I recently listened to a webinar sponsored by the American College of Medical Toxicology and the European Association of Poison Centers and Clinical Toxicology regarding the administration of chloroquine (CQ)/hydroxychloroquine (HCQ) for the treatment of COVID-19 and the treatment of overdose of these drugs. Six hundred people were listening to the webinar! One of the speakers was a French toxicologist ICU physician who has significant experience in treating coronavirus and CQ/HCQ overdose (OD). The following are excerpts from the webinar. My comments are in italics.
The webinar started with a discussion of the elderly Arizona couple who ingested chloroquine phosphate because they thought it was the same thing as chloroquine and would prevent coronavirus. One died, the other is expected to recover. The course of CQ overdose can be quiet variable but the patient who recovered vomited soon after ingestion
This couple ingested a product called New Life spectrum powder fish food, which is chloroquine phosphate (not the same as CQ or HCQ). The difference in the products is not appreciated as demonstrated by the fact that chloroquine phosphate fish food is currently out of stock in most pet stores that sell it.
Why is chloroquine plus azithromycin being considered for treatment of COVID-19?
Chloroquine/hydroxychloroquine was administered for treatment of malaria until resistance developed. Hydroxychloroquine has subsequently been administered to treat rheumatoid arthritis and SLE. It is now being administered off label to treat COVID-19.
Chloroquine/hydroxychloroquine has a strong immunomodulatory capacity. It also inhibits receptor binding and membrane fusion which are required for cell entry by coronavirus. Chloroquine exerts an antiviral effect by interfering with glycosylation of ACE which reduces binding efficiency between virus and host. Advantages of these drugs is that they are not immunosuppressant and are distributed well after oral administration.
HCQ has fewer side effects than CQ. Chloroquine is more toxic than HCQ in OD.
Azithromycin has immunomodulatory and antiviral effects in vitro and seems to be especially efficacious if pneumonia is present.
Adverse effects of HCQ include CV, GI, hearing, vision (retinopathy), myopathy, neuropathy, neuropsychiatric effects and hypoglycemia.
Treatment in France
In France, as there is a limited supply, HCQ/azithromycin is only being administered for hospitalized patients with severe coronavirus disease.
-Dosing: 600 mg/day i.e. 200 mg tid for 10 days. With this regimen, plasma concentration is higher than seen when taking therapeutically.
-HCQ drug concentrations
-Main reason HCQ is discontinued is drug-induced QT prolongation (500msec)
(combination of HCQ and Azithromycin-high risk of QT prolongation)
Why not administer chloroquine/ hydroxychloroquine prophylactically?
First, there is a critical shortage of these drugs, so they are being preserved for the sickest patients and are not available in the outpatient setting. However, the limited supply leads to the risk of seeking nonpharmaceutical formulations such as fish food (chloroquine phosphate). Unfortunately, people are asking physicians for HCQ prescriptions in case they or their family get the coronavirus.
Second, there are Public Health considerations:
Lack of clinical guidelines
Special vulnerable populations-children, pregnancy, breast feeding
If these drugs are given to large populations, how would they be monitored? (issue of QT prolongation and potential of already taking QT-prolonging medications)
Currently, in the US, HCQ is being assessed as an early treatment of coronavirus.
OVERDOSE of chloroquine/hydroxychloroquine
There is significant experience in France with this overdose due to a French book (1982) on “instructions for suicide” that recommended chloroquine. At that time chloroquine was sold in pharmacies without a prescription. Not surprisingly, French physicians have treated many CQ/HCQ overdoses.
OVERDOSE Mechanisms
Cardiac Sodium channel blocker ( NCB) QRS prolongation; cardiac potassium channel blocker ( KCB) QT prolongation; shifts K intracellular (adds to QT prolongation)
Predictors of mortality-QRS>120(key indicator) hypotension, ingestion of > 4 gms
Treatment of OD (from the webinar based on the French experience)
EP (hi dose) as opposed to other vasopressors
Diazepam infusion (2 mg/kg bolus over 30 min) then 1-2 mg/kg /hour for 24 hours (There is some indication from animal studies that diazepam improved outcome in HCQ OD. During the suicide epidemic in France, patients seemingly had better outcome if diazepam was ingested with HCQ. There is no clinical data. In the one severely ill HCQ OD patient that I managed, blood pressure (systolic=50) increased immediately after administration of diazepam. I know, n=1 is a bit small.)
K replacement
Sodium bicarb for serum alkalinization (careful of hypokalemia)
Bad prognostic indicators: ingestions of >4g ; QRS >100 msec, and hypotension. If greater than 4 grams is ingested and QRS prolongation is present, patients are intubated and placed on epinephrine (advantage of preventing bradycardia which can lead to torsades in the setting of QT prolongation).
Consider ECMO when epi> 3 mg/h in presence of organ failure
Questions:
If cardiac premorbidity secondary to COVID is present, would you treat with hydroxychloroquine? No, as effectiveness has not been proven.
Prepared by Donna Seger, MD
I am interested in any questions you would like answered in the Question of the Week. Please email me with any suggestion at donna.seger@vumc.org.
Donna Seger, MD
Executive Director
Tennessee Poison Center
Poison Help Hotline: 1-800-222-1222