Immunosuppressants in Organ Transplantation

• What are immunosuppressants?
• What are immunosuppressants used for?
• Drug treatment
• How do immunosuppressants work?
• Side effects of immunosuppressants
• Precautions when taking immunosuppressants
• Immunosuppressants and malignancy
• Immunosuppression and pregnancy

What are immunosuppressants?

Immunosuppressants are a class of drugs that suppress the immune response through various mechanisms. In organ transplantation, immunosuppressants are used to prevent the body from either recognition or attacking the foreign organ via various immune responses. They should only be used under the supervision of appropriately trained and experienced staff. The types of drugs that use for immunosuppression in organ transplant are:

• Calcineurin inhibitors (cyclosporin, tacrolimus)
• Corticosteroids (eg methylprednisolone, dexamethasone, prednisolone)
• Cytotoxic immunosuppressants (azathioprine, chlorambucil, cyclophosphamide, mercaptopurine, methotrexate)
• Immunosuppressant antibodies (eg antithymocyte globulins, basiliximab, infliximab)
• Sirolimus derivatives (everolimus, sirolimus)
• Other immunosuppressants (mycophenolate)

What are immunosuppressants used for?

Immunosuppressants in organ transplant are used for:

• Preventing organ rejection and reverse acute rejection in organ transplantation.
• Prevent and treat graft-versus-host disease.
• Minimise destruction of affected tissues in autoimmune and inflammatory diseases.

Drug treatment

Transplant rejection involves the body producing T and B cell and immune responses that recognise markers on foreign tissue called antigens. Treatment regimens used to prevent rejection employ drugs from different classes taking advantage of their complementary actions and minimising toxicity. Drug choice depends on the organ being transplanted and is tailored for each individual to minimise transplant-related morbidity.

Double drug treatment – usually a calcineurin inhibitor such as Prograf (Tacrolimus) or Neoral (cyclosporine) with either Imuran (azathioprine) or CellCept (mycophenolate).

Triple drug treatment – usually a calcineurin inhibitor such as Prograf (Tacrolimus) or Neoral (cyclosporine), a corticosteroid and either Imuran (azathioprine) or CellCept (mycophenolate).

Quadruple drug treatment – as for triple drug treatment plus an induction course with an immunosuppressant antibody (antithymocyte globulin, basiliximab or daclizumab).

Immunosuppression for organ transplants usually involves triple or quadruple drug treatment. The intensity of immunosuppression is initially high but tends to be reduced to a maintenance level that is determined by individual factors and the type of organ transplant. Your specialist will know which the best therapy is for you.

Initial Treatment

Initially a specialist may give a corticosteroid and either Imuran (azathioprine) or mycophenolate (sometimes with a calcineurin inhibitors such as Prograf (tacrolimus) or Neoral (cyclosporin)) for initial immunosuppression immediately before cadaveric donor transplantation, or for several days before planned live donor transplantation.

How do immunosuppressants work?

Calcineurin inhibitors

Calcineurin inhibitors react in the body to block the acitivity of calcineurin. This results in controlling the body’s immune response and reducing the body recognising and attacking the foreign organ.

Neoral (cyclosporin) is available as a microemulsion, which has greatly enhanced its oral bioavailability, with much less variation in absorption within and between patients.

Evidence suggests that Prograf (tacrolimus) may be slightly more efficacious than Neoral (cyclosporin) and they are now used in equal numbers of patients worldwide. Absorption is hindered by food, so usually it needs to be taken on an empty stomach.

Sirolimus

Rapamune (sirolimus) is a recently developed immunosuppressant, which is very similar to Prograf (tacrolimus). It has many adverse effects, but has much less renal toxicity than calcineurin inhibitors, and is currently mainly used in lung transplantation to ‘rescue’ patients from chronic renal failure, by substituting it for Neoral or Cicloral (cyclosporin).

Cell cycle inhibitors

Imuran (azathioprine) is used in 60% of patients and mycophenolate mofetil in 40%. These drugs stop the production of cells called B and T cell that cause the immune response.

Corticosteroids

Corticosteroids are thought to reduce the synthesis and secretion of a variety of inflammatory mediators.

Side effects of immunosuppressants

The side effects for each type of medication vary but the most common side effects that occur to less than 10% of patients are:

• Alopecia
• Dyspepsia
• Increased susceptibility to infections (eg oral, vaginal and intertriginous candidiasis)
• Masking of signs of infection
• Increased appetite
• Delayed wound healing

Some of the rare serious side effects that can occur in less than 1% are:

• Muscle weakness and wasting (particularly symptomatic on drug withdrawal)
• Amenorrhoea
• Psychosis
• Euphoria
• Depression
• Hirsutism
• Gingival hyperplasia

These side effects may not occur but if you have any concerns, see your doctor about it.

Precautions when taking immunosuppressants

Your specialist may also put you on anti-infective agents or antibiotics to prevent you getting an infection. If you have any concerns please see your doctor about it.

Immunosuppressants and malignancy

Immunosuppression increases the chance of getting skin cancer so take additional measures to protect the skin from the sun such as wearing protective clothing, wearing sunscreen and avoiding exposure to the sun for prolonged periods of time. If you have any concerns talk to your doctor about it.

Immunosuppression and pregnancy

If you are planning to become pregnant or are already pregnant, seek specialist advice.

References

1. Australian Medicines Handbook. [online]. Immunosuppressants. January, 2007. Available at URL: http://www.amh.net.au (last accessed 19/10/07).
2. Therapeutic Guidelines: Respiratory. [online]. Immunomodulators. Available at URL: http://www.tg.com.au (last accessed 19/10/07).
3. MIMS Australia. [online]. Neoral. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).
4. MIMS Australia. [online]. Prograf. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).
5. MIMS Australia. [online]. Rapamune. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).
6. MIMS Australia. [online]. Imuran. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).
7. MIMS Australia. [online]. Cellcept. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).
8. MIMS Australia. [online]. Solu-medrol. 2007. Available at URL: http://www.mims.com.au (last accessed 19/10/07).