CHEARS

In INDIA as of 1st August 2020 more than 1.89 M positive cases have been reported. And the death toll has exceeded 39K. According to the clinical data available, 1 out of 6 cases will develop respiratory distress and need proper medical care. As of the data available until now, the mortality rate of 40%-45% has been reported in patients with respiratory distress. Till now there is no drug or vaccine available for the management or prevention of COVID 19 and the treatment being used now is mainly symptomatic and supportive. Many clinical trials are ongoing to test the efficacy of some antivirals, vaccines, and hydroxychloroquine (anti-malarial) in the treatment and prevention of COVID 19 Hydroxychloroquine is the drug that is being used in India for the treatment of COVID 19.

WHAT ARE CHLOROQUINE & HYDROXYCHLOROQUINE?

Chloroquine (CQ) is a safe and low-cost antimalarial that is being used for decades in many countries. Chloroquine (CQ) and Hydroxychloroquine (HCQ) share a similar chemical structure and action, but HCQ has lower toxicity. So HCQ has been used in place of CQ.

INDICATIONS OF CHLOROQUINE & HYDROXYCHLOROQUINE:

· Malaria

· Lupus Erythematosus

· Rheumatoid Arthritis

MECHANISM OF ACTION OF HYDROXYCHLOROQUINE:

· It has been shown that hydroxychloroquine concentrates within the lysosomes of the plasmodium, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyze hemoglobin, preventing the usual growth and replication of the parasite. Hydroxychloroquine may interfere with the action of parasitic heme polymerase, with the buildup of the toxic product beta-hematin.

· Hydroxychloroquine (HCQ) accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the foremost histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH within the vesicles may alter the recycling of MHC complexes so that only the high-affinity complexes are presented on the cell surface. Self-peptides bind to MHC complexes with low affinity then they're going to be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the discharge of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors.

· Hydroxychloroquine (HCQ) has a long duration of action as it may be taken every week. A 200mg oral dose of hydroxychloroquine has a half-life of 537 hours or 22.4 days in blood, and 2963 hours or 123.5 days in plasma.

WHY HCQ AS A PROPHYLACTIC DRUG?

· Earlier studies have shown HCQ to be highly effective in vivo to treat avian influenza A (H5N1) and in vitro against severe acute respiratory syndrome coronavirus (SARS-CoV). HCQ raises the intracellular pH by sequestering the protons into lysosomes, which affects the fusion and uncoating of the virion, and viral replication. Also, it has been suggested that HCQ can interfere with the terminal glycosylation process of the angiotensin-converting enzyme-2, the cellular receptor for entry of SARS-CoV. HCQ has been shown to augment the early virological response against hepatitis C and also reduce the HIV-1 load. Apart from that HCQ also has immunosuppressive properties that may help reduce the cytokine storm in severe COVID-19. Even though HCQ is relatively safe, in adverse conditions, it can lead to cardiac disorders such as QT segment prolongation, which could lead to arrhythmia and cardiac arrest.

WHO SHOULD TAKE HCQ AS A CHEMOPROPHYLAXIS:

· Vulnerable And High-Risk Groups: People who are older than 60 years or who have health conditions like lung or heart disease, diabetes or conditions that affect their immune system like cancers and those using immune suppressants and people living in areas with a higher incidence of COVID 19 cases should use HCQ as chemoprophylaxis under the supervision of community health care professionals.

DOSING OF HCQ FOR CHEMOPROPHYLAXIS:

As per the protocol given by ICMR 800 mg on 1stday followed by 400mg once a week for 7 weeks is appropriate for prophylaxis of COVID 19 in adults. Use with attention in patients with renal and hepatic impairments.

For adults: Appropriate dosing can be done based on 13mg/kg body weight for loading dose and 6.5 mg/kg body weight for a maintenance dose.

For children: dosing can be done by using Clark's Rule, Young’s Rule, etc.., use the best formula you wish.

Example: Clark's Rule Here is the formula: Adult Dose X (Weight ÷ 150) = Childs Dose

For example a child with 40 kgs weight was diagnosed with COVID 19

Then dosing must be

1. Convert body weight from kgs to lbs i.e., 1kg = 2.205 lbs

So, here 40 x 2.205 = 88 lbs are the weight of the child

2. Substitute wt in the formula Adult Dose X (Weight ÷ 150) = Child’s Dose

Adult Dose X (88 ÷ 150) = Childs Dose

3. Then substitute standard adult dose i.e., 800 mg

800 X (88 ÷ 150) = Child’s Dose

= 469 mg is the loading dose

Sub 400 mg in the adult dose for maintenance dose:

400 X (88 ÷ 150) = Child’s Dose

= 234 mg is the maintenance dose

Measures To Be Taken By Clinicians To Prevent Adverse Effects:

Therapeutic drug monitoring (TDM) could also be performed to optimize dosage regimens supported measurements of drug concentrations at designated intervals. The feedback from TDM can help doctors maintain a therapeutic concentration in a personal patient’s bloodstream while minimizing potential side effects. Us Food and Drug Administration (FDA) outlines potential risk factors for patients using hydroxychloroquine and chloroquine, including:

• Cardiac Effects, including Cardiomyopathy and QT prolongation which can cause cardiac arrhythmias

• Irreversible Retinal Damage

• Worsening of psoriasis and porphyria

• Proximal myopathy and neuropathy

• Neuropsychiatric events

• Hypoglycemia

• Chloroquine should be avoided during pregnancy

• Reduced antibody response to the rabies vaccine

Hydroxychloroquine features a very long elimination half-life of 20 to 50 days, which might raise the complexity of dosing. The subsequent drugs can significantly affect blood concentrations of chloroquine or hydroxychloroquine:

• Antacids and kaolin reduce the absorption of chloroquine when taken together

• Cimetidine causes increased chloroquine concentrations.

Hydroxychloroquine is concentrated in red blood cells and features a pronounced and highly variable blood-to-plasma ratio.

Measures To Be Taken By Patients:

· Don’t take HCQ without prescription and should be taken under medical supervision.

· Must perform blood and urine tests in the 1stweek of treatment to detect any unwanted effects (especially in patients with other medical conditions).

· Must consult your clinician if any undesired outcomes (blurred vision, headache, dizziness, loss of appetite, nausea, diarrhea, stomach pain, vomiting, rash, sweating, shakiness, weakness, fast heartbeat) noted.