Calcineurin Inhibitor

Aka: Calcineurin Inhibitor, Calcineurin

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II. Indications

  1. Solid Organ Transplant Immunosuppression (maintenance prevention of rejection)
    1. Cyclosporine (FDA approved)
  2. Rheumatoid Arthritis
    1. Cyclosporine (FDA approved)
  3. Psoriasis
    1. Cyclosporine (FDA approved)
  4. Autoimmune Conditions
    1. Behcet's Disease
    2. Vasculitis
    3. Inflammatory Myositis
    4. Lupus Nephritis
    5. Interstitial Lung Disease
  5. Thrombocytopenia (chronic, idiopathic, refractory)
  6. Psoriatuc Arthritis

III. Mechanism

  1. Calcineurin
    1. Serine-ThreonineProtein phosphatase that dephosphorylates phosphoproteins
      1. Histones
      2. Myosin light chain
      3. CAMP-dependent Protein kinases
    2. Calcineurin is composed of 2 subunits that are dependent on calmodulin and Calcium
      1. Calcineurin A (catalytic subunit, calmodulin-binding)
      2. Calcineurin B (regulatory subunit, Calcium sensitive)
    3. Calcineurin is key to immune function via the dephosphorylation of NFAT (nuclear factor)
      1. Promotes the transcription and synthesis of Cytokines (e.g. Interleukin 2) with T Cells (esp. T Helper Cells)
      2. Calcineurin also increases the number of Interleukin receptors on cytotoxic T Cells
      3. Calcineurin promotes the activation, proliferation, and differentiation of T Lymphcytes
    4. Calcineurin also increases Proteinuria in Glomerulonephritis (e.g. Lupus Nephritis)
      1. Calcineurin dephosphorylates synaptopodin, triggering further proteolysis to active metabolites
      2. Synaptopodin metabolites destabilize the glomerulus basement membrane podocytes
    5. Calcineurin also plays an important role in other signal transduction and pathway regulation
      1. Glycolysis
      2. Sperm Motility
      3. Nuclear translocation of NFATC1 transcription factor
      4. Dopaminergic signal transduction
      5. NMDA receptor-dependent synaptic plasticity
  2. Calcineurin Inhibitor (CNI)
    1. Inhibit the phosphatase activity of Calcineurin via immunophilin (cytoplasmic receptor) binding
      1. Voclosporin and Cyclosporine bind cyclophilin
      2. Pimecrolimus and Tacrolimus bind FK-binding Proteins
    2. CNIs are primarily used as Immunosuppressants in Solid Organ Transplant and Autoimmune Conditions
      1. CNIs inhibit T-Cell mediated Immunity via decreased Interleukin 2 related mechanisms (as above)

IV. Medications

  1. Cyclosporine (Sandimmune)
  2. Tacrolimus (Prograf)
  3. Voclosporin
  4. Pimecrolimus
    1. Topical only (used in Atopic Eczema)

V. Adverse Effects

  1. Cardiovascular adverse effects
    1. Hypertension
    2. Hyperlipidemia (Cyclosporine)
  2. Neurologic adverse effects
    1. Headaches
    2. Tremor
    3. Neuropathy
    4. Seizures
  3. Secondary Malignancy
    1. Squamous cell cancer
    2. Lymphoproliferative disorders
  4. Miscellaneous adverse effects
    1. Nephrotoxicity
    2. Hyperkalemia
    3. Gingival Hyperplasia (Cyclosporine)
    4. Diabetes Mellitus (Tacrolimus)

VI. Drug Interactions: Agents that increase Calcineurin Inhibitor concentrations

  1. See Cytochrome P-450 3A4
  2. Applies to Cyclosporine, Tacrolimus and Voclosporin
  3. Antibiotics
    1. Aminoglycosides
    2. Ofloxacin (other Fluoroquinolones such as Ciprofloxacin and Levofloxacin may be used with caution)
    3. Erythromycin (and Clarithromycin to a lesser extent)
    4. Metronidazole (Flagyl)
  4. Antifungal agents
    1. Amphoteracin B
    2. Fluconazole
    3. Itraconazole
    4. Ketoconazole
  5. Cardiovascular agents
    1. Amiodarone
    2. Spironolactone (Hyperkalemia risk)
    3. Nondihydropyridine Calcium Channel Blockers (Diltiazem, Verapamil)
  6. Foods
    1. Grapefruit (and juice)
    2. Pineapple, papaya (affect Cyclosporine)
    3. Pomegantes (and juice)
  7. Misellaneous agents
    1. Ethinyl Estradiol (Oral Contraceptives)
    2. Warfarin (Coumadin)
    3. NSAIDS (Nephrotoxicity Risk)

VII. Drug Interactions: Agents that decrease Calcineurin Inhbitor concentrations

  1. See Cytochrome P-450 3A4
  2. Applies to Cyclosporine, Tacrolimus and Voclosporin
  3. Antibiotics
    1. Nafcillin
    2. Rifampin
  4. Seizure medications
    1. Carbamazepine (Tegretol)
    2. Phenytoin (Dilantin)
    3. Valproic Acid
  5. Supplements
    1. Echinacea (risk of Transplant Rejection)
    2. St. John's Wort
  6. Gastrointestinal agents
    1. Antacids
    2. Loperamide (Imodium)
  7. Miscellaneous agents
    1. Cholestyramine

VIII. Resources

  1. Calcineurin Inhibitors (Stat Pearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK558995/

IX. References

  1. Cimino (2016) Am Fam Physician 93(3): 203-10 [PubMed]
  2. Costanzo (2010) J Heart Lung Transplant 29(8): 914-56 [PubMed]

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