Antiparasitic Drugs For Malaria

Introduction

Malaria is a concerning illness transmitted by mosquitoes. When an infected mosquito bites a person, tiny Plasmodium parasites enter the bloodstream, giving rise to the disease we recognise as malaria.¹ The symptoms of malaria typically surface 10-15 days after the bite, and their nonspecific nature makes diagnosis challenging based solely on symptoms.² These symptoms include nausea, fever, chills, coughs, and headaches.³

If not promptly treated, malaria can progress to severe stages, potentially leading to kidney failure, anaemia, and, in severe cases, proving fatal. While malaria has been successfully eliminated in temperate regions such as Europe and North America, it continues to be a prevalent concern in South America, Africa, and South Asia.³ This poses a serious threat to both the local population and travellers, emphasising the importance of understanding malaria.

Fortunately, malaria can be effectively cured with prompt treatment. However, challenges have arisen in contemporary malaria treatments due to the emergence of Plasmodium strains resistant to common antimalarial drugs, such as chloroquine and quinine.⁴ In this article, we will explore new and promising antiparasitic drugs designed to address these challenges. Additionally, we will delve into the mechanisms through which the malaria parasite causes the disease and the reasons behind its resistance to conventional medications. Understanding these aspects is crucial for fostering compassion and awareness in our collective efforts to combat malaria.

Malaria parasite life cycle

Plasmodium is the microorganism responsible for malaria and is so small it is just a single cell in size. They can infect a plethora of different animals, however, only four species of Plasmodium can infect humans; Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.¹ All of these differ from one another when it comes to prevalence, where in the world they are found, and the severity of the disease they cause. They are also different when it comes to drug resistance. P. falciparum results in the most severe cases of malaria whilst P. vivax is the most common, but more mild.¹

Life Cycle

• Plasmodium starts in a spore-like state, a sporozoite, in the saliva of mosquitoes.
• The infected mosquito bites a person, injecting the sporozoite into the bloodstream alongside its saliva.
• The sporozoites travel in the bloodstream to the liver where they enter the liver cells.
• The sporozoites will remain in the liver cells for 9-16 days where they will replicate into thousands of merozoites.
• The liver cells then burst, releasing the merozoites into the bloodstream, where they invade red blood cells.
• Once inside, the merozoite forms a ring-like structure, becoming a trophozoite, and feeds on the contents of the red blood cell.
• When the trophozoite has grown big enough it will divide into around 20 merozoites and the red blood cells will burst, releasing them to continue the cycle of infection. This is what causes symptoms.
• A very small number of merozoites will form into gametocytes, which, when the infected person is bitten by a mosquito, will enter the mosquito, starting the life cycle over again.¹ 

What are the antiparasitic drugs for malaria?

Quinoline antimalarials

Malaria can be treated through the use of many different drugs, however, the preferred treatment will depend on which species of Plasmodium the patient has, and whether the state of malaria is severe or not.⁵ Antiparasitic drugs for malaria can either be used as a treatment option for those who have contracted malaria, or as a prophylaxis, which is taken to prevent malaria.

This branch of antimalarials includes chloroquine, quinine, and mefloquine.⁶ Quinine was the original antimalarial drug, being discovered in the 1600s, but is now considered too toxic for use, and is only used in extreme cases.^6,7 In search of new drugs, a plethora of quinine analogues have been discovered including chloroquine.

Chloroquine

After chloroquine was discovered it quickly became the most used drug to treat malaria.⁶ It works as follows:

• The Plasmodium grows inside of the host red blood cells, feeding on its contents.
• Haemoglobin, responsible for transporting oxygen, starts to degrade leading to the release of toxic iron products.
• Normally the Plasmodium can detoxify the iron, allowing it to continue growing.
• Chloroquine works by entering the red blood cells and prevents the detoxification of iron.
• The buildup of toxic iron results in the death of the Plasmodium.⁸

However, malarial resistance to chloroquine has grown to immense numbers. This has led to the withdrawal of chloroquine as an effective antimalarial drug in many countries. It is now mainly used in parts of Central America and the Caribbean.

Mefloquine

Mefloquine is yet another quinine analogue, but this one is used as a malaria prevention drug by people travelling to countries with a tropical climate. Mefloquine resistance has been noted but is not as severe as chloroquine, and as such it is still actively prescribed.⁹ The exact mechanism of action is unknown however studies have garnered a general overview of the process.

• Mefloquine is said to act on Plasmodium both within the blood and in red blood cells.
• For Plasmodium within the red blood cells, mefloquine can attach to the surface of the cell and enter, being able to make contact with the Plasmodium.
• Mefloquine binds to the surface of Plasmodium. 
• It then is thought to act to disrupt the surface membrane of the Plasmodium, specifically affecting the transport of lipids.
• This will have a knock-on effect on growth and eventually kill the parasite.⁶

Antifolates

Antifolates are a class of drugs originally used to treat cancers such as leukaemia. They can be either class I or class II and work in unison to treat the disease. As such they are generally prescribed together.

Class I antifolates

Class I antifolates are inhibitors of dihydropteroate synthase, a protein in Plasmodium that is involved in making the chemical folate.¹⁰ This is an ideal drug target as this enzyme is not present in humans. 

• Fansidar: a combination of pyrimethamine and sulfadoxine, is widely used as an antimalarial in endemic areas.
• Fansidar has been further combined with a drug called sulfalene to make metakelfin, a drug which works just as well as fansidar, but is less popular.¹⁰

Class II antifolates

Class II antifolates are inhibitors of dihydrofolate reductase, an enzyme which produces tetrahydrofolate. These enzymes are present in both humans and Plasmodium so any drugs of this nature need to be made to prefer the parasite enzymes rather than humans, to not cause too many side effects for the patient. 

• Proguanil: the first antifolate antimalarial drug. It has been used both alone and in combination with chloroquine but has recently been used in combination with a drug called atovaquone.
• Chlorproguanil: more potent than proguanil but less popular. It is used for prophylaxis but is now used in combination with dapsone.
• Pyrimethamine: also known as daraprim, is the most widely used antifolate antimalarial drug. It can be used alone but is more commonly used alongside sulfadoxine or sulfalene.¹⁰

Artemisinin derivatives

Artemisinin derivatives are a group of potent antimalarial drugs that are noteworthy due to how quickly they kill Plasmodium. They are used to treat patients with severe malaria due to their fast-acting nature.¹¹ 

• Artemether: used in combination with lumefantrine, it is a safe and effective treatment for severe malaria, rivalling the effectiveness of quinine derivatives.¹²
• Artesunate: another potent medicine. Artesunate is combined with the quinoline antimalarial; mefloquine. When used in combination the treatment time can be cut down to just 3 days.¹³ 
• Dihydroartemisinin: used in combination with piperaquine. It can be used to treat less severe types of malaria with good efficacy.¹⁴

Challenges and limitations

Despite being extensively studied, malaria cases are on the rise, causing over 600,000 deaths in 2021 alone. Approximately 90% of malaria-related deaths occur in Africa and as such, a major concern associated with antiparasitic antimalarial drugs is cost and patient access.¹⁵ Healthcare systems in developing countries may not be robust enough to deal with excess malaria cases, and patients may not be able to access healthcare and medicine.

Additionally, the surge in drug-resistant strains of P. falciparum and P. vivax have led to the limited efficacy of chloroquine and other common antimalarial drugs. This isn't just a local issue, it is a global issue affecting travellers as well as the native population. Creating a vaccine for malaria has proven extremely difficult so a push to design new treatments and preventative medications is of the utmost importance to curbing the rise in cases.¹⁵

Summary

Malaria, transmitted by mosquitoes, is a global health concern with symptoms appearing 10-15 days post-infection. These symptoms are general, making diagnosis challenging. If left untreated, severe malaria can lead to kidney failure, anaemia and eventually mortality. While eradicated in temperate regions, malaria persists in South America, Africa, and South Asia, posing a risk to both locals and travellers. Despite a range of effective medicines, emerging resistance to common drugs like chloroquine and quinine necessitates exploring new antiparasitic drugs. Plasmodium life cycle involves mosquito transmission, liver cell invasion, and red blood cell infection, the latter of which causes symptoms like fever, coughing, and nausea. 
Quinoline antimalarials like chloroquine and mefloquine target parasite growth, but resistance challenges their efficacy. Antifolated inhibit enzymes crucial for Plasmodium survival, and artemisinin derivatives are potent, fast-acting treatments for severe malaria. Issues with antimalarial drugs include rising malaria cases, limited access to healthcare, and drug-resistant strains, emphasising the need for innovative treatments and preventative measures.