What Is the Antidote for Coumadin?

Coumarins are a class of substances that contain the basic structure of 4-hydroxycoumarin. They are known as oral anticoagulants because they take part in metabolism in the body to exert anticoagulant effects.

Drug Name: Coumarins
Alias: Oxanthone and coumarol
Foreign name: coumarin

Main indications: Inhibit the synthesis of coagulation factors in the liver
Adverse reactions: Overdose is prone to bleeding
Main medication contraindications: Contraindications are the same as heparin.
Dosage form: oral

Coumarins I. Introduction

Coumarin was discovered in the process of ranching livestock caused by internal bleeding caused by anticoagulation. After realizing that this kind of substance has anticoagulant effect, it led to the research and synthesis of coumarin drugs. One more important coagulation drug is provided.

Coumarins are a class of substances that contain the basic structure of 4-hydroxycoumarin. They are administered orally to participate in metabolism in the body to exert anticoagulant effects, so they are called oral anticoagulants.

Coumarins II. Source

Plants containing coumarin or coumarin. Plantain, Tonkabean, cherry tree, vanilla, etc., all belong to this plant. In the vacuoles of these plants, coumaric acid mainly exists in the form of non-fragrance glycosides, which are contacted with glucosidase due to drying, grinding, etc., but coumarins are closed-looped and hydrolyzed at the same time to release aroma.

Coumarins III. Classification

Coumarin compounds are lactones of o-hydroxycinnamic acid and have an aromatic odor. The core structure of this class of compounds includes simple coumarins, furanocoumarins, and pyrancoumarins, which are an important class of active ingredients in crude drugs, mainly distributed in the umbelliferae and leguminous families. , Asteraceae, Rutaeaceae, Solanaceae, Ruixiangaceae, Orchidaceae and other plants. Such as psoralen (psolalen) has a photoactive activity for the treatment of white spot disease. Osthole is a coumarin-based active ingredient derived from the seeds of Cnidium and Angelica sinensis, and has pharmacological activity to inhibit hepatitis B surface antigen (HBsAg). Begonia lactone (calophylloide) has a strong anticoagulant effect. Artemisinin (scoparon) is the main active ingredient of the crude drug Chenhaoping for liver choleretic and smooth muscle relaxation ^[2] .

Coumarins IV. Common Coumarin Drugs

Common coumarins are dicoumarol, warfarin (benzylacetone coumarin), and acenocoumarol (new anticoagulant). Their pharmacological effects are basically the same.

Coumarins V. Pharmacological effects

Coumarins are vitamin K antagonists that inhibit the conversion of vitamin K from epoxides to hydroquinones in the liver, thereby preventing the repeated use of vitamin K and affecting coagulation factors , , , containing glutamic acid residues The carboxylation of these factors causes these factors to stay in the precursor stage without coagulation activity, thereby affecting the coagulation process. There is no inhibitory effect on the above factors that have been formed, so the anticoagulant effect appears slowly. It usually takes 8 to 12 hours for it to take effect and reach its peak in 1 to 3 days. The anticoagulant effect can be maintained for several days after drug withdrawal. The anticoagulant effect of dicoumarin is slow and long lasting for 4-7 days. Warfarin appears rapidly, lasting 2 to 5 days ^[2] .

Coumarins VI. In vivo processes

Coumarin and coumarin compounds can be quickly absorbed in the gastrointestinal tract and distributed in the body after oral administration. Warfarin is completely absorbed orally and can be detected in plasma after 1 hour, reaching a peak in 2-8 hours. The binding rate to plasma proteins is 90% to 99%. t1 / 2 is 10 to 60 hours. Metabolized mainly in the liver and kidneys. Dicoumarin is irregularly absorbed. The binding rate to plasma proteins is 90% to 99%. t1 / 2 is 10 to 30 hours. The acenocoumarol t1 / 2 is 8 hours, and the reduced metabolites still have anticoagulant effects, and t1 / 2 is 20 hours.

Coumarins 7. Drug Metabolism

Coumarin is easily absorbed after entering the body. Metabolic reactions are catalyzed by cytochrome P450. The metabolism of coumarins requires the participation of a large number of biological enzymes. The metabolic pathways are mainly hydroxylation, dehydrogenation, demethylation, and lactones. Ring-opening, as well as binding reactions, finally produce a variety of compounds ^[3] .

1. Coumarins 1. Oxidative metabolism

Oxidation is a common drug metabolism reaction, including hydroxylation, dehydrogenation, etc. Among them, the hydroxylation reaction is the most common. Coumarins are easily catalyzed by CYP2A6 to undergo hydroxylation reactions. The hydroxylated coumarins are more likely to react with glucuronic acid, sulfuric acid, etc., and finally excreted in the form of conjugates through the kidneys. The 8-methyl psoralen in Angelica sinensis is hydroxylated to produce 5-hydroxy-8-methoxypsoralide.

2. Coumarins 2. Demethylation metabolism

Demethylation is an important pathway for coumarin metabolism. After oral administration of 6,7-dimethoxycoumarin, rats mainly have two metabolites (M1 and M2) in the body. The analysis found that M1 and M2 are isomers of each other. It is a product of 6,7-dimethoxycoumarin hydrolyzed and demethylated to produce 6-hydroxy-7-methoxycoumarin, and then formed with sulfuric acid molecule. Sulfate conjugate. The coumarin component of Angelica sinensis, 8-methoxypsoralide, can be demethylated in the body to produce metabolite 8-hydroxypsoralide. Methoxyparin can also be demethylated in hepatic microsomes to produce demethylmethoxyparin.

3. Coumarins 3. Binding Metabolism

Coumarin compounds all contain one or more hydroxyl groups. After the hydroxylation reaction of phase metabolism, it is easy to combine with glucuronic acid, sulfuric acid and glutathione, and the combined metabolism (phase metabolism) occurs. Large compounds are excreted afterwards. Combined metabolism mainly occurs in the liver and intestine. Small intestinal mucosa epithelial cells have phase II metabolizing enzymes such as glucuronyltransferase (UDPGT), sulfate transferase (ST), and methyltransferase (MT). Part of coumarin is absorbed or metabolized by the intestinal tract and continues to be metabolized and transformed from the portal vein to the liver. The combined metabolism of coumarins is mainly glucuronidation, sulfated, glutathione binding and methylation. In humans, coumarin is catalyzed by liver cell CYP to detoxify to form 7-hydroxycoumarin. Most of 7-hydroxycoumarin is further metabolized into its corresponding glucuronic acid or sulfuric acid conjugate and excreted from urine. The main two metabolites of 6,7 dimethoxycoumarin in rats are the sulfate metabolites of 6,7 dimethoxycoumarin after hydrolysis and demethylation, and then combined with sulfuric acid. Metabolites of psoralen and isopsoralen are also sulfate conjugates of their monohydroxylated products. Qinpiting is catalyzed by catechol orthomethyltransferase in the liver to produce qinpidin.

Coumarins 8. Clinical application

Can prevent thrombosis and development. Can also be used as an adjuvant for myocardial infarction. It is effective when taken orally and has a longer duration of action. But the effect appears slow and the dose is not easy to control. It is also used to prevent venous thrombosis after rheumatic heart disease, hip fixation, and artificial heart valve replacement.

Coumarins Nine, adverse reactions

The dose should be adjusted according to the prothrombin time control within 25-30 seconds (normal value 12 seconds). Overdose is prone to bleeding, which can be counteracted with vitamin K, and fresh plasma or whole blood is transfused if necessary. Contraindications are the same as heparin. Other adverse reactions include gastrointestinal reactions and allergies.

Coumarins X. Drug Interactions

1. The lack of vitamin K in food or the use of broad-spectrum antibiotics to inhibit intestinal bacteria and reduce the vitamin K content in the body can strengthen the role of this class of drugs.

2. Aspirin and other platelet inhibitors can work synergistically with this class of drugs.

3. Plasma proteins such as chloral hydrate, hydroxybutazone, metsulfuron urea, quinidine, etc. can be replaced by salicylates, imipramine, metronidazole, cimetidine, etc. Strengthen the role of this class of drugs.

4. Barbiturates and phenytoin can induce liver drug enzymes, and oral contraceptives can weaken the effects of these drugs due to increased coagulation.