The COVID-19 pandemic has spread globally, not only producing a huge number of cases and deaths but also massively impacting all areas of daily life. As of this blog post, there are currently no approved vaccines and treatments for COVID-19. Existing drugs are tested to see if it can treat COVID-19, including chloroquine and its chemical relative hydroxychloroquine. Despite no sound evidence that they are effective against COVID-19, Donald Trump’s endorsement of these drugs has led some countries to produce and stockpile these drugs to combat COVID-19 and deaths due to self-medication of chloroquine. At the same time, patients that need these drugs to control their conditions fear that they will not be able to obtain them, leading to restrictions on who can prescribe and use these drugs and when these drugs can be used to treat COVID-19.
Over the next two blog posts, I will be talking about the science behind chloroquine and hydroxychloroquine and why their use in COVID-19 is controversial. In this blog post, I will talk about what chloroquine and hydroxychloroquine are, what diseases they treat and their side effects. In the next blog post, I will describe the studies on chloroquine and hydroxychloroquine in COVID-19 and argue that more comprehensive studies are needed to fully test their effectiveness.
What are chloroquine and hydroxychloroquine?
Chloroquine (brand name Aralen®) and hydroxychloroquine (brand name Plaquenil®) are artificial compounds of quinine, a bitter compound derived from the bark of the cinchona tree. While quinine was first isolated in 1820, chloroquine was first synthesised in Germany in 1934 and hydroxychloroquine in the USA in 1950. Hydroxychloroquine, different from chloroquine by its OH group, is a less toxic form of chloroquine that retains its effectiveness in treating disease. Consequently, even though both drugs are listed on the FDA (US Food and Drug Administration) and TGA (Australian Therapeutic Goods Administration), hydroxychloroquine but not chloroquine is widely sold in Australia.
Both chloroquine and hydroxychloroquine are 4-aminoquinolines. They have a flat aromatic core structure that resembles quinine (black in figure). They also have a tertiary amine group in the side chain (blue in figure) which acts as a weak base. Here, it attracts a hydrogen ion from an acid to become positively charged, neutralising the acid in the process.
Did you know? Quinine is found in small amounts in tonic water, a bitter drink that is commonly mixed with spirits such as gin (gin and tonic) and vodka (vodka tonic).
The drugs as an antimalarial
Chloroquine and hydroxychloroquine are commonly used to treat malaria, a parasitic disease caused by the single-celled Plasmodium species. These parasites are carried by mosquitos, where they are injected into the human body as the mosquito is sucking blood. They initially replicate in the liver before they infect red blood cells. While inside the red blood cell, malarial parasites form a food vacuole to break down hemoglobin to amino acids in order to grow. This process releases heme which is toxic to the parasite. This toxicity can be neutralised by joining heme molecules to form hemazoin which is mediated by the parasitic enzyme heme polymerase.
Chloroquine and hydroxychloroquine can enter red blood cells to target and inhibit heme polymerase inside the food vacuole. Both drugs bind to the ends of hemazoin, preventing more heme molecules from joining up. Toxic heme builds up inside the food vacuole which kills the malarial parasite. Hence, chloroquine and hydroxychloroquine are taken to prevent and treat malaria. In fact, these drugs are commonly taken weekly before, during and after travelling to countries where malaria is endemic and is not resistant to these drugs.
Did you know? Most malarial parasites of the Plasmodium falciparum species are resistant to chloroquine and hydroxychloroquine. This is because they possess a mutated protein channel (called PfCRT) that transports chloroquine and hydroxychloroquine out of the food vacuole, preventing these drugs from inhibiting heme polymerase.
The drugs as anti-inflammatories
In addition to malaria, chloroquine and hydroxychloroquine are commonly prescribed to treat rheumatoid arthritis and systemic lupus erythematosus (SLE). These are autoimmune diseases where the immune system attacks its own cells and tissues. For example, rheumatoid arthritis is associated with the immune system damaging joints around the body, causing pain and swelling. In contrast, SLE involves antibody complexes depositing onto small blood vessels, activating the immune system around the body which can damage organs and cause symptoms, most notably the butterfly rash on the face.
Chloroquine and hydroxychloroquine inhibit immune responses and inflammation that drive these diseases. Entering white blood cells from the bloodstream, they accumulate in acidic compartments such as lysosomes, Golgi apparatus and endosomes. As weak bases, they neutralise acids inside these compartments by taking up hydrogen ions, increasing the pH. This impairs the ability of enzymes to break down and present antigens to T cells, reducing inappropriate immune responses and inflammation to relieve symptoms. In addition, these drugs may also reduce inflammation by inhibiting pathways that lead to the release of pro-inflammatory factors such as IL-1, IL-6 and TNF-α.
Side effects of the drugs
Chloroquine and hydroxychloroquine are widely prescribed to treat malaria and autoimmune diseases, but they also produce well-known side effects. High concentrations of chloroquine and hydroxychloroquine are toxic to the body, damaging cells and tissues in a variety of organs to produce side effects. These high concentrations can be maintained over long periods of time as these drugs take a long time to exit from the body (having a half-life of 40-60 days), increasing the chances that they can cause side-effects. In particular, chloroquine and hydroxychloroquine can accumulate in the skin and eyes by binding strongly to melanin, a pigment molecule. This can damage the skin and eyes, causing skin side effects such as rash and retinopathy (retina damage that leads to blindness). These drugs also produce other side effects around the body, causing symptoms such as diarrhoea, headache and hair loss.
Hence, chloroquine and hydroxychloroquine must be carefully prescribed by a qualified medical professional to ensure that patients are appropriately treated without getting serious side effects. Regular checks, particularly the eyes, must be conducted to ensure that these drugs are not causing long-term damage to the body. As these side effects are well-known, in trialling these drugs in new diseases, the potential benefits must outweigh the risks before they are widely prescribed to treat the disease.
Did you know? The same effects of chloroquine and hydroxychloroquine may also be harnessed to treat other diseases. Trials are currently being run to see if other properties of these drugs can be used to treat diseases such as diabetes and cancer.
Conclusion
Chloroquine and hydroxychloroquine are drugs that have wide-ranging properties and are used treat a variety of diseases. They are used to treat malaria, acting on the parasite itself to impede its survival. They were later used to treat rheumatoid arthritis and SLE by inhibiting immune activity and inflammation, reducing the severity of disease and symptoms. However, these same drugs can also cause a lot of side effects, some of which can be deleterious such as retinopathy. Hence, the severity of these side effects must be weighed against any potential benefits the drugs may have to a particular disease or infection before they are widely prescribed. This is something that must be considered when testing the effectiveness of chloroquine and hydroxychloroquine in COVID-19, and it is something that will be discussed in the next blog post.