Hydroxocobalamin at standard conditions is a solid composed of dark red crystals.
Hydroxocobalamin injection USP (1000 μg/mL) is a clear red liquid solution. Shown is 500 μg B-12 prepared for subcutaneous injection.
Vitamin B12 deficiency
Standard therapy for treatment of vitamin B12 deficiency has been intramuscular (IM) or intravenous (IV) injections of hydroxocobalamin (OHCbl), since the majority of cases are due to malabsorption by the enteral route (gut).[11] It is used 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.[12]
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.[citation needed]
Cyanide poisoning
Hydroxocobalamin is first line therapy for people with cyanide poisoning.[3] Hydroxocobalamin converts cyanide to the much less toxic cyanocobalamin. Cyanocobalamin is renally cleared. The use of hydroxocobalamin became first line due to its low adverse risk profile, rapid onset of action, and ease of use in the prehospital setting.[13]
Injectable hydroxocobalamin
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)
Dietary deficiency of vitamin B12 occurring in strict vegetarians and in their breastfed infants (isolated vitamin B12 deficiency is very rare)
Malabsorption of vitamin B12 resulting from damage to the stomach, where intrinsic factor is secreted, or damage to the ileum, where intrinsic factor facilitates vitamin B12 absorption. These conditions include tropical sprue and nontropical sprue (celiac disease).
Inadequate use of vitamin B12, which may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia
Pernicious anemia is the most common cause of vitamin B12 deficiency.[14] 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.
Side effects
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.[15][16] The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning.
The drug causes a reddish discoloration of the urine (chromaturia), which can look like blood in the urine.[17]
Properties
Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic crystals. 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.
Mechanism of action
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 benzimidazolylnucleotide 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.[18] 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).[18][19]
Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin. 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.[20] 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.
^ abcdef"Vitamin B12". The American Society of Health-System Pharmacists. from the original on 30 December 2016. Retrieved 8 December 2016.
^MacLennan L, Moiemen N (February 2015). "Management of cyanide toxicity in patients with burns". Burns. 41 (1): 18–24. doi:10.1016/j.burns.2014.06.001. PMID 24994676.
^"Hydroxocobalamin 1mg in 1ml solution for injection - Summary of Product Characteristics (SPC) - (eMC)". www.medicines.org.uk. from the original on 30 December 2016. Retrieved 30 December 2016.
^Bullock S, Manias E (2013). Fundamentals of Pharmacology. Pearson Higher Education AU. p. 862. ISBN9781442564411. from the original on 2016-12-31.
^ ab"Office of Dietary Supplements - Dietary Supplement Fact Sheet: Vitamin B12". ods.od.nih.gov. 11 February 2016. from the original on 31 December 2016. Retrieved 30 December 2016.
^Eitenmiller RR, Landen WO (2010). Vitamin Analysis for the Health and Food Sciences. CRC Press. p. 467. ISBN9781420050165. from the original on 2016-12-31.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^"Vitamins, 6. B Vitamins". Ullmann's encyclopedia of industrial chemistry. Weinheim: Wiley-VCH. 2011. ISBN9783527303854.
^Thakkar K, Billa G (January 2015). "Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion". European Journal of Clinical Nutrition. 69 (1): 1–2. doi:10.1038/ejcn.2014.165. PMID 25117994.
^Carethers M (March 1988). "Diagnosing vitamin B12 deficiency, a common geriatric disorder". Geriatrics. 43 (3): 89–94, 105–7, 111–2. PMID 3277892.
^Shepherd G, Velez LI (May 2008). "Role of hydroxocobalamin in acute cyanide poisoning" (PDF). The Annals of Pharmacotherapy. 42 (5): 661–9. doi:10.1345/aph.1K559. PMID 18397973. S2CID 24097516.
^Qudsiya, Zainab; De Jesus, Orlando (2022). Subacute Combined Degeneration of the Spinal Cord. StatPearls. StatPearls Publishing. PMID 32644742.
^Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH (1993). "Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers". Journal of Toxicology. Clinical Toxicology. 31 (2): 277–94. doi:10.3109/15563659309000395. PMID 8492341.
^Riou B, Berdeaux A, Pussard E, Giudicelli JF (1993). "Comparison of the hemodynamic effects of hydroxocobalamin and cobalt edetate at equipotent cyanide antidotal doses in conscious dogs". Intensive Care Medicine. 19 (1): 26–32. doi:10.1007/BF01709274. PMID 8440794. S2CID 19462753.
^Koratala A, Chamarthi G, Segal MS (June 2018). "Not all that is red is blood: a curious case of chromaturia". Clinical Case Reports. 6 (6): 1179–1180. doi:10.1002/ccr3.1514. PMC5986001. PMID 29881591.
"Hydroxocobalamin". Drug Information Portal. U.S. National Library of Medicine.
January 23, 2023
hydroxocobalamin, also, known, vitamin, b12a, hydroxycobalamin, vitamin, found, food, used, dietary, supplement, supplement, used, treat, vitamin, deficiency, including, pernicious, anemia, other, uses, include, treatment, cyanide, poisoning, leber, optic, atr. Hydroxocobalamin also known as vitamin B12a and hydroxycobalamin is a 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 treatment for cyanide poisoning Leber s optic atrophy and toxic amblyopia 4 5 It is given by injection into a muscle or vein 3 HydroxocobalaminClinical dataOther namesvitamin B12 vitamin B12a hydroxycobalaminAHFS Drugs comMonographMedlinePlusa605007License dataEU EMA by INNRoutes ofadministrationIM IVATC codeB03BA03 WHO V03AB33 WHO Legal statusLegal statusUS OTC by prescription when injectable not DEA controlledPharmacokinetic dataProtein bindingVery high 90 MetabolismPrimarily liver cobalamins are absorbed in the ileum and stored in the liver Elimination half life 6 daysIdentifiersIUPAC name Coa a 5 6 dimethylbenzimidazolyl Cob hydroxocobamideCAS Number13422 51 0 YPubChem CID6433575DrugBankDB00200 YChemSpider28534326UNIIQ40X8H422OKEGGD01027 YChEBICHEBI 27786ChEMBLChEMBL1237097 NCompTox Dashboard EPA DTXSID60897433ECHA InfoCard100 033 198Chemical and physical dataFormulaC 62H 89Co N 13O 15PMolar mass1346 377 g mol 13D model JSmol Interactive imageSMILES Cc1cc2ncn c2cc1C C9OC CO C OP3 O OC C CNC O CCC5C4 C C C8 NC CC7 NC C C C6 NC C C N4 Co O O3 C5 C CC N O C C CC N O C6CCC N O C C CC N O C7CCC N O C CCC N O C8 C C C9OInChI InChI 1S C62H90N13O14P Co H2O c1 29 20 40 41 21 30 29 2 75 28 70 40 56 52 84 53 42 27 76 87 56 89 90 85 86 88 31 3 26 69 49 83 19 15 36 50 32 4 54 58 6 7 34 12 16 43 63 77 38 71 54 22 39 35 13 17 44 64 78 59 8 23 46 66 80 55 72 39 33 5 51 37 14 18 45 65 79 61 10 25 48 68 82 62 11 74 51 57 73 50 60 36 9 24 47 67 81 h20 22 28 31 34 37 42 52 53 56 57 76 84H 12 19 23 27H2 1 11H3 H15 63 64 65 66 67 68 69 71 72 73 74 77 78 79 80 81 82 83 85 86 1H2 q 3 p 3 YKey GTSMWDDKWYUXGH UHFFFAOYSA K Y N Y what is this verify Side effects are generally few 3 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 7 Hydroxocobalamin was first isolated in 1949 8 It is on the World Health Organization s List of Essential Medicines 9 Hydroxocobalamin is available as a generic medication 3 Commercially it is made using one of a number of types of bacteria 10 Contents 1 Medical uses 1 1 Vitamin B12 deficiency 1 2 Cyanide poisoning 1 3 Injectable hydroxocobalamin 2 Side effects 3 Properties 4 Mechanism of action 5 See also 6 References 7 External linksMedical uses Edit Hydroxocobalamin at standard conditions is a solid composed of dark red crystals Hydroxocobalamin injection USP 1000 mg mL is a clear red liquid solution Shown is 500 mg B 12 prepared for subcutaneous injection Vitamin B12 deficiency Edit Standard therapy for treatment of vitamin B12 deficiency has been intramuscular IM or intravenous IV injections of hydroxocobalamin OHCbl since the majority of cases are due to malabsorption by the enteral route gut 11 It is used 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 12 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 mg 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 citation needed Cyanide poisoning Edit Hydroxocobalamin is first line therapy for people with cyanide poisoning 3 Hydroxocobalamin converts cyanide to the much less toxic cyanocobalamin Cyanocobalamin is renally cleared The use of hydroxocobalamin became first line due to its low adverse risk profile rapid onset of action and ease of use in the prehospital setting 13 Injectable hydroxocobalamin 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 Dietary deficiency of vitamin B12 occurring in strict vegetarians and in their breastfed infants isolated vitamin B12 deficiency is very rare Malabsorption of vitamin B12 resulting from damage to the stomach where intrinsic factor is secreted or damage to the ileum where intrinsic factor facilitates vitamin B12 absorption These conditions include tropical sprue and nontropical sprue celiac disease Inadequate secretion of intrinsic factor resulting from lesions that destroy the gastric mucosa which can be caused by ingestion of corrosives extensive tumors and conditions associated with gastric atrophy such as multiple sclerosis certain endocrine disorders iron deficiency and subtotal gastrectomy Structural lesions leading to vitamin B12 deficiency including regional ileitis ileal reactions and malignancies Competition for vitamin B12 by intestinal parasites or bacteria The tapeworm from undercooked fish Diphyllobothrium latum absorbs huge quantities of vitamin B12 and infested patients often have associated gastric atrophy The blind loop syndrome may produce deficiency of vitamin B12 or folate Inadequate use of vitamin B12 which may occur if antimetabolites for the vitamin are employed in the treatment of neoplasiaPernicious anemia is the most common cause of vitamin B12 deficiency 14 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 Side effects EditThe 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 15 16 The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning The drug causes a reddish discoloration of the urine chromaturia which can look like blood in the urine 17 Properties EditHydroxocobalamin acetate occurs as odorless dark red orthorhombic crystals 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 Mechanism of action EditVitamin 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 the mitochondrial methylmalonyl CoA mutase conversion of methylmalonic acid MMA to succinate which links lipid and carbohydrate metabolism and the activation of methionine synthase which is the rate limiting step in the synthesis of methionine from homocysteine and 5 methyltetrahydrofolate 18 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 18 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 18 19 Intracellular vitamin B12 is maintained in two active coenzymes methylcobalamin and 5 deoxyadenosylcobalamin 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 20 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 Medicine portalMethylcobalamin Cyanocobalamin Adenosylcobalamin Vitamin B12 Cobalamin biosynthesis Nitric oxideReferences Edit a b Hydroxocobalamin Use During Pregnancy Drugs com www drugs com Archived from the original on 1 January 2017 Retrieved 30 December 2016 a b World Health Organization 2009 Stuart MC Kouimtzi M Hill SR eds WHO Model Formulary 2008 World Health Organization p 251 hdl 10665 44053 ISBN 9789241547659 a b c d e f Vitamin B12 The American Society of Health System Pharmacists Archived from the original on 30 December 2016 Retrieved 8 December 2016 MacLennan L Moiemen N February 2015 Management of cyanide toxicity in patients with burns Burns 41 1 18 24 doi 10 1016 j burns 2014 06 001 PMID 24994676 Hydroxocobalamin 1mg in 1ml solution for injection Summary of Product Characteristics SPC eMC www medicines org uk Archived from the original on 30 December 2016 Retrieved 30 December 2016 Bullock S Manias E 2013 Fundamentals of Pharmacology Pearson Higher Education AU p 862 ISBN 9781442564411 Archived from the original on 2016 12 31 a b Office of Dietary Supplements Dietary Supplement Fact Sheet Vitamin B12 ods od nih gov 11 February 2016 Archived from the original on 31 December 2016 Retrieved 30 December 2016 Eitenmiller RR Landen WO 2010 Vitamin Analysis for the Health and Food Sciences CRC Press p 467 ISBN 9781420050165 Archived from the original on 2016 12 31 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO Vitamins 6 B Vitamins Ullmann s encyclopedia of industrial chemistry Weinheim Wiley VCH 2011 ISBN 9783527303854 Thakkar K Billa G January 2015 Treatment of vitamin B12 deficiency methylcobalamine Cyancobalamine Hydroxocobalamin clearing the confusion European Journal of Clinical Nutrition 69 1 1 2 doi 10 1038 ejcn 2014 165 PMID 25117994 Carethers M March 1988 Diagnosing vitamin B12 deficiency a common geriatric disorder Geriatrics 43 3 89 94 105 7 111 2 PMID 3277892 Shepherd G Velez LI May 2008 Role of hydroxocobalamin in acute cyanide poisoning PDF The Annals of Pharmacotherapy 42 5 661 9 doi 10 1345 aph 1K559 PMID 18397973 S2CID 24097516 Qudsiya Zainab De Jesus Orlando 2022 Subacute Combined Degeneration of the Spinal Cord StatPearls StatPearls Publishing PMID 32644742 Forsyth JC Mueller PD Becker CE Osterloh J Benowitz NL Rumack BH Hall AH 1993 Hydroxocobalamin as a cyanide antidote safety efficacy and pharmacokinetics in heavily smoking normal volunteers Journal of Toxicology Clinical Toxicology 31 2 277 94 doi 10 3109 15563659309000395 PMID 8492341 Riou B Berdeaux A Pussard E Giudicelli JF 1993 Comparison of the hemodynamic effects of hydroxocobalamin and cobalt edetate at equipotent cyanide antidotal doses in conscious dogs Intensive Care Medicine 19 1 26 32 doi 10 1007 BF01709274 PMID 8440794 S2CID 19462753 Koratala A Chamarthi G Segal MS June 2018 Not all that is red is blood a curious case of chromaturia Clinical Case Reports 6 6 1179 1180 doi 10 1002 ccr3 1514 PMC 5986001 PMID 29881591 a b c Katzung 1989 full citation needed Hardman 2001 full citation needed Lindenbaum et al 1994 full citation needed External links EditHydroxocobalamin in the ChEBI database Hydroxocobalamin Drug Information Portal U S National Library of Medicine Retrieved from https en wikipedia org w index php title Hydroxocobalamin amp oldid 1101061874, wikipedia, wiki, book, books, library,
