VA Class:VT400
ATC Class:A11GA01
Ascorbic acid is the functional and principal in vivo form of vitamin C,109 an essential water-soluble vitamin.
Ascorbic acid is used to prevent and to treat scurvy. Scurvy may be treated with dietary vitamin C; however, administration of therapeutic doses of ascorbic acid probably results in more prompt saturation of tissue stores. Whenever possible, poor dietary habits should be corrected, and many clinicians recommend administration of multivitamin preparations containing ascorbic acid in patients with vitamin deficiencies since poor dietary habits often result in concurrent deficiencies. (See Multivitamins 88:28.)
The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.109 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).109 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).109
The NAS has established an EAR and RDA for vitamin C for adults based on near maximal neutrophil concentrations with minimal urinary excretion of ascorbate; in addition, the determination of an EAR for the vitamin corresponds to the amount estimated to provide antioxidant protection.109 Because evidence currently available on the role of vitamin C in reducing oxidative damage to DNA and chromosomes, or on immune function studies, collagen-related measures, measures of carnitine status, oral health end points, or protective effects (e.g., protection against cardiovascular disease, cancer, cataracts, asthma or pulmonary disease, the common cold) is limited, the NAS did not use reduction of oxidative damage, measures of immune function, collagen, carnitine, or oral health, or risk reduction as a basis for setting the EAR or RDA.109 The EAR and RDA for children and adolescents 1-18 years of age were established based on data in adults, since specific data in children and adolescents currently are unavailable.109 An AI has been set for infants through 6 months of age based on the observed mean vitamin C intake of infants fed principally human milk.109 An AI for infants 7-12 months of age has been set based on the observed mean vitamin C intake from human milk and from solid food.109 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)
The principal goal of maintaining an adequate intake of vitamin C in the US is to prevent scurvy and to provide antioxidant protection.109 In industrialized countries, vitamin C deficiency generally is associated with consumption of few fruits and vegetables, peculiar or restricted diets, or high alcohol or drug consumption.109 Adequate intake of vitamin C generally can be accomplished through consumption of food stuffs.109 In the US, about 90% of dietary vitamin C is obtained from fruits and vegetables, principally citrus fruits, tomatoes, and potatoes.109 Other dietary sources include brussel sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach.109 Vitamin C also is added to certain processed foods as an antioxidant.109 Patients receiving long-term parenteral nutrition or chronic hemodialysis should receive supplemental vitamin C.
Some clinicians have recommended high-dose antioxidant supplements containing ascorbic acid, beta carotene, and vitamin E supplements with zinc in high-risk patients with age-related macular degeneration†.111, 112 This recommendation is based on results of a randomized, placebo-controlled study in adults 55-80 years of age with age-related macular degeneration who received a high-dose antioxidant vitamin supplement (ascorbic acid 500 mg, vitamin E 400 units, beta carotene 15 mg) daily, zinc 80 mg (as zinc oxide) daily (with copper 2 mg [as cupric oxide] daily to prevent potential anemia), high-dose antioxidant vitamin supplement plus zinc, or placebo for about 6.3 years.111, 112 Although patients in all treatment groups continued to progress toward advanced age-related macular degeneration and lost vision over the study period, results indicated that administration of zinc or high-dose antioxidant vitamin supplement plus zinc lowered the risk of developing advanced age-related macular degeneration in high-risk patients (i.e., those with intermediate stage age-related macular degeneration or advanced stage macular degeneration in only one eye).111, 112 In addition, administration of high-dose antioxidant vitamin supplement plus zinc reduced the risk of visual acuity loss caused by advanced age-related macular degeneration in high-risk patients 111 Administration of a high-dose antioxidant vitamin supplement, zinc, or high-dose antioxidant vitamin supplement plus zinc did not delay progression of age-related macular degeneration in adults with early disease.111, 112 However, patients in these groups had a lower incidence of developing advanced age-related macular degeneration during the study period, and it is not known whether longer-term (e.g., 10-20 years) supplementation with high-dose antioxidant vitamins and zinc would be effective in these patients.111, 112 Based on results of this study, some clinicians suggest that adults with extensive intermediate size drusen, at least one large drusen, noncentral geographic atrophy in one or both eyes, or advanced age-related macular degeneration or vision loss due to macular degeneration in one eye should consider taking a vitamin and zinc supplement similar to the one evaluated in this study.111, 112 Because beta carotene has been associated with an increased incidence of lung cancer in smokers, these individuals may choose a vitamin and zinc supplement with only some of the ingredients used in this study.111
Large doses of ascorbic acid have been advocated for lessening the severity of and for preventing the common cold†. Routine supplementation with ascorbic acid modestly decreases the duration of common cold symptoms; it also appears to decrease the incidence in individuals under heavy physical stress but not in the overall population.202, 203, 211 While fewer studies of ascorbic acid have been conducted in the treatment setting, no consistent effect on the duration or severity of common cold symptoms has been observed with high-dose ascorbic acid therapy initiated following symptom onset.202, 211
Limited study data are available regarding effects of ascorbic acid in the prevention or treatment of pneumonia†; available studies were conducted under specific circumstances and the results may not be applicable to the general population.202, 203 Studies also are required to establish efficacy of adjunctive ascorbic acid therapy in the treatment of severe viral respiratory infections†.206
High-dose IV ascorbic acid therapy has been evaluated in patients with sepsis†;204, 208, 209, 210 however, efficacy remains to be established.209, 210, 212, 213 Theoretical reasons for studying ascorbic acid as adjunctive therapy in the treatment of sepsis include observations that vitamin C is deficient in patients with sepsis, plasma concentrations of vitamin C in early sepsis are inversely correlated with measures of multiorgan dysfunction, vitamin C plays a critical role in many physiologic processes that are altered in patients with sepsis, and vitamin C may support host defenses against infection and protect host cells against infection-induced oxidative stress.204, 205, 212 While a meta-analysis of several small studies suggested beneficial effects from adjunctive IV ascorbic acid therapy in patients with sepsis, primary efficacy end points were not improved in 2 subsequent multicenter, randomized studies.208, 209, 210 Additional studies are under way.204, 213
In the CITRIS-ALI study, a randomized, double-blind, placebo-controlled, multicenter study in 167 mechanically ventilated adults with sepsis and acute respiratory distress syndrome (ARDS) of less than 24 hours' duration, high-dose ascorbic acid therapy (50 mg/kg by IV infusion every 6 hours for 96 hours) failed to improve measures of organ dysfunction or alter markers of inflammation and vascular injury compared with placebo.209 Assessments were based on modified Sequential Organ Failure Assessment (mSOFA) scores (range of 0 [normal organ function] to 20 [worst organ function]) at 96 hours and plasma concentrations of C-reactive protein and thrombomodulin at 168 hours.209 The reduction in mean mSOFA score from baseline to 96 hours was 3 points in patients receiving ascorbic acid (from 9.8 to 6.8) and 3.5 points in those receiving placebo (from 10.3 to 6.8).209 Plasma concentrations of C-reactive protein and thrombomodulin at 168 hours also did not differ between the 2 groups.209 Of 46 exploratory secondary outcomes, 43 showed no statistically significant difference between patients receiving ascorbic acid and those receiving placebo.209
In the VITAMINS study, a randomized, open-label, multicenter study in 216 patients with septic shock enrolled within 24 hours of diagnosis, treatment with ascorbic acid in conjunction with hydrocortisone and thiamine failed to prolong the time alive and free of vasopressor support during the initial 168-hour period following randomization compared with hydrocortisone alone (median 122.1 versus 124.6 hours, respectively).210 Patients in the intervention group received ascorbic acid (1.5 g IV every 6 hours), hydrocortisone (50 mg IV every 6 hours), and thiamine (200 mg IV every 12 hours) while those in the control group received hydrocortisone alone until shock resolution or for up to 10 days.210 Of 10 exploratory secondary outcomes, 9 showed no statistically significant difference between patients receiving ascorbic acid in conjunction with hydrocortisone and thiamine and those receiving hydrocortisone alone.210
Ascorbic acid has been used as a urinary acidifier although its efficacy has been questioned. Ascorbic acid may be useful in correcting tyrosinemia in premature infants on high-protein diets. The drug may also be useful to treat idiopathic methemoglobinemia, although it is less effective than methylene blue. Limited evidence indicates that ascorbic acid administered during deferoxamine therapy increases iron excretion more than deferoxamine alone. Ascorbic acid is used as an antioxidant in formulations of injectable doxycycline and other drugs.
Although ascorbic acid has not been shown by well-controlled trials to have therapeutic value, it has been prescribed for hematuria, retinal hemorrhages, hemorrhagic states, dental caries, pyorrhea, gum infections, anemia, acne, infertility, atherosclerosis, mental depression, peptic ulcer, tuberculosis, dysentery, collagen disorders, cancer, osteogenesis imperfecta, fractures, leg ulcers, pressure sores, physical endurance, hay fever, heat prostration, vascular thrombosis prevention, levodopa toxicity, succinylcholine toxicity, arsenic toxicity, and as a mucolytic agent.
Ascorbic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.
In adults with scurvy, as little as 10 mg of ascorbic acid daily will result in complete improvement; however, this amount may not provide optimum health over long periods of time. In adults, oral or parenteral administration of 100-250 mg of ascorbic acid 1-2 times daily for several days will reverse the skeletal changes and hemorrhagic disorders associated with scurvy within 2 days to 3 weeks. Although much larger doses have been recommended, there is no evidence that they offer any advantage. In infants and children with scurvy, oral or parenteral administration of 100-300 mg of ascorbic acid daily in divided doses for several days results in rapid recovery.
Dietary and Replacement Requirements
The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin C currently recommended by the National Academy of Sciences (NAS) for healthy infants through 6 months of age is 40 mg (about 6 mg/kg) daily and for those 7-12 months of age is 50 mg (about 6 mg/kg) daily.109 The Recommended Dietary Allowance (RDA) of vitamin C currently recommended by NAS for healthy children 1-3 or 4-8 years of age is 15 or 25 mg daily, respectively.109 In establishing the vitamin C dietary requirement for individuals 14 years of age or older, the NAS considered the requirement to be lower in females than in males, based on the water-soluble nature of the vitamin and larger lean body mass and total body water in males relative to females.109 The RDA of vitamin C for boys 9-13 or 14-18 years of age is 45 or 75 mg daily, respectively, and the RDA for girls 9-13 or 14-18 years of age is 45 or 65 mg daily, respectively.109 The RDA for healthy men 19-50 years of age and 51 years of age and older is 90 mg of vitamin C daily and that for healthy women in these age groups is 75 mg of vitamin C daily.109
These RDAs are not expected to be sufficient to meet the needs of individuals who smoke.109 Because smoking increases oxidative stress and metabolic turnover of vitamin C, the requirement for those who smoke is increased by 35 mg daily.109 Like mainstream smoke, environmental or sidestream tobacco smoke appears to result in oxidative damage.109 While data are insufficient to estimate a special requirement for nonsmokers regularly exposed to tobacco smoke, these individuals are advised to ensure that they meet the RDA for vitamin C.109
The role of ascorbate as a cofactor for biosynthesis of carnitine, steroid hormones, and neurotransmitters provides a theoretical basis for increased vitamin C requirements in individuals under excessive physical and emotional stress.109 Studies of vitamin C status and physical activity have shown mixed results, and no definitive conclusions can be made regarding vitamin C requirements and exercise.109
During pregnancy, additional vitamin C is needed to transfer adequate amounts of the vitamin to the fetus since maternal plasma concentrations of the vitamin decrease with pregnancy progression secondary to hemodilution and fetal transfer.109 The RDA of vitamin C recommended by the NAS for pregnant women 14-18 or 19-50 years of age is 80 or 85 mg daily, respectively.109 To ensure an adequate concentration of vitamin C in milk, the NAS recommends an RDA of 115 or 120 mg of vitamin C daily for lactating women 14-18 or 19-50 years of age, respectively.109
Nutritional Status Saturation Test
To determine vitamin C nutritional status using a saturation test, ascorbic acid 11 mg/kg is given orally, and urinary excretion of ascorbate is measured for 24 hours. Excretion of less than 20% of the dose over 24 hours suggests vitamin C deficiency; normal subjects excrete more than 50% of the dose.
To reduce the risk of advanced age-related macular degeneration† in patients at high risk, some clinicians recommend ascorbic acid dosages of 500 mg daily in combination with beta carotene 15 mg daily, vitamin E 400 units daily, and zinc (as zinc oxide) 80 mg daily, with copper (as cupric oxide) 2 mg daily (to prevent anemia).111, 112 This recommendation is based on results of a clinical study in adults with age-related macular degeneration which demonstrated beneficial results in high-risk individuals receiving a high-dose antioxidant vitamin supplement and zinc in these dosages.111, 112
Ascorbic acid dosages of 1-3 g or greater per day have been recommended to prevent and to treat the common cold†.
As a urinary acidifying agent in adults, 4-12 g of ascorbic acid daily in divided doses has been recommended. Because of questionable efficacy of the drug for this purpose, urinary pH should be confirmed with pH paper. To reduce tyrosinemia in premature infants on high-protein diets, 100 mg of ascorbic acid per day has been given orally or IM. In idiopathic methemoglobinemia, 300-600 mg of ascorbic acid per day orally in divided doses has been recommended.
To increase iron excretion resulting from deferoxamine administration, 100-200 mg of oral ascorbic acid daily has usually been given during deferoxamine therapy.75, 100, 101, 102, 103, 106, 107 Although higher dosages have been used,73, 74, 104, 105, 106 some clinicians recommend that the smallest ascorbic acid dosage that effectively augments iron excretion should be used since there is some evidence that relatively high dosages (e.g., 500 mg or more daily) may adversely affect cardiac function during deferoxamine therapy.104, 105
Ascorbic acid is usually nontoxic; however, nausea, vomiting, heartburn, abdominal cramps, fatigue, flushing, headache, insomnia, and sleepiness have been reported.
GI disturbances are the most common adverse effects associated with high vitamin C intake (e.g., 3 g or more daily).109 Diarrhea may occur after oral dosage of 1 g daily or greater. Other GI disturbances associated with high vitamin C intake include nausea, abdominal cramps, transient colic, and flatulent distention.109 Such GI disturbances have been attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine that occurs with relatively high dosages; intestinal absorption of ascorbic acid is a saturable process.109
Ascorbic acid may cause acidification of the urine, precipitation of urate, cystine, or oxalate stones, or drugs in the urinary tract. However, reports of kidney stone formation associated with large dosages of ascorbic acid reportedly have been limited to individuals with preexisting renal disease, and data from epidemiologic studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals.109 A cohort study of 45,000 men aged 40-70 years with no history of renal calculi showed that vitamin C intake was not significantly associated with the risk of stone formation; in addition, vitamin C intake was not associated with kidney stone formation in women.109
About 5% of individuals have been reported to develop hyperoxaluria after large doses of ascorbic acid. However, controversy currently exists as to whether increased intake of vitamin C can substantially increase urinary excretion of oxalate, resulting in an increased risk of renal calcium oxalate stone formation.109 Findings from studies evaluating the effect of vitamin C intake (300 mg to 10 g daily) on urinary oxalate excretion in apparently healthy individuals are conflicting.109 While an intervention study reported clinically important increases in mean urinary oxalate excretion in 39% of apparently healthy adults receiving 1, 3, 6, or 9 g of ascorbic acid daily, another study reported normal plasma oxalate concentrations in healthy individuals receiving 3-10 g of ascorbic acid daily and no significant change in urinary oxalate excretion in 5 of 6 individuals receiving 10 g over the course of 1 day.109 It has been suggested that the lack of findings supporting an association between vitamin C intake and oxalate excretion may be explained by the limited GI absorption of the vitamin at dosages exceeding 200 mg daily.109 In addition, the large majority of excess absorbed vitamin C is excreted in urine as ascorbic acid rather than as degradation products (e.g., oxalate).109 Large doses of ascorbic acid should be avoided in patients with hyperoxaluria.
Uric acid excretion may be increased by ascorbic acid; 1 g of the vitamin daily reportedly caused no change in serum uric acid concentrations while 8 g daily resulted in decreased serum uric acid. Theoretically, large doses of ascorbic acid could result in gouty arthritis in susceptible individuals and in the formation of uric acid stones (especially in individuals who normally excrete large amounts of uric acid in urine).
Urinary calcium may increase, and urinary sodium may decrease after 3-6 g of ascorbic acid daily. Ascorbic acid reportedly may affect glycogenolysis and may be diabetogenic; however, this is controversial.
Other adverse effects reportedly associated with high vitamin C intake include diminished high-altitude tolerance, delayed-type allergic response, and erosion of dental enamel.109
Transient mild pain may develop at the site of subcutaneous or IM injections of ascorbic acid. Rapid IV administration of the drug may result in temporary faintness or dizziness.
Patients with glucose-6-phosphate dehydrogenase deficiency reportedly have developed hemolysis after large IV or oral doses of ascorbic acid. Rarely, decreased blood pH leading to sickle-cell crisis has been reported in patients with sickle-cell disease. Deep-vein thrombosis has also reportedly occurred after large doses of ascorbic acid.
Serum cholesterol concentrations reportedly decreased in healthy individuals younger than 25 years of age and increased in atherosclerotic patients after administration of 1 g of ascorbic acid daily; however, these reports have been disputed. Doses of 600 mg or greater of ascorbic acid have been reported to have a diuretic action.
Precautions and Contraindications
Prolonged use of large doses of ascorbic acid may result in increased metabolism of the drug (“systemic conditioning”) scurvy may occur when intake of the vitamin is reduced to normal. Ingestion of large doses of the vitamin during pregnancy has resulted in scurvy in neonates.
Although high vitamin C intake does not appear to be associated with a substantial risk of excess iron absorption in apparently healthy individuals, it currently is not known whether individuals with hereditary hemochromatosis could be adversely affected by long-term ingestion of large dosages of the vitamin.109 In addition, the strong prooxidant nature of the iron-ascorbate complex raises concern that consumption of vitamin C supplements by individuals with high iron stores may contribute to oxidative damage in vivo; dietary ascorbic acid also can enhance the intestinal absorption of nonheme iron.109 Concerns about a possible in vivo prooxidant effect of the iron-ascorbate complex were heightened by a report of fatal cardiomyopathy in a patient with hemochromatosis who ingested excessive amounts of vitamin C.109
Each gram of sodium ascorbate contains approximately 5 mEq of sodium; this should be considered when the drug is used in patients on salt-restricted diets.
Hemolysis has been associated with ascorbic acid administration in neonates with glucose-6-phosphate dehydrogenase deficiency and in otherwise healthy premature neonates.109
Mutagenicity and Carcinogenicity
Vitamin C has not been shown to be mutagenic or carcinogenic.109
Concurrent administration of more than 200 mg of ascorbic acid per 30 mg of elemental iron increases absorption of iron from the GI tract; however, most individuals are able to absorb orally ingested iron adequately without concurrent administration of ascorbic acid.
Increased urinary excretion of ascorbic acid and decreased excretion of aspirin occur when the drugs are administered concurrently.
Salicylates inhibit uptake of ascorbic acid by leukocytes and platelets. As a result, leukocyte and plasma concentrations of ascorbic acid are decreased to concentrations slightly higher than those associated with tissue depletion of the vitamin; however, there is no evidence to date that salicylate therapy precipitates ascorbic acid deficiency. Although concomitant administration of ascorbic acid supplements in patients receiving salicylates increases plasma ascorbic acid concentrations, leukocyte ascorbic acid concentrations are not increased and tissue stores of the vitamin may not be increased. Therefore, routine administration of ascorbic acid supplements to patients receiving salicylates is not warranted; however, patients receiving high dosages of salicylates who exhibit any signs or symptoms of ascorbic acid deficiency should be evaluated for such a deficiency.
Ascorbic acid has reportedly decreased the anticoagulant effect of warfarin; however, other investigators have failed to show this effect. Concurrent administration of ascorbic acid and fluphenazine reportedly resulted in decreased fluphenazine plasma concentration. Acidification of the urine following administration of ascorbic acid may result in altered excretion of other drugs.
Because ascorbic acid is a strong reducing agent, it interferes with numerous laboratory tests based on oxidation-reduction reactions. The presence of ascorbic acid in the urine results in false increases in glucose determinations measured by cupric sulfate reagent and false decreases in the concentration of glucose determined by the glucose oxidase method. The degree of interference with other laboratory tests depends on several factors (e.g., the concentration of ascorbic acid, the resulting pH, the specific reagents used). Specialized references should be consulted for specific information on laboratory test interferences caused by ascorbic acid.
Ascorbic acid deficiency results in scurvy. Collagenous structures are primarily affected, and lesions develop in bones and blood vessels. Administration of ascorbic acid completely reverses the symptoms of ascorbic acid deficiency.
Effects on Oxidation-Reduction Reactions
The biologic functions of ascorbic acid are based on its ability to provide reducing equivalents for various biochemical oxidation-reduction reactions.109 The vitamin can reduce most physiologically relevant reactive oxygen species, and as such functions principally as a cofactor for reactions requiring a reduced iron or copper metalloenzyme and as a protective antioxidant that operates in the aqueous phase both intracellularly and extracellularly.109 Both the 1- and 2-electron oxidation products of the vitamin are regenerated readily in vivo both chemically and enzymatically by glutathione-, nicotinamide adenine dinucleotide (NADH)-, and nicotinamide adenine dinucleotide phosphate (NAD-PH)-dependent reductases.109
Vitamin C is an electron donor for at least 8 human enzymes, 3 of which participate in collagen hydroxylation, 2 in carnitine biosynthesis, and 3 in hormone and amino acid biosynthesis.109 The enzymes that participate in hormone and amino acid biosynthesis are dopamine-β-hydroxylase, which is necessary for the biosynthesis of catecholamines (epinephrine and norepinephrine); peptidyl-glycine monooxygenase, which is necessary for amidation of peptide hormones; and 4-hydroxyphenylpyruvatedioxygenase, which is involved in tyrosine metabolism.109 Ascorbate's action with these enzymes involves either monooxygenase or dioxygenase activities.109
Ascorbic acid is thought to work as a cofactor for hydroxylase and oxygenase metalloenzymes by reducing the active metal site, resulting in reactivation of the metal-enzyme complex, or by acting as a co-substrate in the reduction of molecular oxygen.109 The best known of these reactions is the posttranslational hydroxylation of peptide-bound proline and lysine residues during formation of mature collagen.109 Ascorbate is believed to reactivate the enzymes involved in these reactions by reducing the metal sites of prolyl (iron) and lysyl (copper) hydroxylases.109 Ascorbate also may play a role in or influence collagen gene expression, cellular procollagen secretion, and the biosynthesis of connective tissue components other than collagen, including elastin, fibronectin, proteoglycans, bone matrix, and elastin-associated fibrillin.109 The importance of the role of ascorbate in connective tissue synthesis is evident in deterioration of elastic tissue that occurs with scurvy, the clinical ascorbic acid deficiency disease.109
Ascorbic acid also functions as a reducing agent for mixed-function oxidases in the microsomal enzyme system involved in drug metabolism.109 The activity of microsomal drug-metabolizing enzymes and cytochrome P-450 (CYP) enzyme transport is lowered by ascorbate deficiency.109 The vitamin is involved in biosynthesis of corticosteroids and aldosterone and in the microsomal hydroxylation of cholesterol in the conversion of cholesterol to bile acids.109 Ascorbate is required along with iron at 2 steps in the carnitine biosynthetic pathway in reactions similar to those involved in the hydroxylation of proline for collagen synthesis.109 Ascorbic acid also modulates iron absorption, transport, and storage.109
Ascorbic acid is an effective antioxidant secondary to its ability to donate electrons.109 The vitamin readily scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS) (e.g., hydroxyl, peroxyl, superoxide, peroxynitrite, and nitroxide radicals) and singlet oxygen and hypochlorite.109 The 1- and 2-electron oxidation products of ascorbate are relatively nontoxic and readily regenerated by the ubiquitous reductants glutathione and NADH or NAD-PH.109 The relatively high tissue concentrations of ascorbate provide antioxidant protection in various tissues such as the eye (against photolytically generated free-radical damage), neutrophils (against ROS produced during phagocytosis), and semen (against oxidative damage to sperm DNA).109 Ascorbic acid protects against plasma low-density lipoprotein (LDL) oxidation by scavenging ROS in the aqueous phase before they initiate lipid peroxidation and possibly by sparing or regenerating vitamin E.109 Ascorbate also may provide antioxidant protection indirectly by regenerating other biologic antioxidants such as glutathione and α-tocopherol back to their active state.109
Dietary antioxidants are substances found in foods that decrease the adverse effects of reactive species, such as ROS and RNS, on normal physiologic function.109 There is considerable biologic evidence that ROS and RNS can be damaging to cells at high concentrations and this may contribute to cellular dysfunction and disease.109 Because the entire population is exposed to oxidative stresses through oxidative metabolism but only some individuals develop a potentially associated chronic disease, the precise role of oxidative stress on the development of chronic disease currently is unclear.109 Some chronic diseases in which oxidative stresses and damage have been implicated include cancer,109 cardiovascular disease (e.g., coronary atherosclerosis and heart disease [CHD]),109 cataracts,109 and asthma and obstructive pulmonary disease;109 however, there currently is insufficient evidence to clearly establish causal relationships.109
Effects on Cardiovascular Disease
There is substantial support for the role of increased oxidative stress in the pathogenesis of cardiovascular disease, especially evidence that the oxidative modification of LDL and other lipoproteins promotes atherogenesis.109 Oxidized LDL (oxLDL) appears to be atherogenic, and vitamin C has been shown in vitro to inhibit the oxidation of isolated LDL induced by transition metals, free-radical initiators, and activated neutrophils and macrophages.109 Thus, vitamin C clearly functions as an antioxidant in vitro by scavenging aqueous ROS and RNS, which prevents them from attacking LDL.109
Effects on Leukocytes and Inflammation
The presence of vitamin C in leukocytes is especially important because the ROS generated during phagocytosis and neutrophil activation are associated with infectious and inflammatory stresses.109 The high intracellular concentration of ascorbate in leukocytes provides cellular protection against oxidative damage associated with the respiratory burst.109 Ascorbate effectively neutralizes phagocyte-derived oxidants without inhibiting the bacteriocidal activity of the phagosome, and appears to modulate the phagocytic action, blastogenesis, immunoglobulin production, and possibly chemotaxis and adhesiveness of leukocytes.109 The antioxidant activity of ascorbate also may protect against proteolytic damage at inflamed sites such as rheumatoid joints and against oxidant damage from activated neutrophils and other sources in the lung (e.g., in adult respiratory distress syndrome, in smokers, and from ozone).109
There has been substantial interest in a potential protective effect of vitamin C against the common cold.109 While most evidence appears to suggest that megadoses of vitamin C have no clinically important effect on the incidence of the common cold, the vitamin may provide a moderate benefit in terms of the severity and duration of episodes.109 Some have suggested that any impact of vitamin C is slight or limited to certain subgroups of individuals, while others view the accumulated evidence as so incomplete and flawed as to offer no convincing evidence of protective effects, and the NAS concluded that current data are not consistent or specific enough to warrant recommendations for dietary requirements of vitamin C based on findings regarding the common cold.109
There is some evidence that ascorbate may modulate prostaglandin synthesis, exerting bronchodilatory, vasodilatory, and anticlotting effects.109 The vitamin also is involved in the conversion of folic acid to folinic acid, carbohydrate metabolism, synthesis of lipids and proteins, resistance to infections, and cellular respiration.
Ascorbic acid is readily absorbed after oral administration; however, absorption involves an active process and may be limited after very large doses. With usual dietary intake of ascorbic acid (30-180 mg daily), about 70-90% of the amount of vitamin ingested is absorbed.109 At dosages exceeding 1 g daily, absorption decreases to about 50% or less.109 In one study in healthy individuals, only 50% of a single 1.5-g oral dose of ascorbic acid was absorbed. GI absorption of ascorbic acid may be reduced in patients with diarrhea or GI diseases. The oral bioavailability of the vitamin found in foods naturally or in supplements does not appear to differ substantially from that of pure synthetic ascorbic acid.109
Normal plasma concentrations of ascorbic acid are about 10-20 mcg/mL; plasma concentrations below 1-1.5 mcg/mL are associated with scurvy. Although leukocyte concentrations of ascorbic acid appear to be a better reflection of ascorbic acid tissue saturation than are plasma concentrations, they are not commonly measured. Total body stores of ascorbic acid have been estimated to be about 1.5 g with about a 30-45 mg daily turnover. Clinical signs of scurvy usually become evident after 3-5 months of deficient ascorbic acid intake.
Ascorbic acid is widely distributed in body tissues. Large concentrations of the vitamin are found in the liver, leukocytes, platelets, glandular tissues, and the lens of the eye. About 25% of the ascorbic acid in plasma is bound to proteins.
Ascorbic acid crosses the placenta; cord blood concentration are generally 2-4 times the concentration in maternal blood. Ascorbic acid is distributed into milk. Milk of nursing mothers on a normal diet contains 40-70 mcg of the vitamin per mL.
Ascorbic acid is reversibly oxidized to dehydroascorbic acid. Some ascorbic acid is metabolized to inactive compounds including ascorbic acid-2-sulfate and oxalic acid which are excreted in the urine. There is a renal threshold for ascorbic acid of approximately 14 mcg/mL; however, the threshold varies among individuals. When the body is saturated with ascorbic acid and blood concentrations exceed the threshold, unchanged ascorbic acid is excreted in the urine; this provides the basis for an ascorbic acid saturation test for vitamin C nutritional status. (See Dosage and Administration: Dosage.) When tissue saturation and blood concentrations of ascorbic acid are low, administration of the vitamin results in little or no urinary excretion of ascorbic acid. Ascorbic acid is removed by hemodialysis.
Vitamin C is an essential water-soluble vitamin which is present in fresh fruits and vegetables. Citrus fruits are a particularly good source of vitamin C. The term vitamin C refers to both ascorbic acid and dehydroascorbic acid (DHA), since both compounds exhibit antiscorbutic activity.109 Ascorbic acid, the functional and principal in vivo form of the vitamin, is the enolic form of an α-ketolactone.109 The 2 enolic hydrogens present in ascorbic acid give the compound its acid character and provide electrons for its activity as a reductant and antioxidant.109 Its one-electron oxidation product, the ascorbyl radical, readily dismutates to ascorbate and DHA, the 2-electron oxidation products.109 Both the ascorbyl radical and DHA are readily reduced back to ascorbic acid in vivo; however, DHA also can be hydrolyzed irreversibly to 2,3-diketogulonic acid.109 Ascorbic acid contains an asymmetric carbon that allows 2 enantiomeric forms; the L form occurs naturally and the D form (isoascorbic or erythorbic acid) provides antioxidant but little if any antiscorbutic activity.109 Ascorbic acid is synthesized for use as a drug.
Ascorbic acid occurs as white or slightly yellow crystals or powder with an acidic taste and is freely soluble in water and sparingly soluble in alcohol. The drug has pKa values of 4.2 and 11.6. Ascorbic acid injection is a solution of sodium ascorbate or ascorbic acid prepared with the aid of sodium hydroxide, sodium carbonate, or sodium bicarbonate; the injection has a pH of 5.5-7.0.
Calcium ascorbate occurs as a white powder and is very soluble in water.
Ascorbic acid gradually darkens upon exposure to light; however, slight coloration does not impair the therapeutic activity of ascorbic acid injection. Solutions of ascorbic acid are rapidly oxidized in air and in alkaline media; the drug should be protected from air and light. In concentrations greater than 100 mg/mL, ascorbic acid may undergo decomposition with the production of carbon dioxide. Since increased pressure may develop after prolonged storage, ampuls containing ascorbic acid injection should be opened carefully.
Ascorbic acid injection has been reported to be incompatible with many drugs. Compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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