Vitamin K

Usage

Vitamin K is essential for the synthesis of clotting factors II (prothrombin), VII, IX, and X in the liver. It is prescribed for the prevention and treatment of vitamin K deficiency bleeding (VKDB) in newborns and for the reversal of warfarin’s anticoagulant effects. It is also used to treat bleeding or excessive blood thinning caused by certain medications or conditions affecting vitamin K absorption or synthesis. Its pharmacological classifications include vitamin, antihemorrhagic, and antidote.

Vitamin K’s mechanism of action involves carboxylation of glutamic acid residues in vitamin K-dependent clotting factors. This carboxylation allows these proteins to bind calcium ions, which is crucial for their activation and participation in the coagulation cascade.

Alternate Names

Vitamin K encompasses a group of fat-soluble vitamins, including vitamin K1 (phytonadione) and vitamin K2 (menaquinone). Phylloquinone, phytonadione, and Mephyton are other names for vitamin K1. Menaquinone is also referred as MK-4 through MK-13, representing variations in the side chains. Konakion and Mephyton are examples of brand names for vitamin K1.

How It Works

Pharmacodynamics: Vitamin K facilitates the post-translational modification of vitamin K-dependent clotting factors, enabling them to bind calcium and participate in the coagulation cascade. This leads to the formation of a stable fibrin clot, preventing bleeding.

Pharmacokinetics:

• Absorption: Vitamin K1 is absorbed in the small intestine in the presence of bile salts and dietary fats.
• Metabolism: Vitamin K is metabolized in the liver.
• Elimination: Metabolites are excreted in bile and urine.

Mode of Action: Vitamin K acts as a cofactor for the enzyme γ-glutamyl carboxylase, which catalyzes the carboxylation of glutamic acid residues in vitamin K-dependent clotting factors. This carboxylation step is crucial for their proper functioning in the coagulation cascade.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Vitamin K’s primary action is as a cofactor for γ-glutamyl carboxylase. There is no direct receptor binding, enzyme inhibition (besides inhibiting vitamin K epoxide reductase at high doses, which can ironically lead to impaired clotting as per source [1]), or neurotransmitter modulation involved in its mechanism of action.

Elimination Pathways: Vitamin K and its metabolites are primarily eliminated via hepatic excretion through bile and to a lesser extent renal excretion through urine.

Dosage

Standard Dosage

Adults:

• Nutritional Supplementation: Recommended Dietary Allowance (RDA) is 90 mcg/day for females and 120 mcg/day for males (Source: [9]).
• Hypoprothrombinemia: 2.5-25 mg (up to 50 mg in rare cases) by oral, subcutaneous (SC), or intravenous (IV) routes, depending on severity and response (Source: [17]). The dose can be repeated as needed. IV administration should be slow (over at least 20 minutes) to minimize the risk of reactions. IM injections are generally avoided due to risk of hematoma formation.
• Warfarin Reversal: Dosage depends on the INR and presence/severity of bleeding. Refer to sections below for detailed guidance.

Children:

• Newborns (VKDB Prophylaxis): 0.5-1 mg IM single dose within 1 hour of birth (Source: [4, 5, 6]). Oral administration (2 mg at birth, repeated at 2-4 weeks and 6-8 weeks) can be considered if IM route is declined by parents, but it’s considered less effective (Source: [6]).
• Other Pediatric Uses: Refer to source or consult specialist for pediatric dosing in other situations as it is weight/age dependent (Source: [7]). Always carefully consider the potential risks and benefits in pediatric patients.

Special Cases:

• Elderly Patients: No specific dosage adjustments are generally recommended for elderly patients, but close monitoring of INR is advised when reversing warfarin.
• Patients with Renal Impairment: No specific dosage adjustments for renal impairment are typically required, as vitamin K is primarily excreted through the biliary route.
• Patients with Hepatic Dysfunction: Close monitoring of INR is crucial in patients with hepatic dysfunction. Dosage adjustments may be necessary based on the severity of the impairment, as vitamin K metabolism is affected.
• Patients with Comorbid Conditions: Individualized dosing considerations might be necessary, taking into account factors such as diabetes, cardiovascular disease, or concomitant medications.

Clinical Use Cases

• Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use: Vitamin K is often administered prophylactically to prevent VKDB in critically ill patients, especially those on broad-spectrum antibiotics or with compromised liver function. The recommended dose is 1-10 mg IV weekly or 1 mg oral daily (Source: [2]). Higher and more prolonged doses might be needed in older ICU patients.
• Emergency Situations (Warfarin Reversal): For major bleeding, 5-10 mg IV is recommended along with other agents (e.g., prothrombin complex concentrate). In less severe cases, or if rapid reversal is needed but the surgery can be delayed, lower IV doses (1-5 mg) can be considered (Source: [3, 10, 12]). Oral administration (1-5 mg) may be preferred in non-bleeding patients requiring less urgent reversal (Source: [1, 10, 27]).

Dosage Adjustments

Dose modifications may be necessary in cases of hepatic dysfunction, malabsorption syndromes, or long-term antibiotic use. Consult specific guidelines for dosage recommendations in these situations. For example, in case of supratherapeutic INR, the recommended dose and route varies based on whether the patient is experiencing bleeding and the urgency of warfarin reversal (Source: [1, 3, 10, 12]). Consider genetic polymorphisms affecting drug metabolism when determining the appropriate dose, specifically VKORC1 and CYP2C9 genotype.

Side Effects

Common Side Effects

Generally, vitamin K is well-tolerated. Oral administration rarely causes side effects. Rapid intravenous injection can cause flushing, altered taste, dizziness, or, rarely, anaphylaxis or cardiac arrest.

Rare but Serious Side Effects

Hypersensitivity reactions, including anaphylaxis (particularly with IV administration), have been reported.

Long-Term Effects

No significant long-term adverse effects have been associated with vitamin K use. However, high doses may interfere with warfarin therapy, causing resistance for up to a week.

Adverse Drug Reactions (ADR)

Severe allergic reactions (anaphylaxis) can occur.

Contraindications

Hypersensitivity to vitamin K or any component of the formulation is a contraindication. Use caution in patients with severe liver disease.

Drug Interactions

Vitamin K primarily interacts with warfarin, reducing its anticoagulant effect. Orlistat and cholestyramine can reduce vitamin K absorption. Certain antibiotics can disrupt vitamin K synthesis by gut bacteria.

Pregnancy and Breastfeeding

Vitamin K is considered safe during pregnancy and breastfeeding. It is routinely administered to newborns to prevent VKDB.

Drug Profile Summary

• Mechanism of Action: Carboxylates vitamin K-dependent clotting factors, enabling blood clotting.
• Side Effects: Generally well-tolerated; rare hypersensitivity reactions, potential for injection site reactions.
• Contraindications: Hypersensitivity.
• Drug Interactions: Warfarin, orlistat, cholestyramine, some antibiotics.
• Pregnancy & Breastfeeding: Safe.
• Dosage: Varies depending on indication and patient characteristics (see above).
• Monitoring Parameters: INR (especially when used for warfarin reversal).

Popular Combinations

Vitamin K is often used in conjunction with prothrombin complex concentrate (PCC) for rapid reversal of warfarin-induced major bleeding (Source: [3, 12]).

Precautions

• General Precautions: Assess for history of hypersensitivity, liver disease, and concomitant medications.
• Specific Populations:
  • Pregnant Women: No specific precautions.
  • Breastfeeding Mothers: No specific precautions.
  • Children & Elderly: Use age-appropriate dosing.
• Lifestyle Considerations: No specific lifestyle considerations.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Vitamin K?

A: The dosage varies depending on the indication and patient characteristics. Refer to the dosage section above.

Q2: What is the difference between vitamin K1 and vitamin K2?

A: Vitamin K1 (phytonadione) is primarily found in green leafy vegetables and is the form used to prevent and treat VKDB and reverse warfarin’s effects. Vitamin K2 (menaquinone) is produced by bacteria in the gut and is also found in fermented foods.

Q3: How quickly does vitamin K reverse the effects of warfarin?

A: IV administration provides the most rapid reversal, with a noticeable effect on INR within 4-6 hours. Oral administration can take up to 24 hours to achieve a significant reduction in INR.

Q4: What are the signs and symptoms of vitamin K deficiency?

A: Easy bruising, bleeding gums, nosebleeds, heavy menstrual bleeding, and gastrointestinal bleeding. In newborns, VKDB can manifest as bleeding from various sites, including the umbilical cord, gastrointestinal tract, and intracranial hemorrhage.

Q5: Can vitamin K be given intramuscularly?

A: While the IM route can be used, it is generally avoided due to the risk of hematoma formation. Subcutaneous administration is also not ideal due to its less predictable effects. IV or oral routes are generally preferred.

Q6: What are the monitoring parameters for vitamin K therapy?

A: INR is the primary monitoring parameter, especially when vitamin K is used to reverse warfarin’s effects. Other clotting factors (II, VII, IX, and X) may also be monitored as clinically indicated.

Q7: Are there any drug interactions I should be aware of with vitamin K?

A: Vitamin K primarily interacts with warfarin, decreasing its efficacy. It can also interact with medications that interfere with fat absorption, like orlistat and cholestyramine, and certain antibiotics that can affect vitamin K production in the gut.

Q8: Is vitamin K safe for use in pregnancy?

A: Yes, vitamin K is considered safe during pregnancy and is often given to pregnant women prior to delivery or to newborns to prevent VKDB.

Q9: What are the potential adverse effects of IV vitamin K administration?

A: While generally safe, rapid IV administration of vitamin K can cause flushing, dysgeusia (altered taste), dizziness, and rarely, severe reactions like anaphylaxis or cardiac arrest. Slow infusion is recommended to minimize these risks.

Q10: How is vitamin K deficiency diagnosed?

A: Diagnosis involves evaluating a patient’s medical history, physical examination, and coagulation studies like prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Measuring vitamin K levels directly is not always necessary.