Hydroxocobalamin

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Hydroxocobalamin
Hydroxocobalamin.svg
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a605007
Pregnancy
category
Routes of
administration
IM, IV
ATC code
Legal status
Legal status
  • US: OTC
  • Prescription injectable in U.S. Not DEA-controlled
Pharmacokinetic data
Protein binding Very high (90%)
Metabolism Primarily liver, cobalamins are absorbed in the ileum and stored in the liver.
Biological half-life ~6 days
Identifiers
Synonyms vitamin B12, vitamin B12a, hydroxycobalamin
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.033.198
Chemical and physical data
Formula C62H89CoN13O15P
Molar mass 1346.37 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is vitamin found in food and used as a dietary supplement.[2] As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia.[2][3] Other uses include cyanide poisoning, Leber's optic atrophy, and toxic amblyopia.[4][5] It is given by injection into a muscle or vein.[3]

Side effects are generally few. They may include diarrhea, low blood potassium, allergic reactions, and high blood pressure.[3] Normal doses are considered safe in pregnancy.[1] Hydroxocobalamin is the natural form of vitamin B12 and a member of the cobalamin family of compounds.[6][7] Hydroxocobalamin, or another form of vitamin B12, are required for the body to make DNA. Foods that naturally contain vitamin B12 include meat, eggs, and dairy products.[7]

Hydroxocobalamin was first isolated in 1949.[8] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] Hydroxocobalamin is available as a generic medication.[3] The wholesale cost in the developing world is about 0.12 to 0.84 USD per dose.[10] In the United States this amount wholesale costs about 0.84 USD.[11] Commercially it is made from one of a number of different types of bacteria.[12]

Medical uses[edit]

Hydroxocobalamin at standard conditions is a solid composed of dark red crystals.
Hydroxocobalamin injection USP (1000 mcg/mL) is a clear red liquid solution. Shown is 500 mcg B-12 prepared for subcutaneous injection.

Vitamin B12 deficiency[edit]

Vitamin B12 compounds are used as a prescription medicine (injection) for vitamin B12 replacement therapy, usually at 100 µg/dose. In the UK, 1,000 µg (1 mg) per dose is generally used.[citation needed] Damage that results from vitamin B12 deficiency can be prevented with early diagnosis and adequate treatment.

For most, the standard therapy for treatment of vitamin B12 deficiency has been intramuscular (IM) injections in the form of cyanocobalamin (CNCbl) or hydroxocobalamin (OHCbl). Cyanocobalamin is traditionally prescribed in the United States. Outside of the United States, hydroxocobalamin is most generally used for vitamin B12 replacement therapy and is considered the “drug of choice” for vitamin B12 deficiency by the Martindale Extra Pharmacopoeia (Sweetman, 2002) and the World Health Organization (WHO) Model List of Essential Drugs. This preference for hydroxocobalamin in many countries is due to its long retention in the body and the need for less-frequent IM injections in restoring vitamin B12 (cobalamin) serum levels. Furthermore, IM administration of hydroxocobalamin is also the preferred treatment for pediatric patients with intrinsic cobalamin metabolic diseases; vitamin B12-deficient patients with tobacco amblyopia due to cyanide poisoning; and patients with pernicious anemia who have optic neuropathy.[13][14][15][16]

In a newly diagnosed vitamin B12-deficient patient, normally defined as when serum levels are less than 200 pg/ml, daily IM injections of hydroxocobalamin up to 1,000 μg (1 mg) per day are given to replenish the body’s depleted cobalamin stores. In the presence of neurological symptoms, following daily treatment, injections up to weekly or biweekly are indicated for six months before initiating monthly IM injections. Once clinical improvement is confirmed, maintenance supplementation of B12 will generally be needed for life.

Cyanide poisoning[edit]

Hydroxocobalamin has also been used in the treatment of cyanide poisoning. Cyanide displaces the hydroxo ligand forming a stable cyanocobalamin.[17]

Side effects[edit]

The literature data on the acute toxicity profile of hydroxocobalamin show it is generally regarded as safe with local and systemic exposure. The ability of hydroxocobalamin to rapidly scavenge and detoxify cyanide by chelation has resulted in several acute animal and human studies using systemic hydroxocobalamin doses at suprapharmacological doses as high as 140 mg/kg to support its use as an intravenous (IV) treatment for cyanide exposure.[18][19] The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning.

Properties[edit]

Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic needles. The injection formulations appear as clear, dark-red solutions. It has a distribution coefficient of 1.133 × 10-5 and a pKa of 7.65.

Causes of deficiency[edit]

Injection of hydroxocobalamin is used to rectify the following causes of vitamin B12 deficiency (list taken from the drug prescription label published by the U.S. Food and Drug Administration)

Pernicious anemia, is not a cause of vitamin B12 deficiency, but rather the result of vitamin B12 deficiency. While it technically refers to anemia caused specifically by autoimmune deficiency of intrinsic factor, it is commonly used to refer to B12-deficient anemia as a whole, regardless of cause.

Mechanism of action[edit]

Vitamin B12 refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folate, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions:

Cobalamins are characterized by a porphyrin-like corrin nucleus that contains a single cobalt atom bound to a benzimidazolyl nucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins: CNCbl, methylcobalamin, 5-deoxyadenosylcobalamin, and OHCbl. In the serum, hydroxocobalamin and cyanocobalamin are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and 5-deoxyadenosylcobalamin are the active forms of the coenzyme required for cell growth and replication.[21][full citation needed] Cyanocobalamin is usually converted to hydroxocobalamin in the serum, whereas hydroxocobalamin is converted to either methylcobalamin or 5-deoxyadenosyl cobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. Hydroxocobalamin has a higher affinity to the TC II transport protein than cyanocobalamin, or 5-deoxyadenosylcobalamin. From a biochemical point of view, two essential enzymatic reactions require vitamin B12 (cobalamin).[20][22]

Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin, which are both involved in specific enzymatic reactions. In the face of vitamin B12 deficiency, conversion of methylmalonyl-CoA to succinyl-CoA cannot take place, which results in accumulation of methylmalonyl-CoA and aberrant fatty acid synthesis. In the other enzymatic reaction, methylcobalamin supports the methionine synthase reaction, which is essential for normal metabolism of folate. The folate-cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate, the substrate for metabolic steps that require folate. In a state of vitamin B12 deficiency, the cell responds by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate. The resulting elevated concentrations of homocysteine and MMA are often found in patients with low serum vitamin B12 and can usually be lowered with successful vitamin B12 replacement therapy. However, elevated MMA and homocysteine concentrations may persist in patients with cobalamin concentrations between 200 and 350 pg/mL.[23] Supplementation with vitamin B12 during conditions of deficiency restores the intracellular level of cobalamin and maintains a sufficient level of the two active coenzymes: methylcobalamin and deoxyadenosylcobalamin.

See also[edit]

References[edit]

  1. ^ a b "Hydroxocobalamin Use During Pregnancy | Drugs.com". www.drugs.com. Retrieved 30 December 2016. 
  2. ^ a b WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 251. ISBN 9789241547659. Retrieved 8 December 2016. 
  3. ^ a b c d "Vitamin B12". The American Society of Health-System Pharmacists. Retrieved 8 December 2016. 
  4. ^ MacLennan, L; Moiemen, N (February 2015). "Management of cyanide toxicity in patients with burns.". Burns : journal of the International Society for Burn Injuries. 41 (1): 18–24. PMID 24994676. 
  5. ^ "Hydroxocobalamin 1mg in 1ml solution for injection - Summary of Product Characteristics (SPC) - (eMC)". www.medicines.org.uk. Retrieved 30 December 2016. 
  6. ^ Bullock, Shane; Manias, Elizabeth (2013). Fundamentals of Pharmacology. Pearson Higher Education AU. p. 862. ISBN 9781442564411. 
  7. ^ a b "Office of Dietary Supplements - Dietary Supplement Fact Sheet: Vitamin B12". ods.od.nih.gov. 11 February 2016. Retrieved 30 December 2016. 
  8. ^ Eitenmiller, Ronald R.; Jr, W. O. Landen (2010). Vitamin Analysis for the Health and Food Sciences. CRC Press. p. 467. ISBN 9781420050165. 
  9. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016. 
  10. ^ "Vitamin B12". International Drug Price Indicator Guide. Retrieved 8 December 2016. 
  11. ^ "NADAC as of 2016-12-07 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Retrieved 30 December 2016. 
  12. ^ "Vitamins, 6. B Vitamins". Ullmann's encyclopedia of industrial chemistry. Weinheim: Wiley-VCH. 2011. ISBN 9783527303854. 
  13. ^ Carethers, 1988[full citation needed]
  14. ^ Chisholm et al., 1967[full citation needed]
  15. ^ Freeman, 1992[full citation needed]
  16. ^ Markle, 1996[full citation needed]
  17. ^ Shepherd G, Velez LI (May 2008). "Role of hydroxocobalamin in acute cyanide poisoning". Ann Pharmacother. 42 (5): 661–9. doi:10.1345/aph.1K559. PMID 18397973. 
  18. ^ Forsyth et al., 1993[full citation needed]
  19. ^ Riou et al., 1993[full citation needed]
  20. ^ a b Katzung, 1989[full citation needed]
  21. ^ Katzung, 1989
  22. ^ Hardman, 2001[full citation needed]
  23. ^ Lindenbaum et al. 1994[full citation needed]

External links[edit]