Chloroquine Toxicity - Pathophysiology, Symptoms, Diagnosis, and Treatment

Introduction

While Hydroxychloroquine (HCQ) is now used to treat diseases like rheumatoid arthritis (an inflammatory condition that affects bone joints) and systemic lupus erythematosus (an autoimmune disease where one’s immune system fights against its own tissues), Chloroquine (CQ), a quinine derivative, has been used as an antimalarial for 70 years. As a potential treatment for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), Hydroxychloroquine (and, to a lesser extent, Chloroquine) attracted attention in 2020. Serious adverse events were a worry during research into treating Coronavirus illness 2019 (COVID-19), which was brought on by the SARS-CoV-2 virus.

What Happens in Chloroquine Toxicity?

The Chloroquine and Hydroxychloroquine drugs harm the macular cones outside the fovea because they bind to melanin in the retinal pigment epithelium (RPE). Medications reduce phagocytosis of shed outer photoreceptor segments, inhibit RPE lysosome activity, and result in a buildup of outer receptor segments. RPE atrophy and irreversible photoreceptor loss follow the migration of pigment-containing RPE cells into the retina's outer nuclear and outer plexiform layers in response. Managing minor side effects like itching and corneal deposits and major ones like retinal toxicity is important because HCQ has a long half-life (about one month), and it takes the body about half a year to eliminate it from the body fully. This also explains why maculopathy persists even after stopping the medication.

What Is the Pathophysiology of Chloroquine?

Chloroquine and Hydroxychloroquine work as chemotherapy drugs to treat malaria by killing off the parasites' erythrocytic forms of Plasmodium (a stage where the parasite is in human red blood cells). When the parasite enters the body of a patient consuming Chloroquine, the pH (potential of hydrogen) becomes acidic. As a result, the parasite is unable to grow or multiply further. The medications also prevent parasite growth by impeding the process by which toxic heme, which is generated when a parasite digests hemoglobin, is changed into non-toxic hemozoin. HQ or HCQ elevates the pH in the body cells thus, interfering with the inflammatory process and resulting in the lowering of inflammation. Additionally, the medications build up in white blood cells, where they prevent the activity of enzymes like collagenase and protease that break down cartilage by stabilizing lysosomal membranes. TLR 9 identifies immune complexes containing DNA, and CQ/HCQ suppression of TLR 9 inhibits anti-DNA auto-inflammatory activities, such as those seen in SLE (systemic lupus erythematosus).

What Are the Symptoms of Chloroquine Toxicity?

Within the first several hours after intake, Hydroxychloroquine/Chloroquine poisoning signs and symptoms appear swiftly (one to three hours). Significant ingestions can demonstrate quick progression to coma and circulatory collapse in this time frame. The primary systems influencing these clinical characteristics are as follows:

Cardiac:

• Torsades de Pointes - A kind of extremely rapid heartbeat (tachycardia) that begins in the lower chambers of the heart (ventricles).

• QRS Prolongation - An electrocardiogram finding indicating a ventricular malfunction.

• Bradycardia - Abnormally low heart rate.

• QT Prolongation - An electrocardiogram finding indicating irregular heart rhythm.

• Cardiogenic Shock - A condition where the heart cannot pump enough blood to the body parts.

Central Nervous System (CNS):

• Respiratory depression.

• Decreased level of consciousness (LOC).

• Disorientation.

• Seizures.

Metabolic:

• Severe hypokalemia (low potassium level in blood) brought on by an intracellular change.

• Rebound hyperkalemia (excess potassium level in blood) can happen if potassium replacement is carried out too aggressively, but it dissipates after the acute toxicity improves.

• Hypoglycemia (low blood sugar).

• Acute kidney injury from hepatitis (liver inflammation).

Others:

• Early nausea.

• Early vomiting.

• Changes in hearing or tinnitus (ringing noise in the ear).

• Vision changes.

• Muscle weakness.

How Is Chloroquine Toxicity Diagnosed?

Chloroquine toxicity is diagnosed using various factors:

History

To rule out retinopathy (damage to the eye's retina), patients will be questioned about their:

Central vision problems.

• Color vision changes.

• Central blind spots.

• Reading difficulties.

• Metamorphopsia (a condition when items appear to have distorted shapes).

• Photophobia (brightness-induced eye irritation).

• Poor visual acuity (low vision).

• Halos around light.

Patients with ciliary body dysfunction should be questioned about their:

• Difficulties with reading.

• Other tasks that call for accommodations.

They should be questioned about when they began taking Plaquenil (an antirheumatic medication), their current dosage, their body weight, whether they have ever had an eye exam, how frequently they see their rheumatologist, whether they have liver or kidney disease, and whether they are taking any other medications known to cause retinal toxicity, such as Tamoxifen (a drug to treat breast cancer).

Physical Examination - The focus of the physical examination should be the illness that necessitated the start of Hydroxychloroquine or Chloroquine medication. Knowing the state of the main illness process will be useful when deciding whether to stop therapy altogether or reduce drug dosage.

Diagnostic Tests

• Visual Field - Except for Asian individuals, where the defect may be more than 10 degrees from the center, visual field defects are most frequently found about 5 degrees from the center. To evaluate whether the results are significant, use statistical analysis.

• Spectral-Domain Optical Coherence Tomography (SD-OCT) - This test will show parafoveal thinning (thinning of the inner retinal layer) of the photoreceptor integrity line and the outer nuclear layer of the retina; this causes a flattening of the foveal depression (decreased thickness of the fovea- a part of the retina) and the flying saucer sign, where the outer nuclear layer is unaffected in the center of the fovea but much thinner just around it (the edge of the saucer).

• Fundus Autofluorescence (FAF): This test displays a ring of hyper fluorescence (produced by the buildup of lipofuscin - pigment with fluorescent properties) in early maculopathy and a ring of hypofluorescence in later stages (caused by the loss of photoreceptor and retinal pigment epithelial layers).

• Multifocal Electroretinography (mf-ERG): A more recent development in electroretinographic testing is the multifocal electroretinogram (mfERG), which allows for a quick evaluation of retinal function from multiple spots at once. Ring 2 is most frequently affected by amplitude reduction, followed by rings 3, 4, and 1. Less frequently, implicit times are delayed.

• The Dilated Fundus Exam: In this diagnostic method, mydriatic eye drops, like Tropicamide, are used during a diagnostic process to widen or dilate the pupil, which allows for a clearer view of the eye's fundus. 2016 recommendations show that end-stage bull's eye maculopathy (damage in the macula - a part of the retina at the back) occurs less frequently with better dosing guidelines and earlier identification.

• A clinician should be familiar with the fundus look of uneven macular pigmentation (pigmentation in the inside of the back of the eye) in the early stage, a ring of macular pigment dropout in the advanced stage, peripheral bone spicule (bony projection) development, vascular attenuation (weakened vessels), and optic disc pallor (irreversible damage to the optic nerve) in the end stage.

How Is Chloroquine Toxicity Managed?

The various treatment modalities used for Chloroquine toxicity are:

Decontamination

• Gastric Lavage: If there is an early presentation post-ingestion (one hour) with a large amount of ingestion and the provider is comfortable with the procedure, gastric lavage (a process of removing toxic products from the stomach) may be attempted.

• Activated Charcoal: It is suitable if the presentation occurs less than two hours after intake and during intubation for airway protection. To reduce the risk of charcoal aspiration, charcoal should only be given to moderately to severely poisoned patients after airway protection. Keep in mind that these medications bind charcoal strongly and may be considered after ingestion with the help of a poison center.

In Shock

• Early Intubation - For patients who are badly poisoned and are expected to experience a rapid clinical decline, IV (intravenous) bolus (large dose of medication administered through the vein).

• Epinephrine Infusion - Should be started as soon as possible; start at 0.25 mcg/kg/min (microgram per kilogram per minute) and titrate as needed. The preferred vasopressor is Epinephrine because of its added inotropy (helps the heart to beat fast) benefits. Epinephrine and Diazepam bundle therapy has been shown to reduce mortality in patients who have consumed too much Chloroquine.

• Diazepam - Start with a high dose of Diazepam (2 mg/kg (milligram per kilogram) IV over 30 minutes), then move on to 1 to 2 kg/kg daily for two to four days. Demonstrates a possible mortality advantage for patients who have been poisoned severely. Although the exact mechanism is unknown, Diazepam might be a particular cardiac antagonist of Chloroquine. Other research on patients with milder poisonings failed to demonstrate any benefits.

• Others - Depending on the treatment outcome, other vasopressors and inotropes (norepinephrine and Dobutamine) may be added.

In QRS Widening

Sodium Bicarbonate: 1 to 2 ampoules IV boluses of sodium bicarbonate are adminstered. One should check for the potassium level before administering since it may aggravate hypokalemia (low potassium levels in the blood) and increase the risk of QT prolongation. Consider using 3% (percent) saline instead of potassium if QT is severely prolonged or unclear.

QT Prolongation and Hypokalemia

• Potassium (K) Replacement - Replacement of K is done if significant hypokalemia or arrhythmias (irregular heartbeat) occur, but one should watch out for rebound hyperkalemia, which results from a shift in intracellular K levels rather than a depletion of the entire body.

• For severely resistant QT prolongation, magnesium sulfate 2 to 4 g (gram) IV or Isoproterenol can be administered.

• Treatment for Torsades de Pointes follows standard procedures, such as cardioversion or defibrillation and chemical or electrical overdrive pacing.

For Seizures - Benzodiazepines are the treatment of choice.

Conclusion

With increased use and public attention during the COVID-19 pandemic, poisoning from CQ or HCQ may become more common and pose a life-threatening risk. Hypokalemia, sudden circulatory collapse, and direct cardiotoxicity are symptoms of acute toxicity. Treatment options for patients with severe poisoning and signs of shock include intensive gastrointestinal decontamination, sodium bicarbonate for QRS interval widening, and high-dose Benzodiazepines and Epinephrine. And with prompt treatment, Chloroquine toxicity can be managed, and the lifespan of the patients can be improved.