Cyclosporine Pharmacology!

Cyclosporine Pharmacology

Cyclosporine – also spelled ciclosporin – is an important immunosuppressant drug. Here in today’s study guide, we review the indications, mechanism of action, side effects, and drug and food interactions associated with this drug.

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

Cyclosporine is used because it weakens the immune response.

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

Indications of cyclosporine 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.

Cyclosporine 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 cyclosporine is to dampen the immune system.

More specifically, it achieves this effect by lowering the activity of T-cells. Cyclosporine 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, cyclosporine prevents that dephosphorylation step from taking place and, from there, reduces the transcription of IL-2 and other immunomodulatory cytokines.

To summarise:

• Cyclosporine 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.

Now, let’s take a look at how this mechanism translates into the side effect profile of this immunosuppressant drug.

Side Effects

Cyclosporine 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, cyclosporine is – due to its mechanism – likely to increase the risk of infections.

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

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

Clinical Pharmacology

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

• Reduced doses are warranted in patients with cardiovascular disease, not least because cyclosporine is linked to hypertension.
• Cyclosporine 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.
• Regular blood checks may be required to decrease the risk of adverse effects.
• Taking cyclosporine 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.
• Elevated levels of cyclosporine may occur when taken with macrolides, such as erythromycin or clarithromycin.
• Some medicines – such as phenytoin, carbamazepine and St. John’s wort – may reduce cyclosporine levels in the body.
• Patients should avoid grapefruit juice, as it can increase cyclosporine levels in the body.

That concludes our rapid review of cyclosporine pharmacology! Check back to our PharmaFactz blog soon for more exclusive content to help you master the science of medicines.