What is Carbamazepine Toxicity?
Carbamazepine is a medication often used to treat conditions like focal epilepsy (a type of epilepsy which affects just one part of the brain), neuropathic pain (pain caused by damage to the nerves), schizophrenia and bipolar disorder in both children and adults. The first case of taking too much of this medication was reported back in 1967. High levels of this drug, specifically more than 40 mg/L, can be harmful, whereas the typical safe amount is usually between 4 to 12 mg/L.
What Causes Carbamazepine Toxicity?
Carbamazepine toxicity, when too much of the drug is in your body, usually happens when it’s taken with other medications. This is common for patients who are taking antiepileptic drugs along with carbamazepine. Lamotrigine, a medication often used by these patients, can increase the risk of exceptionally high carbamazepine levels in the body. The same risk applies when taking carbamazepine and levetiracetam. Certain substances that affect the function of a group of enzymes known as cytochrome P450, such as grapefruit juice, can also raise carbamazepine levels.
Intentional overdosing on carbamazepine is rare and typically happens when a patient tries to harm themselves. This is often seen in people who are severely depressed and happens when they first start taking the medication.
Risk Factors and Frequency for Carbamazepine Toxicity
Overdose on Carbamazepine, a type of medication, is quite common. In 2014, the American Association of Poison Control Centers report recorded 1880 cases of negative side effects caused by this drug. The reports revealed that 37% of the cases were due to intentional overdose, 57% were accidental, and 4% were negative reactions to the medicine.
Signs and Symptoms of Carbamazepine Toxicity
If a person consumes too much carbamazepine at once, it’s usually a while before any symptoms show up. Why? Because this drug takes time to absorb into the body. When symptoms do appear, they can include feeling dizzy, off-balance, or extremely sleepy. Some people may even fall into a coma or have seizures where their whole body shakes or jerks uncontrollably. A particularly risky side effect is disruption to the heart’s normal rhythm, which could lead to an irregular heartbeat that is potentially dangerous. An EEG (a test that checks electrical activity in the brain) might show a pattern called spindle coma. Other symptoms that can arise include those similar to anticholinergic toxicity, which include things like dry mouth, red skin, constipation, blurred vision, and difficulty peeing.
- Delayed onset of symptoms
- Dizziness
- Imbalance
- Drowsiness
- Coma
- Generalized seizures
- Abnormal heart rhythm
- Specific pattern seen on EEG
- Anticholinergic symptoms
- Hyperchromic anemia
- Minor rhabdomyolysis
- Movement disorders
Testing for Carbamazepine Toxicity
Patients should be carefully observed and undergo a neurological exam because symptoms may worsen over time. It’s essential to have an anesthesia and a tool kit for inserting a tube into the windpipe (intubation) ready by the patient’s bed. If there are any signs of even minor worsening symptoms and the anticipation of more severe symptoms, it may be necessary to carry out this intubation as a preventive measure. An EKG, a test that records the heart’s electrical activity, must be carried out. It’s also necessary to routinely check the level of carbamazepine, a medication often used to treat certain types of seizures, in the patient’s blood every 4 hours.
Treatment Options for Carbamazepine Toxicity
Treatment for carbamazepine overdose can vary and include steps to hasten the drug’s removal from your body, using activated charcoal, or undergoing therapies such as hemodialysis or plasmapheresis.
Activated charcoal is a special type of charcoal that’s used in medicine to help absorb the drug and stop it from being absorbed in your intestines. It also helps get rid of the drug by interrupting the natural cycle of how the drug passes through your liver and intestine back into the main part of your body. However, the use of activated charcoal comes with risks, especially if the patient’s mental state is deteriorating, as they could accidentally inhale the charcoal.
Charcoal hemoperfusion is another way of removing the drug from your body. In this process, blood is passed through a special machine containing activated charcoal that is designed to absorb the drug. But this treatment also has risks, such as low blood sugar (hypoglycemia), low calcium levels in blood (hypocalcemia), and low levels of platelets in the blood (thrombocytopenia), which are essential for blood clotting.
Another treatment reported to be successful is intravenous lipid emulsion (ILE) therapy. This involves injecting a solution made of fats directly into the vein, which is believed to draw the drug out of cells and help remove it from the body.
Because the overdose can potentially be fatal in 13% of severe cases, a strong treatment plan is necessary. This can include a combination of hemoperfusion (filtering the blood through charcoal), hemodialysis (filtering the blood through a machine to remove waste products), multiple doses of activated charcoal, and intravenous lipid emulsion therapy.
For children, who are more susceptible to adverse effects and symptoms of drug toxicity, continuous venovenous hemodiafiltration (CVVHDF) could be used. This therapy uses a combination of diffusion (moving particles from an area of high concentration to low concentration) and convection (the transfer of heat through a fluid) to remove the drug from the body. This method is considered more effective than using diffusion alone because it can remove larger molecules, like carbamazepine. This treatment plan can be controlled easily and is a safer option for patients who may be unstable.
If treatment begins within one hour of drug ingestion, washing out the stomach – known as gastric lavage – can be useful. However, due to the properties of carbamazepine that might slow down digestion and processing of the drug, doctors need to take extra care.
In severe cases, a procedure called whole bowel irrigation can be performed. This is done through a tube inserted into the nose or mouth to flush out the entire digestive tract. However, this should only be done if the patient’s breathing path has been secured beforehand. Also, this method may lead to a complete blockage in the intestines (ileus) and, in extreme cases, may require a surgical procedure known as ileostomy to create a new opening for waste to leave the body. This blockade is due to the effect of carbamazepine on the natural movement of the intestines (peristalsis).
What else can Carbamazepine Toxicity be?
If someone taking carbamazepine, a medicine often used to treat epilepsy, comes in with a change in mental state or vague neurological symptoms, it’s critical to consider certain possible causes. They could be having a seizure, either focal (affecting just one part of the brain) or postictal (after a seizure). Remember, all epilepsy medications, including carbamazepine, carry a risk of encouraging suicidal thoughts. It’s also possible that they’ve taken too much of another substance, such as acetaminophen. This isn’t unusual for people with epilepsy or chronic nerve pain, both conditions that carbamazepine is often prescribed for.
The following possible causes should also be considered:
- Allergic responses
- A significant drop in all types of blood cells (pancytopenia)
- Interactions with other drugs
- Antidepressant overdose
- Brain inflammation
- Overdose of drugs that affect the nervous system (anticholinergic toxicity)
- Significantly low body temperature (hypothermia)
- Lithium overdose
- A severe reaction to antipsychotic drugs (neuroleptic malignant syndrome)
- Phenytoin overdose
- Unnatural muscle contraction caused by medication
- Slow heart rate
- An adverse drug reaction that affects the skin (Stevens-Johnson syndrome)
- An inappropriate increase in a hormone that regulates water balance (syndrome of inappropriate antidiuretic hormone secretion)
- Valproate overdose
What to expect with Carbamazepine Toxicity
The seriousness of symptoms at the time a patient reaches medical attention can have a big impact on the final results of their treatment. Some patients might experience a change in their mental state for several days following an acute overdose, but the majority will get better with time.
Teaching the patient about their condition and how to prevent it from happening again is key. It’s important that they understand how their medication works, especially if they are taking other medications. They should also be advised to store all medicines in a safe and secure place to avoid the risk of an overdose, especially amongst children.
In 2014, there were 1880 recorded cases of overdose. Out of that number, only 62 patients ended up with a serious result, which included a stay in the intensive care unit and the need for mechanical ventilation to help their breathing. Importantly, no patients died from their overdose.
Possible Complications When Diagnosed with Carbamazepine Toxicity
Carbamazepine, a medication commonly used for epilepsy, can interact with many other drugs as it influences the metabolism of these medications. This effect is particularly noted with drugs that interact with a family of enzymes known as CYP450, including some HIV medications.
Another drug often used in conjunction with carbamazepine for treating epilepsy is lamotrigine. However, this combination can cause carbamazepine toxicity, especially if initial lamotrigine levels were above 8 mg/L. This is thought to happen because lamotrigine may slow down the activity of an enzyme called ‘epoxide hydrolase’, which is responsible for breaking down carbamazepine in the body.
The introduction of levetiracetam, yet another antiepileptic drug, has caused noticeable symptoms of carbamazepine toxicity in some people. This has necessitated the reduction of either drug or, in some cases, the complete cessation of levetiracetam. While it was difficult to pinpoint a clear drug interaction based on repeated blood tests, the symptoms seemed to suggest a pharmacodynamic interaction where both drugs influenced each other’s effects within the body. These symptoms included double vision, dizziness, uncontrolled eye movement (nystagmus), lack of coordination (ataxia), nausea, and vomiting. Fortunately, slight reductions in the dosage of carbamazepine often improved these symptoms.
However, it is advisable to adjust the dosages of carbamazepine and levetiracetam until seizures are better controlled, given the relatively safer profile of levetiracetam. Additionally, it is recommended that patients on carbamazepine refrain from drinking grapefruit juice, as it can increase the levels of carbamazepine in the blood. This happens because substances in grapefruit, known as furanocoumarins, inhibit the function of the enzyme cytochrome P450 3A4, thereby slowing down the breakdown of carbamazepine.
_problematic drug combinations_
- Carbamazepine and HIV medication
- Carbamazepine and lamotrigine
- Carbamazepine and levetiracetam
_potential symptoms of carbamazepine toxicity_
- Double vision
- Dizziness
- Uncontrolled eye movement (nystagmus)
- Lack of coordination (ataxia)
- Nausea
- Vomiting
_food and drink restrictions_
- Grapefruit juice