Pharmacology of Ciclosporin

Ciclosporin – also spelled cyclosporine – is an immunosuppressant medicine used to prevent organ transplant rejection. It may also be used to reduce inflammation in patients with conditions such as rheumatoid arthritis and psoriasis.

First isolated from the fungus Tolypocladium inflatum in 1971, Ciclosporin was first approved for medical use in 1983. It has since been listed on the World Health Organization’s List of Essential Medicines

Ciclosporin is used because it weakens the immune system.

In autoimmune states and cases of organ transplant, the immune system attacks the body. By weakening the immune system, it prevents the body from attacking transplanted organs and increasing inflammatory states in cases such as rheumatoid arthritis.

Indications of ciclosporin include:

  • Organ transplant rejection – bone marrow suppression; kidney; heart; liver
  • Rheumatoid arthritis
  • Psoriasis
  • Dry eye syndrome / keratoconjunctivitis

The medicine has also been used to treat atopic dermatitis, severe ulcerative colitis and Kimura disease – a rare, chronic inflammatory disorder that is characterised by the presence of subdermal lesions in the head, neck and lymph nodes.

Ciclosporin is available as an oral capsule, oral solution and as eye drops. It may also be administered via the intravenous route.

Mechanism of action

The primary mechanism of ciclosporin is to dampen the immune system.

More specifically, it achieves this effect by lowering the activity of T-cells. Ciclosporin binds to the cytosolic protein cyclophilin of T-cells – a complex that inhibits calcineurin.

Calcineurin is responsible for activating transcription of interleukin-2. It dephosphorylates the transcription factor NF-AT – nuclear factor of activated T-cells. Once NF-AT becomes dephosphorylated, it transitions to the T-cell nucleus to increase transcription of IL-2 and a variety of other cytokines.

As a calcineurin inhibitor, ciclosporin prevents that dephosphorylation step from taking place and, from there, reduces the transcription of IL-2 and other immunomodulatory cytokines.

To summarise then:

  • Ciclosporin works to lower the activity of T-cells.
  • It binds to cytosolic cyclophilin, becoming ciclosporin-cyclophilin complex.
  • This complex inhibits calcineurin.
  • Calcineurin works to increase activity in the immune system by dephosphorylating NF-AT, which then moves to the T-cell nucleus to increase transcription of IL-2.
  • Because calcineurin is now inhibited, this transcription no longer takes place.

Let’s take a few minutes to review how this mechanism produces the many side effects that ciclosporin has become known for.

Side effects

Ciclosporin is associated with the following side effects:

  • Hypertension
  • Hypomagnesemia
  • Increased hair growth
  • Headache
  • Gingival hyperplasia
  • Vomiting
  • Kidney / liver dysfunction
  • Hyperkalemia
  • Tingling sensations on lips / fingertips

In addition, ciclosporin is – due to its mechanism – likely to increase the risk of infections.

Hypertension occurs because ciclosporin causes vasoconstriction in the kidneys, as well as increasing sodium reabsorption.

If used after a kidney transplant, ciclosporin can increase uric acid levels / risk of gout.

Clinical considerations

When we talk about the clinical pharmacology of ciclosporin, we need to think about the following factors:

  • That reduced doses are warranted in patients with cardiovascular disease, not least because ciclosporin is linked to hypertension.
  • That ciclosporin causes potassium retention. Consider the risk of hyperkalemia if the medicine is taken with other drugs – such as potassium supplements or K-sparing diuretics – that also increase potassium levels.
  • That regular blood checks may be required to decrease the risk of adverse effects.
  • That taking ciclosporin alongside antibacterial drugs – such as aminoglycosides and vancomycin – increases the risk of kidney damage. NSAIDs, azole antifungals, statins, H2 antagonists and colchicine also increase this risk.
  • That elevated levels of ciclosporin may occur when taken with macrolides, such as erythromycin or clarithromycin.
  • That some medicines – such as phenytoin, carbamazepine and St. John’s wort – may reduce ciclosporin levels in the body.
  • That patients should avoid grapefruit juice while taking ciclosporin, as it can increase ciclosporin levels in the body.

Ciclosporin is an important immunosuppressant medicine. However, it comes with its own share of serious side effects and drug interactions. The clinician should take these many factors into consideration while the patient is on therapy.

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