Primaquine

Primaquine
Systematic (IUPAC) name
(RS)-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a607037
  • ?
Oral
Pharmacokinetic data
Bioavailability 96%[1]
Metabolism Liver
Half-life 6 hours
Excretion ?
Identifiers
90-34-6 Yes
P01BA03
PubChem CID 4908
DrugBank DB01087 Yes
ChemSpider 4739 Yes
UNII MVR3634GX1 Yes
KEGG D08420 Yes
ChEBI CHEBI:8405 Yes
ChEMBL CHEMBL506 Yes
Chemical data
Formula C15H21N3O
259.347 g/mol
 Yes (what is this?)  (verify)

Primaquine (or primaquine phosphate) is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.

Primaquine was first synthesised by Robert Elderfield of Columbia University in the 1940s.[2] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]

Medical uses

Primaquine is mainly used to treat P. vivax or P. ovale malaria, specifically to clear the dormant liver forms of these parasites (hypnozoites) once the parasite has been eliminated from the bloodstream. This requires a 14-day course of primaquine.[4] The process of clearing the hypnozoites is termed radical cure (as opposed to simply clearing the blood of parasites). If primaquine is not administered to patients with proven P. vivax or P. ovale infection, a very high likelihood of relapse exists for weeks or months (sometimes years). The interaction between primaquine and quinine or chloroquine is thought to improve the rate of radical cure.[5] Whether other antimalarials such as mefloquine are likewise able to potentiate the effect of primaquine is not known.

Interruption of transmission

A single dose of primaquine has rapid and potent gametocytocidal activity against the most mature gametocytes (stage V) of P. falciparum, a property not held by other commonly used antimalarials which have actions against earlier gametocyte stages.[6] This leads to a rapid reduction in transmission, and primaquine given at the same time as treatment for the asexual blood stage P. falciparum is likely to be useful in controlling P. falciparum malaria in areas of low transmission. The WHO has recommended that a single dose of primaquine (0.25 mg/kg) is safe to give (even in individuals with G6PD deficiency), for the purpose of preventing transmission of P. falciparum malaria.[7]

Prevention

Primaquine is not routinely used to prevent malaria in travelers, but can be used in individuals without G6PD deficiency when other alternatives are inappropriate.[8] In areas where vivax malaria is more prevalent than falciparum malaria, primaquine may be more effective than doxycycline or mefloquine.[9]

Pneumocystis pneumonia

Primaquine is also used in the treatment of Pneumocystis pneumonia (PCP), a fungal infection commonly occurring in people with AIDS and, more rarely, in those taking immunosuppressive drugs. To treat PCP effectively, it is usually combined with clindamycin.

Adverse reactions

Common side effects of primaquine administration include nausea, vomiting, and stomach cramps. Other known adverse effects that occasionally occur are headache, visual disturbances, and intense itching.

The most dangerous adverse effect of primaquine is hemolysis in patients with G6PD deficiency (Africans or Caucasians of Mediterranean descent).[10] This is associated with the administration of large doses over several days and can be fatal, although the number of reports remains small.

Primaquine causes methemoglobinemia in all patients who take it (levels of up to 18% are reported, normal level is <1%), but this seldom causes symptoms and is always self-limiting.[11] There may be an association with NADH methemoglobin reductase deficiency.[12]

Contraindications

In broad terms, primaquine should not be administered to anyone with G6PD deficiency because a severe reaction can occur, resulting in hemolytic anemia.[10] However, the WHO has recommended that a single dose of primaquine (0.25 mg/kg) is safe to give even in individuals with G6PD deficiency, for the purpose of preventing transmission of P. falciparum malaria.[7]

Primaquine is contraindicated in pregnancy, because the glucose-6-phosphate dehydrogenase status of the fetus would be unknown.

The packaging label states that primaquine should not be given to patients with systemic lupus erythematosus or rheumatoid arthritis, but the rationale behind this is questionable.[8]

Dosing

Primaquine doses are always expressed as base, not as salt (15 mg base=26.3 mg phosphate salt).

Manufacturing and availability

Primaquine was first tested on humans during the Stateville Penitentiary Malaria Study in 1944. Primaquine was licensed for use in the USA by the Food and Drug Administration in 1952 and is available as a generic drug from a variety of manufacturers.

Primaquine is not licensed for use in the United Kingdom. It is available on a named patient basis only from certain pharmaceutical providers. Primaquine tablets available in the UK contain 7.5 mg primaquine base (13.2 mg phosphate salt). Primaquine tablets available in the US contain 15 mg base (26.3 mg phosphate salt).

Veterinary use

Primaquine is the drug of choice for treating feline babesiosis.[13]

Appearance in the media

This was a plot point in the M*A*S*H episode "The Red/White Blues", in which Lebanese-American Max Klinger and Jewish-American orderly Goldman developed anemia while taking primaquine, confusing the doctors who thought it was only a possibility if the person were black.

References

  1. ↑ Mihaly GW, Ward SA, Edwards G et al. (1985). "Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size". Br J Clin Pharmacol 19 (6): 745–50. doi:10.1111/j.1365-2125.1985.tb02709.x. PMC 1463857. PMID 4027117.
  2. ↑ Edgcomb JH, Arnold J, Young EH et al. (1950). "Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report.". Journal National Malaria Society 9 (4): 285–92. PMID 14804087.
  3. ↑ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
  4. ↑ Baird JK, Rieckmann KH (March 2003). "Can primaquine therapy for vivax malaria be improved?". Trends Parasitol. 19 (3): 115–20. doi:10.1016/S1471-4922(03)00005-9. PMID 12643993.
  5. ↑ Gordon, H. H.; Dieuaide, F. R. (1947). "Treatment of Plasmodium vivax malaria of foreign origin; a comparison of various drugs". Archives of internal medicine (Chicago, Ill. : 1908) 79 (4): 365–80. PMID 20294552.
  6. ↑ Eziefula, A. C.; Bousema, T; Yeung, S; Kamya, M; Owaraganise, A; Gabagaya, G; Bradley, J; Grignard, L; Lanke, K. H.; Wanzira, H; Mpimbaza, A; Nsobya, S; White, N. J.; Webb, E. L.; Staedke, S. G.; Drakeley, C (2014). "Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: A randomised, controlled, double-blind, dose-ranging trial". The Lancet Infectious Diseases 14 (2): 130–9. doi:10.1016/S1473-3099(13)70268-8. PMID 24239324.
  7. ↑ 7.0 7.1 Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva, Switzerland: World Health Organization. October 2012. Retrieved 2 January 2014.
  8. ↑ 8.0 8.1 Hill, D. R.; Baird, J. K.; Parise, M. E.; Lewis, L. S.; Ryan, E. T.; Magill, A. J. (2006). "Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis I". The American journal of tropical medicine and hygiene 75 (3): 402–15. PMID 16968913.
  9. ↑ Schwartz, E; Regev-Yochay, G (1999). "Primaquine as prophylaxis for malaria for nonimmune travelers: A comparison with mefloquine and doxycycline". Clinical Infectious Diseases 29 (6): 1502–6. doi:10.1086/313527. PMID 10585803.
  10. ↑ 10.0 10.1 Tarlov, A. R.; Brewer, G. J.; Carson, P. E.; Alving, A. S. (1962). "Primaquine sensitivity. Glucose-6-phosphate dehydrogenase deficiency: An inborn error of metabolism of medical and biological significance". Archives of internal medicine 109: 209–34. PMID 13919680.
  11. ↑ Clayman, C. B.; Arnold, J; Hockwald, R. S.; Yount Jr, E. H.; Edgcomb, J. H.; Alving, A. S. (1952). "Toxicity of primaquine in Caucasians". Journal of the American Medical Association 149 (17): 1563–8. doi:10.1001/jama.1952.72930340022010b. PMID 14945980.
  12. ↑ Cohen, R. J.; Sachs, J. R.; Wicker, D. J.; Conrad, M. E. (1968). "Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam". New England Journal of Medicine 279 (21): 1127–31. doi:10.1056/NEJM196811212792102. PMID 5686480.
  13. ↑ Jacobsona LS, Schoemana T and Lobetti RG (2000). "A Survey of Feline Babesiosis in South Africa". Journal of the South African Veterinary Association. 71 (4): 222–8. doi:10.4102/jsava.v71i4.719.

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