Vitamin A

VITAMIN A

General Monograph,

Vitamin

Pharmacology: The term vitamin A is applied to a number of substances with very similar structure and similar activity. The principal and most active substance is all-trans retinol (vitamin A alcohol). Vitamin A activity is assayed biologically and 1 IU equals 1 USP unit which is equal to 0.3 µg of all-trans retinol or 0.6 g of beta-carotene. One retinol equivalent (RE) is the specific biologic activity of 1 g of all-trans retinol (3.33 IU) or 6 g (10 IU) of beta-carotene.

Derivatives of vitamin A such as tretinoin (all trans-retinoic acid) and isotretinoin (13-cis-retinoic acid) are used in the treatment of acne and certain other skin disorders.

Beta-carotene, retinol and retinal (vitamin A aldehyde) possess effective and reliable vitamin A activity. Exogenous sources of vitamin A are required for growth and bone development, vision, reproduction and maintenance of the integrity of mucosal and epithelial surfaces. Beta-carotene has antioxidant activity. Although some studies have suggested that antioxidants may be beneficial in disease prevention, further studies are required before antioxidant vitamins can be recommended for the prevention of cancer and cardiovascular disease.

Retinal and retinol are in chemical equilibrium in the body and possess equivalent antixerophthalmic activity. Dietary vitamin A deficiency is a major cause of blindness in children in some developing countries. In developed areas, deficiency is rare in the absence of concurrent illness such as liver disease or intestinal malabsorption. Night blindness is the earliest symptom of deficiency, followed by degenerative changes in the retina such as xerophthalmia and keratomalacia.

Pharmacokinetics: Vitamin A is a fat soluble vitamin and is readily absorbed from the normal gastrointestinal tract. Plasma concentrations reach a peak level within 3 to 5 hours. Beta-carotene is converted to retinal, which is mostly reduced to retinol and conjugated with glucuronic acid and excreted in the urine and feces. Some retinol is esterified mainly to retinyl palmitate. Normal plasma concentration is approximately 1.4 mol/L (130 units/100 mL). Retinyl palmitate and small amounts of retinol and retinal are stored in the liver. Body stores of vitamin A are normally sufficient to meet the body’s needs for up to 2 years.

Indications: Prophylaxis and treatment of vitamin A deficiency.

Contraindications: Hypervitaminosis A; hypersensitivity to vitamin A or any component of a vitamin A containing pharmaceutical preparation.

Precautions: In physiologic doses, vitamin A is relatively nontoxic. Prolonged use of dosages greater than 7 500 RE (25 000 IU) may lead to symptoms of chronic toxicity such as bone and joint pain, hyperostosis, hair loss, anorexia and hepatosplenomegaly.

Excessive consumption of vitamin A supplements or foods rich in beta-carotine such as carrots may cause carotenemia and yellow discoloration of the skin. The same effect may result from defective utilisation of vitamin A precursors in diabetes mellitus and myxedema.

Drug Interactions: Excessive use of mineral oil as a laxative may reduce the utilization of the provitamin by carrying away large amounts in the feces. Cholestyramine and neomycin may affect drug absorption.

Vitamin A should not be used concurrently with isotretinoin since toxic effects may be additive.

Women on oral contraceptives have shown a significant increase in plasma vitamin A concentrations.

Pregnancy: Excessive intake of vitamin A during pregnancy may be a potential hazard to the mother and fetus. Effective measures to avoid pregnancy are necessary with high dose vitamin A therapy.

There is an extremely high risk that major fetal abnormalities will occur if pregnancy occurs during treatment with isotretinoin, which is contraindicated during pregnancy.

Lactation: Vitamin A is distributed into milk. Hypervitaminosis is a theoretical possibility.

Adverse Effects: See Overdose.

Overdose: Symptoms: The amount required to cause toxicity will vary among individuals. The manifestations of toxicity will depend on the patient’s age and hepatic function, and on the dose and duration of administration.

Acute toxicity (single ingestion of 7 500 RE or 25 000 IU per kg or more): Signs and symptoms may be delayed for 8 to 24 hours and include: increased intracranial pressure, headache, irritability, drowsiness, dizziness, lethargy, vomiting, diarrhea, bulging of fontanels in infants, diplopia, papilledema. Peeling of skin around mouth may be observed from 1 to several days after ingestion and may spread to the rest of the body.

Chronic, excessive ingestion (1 200 RE or 4 000 IU/kg daily for 6 to 15 months) may produce symptoms of pseudotumor cerebri, anorexia, weakness, arthralgias, bone pain, bone demineralization, dry skin, cracked lips, brittle nails, hair loss, splenomegaly, hepatomegaly, hypoplastic anemia, leukopenia, optic neuropathy, and blindness. Increased plasma concentrations of vitamin A occur but do not necessarily correlate with toxicity.

Treatment: For an acute overdose, empty stomach and follow with activated charcoal and a cathartic. Treat symptomatically.

Intracranial pressure may be reduced with i.v. dexamethasone or i.v. mannitol. In untreated patients, increased intracranial pressure may persist for 4 weeks after discontinuation of vitamin A.

For chronic ingestions, discontinue vitamin A. Toxicity is slowly reversible but may persist for several weeks. Monitor blood pressure, fluids, electrolytes, CNS status, complete blood count and hepatic function.

Dosage: In preventing vitamin deficiency, adequate dietary intake is preferred over supplementation, whenever possible. For a listing of food sources of vitamin A, see Vitamin Food Sources in the Clin-Info section.

The recommended daily intake of vitamin A to prevent deficiency is 400 RE (1 300 IU) for infants, 400 to 900 RE (1 300 to 3 000 IU) for children and 800 to 1 000 RE (2 700 to 3 300 IU) for adolescents and adults. No additional vitamin A nutrient intake is recommended during pregnancy, however an additional 400 RE (1 300 IU)/day is recommended during lactation. For a complete listing of vitamin A and other nutrient requirements, see Recommended Nutrient Intake in the Clin-Info section.

Severe Deficiency with Xerophthalmia: Children 1 to 8 years: 1 500 to 3 000 RE (5 000 to 10 000 IU)/kg orally for 5 days or until recovery occurs.

Children >8 years and Adults: 150 000 RE (500 000 IU) orally for 3 days, followed by 15 000 RE (50 000 IU) daily for 2 weeks, then 3 000 to 6 000 RE (10 000 to 20 000 IU) daily for 2 months.

Deficiency without Corneal Changes: Infants
Children 1 to 8 years: 1 500 to 3 000 RE (5 000 to 10 000 IU)/kg/day for 5 days, then 5 100 to 10 500 RE (17 000 to 35 000 IU)/day for 10 days.

Children >8 years and Adults: 30 000 RE (100 000 IU)/day for 3 days, then 7 500 to 15 000 RE (25 000 to 50 000 IU)/day for 14 days.

It has been suggested that infants and children (8 years and Adults: 3 000 to 15 000 RE (10 000 to 50 000 IU)/day of water-miscible products.

VITAMIN A General Monograph, Vitamin

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