MALACUR SUSPENSION

Indications

• Uncomplicated malaria caused by Plasmodium falciparum
• Malaria in combination with other antimalarial medications

Dosage

Children: Refer to BNF for Children for age-appropriate dosing recommendations.

Adults: Refer to BNF for specific dosing guidelines based on the severity of malaria and combination therapy used. Commonly used doses may vary.

Mechanism of action

Dihydroartemisinin acts by binding to haem within the Plasmodium falciparum parasite. It is believed to bind to haem produced during the parasite's haem biosynthesis pathway in the early ring stage, and later to haem released from haemoglobin digestion. This binding triggers a reductive scission of the endoperoxide bridge, leading to the generation of a reactive oxygen species. This species further leads to the formation of a reactive carbon radical, which alkylates multiple protein targets within the parasite, contributing to its antimalarial activity. Notably, it irreversibly inhibits the sarco/endoplasmic reticulum Ca2+ ATPase pump of Plasmodium falciparum.

Pharmacodynamics

Dihydroartemisinin forms a reactive carbon radical intermediate that is instrumental in killing Plasmodium falciparum through the alkylation of diverse proteins. This mechanism is thought to disrupt various cellular functions within the parasite, ultimately leading to its death.

Pharmacokinetics

Dihydroartemisinin is rapidly absorbed following oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. It is extensively metabolized in the liver, primarily through cytochrome P450 enzymes, leading to the formation of several metabolites. The elimination half-life is relatively short, ranging from 1 to 3 hours. The drug is primarily excreted in urine and bile, making it effective for short-term treatment but necessitating multiple doses for sustained efficacy.

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Dizziness
• Headache
• Fatigue
• Abdominal pain

Precautions

• Use with caution in patients with a history of hypersensitivity to artemisinin derivatives.
• Monitor for signs of malaria treatment failure, especially in cases of severe malaria.
• Assess liver function prior to and during treatment, as hepatic impairment can affect drug metabolism.

Pregnancy

Dihydroartemisinin is classified as category C. Animal studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in pregnant women. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Dihydroartemisinin is excreted in breast milk. Caution should be exercised when administering to nursing mothers. The effects on the infant are unknown.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Oral tablets
• Injectable solution

Indications

• Treatment of uncomplicated Plasmodium falciparum malaria
• Prevention of malaria in regions where the disease is endemic

Dosage

Children: Refer to the BNF for Children for paediatric dosing information.

Adults: Refer to specific guidelines or local protocols for adult dosing, as it may vary based on treatment regimen and combination therapy.

Mechanism of action

Piperaquine exerts its antimalarial activity by inhibiting the heme polymerization process in the malaria parasite. It interferes with the parasite's ability to detoxify heme, a byproduct of hemoglobin degradation, leading to the accumulation of toxic heme derivatives within the parasite. This ultimately results in parasite death. Piperaquine has a slow onset of action, contributing to its long-lasting effects.

Pharmacodynamics

Piperaquine displays a dose-dependent inhibition of the Plasmodium species, especially Plasmodium falciparum. It has a long elimination half-life, allowing for once-daily dosing in some treatment regimens. The drug is generally well tolerated, with a side effect profile that may include gastrointestinal disturbances and transient elevations in liver enzymes. Its efficacy is enhanced when used in combination with other antimalarials, reducing the risk of resistance.

Pharmacokinetics

Piperaquine is well absorbed after oral administration, with peak plasma concentrations typically occurring several hours post-dose. It has a high volume of distribution, indicating extensive tissue binding. The drug is primarily metabolized in the liver, and its metabolites are excreted mainly in the feces. The elimination half-life can range from 10 to 30 days, contributing to its effectiveness in malaria treatment regimens.

Contra-indications

• Hypersensitivity to piperaquine or any component of the formulation
• History of retinal toxicity associated with similar compounds
• Severe hepatic impairment

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Fatigue
• Visual disturbances
• QT interval prolongation

Interactions

• May enhance the effect of other antimalarial drugs
• Concomitant use with drugs that prolong the QT interval may increase the risk of arrhythmias
• Potential interactions with cytochrome P450 substrates

Precautions

• Use with caution in patients with a history of cardiac arrhythmias
• Monitor for signs of retinal toxicity in long-term use
• Assess hepatic function prior to initiation in patients with liver disease

Pregnancy

Piperaquine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines for antimalarial use in pregnancy.

Breast-feeding

Piperaquine is excreted in breast milk. Caution is advised when administering to nursing mothers as the effects on the infant are unknown.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension

Mechanism of action

Artemisinins, including Artenimol which is a major active metabolite of many artemisinins, are thought to act via a common mechanism. While the exact mechanism of action is not certain, theories exist as to how artemisinins produce their antimalarial effect. Artemisinins are believed to bind to haem within the *P. falciparum* parasite. The source of this haem varies with the life stage of the parasite. When the parasite is in the early ring stage artemisinins are believed to bind haem produced by the parasite's haem biosynthesis pathway. In later stages artemisinins likely bind to haem released by haemoglobin digestion. Once bound to haem, artemisinins are thought to undergo activation involving ferrous iron via reductive scission which splits the endoperoxide bridge to produce a reactive oxygen. This reactive oxygen is thought to undergo a subsequent intramolecular hydrogen abstraction to produce a reactive carbon radical. The carbon radical is believed to be the source of the drugs potent activity against *P. falciparum* by alkylating a wide array of protein targets. The nature and magnitude of the effect on specific protein function as a result of this alkylation is unknown. One target which has been the focus of research is the sarco/endoplasmic reticulum Ca2+ ATPase pump of *P. falciparum*. Artemisinins have been found to irreversably bind to and inhibit this protein at a binding site similar to that of Thapsigargin. The mechanism is likely the same as for other proteins, namely alkylation via the carbon radical intermediate. Artemisinins appear to preferentially collect in infected erythrocytes, concentrating the drug by several hundred-fold compared to uninfected cells. This may play a role in why little alkylation is seen in uninfected erythrocytes. A 2025 systematic review notes Dihydroartemisinine's pharmacological activities as being antimalarial and anticancer, and that it has shown promise in improving nonalcoholic steatohepatitis (NASH) by reducing  liver fat, inflammation, and fibrosis via Inhibition of  lipogenesis (SREBP-1c, FASN, SCD1) and promotion of  lipolysis (PGC1α, CPT-1a).

Pharmacodynamics

Artenimol is thought to form a reactive carbon radical intermediate which kills *P. falciparum* through alkylation of a wide array of proteins.