Antimalarials: Uses, common brands, and safety info

Mosquitoes can be a nuisance, and we do a lot to avoid them—insect repellents, special clothing, and even swatters or zappers. Fortunately for most of us, mosquitos aren’t much more than a pest that occasionally evades our defenses resulting in a few days of itching and redness at the site of a bite. However, in some areas of the world, a bite from a mosquito infected with certain parasites is a public health crisis since it can result in an infectious disease called malaria. People with malaria suffer from fever, chills, and overall flu-like symptoms that if left untreated may result in serious complications and can even be fatal. Here we will discuss antimalarial agents, a class of drugs used to both prevent and treat the malaria parasite, including important pharmacokinetic and toxicity concerns. 

What are antimalarials?    

Antimalarial drugs are a class of anti-infectives that work to eradicate the parasite known to cause an infectious disease known as malaria. In the United States, about 2,000 cases of malaria are diagnosed each year. Most cases in the United States are in travelers and immigrants returning from countries where malaria transmission is known to occur, including sub-Saharan Africa and South Asia. Areas, where malaria occurs, are dependent on climatic factors and are mostly limited in tropical and subtropical regions. Therefore, transmission within the United States is uncommon.

A parasite is spread to humans through the bites of infected mosquitoes—specifically female Anopheles mosquitoes. The type of parasite to cause malaria infections are known as Plasmodium; several species of this parasite exist including P. falciparum, P.vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum is considered the most virulent and prevalent Plasmodium species. The selection of an antimalarial drug will be dependent on the likelihood of which Plasmodium species is causing infection and can be predicted based upon geographic location of transmission since factors like the incidence of multidrug resistance to certain antimalarial drugs come into play. Other patient factors may also need to be considered which may put the patient at increased risk for serious infection, like the clinical status of the patient and previous use of antimalarial therapy.

Antimalarial drugs should be employed as malaria prophylaxis when traveling to endemic countries, like Cambodia, but are also employed in the management of active infection.

How do antimalarials work?

Infection by Plasmodium species from a mosquito bite results in the parasite growing and multiplying first in liver cells and then in circulating red blood cells, or erythrocytes. In the liver stage of infection, clinical symptoms often do not exist. Both P. vivax and P. ovale form a dormant liver stage called the hypnozoite, which can activate in weeks, months, or even years after initial infection.  In the blood, parasites grow inside erythrocytes and destroy them. This is the stage that causes the symptoms of malaria, as the parasite developing in the red blood cell causes the release of waste substances and other toxic substances when the infected cells are eventually destroyed. This release in vivo stimulates the immune system which results in the development of common initial symptoms of malaria, such as fever and rigors.

The mechanism of action of most antimalarial agents includes targeting the blood stage of the infection. The pharmacology of many agents is to function as inhibitors of the synthesis of proteins crucial to the parasite’s survival, causing parasitic destruction. Some antimalarial drugs act at the liver stage by forming a complex with heme within the parasite, so that when heme is released during hemoglobin breakdown it builds up to toxic levels, ultimately killing the parasite. Atovaquone drug administration is unique in that it targets Plasmodium mitochondria, the energy producers of the parasite, and can inhibit transmission from mosquito to person. Artemisinin derivatives, such as dihydroartemisinin, artemether, and artesunate exhibit their mechanism of action by the production of free radicals which cause fatal damage to the parasite. Tetracyclines and macrolides are anti-infectives that are usually used as combination therapy with other antimalarial drugs to treat malaria.

If the accurate pairing of an active antimalarial agent to the causative Plasmodium species occurs, prevention of malaria with antimalarial drugs is highly effective—higher than an 80% likelihood of preventing infection when taken appropriately. If a person becomes infected, timely identification and initiation of aggressive treatment are critical to prevent progression to severe malaria with its associated complications, including death.

There is no single drug that can eradicate all strains of the Plasmodium species. Additionally, the efficacy of many antimalarial agents is challenged due to the emergence of drug-resistant Plasmodium species, as has been seen with Plasmodium vivax, so the development of new antimalarial drugs with novel targets remains an active and ongoing area of research and clinical trials.  Currently, treatment of malarial infections often employs combinations of drugs, such as co-formulated antimalarials like Coartem and Malarone, or selecting combinations of individual medications, in an attempt to overcome any drug resistance. The Centers for Disease Control and Prevention (CDC) provide treatment recommendations based on presumed drug susceptibility and where the infection was acquired.

What are antimalarials used for?

Antimalarials are used for Malaria treatment, Malaria prevention when traveling abroad, and the management of arthritis

Types of antimalarials

Quinoline derivatives

Quinolines are the most widely used subclass of antimalarial agents for the management of malaria. Quinine was the standard therapy for malaria from the middle of the 19th century until the 1940s when it was replaced as the standard by chloroquine for its improved efficacy and safety. Unfortunately, its excessive use resulted in the development of resistance by P. falciparum. Mefloquine, another quinoline derivative, was developed in the mid-1980s and is recommended for prophylaxis of malaria caused by all species including chloroquine-resistant strains. Primaquine is another quinoline derivative that is used for its efficacy in malaria caused by P. vivax but can cause serious adverse effects in certain patients. Other examples of quinoline derivatives include quinidine, halofantrine, and aminoquinolines like amodiaquine and piperaquine.

Antifolates

Antifolates are antimalarial drugs that inhibit folic acid synthesis, which is crucial for the production of nucleic acids and amino acids; critical building blocks of proteins within the parasite. Antifolates are capable of blocking the division of Plasmodium species within both the liver and blood stage. Sulfadoxine mimics a component of folic acid, and its mechanism of action is to block a crucial enzyme for the synthesis of building blocks for the parasite. Pyrimethamine and proguanil are also examples of antifolates that block different pathways that ultimately are required to produce nucleic acids and amino acids. Sulfadoxine-pyrimethamine is available as a combination therapy in many countries.

Artemisinin derivatives

Artemisinin, first extracted from the herb Artemisia annua in 1972, and its derivatives have potent and rapid broad-spectrum activity against Plasmodium species. Their mechanism of action is to work against the parasite in several of its phases within erythrocytes, most likely resulting in the production of free radicals that result in parasitic death. They are also capable of decreasing transmission from humans to mosquitos and are effective against chloroquine and mefloquine resistant strains. Artesunate is considered first-line therapy in the United States for the treatment of severe malaria.

Antibacterials

Antibacterials, like tetracyclines (e.g., doxycycline) and macrolides (e.g., azithromycin), are used as adjuncts to other antimalarial drugs in treating P. falciparum and may be employed as prophylaxis in regions with a high prevalence of antimalarial drug resistance.

Who can take antimalarials?

Can men and women take antimalarials?

Antimalarial agents are effective in eliminating the Plasmodium parasite. Under the guidance of a healthcare professional, they are generally considered safe with some side effects that can be anticipated and managed.

Primaquine is one exception in that it comes with the possibility of a more severe side effect in individuals with an inherited enzyme deficiency of glucose-6-phosphate dehydrogenase (G6PD). G6PD is an enzyme important for the survival of red blood cells, and exposure to “stressors,” including primaquine, can result in severe anemia. Primaquine should also be used in caution in patients with a tendency to have low white blood cells, either due to other conditions or medications, because it may worsen the white blood cell count.

Can you take antimalarials while pregnant or breastfeeding?

Malaria in pregnant women is associated with high risks of both maternal and fetal complications, so treatment should be prioritized. Specific treatment options, such as doxycycline, should be avoided in pregnant women or breastfeeding women due to the risk of permanent discoloration of teeth following in utero exposure. Primaquine should also be avoided in pregnancy due to the risk of severe hemolysis (or breakdown of erythrocytes). However, the risk to benefit should always be carefully weighed, and exceptions to avoid many antimalarial drugs in pregnancy may need to be abandoned.

Can children take antimalarials?

Children should receive treatment for malaria, although they should be monitored closely for differences in pharmacokinetic parameters and potential for toxicity. Aralen and primaquine can be used in children of all ages, whereas Malarone may be used in children older than one month and mefloquine may be used in children older than 3 months. Tetracyclines are generally avoided in children younger than 8 years of age due to the risk of permanent discoloration of teeth, but a risk-to-benefit analysis should always be performed to determine the most appropriate regimen for a patient.

In October of 2021, the World Health Organization made a historic recommendation for the widespread use of a malaria vaccine among children in sub-Saharan Africa and other regions with moderate to high Plasmodium falciparum malaria transmission. This is the first time that a vaccine has been recommended in the fight against malaria. In these regions, malaria remains a cause of childhood death illness, with more than 260,000 African children less than 5 years of age dying annually from malaria. As part of a pilot program in which more than 2.3 million doses have been administered, a 30% reduction in deadly severe malaria has been observed.

Can seniors take antimalarials?

There are no specific reasons seniors cannot take antimalarial drugs, although they should be monitored closely for related toxicity.  Primaquine should be avoided in those with a known G6PD deficiency or low white blood cells. Some medications, such as Malarone, should be avoided in scenarios of altered pharmacokinetics such as severe renal impairment, which may be more common in older patients as renal function generally diminishes with age. Other medications may cause cardiac conduction issues, such as mefloquine, and should be used with caution in patients with underlying cardiac issues, such as arrhythmias.

Are antimalarials safe?

Certain antimalarials do carry black box warnings. Qualaquin (quinine) is associated with hematologic toxicity that can also result in severe renal impairment so use should be limited to approved conditions. Mefloquine should not be prescribed for patients with major psychiatric disorders since it may cause neuropsychiatric reactions that persist beyond treatment.

Recalls

There are no current recalls as of December 2021.

Restrictions

• Do not takeMalarone if your renal function is severely diminished.

• Do not take Mefloquine if you have a history of abnormal cardiac conduction, as this medication may cause worsening of these issues.

• Artesunate was recently FDA approved and is now available for purchase in the United States, but hospital pharmacies that do not have it in stock when it is needed to treat a patient with severe malaria should contact their drug distributor to request an emergency procurement. If the drug distributor is unable to provide artesunate within 24 hours, healthcare providers should contact the CDC Malaria Hotline (770-488-7788) to obtainartesunate.

Are antimalarials controlled substances?

No, antimalarials are not controlled substances.

Common antimalarials side effects

Some antimalarial agents come with unique side effects that generally result in restrictions in their use, described above. Common adverse effects of all antimalarials include:

• Abdominal pain

• Nausea

• Vomiting

How much do antimalarials cost?

Antimalarials have a wide range of costs. Many are available in generic formulations and are used in other, more common indications (for example, arthritis) which drives the cost to around $10 per month. Others used for prophylaxis or treatment of malaria as their only clinical indication have a more specific niche, which can drive the cost to a couple of hundred dollars per course. A SingleCare Prescription Discount Card could reduce prescription costs significantly.