Continuing Education Activity

Calcineurin inhibitors (CNI) are composed of three drugs (cyclosporine, tacrolimus, and pimecrolimus). They are primarily used as immunosuppressive drugs, and inhibit the key signaling phosphatase calcineurin, thus called calcineurin inhibitors. This activity shows these drugs as a valuable agent in the chronic management of patients with allografts.

Objectives:

• Identify the mechanism of action of calcineurin inhibitors.
• Describe the adverse effects of calcineurin inhibitors.
• Outline appropriate monitoring of calcineurin inhibitors.
• Discuss interprofessional team strategies for improving care coordination and communication to advance calcineurin inhibitors and improve them. Summarize the severity of adverse effects and complications of overdosing of calcineurin inhibitors.

Indications

Calcineurin inhibitors (CNI) are a family of three drugs (cyclosporine, tacrolimus, and pimecrolimus) that clinicians can use to suppress the immune system.

According to the Food and Drug Administration (FDA):

• Oral cyclosporine is indicated as an adjuvant to glucocorticoids for prophylaxis of allogenic post-transplant organ rejection.
• Oral tacrolimus is also indicated as an adjuvant to other immunosuppressive drugs for organ rejection prophylaxis in patients with allogenic grafts of liver, kidney, or heart. In addition, tacrolimus ointment is indicated for the short-term treatment of moderate to severe chronic atopic dermatitis in non-immunocompromised adults and for children who are nonresponsive to other topical treatments for atopic dermatitis.
• Pimecrolimus ointment also has indications for treating mild to moderate chronic atopic dermatitis for non-immunocompromised patients with ages equal to or greater than two years old as second-line therapy. 

N.B.: a recent study conducted in 2019 showed that tacrolimus effectively reduces pancreatitis in patients who have undergone liver transplantation after endoscopic retrograde cholangiopancreatography.[1]

Mechanism of Action

They suppress the immune system by blocking T-cell proliferation by inhibiting its key signaling phosphatase calcineurin, thus called calcineurin inhibitors.[2]

These drugs work by binding specifically to the following intracellular proteins:

• Cyclosporine -> cyclophilin.
• Tacrolimus -> FK-binding protein
• pimecrolimus -> macrophilin-12

These complexes subsequently inhibit calcineurin and T-cell activation.[3]

Administration

Calcineurin inhibitors are a family of three drugs; each drug has administered differently.

Cyclosporine can be administered orally, as ophthalmic drops, or by injections.

Tacrolimus administration is primarily via the oral route, although administration can also be via the sublingual or rectal routes if the oral form is not feasible.[4] Additionally, patients can use tacrolimus as an ointment for the treatment of dermatitis.

Pimecrolimus is only administered topically as an ointment. 

Adverse Effects

Although cyclosporine side effects are dose-dependent, the drug can cause several serious adverse effects. These include:

• Nephrotoxicity[5]
• Hepatotoxicity (quercetin protects against its hepatotoxicity)[6]
• Life-threatening infections [7]
• Lymphomas[8]
• Hypertension[9]
• Hyperlipidemia[10]
• Hyperkalemia 
• Hyperuricemia[11]
• Hypomagnesemia 
• Tremors[12]
• Hirsutism[13]
• Glucose intolerance[14]
• Gum hyperplasia[15]

The side effects of tacrolimus are mostly similar to that of cyclosporine. Tacrolimus differs from cyclosporine in that its use can result in alopecia and does not cause hirsutism or gingival hyperplasia as cyclosporine. In earlier studies, researchers observed post-transplant insulin-dependent diabetes in patients administering tacrolimus.[16]

Pimecrolimus's side effects are numerous, as mentioned below:[17] 

• Burning, stinging, and pruritus (main side effects)
• Application site reaction (erythema, skin discoloration)
• Fever
• Headache
• Nausea
• Flu-like symptoms
• Cough
• Nasal congestion
• Nasopharyngitis 
• Epistaxis
• Sinusitis 
• Upper respiratory tract infections
• Bronchitis
• Tonsilitis
• Sore throat
• Pneumonia
• Dyspnea
• Acne
• Folliculitis
• Asthma or asthma exacerbation
• Constipation
• Urticaria
• Gastroenteritis 
• Abdominal pain
• Vomiting
• Anaphylaxis
• Lymphadenopathy
• Angioedema
• Malignancy (squamous/basal cell carcinomas, malignant melanoma, and lymphoma)[18]

Contraindications

According to the FDA, calcineurin inhibitors contraindications are:

• Cyclosporine is contraindicated in any patient with a history of hypersensitivity to it or polyoxyethylated castor oil.
• Tacrolimus is contraindicated in any patient with a history of hypersensitivity to it or to polyxyl 60 hydrogenated castor oil (HCO-60).
• Pimecrolimus is contraindicated in any patient with a history of hypersensitivity to it or any of its components. Additionally, the FDA advised that clinicians should not use pimecrolimus for the long term in any age group, and the use should be limited to the area of atopic dermatitis. 

Monitoring

According to the FDA, calcineurin inhibitors should have monitoring as follows:

• Cyclosporine undergoes metabolized in the liver, and increased exposure to the drug could cause severe hepatic impairment. Additionally, it causes hypertension, so blood pressure should be monitored very closely. (The recommendation is to prescribe an anti-hypertensive drug other than the potassium-sparing drugs to keep the blood pressure controlled without causing hyperkalemia). 
• The CYP3A enzymes metabolize tacrolimus; therefore, frequent monitoring for the drug is necessary when the patient is using any medication that activates or inhibits these enzymes. Black patients using the drug may require higher doses to reach comparable trough values. Patients with hepatic or renal impairment should receive the lowest values of the initial oral dosing range.
• Similar to tacrolimus, pimecrolimus undergoes metabolized by the CYP3A enzymes. The FDA recommends not using tanning beds, sun lamps, receiving treatment by ultraviolet light, or engaging in excessive sun exposure while using the drug. Patients taking the medication should not wear bandages or dressings that cover the skin and should wear regular clothes. 

Toxicity

In the case of overdosage, forced vomiting and gastric lavage would be valuable for up to two hours after administration. Transient hepatotoxicity and nephrotoxicity could occur that should resolve after drug withdrawal. Generally, oral doses of cyclosporine up to ten grams (about a hundred and fifty mg/kg) have been tolerated with comparatively minor clinical consequences, like physiological reactions, drowsiness, headache, tachycardia, and in few patients, moderately severe reversible renal impairment. However, serious symptoms of intoxication would follow accidental intramuscular administration overdosage with cyclosporine in premature neonates. Therefore, the treatment of the overdosage is only supportive and symptomatic.

Regarding tacrolimus, limited overdosage expertise is available. Reports exist of acute overdosages of up to thirty times the mean dose. Almost all patients recovered with no sequelae. Acute overdosage was typically followed by adverse reactions such as tremors, abnormal renal function, high blood pressure, and peripheral edema. In one case of acute overdosage, lethargy and transient urticaria were observed. The treatment of the overdosage is supportive and symptomatic, as tacrolimus is not dialyzable to any extent. There is no expertise with charcoal hemoperfusion. There are reports of using activated charcoal in treating acute overdoses; however, evidence has not been adequate to recommend its use.

There has been no experience with overdosage with pimecrolimus, and there are no reports of incidents of accidental oral intake. However, if oral ingestion occurs, the patient ought to seek medical intervention.

Enhancing Healthcare Team Outcomes

Management of drug overdosage requires an interprofessional team of healthcare professionals, including a nurse, pharmacist, laboratory technologists, and a variety of clinicians in several specialties. Without proper management, the severity of the complications from calcineurin inhibitor overdose is high. The emergency department practitioner and assigned nurse are liable for coordinating the supportive and symptomatic care for drug overdosages. 

An interprofessional team approach can help to improve outcomes and reduce adverse effects when using this drug class. A pharmacist consult can be extremely beneficial to the interprofessional team by verifying both dosing and potential drug-drug interactions. [Level 5]