What is Chloroquine and Hydroxychloroquine Toxicity?
Chloroquine and hydroxychloroquine are types of drugs known as 4-aminoquinoline compounds. The first one, chloroquine, is often used to fight malaria. In the past, it was widely used as a precautionary measure to prevent the onset of malaria caused by the Plasmodium parasite. Now, because the Plasmodium parasite has grown more resistant, chloroquine is only used in certain parts of the world.
The second drug, hydroxychloroquine, is less harmful than chloroquine, and it is mainly used to treat rheumatic diseases, which cause joint pain and stiffness. These diseases include systemic lupus erythematosus (SLE) – an immune system ailment that can affect many parts of the body including joints, skin and organs – and rheumatoid arthritis (RA), a chronic inflammatory disorder affecting many joints, including those in the hands and feet.
Chloroquine works against the Plasmodium parasite by stopping the growth of DNA and RNA, components necessary for the parasite’s survival, and by blocking its usage of hemoglobin, a protein that carries oxygen in the blood. Similarly, hydroxychloroquine fights against the parasite by disrupting its digestion process and breaking down of hemoglobin. Furthermore, hydroxychloroquine also works as an anti-rheumatic drug by slowing down the actions of specific white blood cells (neutrophils and eosinophils) and reducing immune system responses that can cause inflammation.
However, chloroquine and hydroxychloroquine can produce several side effects like stomach upset, allergic reactions, heart muscle disease, heartbeat irregularities, nerve and muscle damage, reduction in blood cells, and skin discoloration. Long-term use of these drugs can also lead to eye problems such as deposits in the cornea, _ the transparent front part of the eye, cloudiness in the backside of the lens, problems in the ciliary body, (a part of the eye that produces the fluid in the eye), retinopathy (a disease of the retina,), changes in the macula (the part of the retina responsible for central vision), formation of extra bony growths in peripheral areas, thinning of blood vessels, and pale optic disc. These toxic effects may lead to the loss of vision.
What Causes Chloroquine and Hydroxychloroquine Toxicity?
Chloroquine and hydroxychloroquine, two types of drugs, interact with a substance called melanin found in the retinal pigment epithelium (RPE). The RPE is a layer of cells in your eye involved in visual clarity. When these drugs interact with melanin, it can harm the cells responsible for color vision located in the macular region (centre part) of your eyes, but outside of the fovea which is the part of the eye that provides sharpest vision.
These drugs can disrupt the activity of lysosomes, which are like the waste disposal system of a cell, hindering them from getting rid of waste. In this case, the waste are the used up parts of photoreceptor cells that capture light for vision. This waste accumulation triggers RPE cells filled with pigment to move into parts of the retina that they shouldn’t. This leads to a permanent loss of photoreceptor cells and RPE atrophy, which is shrinkage or wasting away of the cells.
Hydroxychloroquine has a long duration where it remains in your body even after you stop taking it; it typically takes about 6 months to completely leave your body. This is particularly important when managing side effects like damage to the retina (a layer at the back of your eyeball) as this explains why vision problems may persist even after you stop the medication.
Deposits can also form in your corneas (the clear, dome-shaped front part of your eye), which result from the drug binding to fats in cells and gathering in the base layer of the cornea. These deposits typically disappear once you stop taking the drug.
When taken orally, chloroquine is entirely absorbed by your body and collects in various tissues. After intake, chloroquine temporarily increases in your blood compartment before distributing into the tissues. The high level of the drug in the blood can cause heart toxicity, imbalance in your circulatory system, and collapse when taken in very high doses. Both chloroquine and hydroxychloroquine can block sodium and potassium channels, which are crucial in maintaining the heart’s rhythm. This blockade can lead to irregular heartbeats and can potentially extend QRS and QT intervals in an EKG reading, a measure of time it takes for electrical signals to move through the heart. In acute overdose, this can cause heart rhythm disorders.
Risk Factors and Frequency for Chloroquine and Hydroxychloroquine Toxicity
Researchers have found that long-term use of hydroxychloroquine can sometimes cause damage to the retina, the sensitive area at the back of the eye. In one study in 2003, this happened in about 0.38% of patients, while a 2010 study found a slightly higher rate of 0.68%. The 2010 study involved patients who had been taking the medication for 5 to 7 years. These findings led the American Academy of Ophthalmology to issue new guidelines about checking for eye problems in 2011.
- The studies showed that the most important factor in predicting damage was how long the medication had been used. Other factors like age, daily dosage, and patient weight were not significantly linked with the chance of eye damage.
- A different study found a much higher overall risk of 7.5% among the studied patients. This study also showed that if a person has kidney disease or is undergoing treatment with a medication called tamoxifen, they are more likely to develop eye problems due to hydroxychloroquine use.
- A 2015 report found that a certain type of damage to the retina without the standard parafoveal damage was more common in Asian patients (50%) compared to Caucasian patients (2%), suggesting that Asian patients might need different kinds of screening tests.
During the early part of the COVID-19 pandemic, hydroxychloroquine was sometimes used to treat the virus off-label. This led to an increased rate of heart problems, including a prolongation of the QT interval on EKG, a specific type of abnormal heart rhythm called “torsades de pointes,” and cardiac arrest. Long-term use of hydroxychloroquine can also cause eye problems, but these were not a significant issue with the short-term use for COVID-19 treatment. One common side effect of both hydroxychloroquine and a related medication, chloroquine, is stomach upset, which can occur even with short-term use. Overdoses on chloroquine are rare in the US but are more common in parts of the world where malaria is common.
Signs and Symptoms of Chloroquine and Hydroxychloroquine Toxicity
When developing an eye history, specific inquiries about any pre-existing retinal disease should be made. There should also be questions regarding central vision sharpness, the ability to focus on close objects, and sensitivity to bright light. Chloroquine (CQ) and Hydroxychloroquine (HCQ), commonly used medicines, can produce non-eye related side effects like itchiness, headaches, dizziness, and stomach issues. These effects ought to be checked because they could lead to patients avoiding taking their medicine. A rare side effect of HCQ is muscle weakness, typically affecting the larger muscles near the body’s center. If this occurs, a muscle biopsy can identify key pathological findings.
- Questions regarding pre-existing retinal disease
- Inquiries about central vision sharpness and ability to focus on close objects
- Examining sensitivity to bright light
- Discussing possible non-eye related side effects like itchiness, headaches, dizziness, and stomach disturbances caused by Chloroquine (CQ) and Hydroxychloroquine (HCQ)
- Checking for muscle weakness if Hydroxychloroquine (HCQ) use is present
For instances of acute toxicity, you should include the medical conditions that called for CQ or HCQ treatment, the time since the last prescription refill, the time of ingestion, the daily dosage, and the quantity taken in. Patients attempting suicide or those critically ill and unable to communicate effectively might not disclose this information readily. In these situations, a thorough review of all medications can help doctors or medical toxicologists determine if HCQ or CQ is possibly involved. Furthermore, significant changes in vital signs and heart activity could also point to an acute overdose. Although the physical exam may reveal severe central nervous system or respiratory depression, these symptoms are not unique to HCQ and CQ toxicity.
Testing for Chloroquine and Hydroxychloroquine Toxicity
Based on reports in 2002, 2011, and 2016 from the American Academy of Ophthalmology, there are clear guidelines for checking the eyes of patients on CQ/HCQ therapy. The testing process usually starts within the first year of therapy, beginning with a thorough eye examination to note any pre-existing conditions of the retina, the sensitive back part of your eye.
Often additional tests, including automated visual field (VF) testing and spectral domain optical coherence tomography (SD-OCT), might also be conducted during this visit. For people of Asian descent, a wider VF test is needed since half of them might develop retinopathy – a damage to the retina – outside the central 20 degrees of their visual field.
Your doctor might also recommend more screening tests like taking an inner image of your eye (SD-OCT), autofluorescence to capture detailed images of the retina, and multifocal electroretinography, which is highly sensitive but less available. For Asian patients, wide-field SD-OCT and FAF should be performed.
Annual screening is generally recommended after five years on the medication unless you have additional risk factors such as being small, overweight, having liver or kidney disease, or any retinal disease. Under these circumstances, you should have these tests annually right from the start.
As for interpreting results, visual field defects will most typically appear at 5 degrees from the center (or over 10 degrees for Asian patients). An SD-OCT test may show thinning in certain layers of your retina, and an FAF test might show a ring of brightness in early issues, switching to a darker ring in later stages of the disease.
Last but not least, if you have taken an overdose of hydroxychloroquine or chloroquine, doctors will undertake several tests to address specific health concerns. These include measuring your blood sugar, checking blood count and electrolyte levels, and scanning for cardiac abnormalities and arrhythmias.
Treatment Options for Chloroquine and Hydroxychloroquine Toxicity
If you are taking a drug and there is strong evidence that it’s causing long-term harm, you should discuss stopping the drug with your doctor. This is because the negative effects, such as damage to the back part of your eye (retina), can continue for over 6 months, and sometimes even up to 20 years, after you stop taking the medication. The goal is to catch these early signs of harm when you don’t have any symptoms yet.
If you accidentally take too much of a drug, like chloroquine or hydroxychloroquine, immediate and supportive medical care is necessary. This includes setting up an intravenous line for medication and fluid delivery, providing oxygen, heart monitoring, and checking blood pressure. It’s important to remove the drug from your stomach as soon as possible by washing out your stomach (gastric lavage) or giving you a substance called activated charcoal that can absorb the drug. However, doctors need to think carefully before starting these procedures because they can cause side effects, such as depression of the central nervous system, a drastic drop in blood pressure, and seizures. Quick and assertive treatment of serious drug overdoses, including putting a tube down your throat to help you breathe, has been shown to reduce the risk of death. Certain sedative drugs, like barbiturates, should be avoided as they can cause the heart to stop while the breathing tube is being placed.
If your heart is not pumping blood around your body effectively (hemodynamic instability), a medication called epinephrine is usually the most studied and recommended treatment for both chloroquine and hydroxychloroquine overdoses. Taking this along with high doses of a drug called diazepam has been shown to decrease the chances of death. Initial observations in patients who took chloroquine and diazepam together showed that diazepam might decrease heart toxicity and could therefore potentially be helpful. Animal studies and reports from humans have also suggested this benefit. In fact, the survival rates for patients treated with high doses of diazepam, epinephrine, and a machine to help them breathe were 91% compared to only 9% for those who did not receive this combination of treatments. However, exactly how diazepam benefits patients who have taken too much chloroquine is not entirely clear yet.
Although sodium bicarbonate is often used to treat toxic effects caused by certain drugs blocking sodium channels in cells, it’s typically not recommended for treating chloroquine and hydroxychloroquine toxicity. Your doctor might consider it, though, if you have low potassium levels in your blood (hypokalemia) or if the electrical activity of your heart is affected (QT prolongation).
What else can Chloroquine and Hydroxychloroquine Toxicity be?
When diagnosing Vortex Keratopathy (VK), a condition that can affect the cornea, doctors need to consider many possibilities. Here are some of the alternatives:
- Subepithelial deposition of medications: This happens when various medicines accumulate under the epithelium, or skin cells, of the eye. For example, Amiodarone is the most common medicine that can cause verticillata, a condition that appears similar to VK.
- Fabry disease: This is a rare genetic disease that can cause symptoms similar to VK.
- Iron lines: These show up as a line of iron deposits in the basal layer of the skin and can sometimes be confused with VK.
- Gout: It can cause the deposition of uric acid crystals in the eye that might be confused with VK.
- Corneal chrysiasis: It’s due to the accumulation of gold in the corneal stroma. It’s usually identified through a thorough medical history that reveals a history of gold salts treatment.
There are also some conditions that resemble CQ/HCQ Retinopathy, a disorder affecting the retina, including:
- Age-related macular degeneration (GA): Though it resembles CQ/HCQ retinopathy, it has a unique appearance that can help in its identification.
- Central areolar choroidal dystrophy (CACD): Although it can look like CQ/HCQ retinopathy, it develops at a younger age and progresses differently.
- Stargardt disease: It can be differentiated from CQ/HCQ retinopathy by the presence of certain unique characteristics.
- Cone-rod dystrophy (CRD): CRD can present with similar symptoms to CQ/HCQ retinopathy, but testing can accurately differentiate between the two.
- Benign concentric annular dystrophy (BCAD): This rare disorder looks like CQ/HCQ retinopathy, but the visual acuity remains normal.
Lastly, in case of acute toxicity, some of the substances that can imitate the symptoms caused by CQ/HCQ include:
- Beta-blockers: These can cause hypotension, cardiac fashion abnormalities, and bradycardia.
- Calcium channel blockers: They may cause hypotensive, bradycardia, and irregular heartbeat.
- Loperamide: Often abused in patients with opioid use disorder, it can cause both heart-related and nervous system conditions.
- Clonidine: It’s an alpha-2 adrenergic agonist that causes bradycardia and hypotension, making it resemble opioid toxicity.
- Quinine: Quinine overdoses are often associated with low potassium levels, which can be accompanied by low blood sugar levels.
All these conditions exhibit similar clinical features to VK and CQ/HCQ toxicity, which makes thorough testing and examination crucial for correct diagnosis.
What to expect with Chloroquine and Hydroxychloroquine Toxicity
If a healthcare professional identifies early signs of retinopathy – a disease that damages the retina in your eye – but does not stop the medication chloroquine/hydroxychloroquine (CQ/HCQ), the patient may experience a progressive loss of vision. First, they could lose their paracentral vision, which is the vision right next to the center of the gaze, and eventually, it could lead to loss of central vision and difficulty seeing at night. Retinopathy can still progress even when medication is discontinued and may continue to do so for years afterward.
The condition known as vortex keratopathy, where spiral patterns appear on the cornea of the eye, can cause increasing issues with seeing halos and blurry vision. However, these symptoms can fully reverse once the medication is stopped.
If a patient accidentally consumes too much chloroquine and hydroxychloroquine, the prognosis or likely outcome depends on the amount they’ve taken. In some cases, children have tragically died after taking just 1 to 2 tablets. It’s believed that consuming 2 to 3 times the recommended prescription dose can lead to a fatal outcome in less than three hours. In adults, taking between 8 to 22 grams of the medication can cause serious toxicity that can be life-threatening.
Possible Complications When Diagnosed with Chloroquine and Hydroxychloroquine Toxicity
Even when a doctor and his or her patient follow the guidelines for ongoing check-ups when using chloroquine or hydroxychloroquine, stopping these drugs might not prevent the eye disease from progressing to a stage where the patient’s vision is protected.
If someone takes these drugs in an extreme amount abruptly, it can lead to detrimental effects on multiple organs and might cause death due to the failure of the circulatory system. Patients may experience lasting and irreversible effects, even when the immediate signs of high-level toxicity have faded.
Effects of Chloroquine or Hydroxychloroquine:
- Eye disease progression even after discontinuing use
- Multiorgan failure after heavy dosage
- Potential death due to severe circulatory system issues
- Prolonged and irreversible effects despite the cessation of high-level toxicity
Preventing Chloroquine and Hydroxychloroquine Toxicity
As mentioned before, it is essential to understand the latest testing guidelines and to clearly communicate the risks and benefits of using CQ/HCQ, a type of medicine. This is needed to lower the risk of long-term harmful effects, while still enjoying the vast benefits this medicine offers in treating certain diseases caused by parasites and inflammation of joints. Furthermore, patients should be taught how to correctly use and store their medicine to avoid sudden and severe harmful effects. This point is crucial particularly in homes where children live.
