Vitamin K

VITAMIN K

It is a fatsoluble dietary principle required for the synthesis of clotting factors.

Dam (1929) produced bleeding disorder in chicken by feeding deficient diet. This was later found to be due to decreased concentration of prothrombin in blood and that it could be cured by a fat soluble fraction of hog liver. This factor was called Koagulations vitamin (vit K) and soon its structure was worked out. A similar vitamin was isolated in 1939 from alfalfa grass and labelled vit K₁, while that from sardine (sea fish) meal was labelled K₂. Synthetic compounds have been produced and labelled K₃.

Chemistry And Source

Vit K has a basic naphthoquinone structure, with or without a side chain (R) at position 3. The side chain in K₁ is phytyl, in K₂ prenyl, while in K₃ there is no side chain.

Dietary sources are—green leafy vegetables, such as cabbage, spinach; and liver, cheese, etc.

Daily Requirement

It is uncertain, because a variable amount of menaquinone (vit K₂) produced by colonic bacteria becomes available. Even 3–10 μg/day external source may be sufficient. However, the total requirement of an adult has been estimated to be 50–100 μg/day.

Action

Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins— prothrombin, factors VII, IX and X. The vit K dependent change (γ carboxylation of glutamate residues of these zymogen proteins) confers on them the capacity to bind Ca2+ and to get bound to phospholipid surfaces—properties essential for participation in the coagulation cascade.

Utilization

Fat-soluble forms of vit K are absorbed from the intestine via lymph and require bile salts for absorption, while water-soluble forms are absorbed directly into portal blood. An active transport process in the jejunum has been demonstrated for K₁, while K₂ and K₃ are absorbed by simple diffusion. Vit K is only temporarily concentrated in liver, but there are no significant stores in the body. It is metabolized in liver by side chain cleavage and glucuronide conjugation; metabolites are excreted in bile and urine.

Deficiency

Deficiency of vit K occurs due to liver disease, obstructive jaundice, malabsorption, long-term antimicrobial therapy which alters intestinal flora. However, deficient diet is rarely responsible. The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood. Haematuria is usually first to occur; other common sites of bleeding are g.i.t., nose and under the skin—ecchymoses.

Preparations

Phytonadione: VITAMINK, KENADION 10 mg/ml for i.m. injection.

Menadione: 0.66 mg in GYNAE CVP with vit C 75 mg, ferrous gluconate 67 mg, Cal. lactate 300 mg and citras bioflavonoid 150 mg per cap:

Acetomenaphthone: ACETOMENADIONE 5, 10 mg tab; KAPILIN 10 mg tab.

Menadione sod. bisulfite: 20 mg, in CADISPERC with vit C 100 mg, adrenochrome monosemicarbazone, 1 mg, rutin 60 mg, methylhesperidin 40 mg, Cal. phosphate 100 mg per tab.

STYPTOCID 10 mg with adrenochrome monosemicarbazone 0.5 mg, rutin 50 mg, vit C 37.5 mg, vit D 200 i.u., Cal. phosphate 260 mg per tab.

Use

The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following situations:

a)   Dietary Deficiency: of vit K is very rare in adults. However, when it occurs 5–10 mg/day oral or parenteral vit K rapidly corrects the defects.

b)  Prolonged Antimicrobial Therapy: treat in the same way as dietary deficiency of vit K.

c)   Obstructive Jaundice Or Malabsorption Syndromes (sprue, regional ileitis, steatorrhoea, etc.): vit K 10 mg i.m./day, or orally along with bile salts.

d)  Liver Disease (Cirrhosis, Viral Hepatitis): associated bleeding responds poorly to vit K. Because of hepatocellular damage, synthesis of clotting factors is inadequate despite the presence of vit K. However, vit K may be of some use if its absorption had been affected due to lack of bile salts.

e)   Newborns: All newborns have low levels of prothrombin and other clotting factors. Further decrease occurs in the next few days. The cause is both lower capacity to synthesize clotting factors as well as deficiency of vit K. The defect is exaggerated in the premature infant. Vit K 1 mg i.m. soon after birth has been recommended routinely. Some prefer administering 5–10 mg i.m. to the mother 4–12 hours before delivery. Haemorrhagic disease of the newborn can be effectively prevented/treated by such medication.

Menadione (K₃) should not be used for this purpose (see below).

f)    Overdose Of Oral Anticoagulants: This is the most important indication of vit K. Phytonadione (K₁) is the preparation of choice, because it acts most rapidly; dose depends on the severity of hypo-prothrombinaemia (measured INR) and bleeding. Unnecessary high dose is to be avoided because it will render the patient unresponsive to oral anticoagulants for several days.

Severe: 10 mg i.m. followed by 5 mg 4 hourly; bleeding generally stops in 6–12 hours, but normal levels of coagulation factors are restored only after 24 hr. This dose of vit-K will block anticoagulant action for 7–10 days.

Moderate: 10 mg i.m. followed by 5 mg once or twice according to response.

Mild: Just omit a few doses of the anticoagulant.

g) Prolonged high dose salicylate therapy causes hypoprothrombinemia; vit K should be given prophylactically. If bleeding occurs—treat as for oral anticoagulants.

Toxicity

Rapid i.v. injection of emulsified vit K produces flushing, breathlessness, a sense of constriction in the chest, fall in BP; few deaths are on record. It is probably due to emulsion form of the preparation.

Menadione and its water soluble derivatives can cause haemolysis in a dose-dependent manner. Patients with G6PD deficiency and neonates are especially susceptible. In the newborn menadione or its salts can precipitate kernicterus:

·      by inducing haemolysis and increasing bilirubin load.

·      by competitively inhibiting glucuronidation of bilirubin. Glucuronide conjugation is, as such, inadequate in neonates.

Because of poor efficacy and higher toxicity, there is little justification to use menadione and its water-soluble salts for any indication.