Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Antimalarial drugs: An overview

Mark Travassos, MD, MSc
Miriam K Laufer, MD, MPH
Section Editor
Johanna Daily, MD, MSc
Deputy Editor
Elinor L Baron, MD, DTMH


Antimalarial drugs are used for the treatment and prevention of malaria infection. Most antimalarial drugs target the erythrocytic stage of malaria infection, which is the phase of infection that causes symptomatic illness (figure 1). The extent of preerythrocytic (hepatic stage) activity for most antimalarial drugs is not well characterized.

Treatment of the acute blood stage infection is necessary for malaria caused by all malaria species. In addition, for infection due to Plasmodium ovale or Plasmodium vivax, terminal prophylaxis is required with a drug active against hypnozoites (which can remain dormant in the liver for months and, occasionally, years after the initial infection).

The mechanisms of action, resistance, and toxicities of antimalarial drugs will be reviewed here. Use of these agents for prevention and treatment of malaria is discussed in detail separately. (See "Prevention of malaria infection in travelers" and "Treatment of severe malaria" and "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)


Quinoline derivatives include chloroquine, amodiaquine, quinine, quinidine, mefloquine, primaquine, lumefantrine, and halofantrine. These drugs have activity against the erythrocytic stage of infection; primaquine also kills intrahepatic forms and gametocytes (figure 1). The drugs act by accumulating in the parasite food vacuole and forming a complex with heme that prevents crystallization in the Plasmodium food vacuole. Heme polymerase activity is inhibited, resulting in accumulation of cytotoxic-free heme.


Chloroquine — Chloroquine was the first drug produced on a large scale for treatment and prevention of malaria infection. Chloroquine has activity against the blood stages of P. ovale, P. malariae, and susceptible strains of P. vivax and P. falciparum [1]. Widespread resistance in most malaria-endemic countries has led to decline in its use for the treatment of P. falciparum, although it remains effective for treatment of P. ovale, P. malariae, and, in most regions, P. vivax. (See "Overview of non-falciparum malaria in nonpregnant adults and children".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Dec 14, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. White NJ. The treatment of malaria. N Engl J Med 1996; 335:800.
  2. Warhurst DC, Steele JC, Adagu IS, et al. Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties. J Antimicrob Chemother 2003; 52:188.
  4. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf 2004; 27:25.
  5. Severe and complicated malaria. World Health Organization Malaria Action Programme. Trans R Soc Trop Med Hyg 1986; 80 Suppl:3.
  6. SCOTT V. Single intravenous injections of chloroquine in the treatment of falciparum malaria: toxic and immediate therapeutic effects in 110 cases. Am J Trop Med Hyg 1950; 30:503.
  7. Djimdé A, Doumbo OK, Cortese JF, et al. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 2001; 344:257.
  8. Fidock DA, Nomura T, Talley AK, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 2000; 6:861.
  9. Wellems TE, Plowe CV. Chloroquine-resistant malaria. J Infect Dis 2001; 184:770.
  10. Wootton JC, Feng X, Ferdig MT, et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 2002; 418:320.
  11. Valderramos SG, Fidock DA. Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci 2006; 27:594.
  12. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002; 298:210.
  13. Olliaro P, Mussano P. Amodiaquine for treating malaria. Cochrane Database Syst Rev 2003; :CD000016.
  14. Venkatesan M, Gadalla NB, Stepniewska K, et al. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg 2014; 91:833.
  15. World Health Organization. WHO List of Prequalified Medicinal Products. http://www.who.int/prequal/query/ProductRegistry.aspx (Accessed on February 13, 2009).
  16. Olliaro P, Nevill C, LeBras J, et al. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet 1996; 348:1196.
  17. Massaga JJ, Lusingu JP, Makunde R, et al. Biological and haematological safety profile of oral amodiaquine and chloroquine in healthy volunteers with or without Plasmodium falciparum infection in northeast Tanzania. Tanzan J Health Res 2008; 10:144.
  18. Adjuik M, Agnamey P, Babiker A, et al. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial. Lancet 2002; 359:1365.
  19. Zwang J, Ndiaye JL, Djimdé A, et al. Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa. Malar J 2012; 11:25.
  20. Phillips-Howard PA, West LJ. Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J R Soc Med 1990; 83:82.
  21. Hatton CS, Peto TE, Bunch C, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1986; 1:411.
  22. Neftel KA, Woodtly W, Schmid M, et al. Amodiaquine induced agranulocytosis and liver damage. Br Med J (Clin Res Ed) 1986; 292:721.
  23. Keating GM. Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. Drugs 2012; 72:937.
  24. Tarning J, Zongo I, Somé FA, et al. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther 2012; 91:497.
  25. Hung TY, Davis TM, Ilett KF, et al. Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol 2004; 57:253.
  26. Manning J, Vanachayangkul P, Lon C, et al. Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval. Antimicrob Agents Chemother 2014; 58:6056.
  27. Baiden R, Oduro A, Halidou T, et al. Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim® (dihydroartemisinin/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania. Malar J 2015; 14:160.
  28. Phillips RE, Warrell DA, White NJ, et al. Intravenous quinidine for the treatment of severe falciparum malaria. Clinical and pharmacokinetic studies. N Engl J Med 1985; 312:1273.
  29. Pukrittayakamee S, Supanaranond W, Looareesuwan S, et al. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg 1994; 88:324.
  30. Lesi A, Meremikwu M. High first dose quinine regimen for treating severe malaria. Cochrane Database Syst Rev 2004; :CD003341.
  31. Phillips RE, Looareesuwan S, White NJ, et al. Hypoglycaemia and antimalarial drugs: quinidine and release of insulin. Br Med J (Clin Res Ed) 1986; 292:1319.
  32. Ferdig MT, Cooper RA, Mu J, et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol 2004; 52:985.
  33. Deen JL, von Seidlein L, Dondorp A. Therapy of uncomplicated malaria in children: a review of treatment principles, essential drugs and current recommendations. Trop Med Int Health 2008; 13:1111.
  34. Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007; 297:2251.
  35. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 2004; 27:203.
  36. Katsenos S, Psathakis K, Nikolopoulou MI, Constantopoulos SH. Mefloquine-induced eosinophilic pneumonia. Pharmacotherapy 2007; 27:1767.
  37. Soentjens P, Delanote M, Van Gompel A. Mefloquine-induced pneumonitis. J Travel Med 2006; 13:172.
  38. Inoue T, Tanaka E, Sakuramoto M, et al. [Case of drug-induced pneumonia possibly due to mefloquine (antimalarial drug)]. Nihon Kokyuki Gakkai Zasshi 2005; 43:103.
  39. Udry E, Bailly F, Dusmet M, et al. Pulmonary toxicity with mefloquine. Eur Respir J 2001; 18:890.
  40. Food and Drug Administration. Postmarketing Reviews - Volume 1, Number 4, Summer 2008. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm120613.htm (Accessed on September 19, 2008).
  41. Price RN, Uhlemann AC, Brockman A, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 2004; 364:438.
  42. Rogers WO, Sem R, Tero T, et al. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J 2009; 8:10.
  43. Chaorattanakawee S, Saunders DL, Sea D, et al. Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance. Antimicrob Agents Chemother 2015; 59:4631.
  44. Baird JK, Fryauff DJ, Hoffman SL. Primaquine for prevention of malaria in travelers. Clin Infect Dis 2003; 37:1659.
  45. US Food and Drug Administration. Primaquine: Phosphate Tablets, USP. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/008316s021lbl.pdf (Accessed on April 29, 2015).
  46. World Health Organization. Guidelines for the treatment of malaria, 3rd ed, WHO, Geneva 2015. http://www.who.int/malaria/publications/atoz/9789241549127/en/ (Accessed on September 10, 2015).
  47. Shekalaghe S, Drakeley C, Gosling R, et al. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PLoS One 2007; 2:e1023.
  48. Sutanto I, Suprijanto S, Kosasih A, et al. The effect of primaquine on gametocyte development and clearance in the treatment of uncomplicated falciparum malaria with dihydroartemisinin-piperaquine in South sumatra, Western indonesia: an open-label, randomized, controlled trial. Clin Infect Dis 2013; 56:685.
  49. Goodman CD, Su V, McFadden GI. The effects of anti-bacterials on the malaria parasite Plasmodium falciparum. Mol Biochem Parasitol 2007; 152:181.
  50. Miller KD, Lobel HO, Satriale RF, et al. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986; 35:451.
  51. Gimnig JE, MacArthur JR, M'bang'ombe M, et al. Severe cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in Blantyre District, Malawi. Am J Trop Med Hyg 2006; 74:738.
  52. ter Kuile FO, van Eijk AM, Filler SJ. Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review. JAMA 2007; 297:2603.
  53. Fidock DA, Nomura T, Wellems TE. Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase. Mol Pharmacol 1998; 54:1140.
  54. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 1999; 43:1334.
  55. GlaxoSmithKline. Malarone prescribing information. 2008.
  56. Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg 1999; 60:533.
  57. Happi CT, Gbotosho GO, Folarin OA, et al. Confirmation of emergence of mutations associated with atovaquone-proguanil resistance in unexposed Plasmodium falciparum isolates from Africa. Malar J 2006; 5:82.
  58. Schwöbel B, Alifrangis M, Salanti A, Jelinek T. Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker. Malar J 2003; 2:5.
  59. Goodman CD, Siregar JE, Mollard V, et al. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science 2016; 352:349.
  60. Nakato H, Vivancos R, Hunter PR. A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemother 2007; 60:929.
  61. Krudsood S, Patel SN, Tangpukdee N, et al. Efficacy of atovaquone-proguanil for treatment of acute multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 2007; 76:655.
  62. Dahl EL, Shock JL, Shenai BR, et al. Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother 2006; 50:3124.
  63. Al-Mofarreh MA, Al Mofleh IA. Esophageal ulceration complicating doxycycline therapy. World J Gastroenterol 2003; 9:609.
  64. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 2003; 424:957.
  65. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41:1413.
  66. White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994; 88 Suppl 1:S41.
  67. Adjuik M, Babiker A, Garner P, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363:9.
  68. Nosten F, van Vugt M, Price R, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 2000; 356:297.
  69. Dondorp A, Nosten F, Stepniewska K, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717.
  70. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376:1647.
  71. Center for Disease Control and Prevention. Artesunate now available to treat severe malaria in US. In: Centers for Disease Control and Prevention [electronic mail system]. 2008.
  72. Gomes M, Ribeiro I, Warsame M, et al. Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infect Dis 2008; 8:39.
  73. Myint HY, Tipmanee P, Nosten F, et al. A systematic overview of published antimalarial drug trials. Trans R Soc Trop Med Hyg 2004; 98:73.
  74. Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60:547.
  75. Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg 2001; 95:182.
  76. Bethell D, Se Y, Lon C, et al. Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. Clin Infect Dis 2010; 51:e105.
  77. Clark RL, Lerman SA, Cox EM, et al. Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count. Birth Defects Res B Dev Reprod Toxicol 2008; 83:397.
  78. Clark RL, Arima A, Makori N, et al. Artesunate: developmental toxicity and toxicokinetics in monkeys. Birth Defects Res B Dev Reprod Toxicol 2008; 83:418.
  79. Moore KA, Simpson JA, Paw MK, et al. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis 2016; 16:576.
  80. Dellicour S, Desai M, Aol G, et al. Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya. Malar J 2015; 14:461.
  81. World Health Organization. World malaria report 2009. WHO Press, Geneva 2009. http://whqlibdoc.who.int/publications/2009/9789241563901_eng.pdf (Accessed on December 16, 2010).
  82. Noedl H, Se Y, Schaecher K, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359:2619.
  83. Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009; 361:455.
  84. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014; 371:411.
  85. Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014; 505:50.
  86. Takala-Harrison S, Jacob CG, Arze C, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis 2015; 211:670.
  87. Phyo AP, Ashley EA, Anderson TJ, et al. Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai-Myanmar Border (2003-2013): The Role of Parasite Genetic Factors. Clin Infect Dis 2016; 63:784.
  88. Leang R, Barrette A, Bouth DM, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother 2013; 57:818.
  89. Saunders DL, Vanachayangkul P, Lon C, et al. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med 2014; 371:484.
  90. Amaratunga C, Lim P, Suon S, et al. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis 2016; 16:357.
  91. White NJ, Pukrittayakamee S, Phyo AP, et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med 2014; 371:403.
  92. White NJ, Duong TT, Uthaisin C, et al. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria. N Engl J Med 2016; 375:1152.
  93. Bukirwa H, Unnikrishnan B, Kramer CV, et al. Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev 2014; :CD006404.
  94. Held J, Supan C, Salazar CL, et al. Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study. Lancet Infect Dis 2015; 15:1409.
  95. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet 2014; 383:1049.
  96. Rosenthal PJ. Proteases of malaria parasites: new targets for chemotherapy. Emerg Infect Dis 1998; 4:49.
  97. Toure OA, Valecha N, Tshefu AK, et al. A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate-Piperaquine Phosphate vs Artemether-Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa. Clin Infect Dis 2016; 62:964.
  98. Spillman NJ, Allen RJ, McNamara CW, et al. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe 2013; 13:227.
  99. Ringwald P, Bickii J, Basco LK. Efficacy of oral pyronaridine for the treatment of acute uncomplicated falciparum malaria in African children. Clin Infect Dis 1998; 26:946.
  100. Vivas L, Rattray L, Stewart L, et al. Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo. Acta Trop 2008; 105:222.
  101. Ramharter M, Kurth F, Schreier AC, et al. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis 2008; 198:911.
  102. Tshefu AK, Gaye O, Kayentao K, et al. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet 2010; 375:1457.
  103. Rueangweerayut R, Phyo AP, Uthaisin C, et al. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med 2012; 366:1298.
  104. Sagara I, Beavogui AH, Zongo I, et al. Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial. Lancet Infect Dis 2016; 16:189.
  105. Dondorp AM, Newton PN, Mayxay M, et al. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health 2004; 9:1241.
  106. Newton P, Proux S, Green M, et al. Fake artesunate in southeast Asia. Lancet 2001; 357:1948.
  107. Newton PN, Fernández FM, Plançon A, et al. A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med 2008; 5:e32.
  108. Bate R, Coticelli P, Tren R, Attaran A. Antimalarial drug quality in the most severely malarious parts of Africa - a six country study. PLoS One 2008; 3:e2132.
  109. Nayyar GM, Breman JG, Newton PN, Herrington J. Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa. Lancet Infect Dis 2012; 12:488.