Calcineurin Inhibitor

Aka: Calcineurin Inhibitor, Calcineurin

advertisement

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]

Images: Related links to external sites (from Bing)

These images are a random sampling from a Bing search on the term "Calcineurin Inhibitor." Click on the image (or right click) to open the source website in a new browser window. Search Bing for all related images

Related Studies

Ontology: Calcineurin (C0054450)

Definition (MSH) A CALCIUM and CALMODULIN-dependent serine/threonine protein phosphatase that is composed of the calcineurin A catalytic subunit and the calcineurin B regulatory subunit. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including HISTONES; MYOSIN LIGHT CHAIN; and the regulatory subunits of CAMP-DEPENDENT PROTEIN KINASES. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes.
Definition (NCI) Ubiquitous heterodimeric human Calcineurin is Ca(2+)/calmodulin-regulated protein phosphatase involved in many biologic activities as a modifier of phosphorylation status. Composed of widely expressed or tissue-restricted 55-60-kDa calmodulin-binding catalytic subunit (PPP Phosphatase/PP-2B Family) and conserved 19-kD Ca(2+)-sensitive regulatory subunit, Calcineurin appears to regulate glycolytic metabolism, nuclear translocation of NFATC1 transcription factor, sperm motility, and dopaminergic signal transduction and NMDA receptor-dependent synaptic plasticity. (NCI)
Definition (CSP) nonEC; calcium-calmodulin dependent protein phosphatase found in nerve cells and involved in intracellular signal transduction between the calcium and protein phosphorylation pathways.
Concepts Amino Acid, Peptide, or Protein (T116) , Enzyme (T126)
MSH D019703
LNC LP95253-8, MTHU034367
English Protein Phosphatase-2B, Calcineurin, PROTEIN PHOSPHATASE B 02, Protein Phosphatase 2B, Phosphatase 3, Protein, Protein Phosphatase 3, Calcineurin [Chemical/Ingredient], calcineurin, Protein phosphatase 3
Swedish Kalcineurin
Czech kalcineurin, proteinfosfatasa-2B, PP2B
Finnish Kalsineuriini
Italian Proteina fosfatasi-2B, PP2B, Proteina fosfatasi 2B, Calcineurina
Russian KAL'TSINEIRIN A, KAL'TSINEIRIN B, PROTEINFOSFATAZA-2B, KAL'TSINEIRIN, КАЛЬЦИНЕЙРИН A, КАЛЬЦИНЕЙРИН B, КАЛЬЦИНЕЙРИН, ПРОТЕИНФОСФАТАЗА-2B
Japanese カルシニューリン, プロテインホスファターゼ-2B, プロテインフォスファターゼ2B, カルシニューリンA, プロテインホスファターゼ2B, カルシニューリンB, カルシニュウリン, カルモジュリン依存性ホスファターゼ
French Protéine-phosphatase-2B, Protein Phosphatase 3, Protein Phosphatase-2B, Protéine-phosphatase-3, PP2B, Calcineurine
German PPB 02, PROTEIN PHOSPHATASE B 02, Calcineurin, PP2B, Protein-Phosphatase-2B
Polish Kalcyneuryna
Croatian PROTEIN FOSFATAZA 2B, KALCINEURIN
Portuguese Calcineurina, Proteína Fosfatase-2B
Spanish Calcineurina, Fosfatasa-2B de Proteína
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Calcineurin inhibitor (C1562036)

Definition (MSH) Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN.
Concepts Pharmacologic Substance (T121)
MSH D065095
SnomedCT 416587008, 416798007
English Calcineurin inhibitors, Calcineurin inhibitor, Calcineurin Antagonists, Calcineurin Inhibitors, Calcineurin Blockers, Protein Phosphatase-2B Inhibitors, Protein Phosphatase 2B Inhibitors, Protein Phosphatase 3 Inhibitors, Calcineurin antagonist, Calcineurin inhibitor (product), Calcineurin inhibitor (substance)
Spanish inhibidor de la calcineurina (producto), inhibidor de la calcineurina (sustancia), inhibidor de la calcineurina
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pharmacology

advertisement

2025 Family Practice Notebook, LLC. Terms | Privacy | About | Site Map | Newsletter | Blog

Footer Site Logo