Warfarin is a coumarin derivative which is very stable, even to strong acids. Warfarin may be synthesized naturally from coumarins present in many plants, such as sweet clover. It is usually prepared synthetically by the Michael condensation of benzylidene-acetone with 4- hydroxy-coumarin (Budavari, 1996).
Gastrointestinal absorption of warfarin is rapid and complete. Significant transcutaneous uptake of warfarin caused many cases of a hemorrhagic syndrome in infants (Martin-Bouyer et al., 1984). The target system of warfarin is the hematological system, with impairment of clotting. The main risks are associated with potentially fatal gastrointestinal and intracerebral hemorrhage.
Special Risks in Warfarin Use
Developmental effects have been reported when warfarin has been administered as a therapeutic agent during pregnancy. There are two types of defects dependent upon the time of administration during pregnancy. The first a characteristic embryopathy described by the terms “warfarin embryopathy” or “fetal warfarin syndrome”, occurs from early, first-trimester use. Fetal wastage and other abnormalities, especially CNS anomalies, result from treatment later during gestation (usually the second or third trimesters) (WHO 1995).
Nasal hypoplasia is the most consistent feature of warfarin embryopathy. The other common feature is bone abnormalities of the axial and appendicular skeleton. Other non-skeletal abnormalities reported include ophthalmological malformations, low birth weight, mental retardation, hypotonia and ear abnormalities. (WHO, 1995).
In adults, Precise toxic doses are difficult to determine since there is considerable interindividual variation in response. Toxicity has resulted from ingesting amounts ranging from 500 to 1000mg over several days (Baselt & Cravey, 1994).
The lowest toxic dose in humans ranges from 10 mg/kg to 15 mg/kg (RTECS, 1991). Large amounts of warfarin containing grain bait do not usually produce significant toxicity because of the small concentration of the warfarin and poor absorption in large amounts of grain. However, fourteen reported cases of accidental poisoning in Korea involved eating cornmeal containing 0.25% warfarin included in rat bait. The corn meal was eaten over a period of 15 days. All 14 became severely ill with hemorrhage; two of the 14 died. The estimated dosage was 1 to 2 mg/kg/day (Baselt & Cravey, 1994) Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure.
The minimum lethal exposure would depend in part on whether or not an individual is on anticoagulant therapy; individuals on therapy would be expected to react to lower exposures than non-treated persons.
Extrapolation from the amount needed in adults to acutely and reliably prolong the PT (40 milligrams) predicts a dose of about 0.5 milligram/kilogram in children that would be considered potentially toxic. This dose resulted in PTs between 18 and 30 seconds in children receiving a single loading dose after heart valve surgery (Carpentieri et al., 1976). Death can occur from significant transcutaneous uptake of warfarin. In August, 1981, pediatric hospitals in Ho Chi Minh City, Vietnam, reported 741 cases of a hemorrhagic syndrome in infants. The cause of this phenomenon was identified as talcum powder contaminated with warfarin in concentrations between 1.7 and 6.5 %. One hundred seventy-seven (177) of the 741 1984).
High Risk of Poisoning
Children may ingest baits, but single ingestions rarely lead to symptoms. Mislabelled warfarinised grains and flours used as food are likely to lead to hemorrhagic syndromes. The therapeutic use of warfarin may produce adverse effects and in overdose a haemorrhagic syndrome. Also, poisoning may occur in occupations involving chronic exposure to warfarin, eg people manufacturing warfarin, formulating baits or applying the rodenticide (WHO, 1995).
Summary of Clinical Effects
Acute Poisoning through Ingestion and Inhalation
Symptoms of poisoning usually occur after repeated ingestions of warfarin. The degree of hemorrhage depends on individual response, pre-existing liver disease and current drug treatment. After a variable period of time (between 1 and 7 days), external bleeding and internal hemorrhage may occur from any site. Signs may include epistaxis, gingival bleeding (and in other miscellaneous mucocutaneous sites), petechial rash, ecchymoses, large hematomas (including intra-articular), hematuria and melaena. The effects of acute poisoning through inhalation are similar to those of ingestion.
Acute Poisoning through Skin Exposure
Human warfarin intoxication by dermal absorption has been described after prolonged (>24 hours) upper extremity contact with an oil-based warfarin solution. Two days post exposure, hematuria and subcutaneous hematomas appeared, followed by epistaxis and mucocutaneous bleeding from the mouth (Fristedt & Sterner 1965).
Chronic Poisoning through Ingestion and Inhalation
Repeated ingestion of warfarin causes the same hemorrhagic risks as acute exposure because of the cumulative effects on serum concentrations of the clotting factors. Poisoning by inhalation can occur and symptoms are similar to those of ingestion.
Chronic Poisoning through Skin Exposure
Hematomas, epistaxis, punctate hemorrhages of the palate and mouth, bleeding from the lower lip have been reported following prolonged percutaneous exposure (Proctor et al., 1988).
Course, Prognosis, and Cause of Death
Symptoms of poisoning usually occur after repeated ingestions of warfarin. The degree of hemorrhage depends on individual response, pre-existing liver disease and current drug treatment. After a variable period of time (between 1 and 7 days), external bleeding and internal hemorrhage may occur from any site. Death is usually due to shock from intracranial hemorrhage or massive gastrointestinal bleeding (WHO, 1995).
If toxic amounts have been ingested, coagulation will be impaired, with gum bleeding, epistaxis, ecchymosis, hematomata, hematemesis, melena, hematuria. The diagnosis is based on history of exposure (generally by ingestion of a rodenticide); clinical evidence of bleeding, which may appear 1 to 2 days post ingestion; and abnormal prothrombin time.
A sample of the rodenticide should be kept for toxicological analysis (if feasible). The most relevant biomedical analysis is coagulation studies including:
- Determination of clotting factors
- Prothrombin time (PT)
- Activated partial thromboplastin time (PTT)
First-aid Measures and Management Principles
All cases of warfarin ingestion should be taken to a hospital for initial clinical and laboratory evaluation. If ingestion was recent administer activated charcoal. Gastric emptying is not necessary if activated charcoal can be given promptly, and should be avoided in patients who are already anticoagulated.
If more than 24 hours have elapsed since ingestion, decontamination measures are not effective and the patient should be monitored closely using prothrombin time (PT) and plasma thromboplastin time (PTT). Treatment is based on the administration of vitamin K1 (phytomenadione) as indicated by the prothrombin time. Fresh frozen plasma or whole blood are indicated in cases of acute bleeding. Close clinical observation is essential to detect occult bleeding or life-threatening haemorrhage. In cases of suspected serious ingestion, vitamin K1 is indicated before signs and symptoms of haemorrhage appear.
Warfarin vs Blood Clot and Liver Disease
Conventionally, Warfarin has been the oral anticoagulation (OAC) of choice for the prevention and remedy of blood clot problems in liver disease. Cytochrome P-450 (CYPs) are involved in the breakdown and absorption of drugs in the body. The CYPs are also involved in the development of several liver diseases. The international normalized ratio (INR) is a measure of how long it takes blood to clot. A low INR implies the certainty of blood clots, but a high INR means there is a risk of bleeding. Warfarin decreases the body’s potential to form blood clots by blocking the formation of vitamin K-dependent coagulation factors. Vitamin K is needed to prevent bleeding.
The liver cells contain cytochrome P450 enzymes that are involved in the synthesis and metabolism of molecules and chemicals within cells. An enzyme is a chemical that accelerates chemical reactions within the body. Elevated liver enzymes, confirmed with a blood test, is a sign of damaged liver cells.
Unfortunately, warfarin is susceptible to significant drug-drug interactions because of its metabolism through the cytochrome P450 enzyme system. This feature can be unfavorable in patients with liver disease who have higher risks of bleeding and clotting.
Warfarin vs Epilepsy
Warfarin, together with valproic acid (VPA), is typically administered to patients with epilepsy. Clobazam is a prescription drug from a group of medications known as benzodiazepines. Clobazam can be used to treat short-term anxiety, as well as seizures in patients with epilepsy. This medicine works by acting on a chemical imbalance in the brain. Similarly, Xanax is used to treat anxiety and panic disorders. Xanax belongs to a type of drugs called benzodiazepines, which promotes a sedative effect on the brain and the central nervous system.
The response of patients to benzodiazepines vary. Some people experience more frequent or more intense seizures if they lower the dose or stop taking it. Other patients may be sustained on a low dose.
CBD: The Natural Alternative
Cannabidiol or CBD oil has become a popular new product in states that have legalized medical marijuana. CBD oil is acknowledged for its contribution to the treatment of a variety of medical problems.
Cannabidiol (CBD) is a cannabinoid found in Cannabis sativa plant. The other well-known cannabinoid is tetrahydrocannabinol (THC). These two cannabinoids are from the same plant, but they produce different side effects on the human body when consumed. THC, the cannabinoid responsible for marijuana’s psychological effects, is known for its ability to give the user a euphoric high. But CBD, being nonpsychoactive, would not give you the same experience.
Cannabinoids affect your body’s endocannabinoid system, which keeps the body in a state of balance, or homeostasis. When the body gets inflicted with inflammation or disease, CBD may help your endocannabinoid system function as a body regulator.
CBD has also been advertised as a substance that can have a positively improve anxiety, chronic pain, and even heart disease. However, over-the-counter CBD products are not regulated by the Food and Drug Administration (FDA) at this time. The only medical condition CBD has been approved to treat, is epilepsy, in the form of the drug Epidiolex.
CBD vs Blood Pressure
CBD’s anti-inflammatory and antioxidative properties may reduce risk factors that can lead to high blood pressure, which is the major cause of heart disease. The blood pressure can increase when you experience stress, but a dose of CBD can lessen that spike. A 2009 study on rats revealed that a dose of CBD lowered both their blood pressure and heart rate. A 2017 study on healthy human volunteers indicated that CBD lowered their blood pressure as well. Although more research is needed to have a well-grounded conclusion, it is reassuring to know that CBD may be valuable in lowering blood pressure and heart rate under stress.
CBD vs Bleeding Complications
The way that CBD breaks down in your body can affect how your body would absorb other medicines you take. If the prescription medications you are taking do not get processed correctly, they remain in your body for a long time. This interference in metabolism can cause adverse side effects and complications, especially if you are taking blood thinners like warfarin. Taking warfarin with CBD can prolong the stay of warfarin in your body, and this becomes an issue because warfarin thins your blood and prevents blood clots.
A case report published by the National Library of Medicine described an interaction between warfarin and cannabidiol. When consuming a CBD product, monitor changes in blood levels of warfarin, and regulate the dosage as prescribed by your doctor.
CBD vs Liver Medications
CBD may interfere with certain liver enzymes. This interference could prevent the liver from breaking down and absorbing other medications, resulting in higher concentrations of the substances in your system. Also, CBD could increase your predisposition to liver toxicity. A recent study has caused alarm about CBD’s potential effects on the liver. Researchers advised that CBD similarly affects the liver as alcohol does. Discuss with your doctor any potential drug interactions before taking CBD.
The Grapefruit Test
An easy way to determine if CBD could interact with your medicines is to do the grapefruit test. CBD interacts with other medicines in your body in the same way as grapefruit juice does. If your doctor instructed you not to take your medicines with grapefruit, then it is probably advisable not to use CBD with that medicine.