disease

Question 20

What is the mechanism of action of methotrexate?

Answer 20

Reversible competitive inhibition of dihydrofolate reductase
Therefore inhibits purine and thymidine synthesis
Inhibition of DNA, RNA and protein synthesis

Question 21

What is the mechanism of action of methotrexate for non-malignant disease?

Answer 21

Not really clear

Not through anti-folate action

Possibly:
Inhibits accumulation of adenosine
Inhibits T cell activation
Suppresses expression of intracellular adhesion molecules

Question 22

Describe pharmacokinetics of methotrexate

Answer 22

Oral bioavailability 33%

Long half life therefore weekly dosing

Renal excretion

Question 23

How is methotrexate used in practice?

Answer 23

Well tolerated
Improved QoL
Retardation of joint damage

Question 24

What are some adverse effects of methotrexate?

Answer 24

Mucositis 
Marrow suppression 
Hepatitis and cirrhosis 
Pneumonitis 
Inc risk of infection 

Highly teratogenic, can cause abortion

Question 25

What is the mechanism of action go sulphasalazine?

Answer 25

Relieves pain and stiffness

Fight infection

Question 26

What are the immunological effects of sulphasalazine?

Answer 26

T cells:
Inhibit proliferation
Apoptosis
Inhibit IL-2 production

Neutrophils:
Reduced chemotaxis
Reduced degranulation

Question 27

What are some adverse effects of sulphasalazine?

Answer 27

Myelosuppression
Hepatitis
Rash

Nausea and vomiting
Abdo pain

Question 28

How is sulphasalazine used in practice?

Answer 28

Effective
V few drug interactions
No carcinogenic potential
Safe in pregnancy

Question 29

How are immunosuppressant “biologicals” produced?

Answer 29

Extracted from living systems eg whole blood, blood components, stem cell therapy

Recombinant DNA technology produces substances that are nearly identical to key signalling proteins eg growth hormone, EPO

Monoclonal antibodies block substances in the body or target a specific cell type

Question 30

What are the effects of blocking TNF-α?

Answer 30

Decreased inflammation
Decreased angiogenesis
Decreased joint destruction

Question 31

What are some risks of blocking TNF-α activity?

Answer 31

TB reactivation

TNF-α released by macrophages in response to TB infection
Essential for development and maintenance of a granuloma

Therefore need to screen for latent TB before anti-TNF treatment

Question 32

What is the mechanism of action of rituximab?

Answer 32

Immunosuppressant

Binds to specific cell-surface markers on B cells
Causes B cell apoptosis

V effective in RA