Antimalarial Medication

Antimalarial medications are antiparasitic agents used for the treatment and prevention of malaria, a parasitic disease caused mainly by Plasmodium falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. They include a wide range of natural and synthetic compounds, many of which are derived historically from plant products such as quinine or from later semi-synthetic and fully synthetic developments, including chloroquine and artemisinin derivatives. Modern antimalarial therapy aims both to save lives from acute infection and to reduce transmission and disease burden in endemic regions, particularly among young children and pregnant women, who are especially vulnerable.

Uses and Therapeutic Strategies

Antimalarial drugs are used in three principal contexts. First, they are employed to treat individuals with suspected or confirmed malaria infection, aiming to clear parasitaemia and resolve clinical symptoms. Secondly, they are prescribed as malaria prophylaxis for non-immune travellers visiting endemic regions, with the objective of preventing primary infection. Thirdly, they are administered as intermittent preventive therapy to broader groups in highly endemic areas, for example pregnant women or infants, where drugs are given at intervals regardless of symptoms in order to reduce morbidity and mortality.
Standard practice emphasises prompt parasitological confirmation of malaria prior to treatment, using either microscopic blood smear examination or rapid diagnostic tests. However, in settings where such facilities are unavailable, treatment may still be given on the basis of clinical suspicion. Combination therapy is now the norm, particularly artemisinin-based combination therapies (ACTs) such as artemether–lumefantrine, which combine rapid parasite clearance with a longer-acting partner drug. Combination approaches lower the risk of treatment failure, delay the development of drug resistance and may permit lower doses, thereby reducing side effects.
Some antimalarial drugs, especially chloroquine and hydroxychloroquine, have additional indications in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, reflecting their immunomodulatory and anti-inflammatory properties.

Global Burden, Resistance and Need for New Agents

Malaria remains a major public health challenge in many tropical and subtropical regions. Despite advances in vector control and chemotherapy, the global burden of disease is expected to remain high for years, particularly in sub-Saharan Africa and parts of Asia and Latin America.
A persistent difficulty in malaria control is the emergence of drug resistance. Resistance has arisen successively to many agents, including chloroquine, sulfadoxine–pyrimethamine and, more recently, to components of ACT regimens such as artemisinin in parts of Southeast Asia. This resistance can manifest as delayed parasite clearance, increased rates of treatment failure or the need for more complex drug regimens. Consequently, the development of new antimalarial agents, novel drug targets and improved combination strategies remains a priority in tropical medicine.
Even with effective treatments, notable side effects may occur in susceptible individuals at standard doses. Examples include retinopathy with prolonged chloroquine use and acute haemolytic anaemia with certain drugs such as tafenoquine in individuals with glucose-6-phosphate dehydrogenase deficiency. Careful dosing, screening where appropriate and monitoring are therefore essential parts of therapeutic practice.

Classification of Antimalarials and Mechanisms of Action

Antimalarial agents can be categorised in several ways, including by:

• Chemical structure (for example quinoline derivatives, artemisinin derivatives, antifolate combinations).
• Stage of parasite targeted, such as blood schizonts (erythrocytic forms), tissue schizonts (hepatic forms), gametocytes or hypnozoites.
• Clinical use, including treatment of acute uncomplicated malaria, severe malaria, prophylaxis or intermittent preventive therapy.

Chemical structure is particularly useful because it often correlates with mechanism of action, pharmacokinetics, spectrum of activity and toxicity.

Quinine and Related Cinchona Alkaloids

Quinine occupies a significant historical position as one of the earliest effective antimalarial drugs, originally derived from the bark of the cinchona tree of South America. It remains in use, particularly for severe or complicated P. falciparum malaria, and in areas where resistance to multiple other drugs is present.
Quinine is an alkaloid with predominantly blood schizonticidal activity and weak gametocytocidal action, especially against P. vivax and P. malariae. It accumulates in the food vacuoles of Plasmodium species and is believed to act by inhibiting haemozoin biocrystallisation. This interferes with the parasite’s ability to detoxify free haem released during haemoglobin digestion, leading to accumulation of cytotoxic haem and parasite death.
Although effective, quinine is less potent and more toxic than chloroquine as a blood schizonticidal agent. It is nonetheless valuable in acute severe P. falciparum infection and in post-exposure treatment of individuals returning from endemic areas. Therapy is often combined with antibiotics such as doxycycline, tetracycline or clindamycin to enhance efficacy and reduce treatment duration.
Dosage regimens are complex and depend on the degree of local resistance and the purpose of therapy (acute treatment versus prophylaxis). A common recommendation is an initial loading dose followed by repeated doses every eight hours for several days, administered orally, intravenously or intramuscularly depending on severity and resources.
Quinine use is associated with a characteristic cluster of adverse effects known as cinchonism. Typical symptoms include tinnitus, hearing impairment, headache, rashes, vertigo, nausea, vomiting and abdominal pain. Neurological manifestations—confusion, delirium and coma—may occur, related to neurotoxic actions on motor neuron end plates and the vestibulocochlear nerve. Quinine can also induce hypoglycaemia by stimulating insulin secretion, an effect that is particularly pronounced in pregnancy; therefore regular monitoring of blood glucose is recommended during therapy. Severe toxicity or overdose can result in renal failure and respiratory depression.
Several related alkaloids are used clinically. Quinimax is a mixture of quinine, quinidine, cinchonine and cinchonidine, thought to act synergistically and in some studies more effective than quinine alone. Quinidine, a stereoisomer of quinine, shares its antimalarial properties and is used mainly for severe malaria, although its use has declined with the availability of more effective agents such as intravenous artesunate. Historically, proprietary preparations such as Warburg’s tincture, formulated in the nineteenth century, combined quinine with other ingredients and were once widely employed as febrifuge and antimalarial remedies.

Chloroquine and Hydroxychloroquine

Chloroquine was for many years the most widely used and best tested antimalarial agent. It is relatively inexpensive, has a long record of safety and was historically the prototype on which many treatment regimens were based. The emergence and spread of chloroquine-resistant P. falciparum, and later resistance in some P. vivax populations, have substantially reduced its usefulness; nonetheless, chloroquine remains a first-line drug in regions where parasites are still susceptible, especially against P. vivax, P. malariae and P. ovale.
Chemically, chloroquine is a 4-aminoquinoline compound. It concentrates within the acidic food vacuoles of the parasite, where, through its alkaline properties, it raises vacuolar pH. As with quinine, chloroquine interferes with the conversion of toxic haem to crystalline haemozoin, thereby poisoning the parasite. Additional proposed mechanisms include interference with nucleic acid synthesis and formation of chloroquine–haem or chloroquine–DNA complexes.
Chloroquine exhibits strong activity against asexual blood schizonts of all human malaria species, except chloroquine-resistant strains, and acts against gametocytes of P. vivax, P. malariae and P. ovale, and immature gametocytes of P. falciparum. It also has notable antipyretic and anti-inflammatory effects, which contribute to symptom relief in P. vivax and are exploited in rheumatological disease management.
Standard treatment dosing in acute malaria typically totals about 25 mg/kg over three days, often divided into an initial higher dose followed by smaller doses to optimise pharmacokinetics. For chemoprophylaxis, lower weekly regimens are used. Chloroquine prophylaxis is now recommended only in areas where P. falciparum remains chloroquine-sensitive and where P. vivax predominates.
Chloroquine has been used extensively in pregnancy without evidence of teratogenic or abortifacient effects and is therefore considered safe during pregnancy at therapeutic doses. Common adverse reactions include gastrointestinal disturbance and pruritus, which may be severe in some individuals. Chronic high-dose use, particularly outside malaria indications, carries a risk of retinopathy, necessitating ophthalmological monitoring. Chloroquine can also exacerbate psoriasis and should be used with caution in affected individuals.
Hydroxychloroquine is a derivative of chloroquine introduced in the mid-twentieth century. It has a similar mechanism of action but a somewhat more favourable safety profile and is used more commonly in the long-term management of autoimmune diseases. It retains antimalarial activity but plays a lesser role in routine malaria treatment compared with newer agents and combination therapies.

Contemporary Practice and Future Directions

Current antimalarial practice relies increasingly on integrated approaches, combining effective drug regimens, vector control strategies, diagnostic testing and public health interventions. Combination therapies, especially ACTs, are central to the management of uncomplicated P. falciparum malaria, while parenteral drugs such as intravenous artesunate or, in some settings, quinine, remain vital for severe disease.
International guidelines underline the importance of surveillance for drug resistance, rational drug use and continued research into novel compounds. Promising areas include next-generation endoperoxides, new quinoline derivatives, inhibitors of parasite metabolism and transmission-blocking agents. As resistance patterns evolve and malaria epidemiology shifts, the portfolio of antimalarial medications must also adapt, sustaining both effective treatment for individual patients and progress towards broader malaria control and, ultimately, elimination goals.