Immunosuppressive medications

Question 1

List the class and uses of azathoprine

Answer 1

• An antimetabolite; purine analog
• autoinflammatory conditions (SLE, 2nd line RA, polymyositis, seronegative inflammatory arthritis), sustaining remission in vasculitis, a steroid-sparing agent, transplant rejection

Question 2

Describe the mechanism of action of azathioprine

Answer 2

A purine analog. It interferes with intracellular purine synthesis, decreases T and B cell proliferation, immunoglobulin synthesis, IL-2 secretion. Its effect is phase restricted (S-phase).

Question 3

Describe the administration and metabolism of azathioprine

Answer 3

Orally administered. Well absorbed. It is converted to 6-mercaptopurine by the action of glutathione on RBCs
- MP is metabolised by XO and TPMT to release the active drug. -TPMT levels must be measured before administration -Renal elimination

Question 4

Describe adverse events and contraindications of azathioprine

Answer 4

AEs: GI issues, bone marrow suppression, infection and malignancy risk. No teratogenicity, mild fertility impairment for males.

Contraindications: Allopurinol - is a xanthine oxidase inhibitor, which slows 6-MP elimination. Avoid altogether or reduce aza to 25-50% of original dose while monitoring WCCs. Pregnsncy, hypersensitivity, malignancy and infection are also contraindicated

NB for tox and monitoring: Allopurinol monitoring. TPMT measuring.

Question 5

Describe class and uses of cyclophosphamide

Answer 5

• class: alkylating agent
• SLE, vasculitis, inflammatory autoimmune conditions especially those threatening major organs (RA), chemotherapy agent (lymphoma and multiple myeloma)

Question 6

Describe the mechanism of action of cyclophosphamide

Answer 6

Crosslinking of DNA (and proteins, RNA) results in impaired DNA replication and transcription. This results in cell death and altered function, thus inhibiting immune function. Cyclophosphamide’s activity is not phase restricted.

Question 7

Describe admin and metabolism of cyclophosphamide

Answer 7

Administered IV monthly or weekly; oral daily dose. Parent drug or prodrug metabolised to active form by cytochrome P450 complex. Metabolism occurs in the liver. 80% of the administered dose is metabolised. Excretion in urine.

Question 8

Describe adverse events and contraindications of cyclophosphamide

Answer 8

Adverse: Bone suppression (WCC drops in 10 to 14 days), infections, bladder toxicity due to acrolein accumulation, malignancy risk, teratogenicity, gonadal toxicity.

Contraindications: Pregnancy and hypersensitivity.

Question 9

Describe monitoring for cyclophosphamide

Answer 9

• metabolite acrolein, risk of haemorrhagic cystitis, minimised by adequate hydration and Mesna in short term–bladder carcinoma in long term - Cumulative dose poses risk of toxicity - IV therapy may be as low as 1/3 the daily oral dose. This helps reduce infection rates and bladder toxicity.

Question 10

Describe the class and uses of cyclosporin

Answer 10

Class: Calcineurin inhibitor - polypeptide
Uses: 2nd line therapy for RA; osteoarthritis and psoriatic arthritis, polymyositis, dermatomyositis, transplants, uveitis.

Question 11

Decribe admin, metabolism and mechanism of action of cyclosporin

Answer 11

Oral bioavailability is 20-50%. Narrow therapeutic index. Metabolised by P4503A in the liver.

Cyclosporin binds cyclophilin, preventing it binding calcineurin. This inhibits movement of NFAT complex to nucleus. NFAT required for induction of a number of cytokine genes including that for IL-2 – a T cell growth and differentiation factor. It thus inhibit cell signalling.

it has some humoral effect, but largely T cell-dependent immunity affected.

Question 12

Describe adverse events associated with cyclosporin

and tacrolimus

Answer 12

Toxicity: - renal dysfunction - hypertension - tremor - gum hyperplasia - hirsutism - diabetes mellitus

Question 13

Describe the contraindications and monitoring required for cyclosporin

Answer 13

Multiple drug interactions: antibiotics (trimethroprim), furosemide, apixaban, ‘nexium’. Avoid grapefruit juice. Hypersensitivity, malignancy, uncontrolled malignancy and hypertension. Poor renal function

Narrow TI – requires monitoring of organ functions, EUCs, blood pressure.

Question 14

Describe the class and uses of tacrolimus

Answer 14

Calcineurin inhibitor.
Transplants, rheumatoid arthritis, uveitis, refractory myositis, systemic sclerosis, severe chronic plaque psoriasis, autoimmune chronic hepatitis.

Question 15

Describe admin, metabolism and mechanism of action of tacrolimus

Answer 15

Oral bioavailability varies. It is administered IV’ly in the case of organ transplant. Metabolised P4503A in liver.

Preventing the production of IL-2 and other cytokines in T cells. Largely affect T response and also affects T-cell dependent B cells. Binds immunophilin and forms a receptor complex that blocks calcineurin.

Question 16

Describe the contraindications and monitoring required for tacrolimus

Answer 16

Drug interactions and hypersensitivity.

Narrow TI – requires monitoring of organ functions, EUCs, blood pressure.

Question 17

Describe the class and uses of mycophenalate mofetil

Answer 17

Class:Purine synthesis inhibitor
Uses: Glucocorticoid sparing effect in rheumatic diseases (SLE, Proliferative Lupus Glomerulonephritis, Polymyositis, Dermatomyositis, Interstitial Lung Disease, Vasculitis, Psoriasis). Prevents transplant graft rejection.

Question 18

Describe admin, metabolism and MoA for mycophenolate mofetil

Answer 18

Oral administration. Prodrug is converted to mycophenolic acid. Conjugation occurs in the liver. Intestinal absorption.Renal and GI excretion.

Mycophenalate mofetil only exhibits effect in activated lymphocytes. MPA interferes with the conversion of IMG to GMD. This results in inhibited B and T cell proliferation, and decreased antibody production. It does not affect other cells because they salvage other pathways.

Question 19

Describe adverse effects and contraindications for mycophenolate mofetil

Answer 19

Adverse Effects:
- Safer than Cyclophosphamide
- GI Side effects – nausea, diarrhoea, abdominal cramping
- Cytopenias – require regular blood count monitoring
- Infections: increased risk of CMV infection noted in renal transplants
- Potentially teratogenic.

Contras: Pregnancy

Question 20

Describe the class and uses of rituximab

Answer 20

Class: Chimeric monoclonal antibody
Uses:
- Used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases.
- Rheumatoid Arthritis as 2nd line if inadequate response to TNFi.
- Used when major organ involved eg lungs, nerves, kidneys in RA, SLE.
- Vasculitis: granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody-associated vasculitises.

Question 21

Describe administration and mechanism of action of rituximab

Answer 21

IV administration.

• Binds to the CD20 surface marker expressed on B cells, including precursor B cells (pre-B cells) and mature and memory B cells. - Reducing B cell inflammatory cascade. Not entirely without B cells
• Following antibody binding, B cells die by a number of mechanisms: antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, apoptosis

Question 22

Describe the adverse effects of rituximab

Answer 22

• Infusion-related reactions (two infusions, dosages vary depending on illness) – need Paracetamol, IV steroid and antihistamine as pre-med.
• Infection risks.
• Vaccinations – avoid live vaccines – need to complete required vaccinations.
• Fertility: not affected. Stop 6 months before pregnancy. (teratogenic?)
• Malignancy: used in malignancy eg Lymphoma

Question 23

Describe the contraindications of rituximab, and monitoring

Answer 23

Pregnancy. Uncontrolled cardiac disease. Hypersensitivity. Severe active infection. Severe heart failure.

Monitoring:
- Important to know baseline Immunoglobulin status and vaccination status.
- Loss of B cells from the circulation is transient (usually for about six months).
- Monitor for adverse events and safety