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Antimalarial drugs: An overview

INTRODUCTION

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 pre-erythrocytic (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 P. 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 indications, availability, and relative cost for the drugs discussed in this overview are outlined in the Tables (table 1).

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 falciparum malaria" and "Treatment of uncomplicated falciparum malaria".)

QUINOLINE DERIVATIVES

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.

4-aminoquinolines

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 Plasmodium 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".)

                  

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Literature review current through: Mar 1314. | This topic last updated: Jun 26, 2012.
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References
Top
  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.
  3. EKPECHI OL, OKORO AN. A PATTERN OF PRURITUS DUE TO CHLOROQUINE. Arch Dermatol 1964; 89:631.
  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. Ursing J, Kofoed PE, Rodrigues A, et al. Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial. J Infect Dis 2011; 203:109.
  13. Kofoed PE, Ursing J, Poulsen A, et al. Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations. Trans R Soc Trop Med Hyg 2007; 101:231.
  14. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002; 298:210.
  15. Olliaro P, Mussano P. Amodiaquine for treating malaria. Cochrane Database Syst Rev 2003; :CD000016.
  16. 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.
  17. Hatton CS, Peto TE, Bunch C, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1986; 1:411.
  18. Neftel KA, Woodtly W, Schmid M, et al. Amodiaquine induced agranulocytosis and liver damage. Br Med J (Clin Res Ed) 1986; 292:721.
  19. http://www.who.int/prequal/query/ProductRegistry.aspx (Accessed on February 13, 2009).
  20. Olliaro P, Nevill C, LeBras J, et al. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet 1996; 348:1196.
  21. 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.
  22. 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.
  23. Gasasira AF, Kamya MR, Achan J, et al. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis 2008; 46:985.
  24. 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.
  25. 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.
  26. Lesi A, Meremikwu M. High first dose quinine regimen for treating severe malaria. Cochrane Database Syst Rev 2004; :CD003341.
  27. 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.
  28. Ferdig MT, Cooper RA, Mu J, et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol 2004; 52:985.
  29. 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.
  30. Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007; 297:2251.
  31. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 2004; 27:203.
  32. Katsenos S, Psathakis K, Nikolopoulou MI, Constantopoulos SH. Mefloquine-induced eosinophilic pneumonia. Pharmacotherapy 2007; 27:1767.
  33. Soentjens P, Delanote M, Van Gompel A. Mefloquine-induced pneumonitis. J Travel Med 2006; 13:172.
  34. 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.
  35. Udry E, Bailly F, Dusmet M, et al. Pulmonary toxicity with mefloquine. Eur Respir J 2001; 18:890.
  36. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm120613.htm (Accessed on September 19, 2008).
  37. Price RN, Uhlemann AC, Brockman A, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 2004; 364:438.
  38. Baird JK, Fryauff DJ, Hoffman SL. Primaquine for prevention of malaria in travelers. Clin Infect Dis 2003; 37:1659.
  39. White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 1999; 37:105.
  40. Ezzet F, van Vugt M, Nosten F, et al. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44:697.
  41. White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007; 7:549.
  42. Makanga M, Premji Z, Falade C, et al. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data. Am J Trop Med Hyg 2006; 74:991.
  43. ter Kuile FO, Dolan G, Nosten F, et al. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 1993; 341:1044.
  44. Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993; 341:1054.
  45. Matson PA, Luby SP, Redd SC, et al. Cardiac effects of standard-dose halofantrine therapy. Am J Trop Med Hyg 1996; 54:229.
  46. Centers for Disease Control and Prevention (CDC). Sudden death in a traveler following halofantrine administration--Togo, 2000. MMWR Morb Mortal Wkly Rep 2001; 50:169.
  47. Goodman CD, Su V, McFadden GI. The effects of anti-bacterials on the malaria parasite Plasmodium falciparum. Mol Biochem Parasitol 2007; 152:181.
  48. 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.
  49. 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.
  50. 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.
  51. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 1999; 43:1334.
  52. GlaxoSmithKline. Malarone prescribing information. 2008.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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.
  58. 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.
  59. Al-Mofarreh MA, Al Mofleh IA. Esophageal ulceration complicating doxycycline therapy. World J Gastroenterol 2003; 9:609.
  60. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 2003; 424:957.
  61. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41:1413.
  62. White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994; 88 Suppl 1:S41.
  63. Adjuik M, Babiker A, Garner P, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363:9.
  64. 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.
  65. Dondorp A, Nosten F, Stepniewska K, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717.
  66. 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.
  67. 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.
  68. 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.
  69. 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.
  70. 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.
  71. 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.
  72. 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.
  73. McGready R, Cho T, Keo NK, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 2001; 33:2009.
  74. Ward SA, Sevene EJ, Hastings IM, et al. Antimalarial drugs and pregnancy: safety, pharmacokinetics, and pharmacovigilance. Lancet Infect Dis 2007; 7:136.
  75. 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.
  76. 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.
  77. Noedl H, Se Y, Schaecher K, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359:2619.
  78. Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009; 361:455.
  79. World Health Organization. Guidelines for the treatment of malaria, 2nd edition, WHO Press, Geneva 2010.
  80. 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).
  81. 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.
  82. 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.
  83. 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.
  84. 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.
  85. 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.
  86. Newton P, Proux S, Green M, et al. Fake artesunate in southeast Asia. Lancet 2001; 357:1948.
  87. 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.
  88. Atemnkeng MA, De Cock K, Plaizier-Vercammen J. Quality control of active ingredients in artemisinin-derivative antimalarials within Kenya and DR Congo. Trop Med Int Health 2007; 12:68.
  89. 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.