Immunosupressive and NSAID Drugs

Question 1

List the immunosuppressant drugs that are commonly used

Answer 1

• Azathioprine
• Calcineurin inhibitors
• Mycophenolate Mofetil
• Cyclophosphamide
• Methotrexate
• Sulfasalazine

Question 2

List the following for: Azathioprine

• Use
• Drug class
• Mechanism of action
• Adverse effects
• Warnings / contraindications

Answer 2

Immunosuppressant

• Maintenance therapy for SLE and vasculitis
• Inflammatory bowel disease
• Atopic dermatitis
• Bullous skin disease

Immunosuppressant

• Azathioprine is cleaved to 6-mercaptopurine (6-MP)
• 6-MP is converted to TIMP by TPMT, the anti-metabolite produced decreases DNA and RNA synthesis
• Bone marrow suppression
• Increased risk of malignancy
• Increased risk of infection
• Hepatitis
• Requires TPMT levels checking prior to starting treatment

Question 3

List the following for: Calcineurin inhibitors

• Use
• Example drugs
• Drug class
• Mechanism of action
• Warnings / contraindications
• Important drug reactions

Answer 3

Immunosuppressant

• Transplantation
• Atopic dermatitis
• Psoriasis

Ciclosporin
Tacrolimus

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
• Calcineurin exerts phosphatase activity of activated T- cells then nuclear factor migration starts IL-2 transcription
• Check BP and eGFR regularly (renal toxicity)
• Cytochrome P-450 enzyme drugs (multiple drug interactions are possible)

Question 4

List the following for: Mycophenolate Mofetil

• Use
• Drug class
• Mechanism of action
• Adverse effects

Answer 4

Immunosuppressant

• Transplantation mainly
• Induction and maintenance of Lupus Nephritis and Vasculitis

Immunosuppressant

• Prodrug
• Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
• Impairs B- and T-cell proliferation
• GI effects - nausea, vomiting, diarrhoea
• Myelosuppression = serious

Question 5

List the following for: Cyclophosphamide

• Use
• Drug class
• Mechanism of action
• Adverse effects
• Warnings / contraindications

Answer 5

Immunosuppressant

• Lymphoma, leukaemia, solid cancers
• Lupus nephritis
• Wegener’s granulomatosis (ANCA-vasculitis)

Immunosuppressant – alkylating agent

• Prodrug – converted in liver by CYP450
• Cross links DNA so that it cannot replicate
• Suppresses T cell activity
• Suppresses B cell activity

Significant toxicity

• Increased bladder cancer, lymphoma, and leukaemia risk
• Infertility
• Haemorrhagic cystitis (avoided with excessive hydration and Mesna)
• Monitor FBC
• Adjust dose in renal impairment

Question 6

List the following for: Methotrexate

• Use
• Drug class
• Mechanism of action
• Adverse effects
• Warnings / contraindications

Answer 6

Immunosuppressant

• Malignancy
• Psoriasis
• Crohn’s disease
• Unlicensed roles: inflammatory myopathies, vasculitis and steroid-sparing agent in asthma

Immunosuppressant

For malignant disease:
- Methotrexate competitively and reversibly inhibits DHFR
- Therefore, inhibits the synthesis of DNA, RNA and proteins
- Methotrexate acts during DNA and RNA synthesis
- Greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
For non-malignant disease:
- Mechanism of action is not sure!

Generally well tolerated

• Mucositis
• Bone marrow suppression
• Hepatitis and cirrhosis
• Pneumonitis
• Infection risk
• Highly teratogenic - abortifacient
• Require folic acid supplementation

Question 7

List the following for: Sulfasalazine

• Use
• Drug class
• Mechanism of action
• Adverse effects

Answer 7

Immunosuppressant

• Relieve pain and stiffness
• Fight infection

Immunosuppressant

T-cell
- Inhibition of proliferation
- Possible T-cell apoptosis
- Inhibition of IL-2 production
Neutrophil
- Reduced chemotaxis 
- Reduced degranulation
Poorly absorbed - main activity is within intestine = effective in IBD

• Myelosuppression
• Hepatitis
• Rash
• GI effects: nausea, abdominal pain, vomiting

Question 8

List the following for: NSAIDs

• Use
• Drug class
• Mechanism of action
• Adverse effects
• Warnings / contraindications
• Important drug reactions

Answer 8

• Analgesic
• Anti-inflammatory
• Anti-pyrexic

NSAIDs

• Inhibition of COX enzyme (competes with arachidonic acid at hydrophobic site)
• Reduces prostanoid synthesis (prostaglandin, prostacyclin, and thromboxane)
  Analgesia:
• Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2
• Reduced neurotransmitter release
• Reduced excitability of neurones in pain relay pathway (to higher brain centres)
  Anti-inflammatory:
• Reduce production of prostaglandins released at the site of injury
• Inhibits vasodilation in post-capillary venules
  Anti-pyretic:
• Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature

GI effects:
- Dyspepsia, nausea, peptic ulceration, bleeding and perforation (decrease mucus and bicarbonate secretion and increase acid secretion)
- Exacerbation of existing inflammatory bowel disease
Renal effects:
- Reversible recued GFR and renal blood flow
- Increased: Na, H2O and BP

• Elderly
• Chronic use
• Alcohol
• History of peptic ulceration
• Presence of H pylori
• CKD
• HF
• Aspirin
• Glucocorticoid steroids
• Anticoagulants