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Pharmacology: Pharmacodynamics: Mechanism of Action: THIAMINE HYDROCHLORIDE BP: Thiamine Hydrochloride is the hydrochloride salt form of thiamine, a vitamin essential for aerobic metabolism, cell growth, transmission of nerve impulses and acetylcholine synthesis. Upon hydrolysis, thiamine hydrochloride is phosphorylated by thiamine diphosphokinase to form active thiamine pyrophosphate (TPP), also known as cocarboxylase.
RIBOFLAVIN SODIUM PHOSPHATE BP: Riboflavin Sodium Phosphate the phosphate sodium salt form of riboflavin, a water-soluble and essential micronutrient that is the principal growth-promoting factor in naturally occurring vitamin B complexes. Riboflavin phosphate sodium is converted to 2 coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are necessary for energy production by aiding in the metabolism of fats, carbohydrates and proteins and are required for red blood cell formation and respiration, antibody production and for regulating human growth and reproduction. Riboflavin phosphate sodium is essential for healthy skin, nails and hair growth.
CYANOCOBALAMIN BP: MECHANISM OF ACTION: Vitamin B12 is a generic term for several cobalt-containing compounds, designated cobalamins, which consist of a macrocyclic tetrapyrrole group (corrin nucleus) linked to a dimethylbenzimidazolyl nucleotide. A variable R group attached to the central cobalt atom determines the type of vitamin B12 congener (cyano group in cyanocobalamin, hydroxy group in hydroxocobalamin, methyl group in methylcobalamin, deoxyadenosyl group in deoxyadenosylcobalamin).
Both vitamin B12 and folic acid are required for synthesis of purine nucleotides and metabolism of some amino acids. Each are essential for normal growth and replication.
A deficiency of either vitamin B12 or folate results in defective DNA synthesis and cellular maturation abnormalities; changes are most evident in tissues with high rates of cell turnover, such as the hematopoietic system. Cyanocobalamin and hydroxocobalamin are the pharmaceutical forms of vitamin B12 used clinically to treat vitamin B12 deficiency as they are stable during storage). After losing its cyanide adduct, cyanocobalamin is equally as active as hydroxocobalamin. The 2 active intracellular coenzyme forms of vitamin B12 are methylcobalamin and deoxyadenosylcobalamin, which are synthesized in vivo from hydroxocobalamin (or cyanocobalamin); the primary cobalamin present in plasma is methycobalamin. Only small amounts of cyanocobalamin are normally present in plasma, although higher concentrations of this form have been detectable in certain conditions (eg, patients with optic neuropathies, inborn errors of cobalamin metabolism, pernicious anemia). Conversion of hydroxocobalamin to cyanocobalamin has been observed as a result of cyanide release during sodium nitroprusside therapy. The ability of hydroxocobalamin to act as a cyanide antidote, by formation of readily excreted cyanocobalamin, has led to the use of hydroxocobalamin in cyanide poisoning and other cyanide-related disorders (eg, Leber's optic atrophy).
In the UK, hydroxocobalamin is the drug of choice for vitamin B12 deficiency because it binds more firmly to plasma proteins and is retained in the body longer. However, in the USA, cyanocobalamin is preferred because administration of hydroxocobalamin has resulted in the formation of antibodies to the transcobalamin II-vitamin B(12) complex in some patients.
LYSINE HYDROCHLORIDE USP: Lysine improves calcium assimilation. Lysine exerts antagonistic actions against arginine via several proposed mechanisms: serving as an antimetabolite of arginine, enhancing the excretion of arginine by competing for reabsorption at the renal tubule, competing for intestinal absorption, inducing arginase to breakdown arginine, and competing for transport into cells. Lysine supplementation may enhance protein nutrition to boost the immune response. Thus, to prevent and treat herpes simplex infections, increasing the intake of lysine and/or lysine-to-arginine may be beneficial.
Cardiovascular effects: Lysine may exert positive cardiovascular effects by blocking a lysine-binding domain on lipoprotein(a). Additionally, lysine can cause vasodilation.
Calcium absorption and osteoporosis: Lysine has been investigated for use in osteoporosis. Specifically, lysine increases the intestinal absorption and reduces the renal elimination of calcium. Additionally, lysine plays a role in the cross-linking process of bone collagen.
Anxiolytic effects: Lysine is believed to exert anxiolytic effects by acting as a partial serotonin receptor 4 antagonist and as a partial benzodiazepine agonist.
Effects on muscle mass: Lysine in combination with other targeted nutritional supplements has been evaluated for its effects on age-associated changes in muscle mass, protein metabolism, and functionality in elderly patients.
PYRIDOXINE HYDROCHLORIDE BP: Pyridoxine Hydrochloride is water-soluble and used in the prophylaxis and treatment of vitamin B6 deficiency and peripheral neuropathy in those receiving isoniazid (isonicotinic acid hydrazide, INH). It has been found to lower systolic and diastolic blood pressure in a small group of subjects with essential hypertension. Human studies have demonstrated that vitamin B6 deficiency affects cellular and humoral responses of the immune system. Vitamin B6 deficiency results in altered lymphocyte differentiation and maturation, reduced delayed-type hypersensitivity (DTH) responses, impaired antibody production, decreased lymphocyte proliferation and decreased interleukin (IL)-2 production, among other immunologic activities.
NICOTINAMIDE BP: MECHANISM OF ACTION: The use of niacin in the treatment of hyperlipoproteinemia is based on its ability to reduce serum lipids. Several possible modes of action have been proposed including, inhibition of hepatic synthesis of lipoproteins containing apolipoprotein B-100; promotion of lipoprotein lipase activity, and reduction of free fatty acid mobilization from adipose tissue with an increase in fecal output of sterols. Niacin also has a vasodilation effect when administered in large doses, identified by flushing of the skin while plasma niacin levels are rising. The normal, physiologic role of niacin is as a component of the coenzymes NAD and NADP which are essential for oxidation-reduction reactions in tissue respiration. Niacin is thought to counteract the effect of enterotoxins, as in cholera, by suppressing the action of camp key messenger involved in secretory stimulation in the intestinal mucosa. Nicotinamide, a metabolite of niacin, possesses similar function as a vitamin but has no pharmacological value in reducing lipids.
Pharmacokinetics: THIAMINE HYDROCHLORIDE BP: ABSORPTION: Thiamine is a water-soluble vitamin. It is absorbed by both diffusion and active transport mechanisms. Absorption following IM administration is rapid and complete.
DISTRIBUTION: Thiamine is widely distributed in all tissues, with highest concentrations in liver, brain, kidney, and heart. When thiamine intake exceeds needs, tissue stores increase more than 2 to 3 times. If intake is insufficient, tissues become depleted of their vitamin content.
METABOLISM: Thiamine undergoes rapid metabolism. Thiamine + ATP → thiamine pyrophosphate (cocarboxylase) coenzyme.
ELIMINATION: Excess thiamine is excreted in urine. Depletion of vitamin B1 occurs about 3 wk with absence of thiamine in diet.
RIBOFLAVIN SODIUM PHOSPHATE BP.
PYRIDOXINE HYDROCHLORIDE BP: ABSORPTION: BIOAVAILABILITY: Readily absorbed from the GI tract.
DISTRIBUTION: Stored mainly in liver with lesser amounts in muscle and brain.
Crosses the placenta; plasma concentrations in the fetus 5 times greater than maternal plasma concentrations. Distributed into milk.
Plasma Protein Binding.
Highly protein bound.
METABOLISM: Metabolized to 4-pyridoxic acid in the liver.
ELIMINATION ROUTE: Metabolite excreted in urine.
NICOTINAMIDE BP: ABSORPTION: Bioavailability: Oral, extended release: 60% to 76%.
According to single-dose bioavailability studies, niacin extended-release 500 milligram (mg) and 1000 mg tablets are dosage form equivalent, meaning, two 500 mg extended-release tablets are equivalent to one 1000 mg extended-release tablet. The 750-mg extended-release tablets are not dosage form equivalent.
Effects of Food: Food minimizes gastrointestinal upset: Administration with a low-fat meal or snack is recommended.
METABOLISM: Metabolism Sites and Kinetics: Liver, rapid (Prod Info NIASPAN(R), 2005).
Metabolites: Nicotinamide adenine dinucleotide (NAD), active (Prod Info NIASPAN(R), 2005).
Nicotinamide, inactive (Prod Info NIASPAN(R), 2005).
Nicotinuric acid, inactive (Prod Info NIASPAN(R), 2005).
EXCRETION: Kidney: Renal Excretion (%): 60% to 76% (Prod Info NIASPAN(R), 2005).
LYSINE HYDROCHLORIDE USP: Oral administration is the preferred route for lysine supplementation. Upon ingestion, it is absorbed from the lumen of the small intestine into the enterocytes via active transport and moves from the gut to the liver via the portal circulation. Once in the liver, lysine joins other amino acids to facilitate protein synthesis. Catabolism of lysine also occurs in the liver, where it undergoes condensation with ketoglutarate to form saccharopine. Saccharopine is converted to L-alpha-aminoadipic acid semialdehyde, which eventually becomes acetoacetyl-CoA. Unlike other amino acids, lysine does not undergo transamination. Lysine is both glycogenic and ketogenic, and thus can aid in the formation of D-glucose, glycogen, lipids, and consequently energy production. Human absorption studies have demonstrated lysine supplements have absorption rates similar to those from digestion of proteins, suggesting supplementation is an effective and efficient means of correcting a dietary lysine deficiency. Lysine is rapidly transported into muscle tissue, within 5-7 hours after ingestion, and is more concentrated in the intracellular space of muscle tissue compared to other essential amino acids. This suggests that muscle may serve as a reservoir for free lysine in the body. Lysine is the most strongly conserved of the essential amino acids.
CYANOCOBALAMIN BP: ONSET AND DURATION: ONSET: INITIAL RESPONSE: Megaloblastic anemia, intramuscular: 8 hours.
Conversion of megaloblastic to normoblastic erythroid hyperplasia within the bone marrow is evident within 8 hours of an intramuscular cyanocobalamin dose in patients with megaloblastic anemia. An increase in reticulocytes usually begins after 2 to 5 days of therapy, followed by rises in hemoglobin, hematocrit, and erythrocyte count.
Psychiatric sequelae of vitamin B12 deficiency: 24 hours.
Psychiatric sequelae of vitamin B12 deficiency may subside within 24 hours of initiation of therapy, while neurologic complications require substantially longer periods (several months); in patients with long-standing neurologic sequelae (months to years) prior to therapy, damage may be irreversible.
Thrombocytopenia: 10 days.
Leukopenia: 2 weeks.
DURATION: MULTIPLE DOSE: Vitamin B12 deficiency, intramuscular: 2 to 4 weeks.
Serum vitamin B12 levels are maintained above 200 pg/mL in most patients with intramuscular cyanocobalamin doses of 100 mcg every 2 to 4 weeks.
Slower rates of decline in vitamin B12 serum levels have been reported with hydroxocobalamin as compared with cyanocobalamin with equivalent parenteral doses (AMA, 1991; Chalmers & Shinton, 1965; Glass et al, 1963). However, in other reports, reductions in plasma concentration of vitamin B12 over a 10- to 30-day period have been similar with each preparation.
A depot cyanocobalamin formulation (cyanocobalamin-tannate complex in sesame oil; Betolvex(R)) is available in some countries and has been effective in maintaining adequate vitamin B12 levels when administered every 2 to 3 months.
Pernicious anemia, parenteral: 6 months to 5 years.
The wide range in time to relapse is attributed to variability in the period required to deplete liver stores of vitamin B12. Because low serum vitamin B12 levels can precede relapse for several years in pernicious anemia, without evidence of deleterious effects, some investigators have suggested a longer interval between injections of cyanocobalamin.
DRUG CONCENTRATION LEVELS: THERAPEUTIC: THERAPEUTIC DRUG CONCENTRATION: Healthy adult, 200 to 900 pg/mL.
Intramuscular doses of cyanocobalamin 100 mcg every 2 to 4 weeks are adequate to maintain therapeutic plasma levels of vitamin B12 (greater than 200 pg/mL).
Serum vitamin B12 levels following administration of intramuscular hydroxocobalamin have been higher than those achieved with equivalent doses of cyanocobalamin. However, this is of doubtful significance clinically. Recommended maintenance doses of cyanocobalamin and hydroxocobalamin are similar.
Total vitamin B12 levels refer to methylcobalamin, adenosylcobalamin, hydroxocobalamin, and cyanocobalamin.
Limited evidence suggests that increases in serum cyanocobalamin concentrations following a single 400 mg intranasal dose of Ener-B(R) (intranasal cyanocobalamin gel formulation) are similar to those achieved after a single dose of intramuscular cyanocobalamin 100 mcg.
TIME TO PEAK CONCENTRATION: Intramuscular, injection: 30 minutes to 2 hours.
Subcutaneous, injection: 30 minutes to 2 hours.
ADME: ABSORPTION: BIOAVAILABILITY (F): Oral, tablet: poor.
The presence of intrinsic factor, calcium and the proper pH influence the absorption of vitamin B12. Binding to intrinsic factor occurs during passage through the gastrointestinal tract, and the intrinsic factor-vitamin B12 complex is absorbed in the ileum in the presence of calcium. Intrinsic factor, bile, and sodium bicarbonate are required for ileal transport of vitamin B12.
Small amounts of vitamin B12 can also be absorbed independent of intrinsic factor via simple diffusion.
The average US diet supplies 5 to 30 micrograms of vitamin B12 daily, of which 1 to 5 micrograms is absorbed in the presence of gastric intrinsic factor.
In the absence of intrinsic factor (pernicious anemia), large oral doses of cyanocobalamin (1000 mcg or more) have been effective in achieving therapeutic vitamin B12 plasma levels as sufficient vitamin is absorbed via passive diffusion. The oral bioavailability of cyanocobalamin in pernicious anemia is reportedly 1.2%
DISTRIBUTION: DISTRIBUTION SITES: Vitamin B12 binds in plasma to transcobalamin II, a beta-globulin, and this complex is transported to tissues (Donaldson et al, 1977; Gilman et al, 1990). Hydroxocobalamin is more tightly bound than cyanocobalamin.
OTHER DISTRIBUTION SITES: LIVER, 90%: Preferential distribution to hepatic parenchymal cells is observed, and the liver serves as a storage site for other tissues. Up to 90% of body stores are in the liver (1 to 10 mg), where the vitamin is stored as the active coenzyme with a turnover rate of 0.5 to 8 micrograms daily.
TISSUES: Vitamin B12 bound to transcobalamin II is rapidly cleared from plasma and transported to tissues (liver, bone marrow, endocrine glands, kidney).
EXCRETION: BREAST MILK: BREASTFEEDING: Safe.
Vitamin B12 is excreted into breast milk, and megaloblastic anemia has been described in some infants breast-fed by vitamin B12-deficient mothers; many of the mothers were vegetarians. Supplementation of the diet with vitamin B12 should be considered during lactation in vegetarians.
For breast-feeding women with adequate nutritional intake, dietary supplementation is not necessary.
KIDNEY: RENAL EXCRETION: 50% to 98%.
Between 50% and 98% of an intramuscular or subcutaneous dose (100 to 1000 mcg) of cyanocobalamin is excreted unchanged in the urine, most within the first 8 hours post injection.
Doses higher than 100 mcg will not result in greater retention of the vitamin, although stores may be replenished more quickly. Renal clearance is more rapid with intravenous administration.
OTHER EXCRETION: BILE: Between 1 and 3 mcg of vitamin B12 is excreted daily in the bile. Up to 50% of this amount is reabsorbed, establishing an enterohepatic recirculation of the vitamin. In patients with pernicious anemia (or following total gastrectomy), enterohepatic recirculation is impaired due to lack of intrinsic factor which results in continuous depletion of hepatic stores of vitamin B12.]
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
