Calcineurin inhibitors are a class of drugs that suppress the body’s immune system, prescribed for specific medical situations where a moderated immune response is beneficial. These drugs are administered either systemically, affecting the whole body, or topically, applied to the skin.
How Calcineurin Inhibitors Work
Calcineurin inhibitors function by disrupting the communication pathway that activates a T-cell, a specific type of white blood cell. When the body detects a threat, T-cells are signaled to mount an attack, a process that depends on a protein called calcineurin. This protein is activated when calcium levels inside the T-cell rise.
Once active, calcineurin triggers another molecule, the nuclear factor of activated T-cells (NFAT). This molecule then travels to the cell’s nucleus, where it initiates the production of interleukin-2 (IL-2). IL-2 is a chemical messenger that tells T-cells to multiply and coordinate an immune response. Calcineurin inhibitors block this entire sequence.
These drugs enter the T-cell and bind to proteins called immunophilins. This drug-protein complex then physically obstructs calcineurin, preventing it from activating NFAT. Without the NFAT signal, the T-cell cannot produce IL-2, which stops the proliferation of T-helper cells.
Conditions Treated with Calcineurin Inhibitors
The primary application for systemic calcineurin inhibitors is in solid organ transplantation. After a patient receives a new kidney, liver, or heart, their immune system recognizes the new organ as foreign and attempts to destroy it in a process called rejection. By suppressing T-cell activation, medications like tacrolimus and cyclosporine prevent this immune attack, allowing the transplanted organ to function. They are important to long-term allograft survival.
These inhibitors are also effective in managing various autoimmune disorders, where the immune system mistakenly attacks the body’s own tissues. For conditions like severe atopic dermatitis (eczema) and psoriasis, suppressing the overactive T-cells that cause skin inflammation can provide relief. Topical formulations, such as pimecrolimus cream, are often used for eczema to limit systemic absorption.
Systemic calcineurin inhibitors are also used to treat other autoimmune conditions, including lupus nephritis, a type of kidney inflammation caused by lupus, and some forms of rheumatoid arthritis. Ophthalmic cyclosporine is also used to treat chronic dry eye associated with inflammation.
Significant Side Effects
Systemic use of calcineurin inhibitors is associated with a range of side effects. One concern is nephrotoxicity, or damage to the kidneys. These drugs can cause the blood vessels within the kidneys to constrict, reducing blood flow and impairing the kidneys’ ability to filter waste. Over time, this can progress to chronic kidney disease.
Hypertension, or high blood pressure, is another common side effect. The mechanisms are complex but involve increased salt retention by the kidneys and constriction of peripheral blood vessels. This effect is dose-dependent and a frequent complication for transplant recipients and other long-term users.
Neurotoxicity can also occur, presenting as tremors, headaches, and in more severe cases, confusion or seizures. The precise reasons for these effects are not fully understood but are a known risk associated with treatment.
Metabolic changes are another area of concern. Calcineurin inhibitors can impair the function of the pancreas’s insulin-producing cells, leading to hyperglycemia (high blood sugar). This can result in new-onset diabetes after transplantation. Tacrolimus, in particular, is more frequently associated with this complication than cyclosporine.
Required Patient Monitoring and Interactions
Due to the narrow therapeutic window of calcineurin inhibitors, patient monitoring is necessary. This is achieved through therapeutic drug monitoring (TDM), which involves regular blood tests to measure the concentration of the drug in the bloodstream. These tests, measuring “trough levels” just before the next dose is due, help ensure the drug concentration remains within a specific target range.
Beyond drug levels, routine monitoring of organ function is standard practice. Regular blood work is performed to check kidney function by measuring creatinine and to monitor for electrolyte imbalances like high potassium. Blood pressure must be checked frequently, and glucose levels are monitored to detect hyperglycemia.
Patients must be aware of drug and food interactions that can alter drug levels. Calcineurin inhibitors are metabolized by the CYP3A4 enzyme system in the liver. Other medications, including certain antibiotics and antifungals, can inhibit this enzyme, causing drug levels to rise to toxic concentrations. Conversely, some substances can induce the enzyme, leading to lower, potentially ineffective drug levels.
A known interaction is with grapefruit and grapefruit juice. Compounds in grapefruit inhibit the CYP3A4 enzyme, which can lead to a dangerous increase in the concentration of the calcineurin inhibitor in the blood. Patients are strictly advised to avoid all grapefruit products while on these medications to prevent toxicity.