Research Journal of Recent Sciences _________________________________________________ ISSN 2277-2502 Vol. 3(IVC-2014), 1-4 (2014) Res. J. Recent. Sci. International Science Congress Association 1 Review Paper Small Bite - Big Threats: Assessment of Pernicious Repercussion of Antimalarial Drugs Tomar Neha and Shukla S.K. Amity University, Noida, Uttar Pradesh, INDIAAvailable online at: www.isca.in, www.isca.me Received 7th July 2014, revised 23rd August 2014, accepted 20th September 2014 AbstractMalaria is one of the most grievous public health problems worldwide. Most of the regions falling in tropical and subtropical areas receiving high rainfall are facing this threat and it is major cause of mortality in these regions. This deadly disease has promulgated into most of the Asian nations which are on the threshold of development. It has been observed that Antimalarial drugs that are prescribed for treatment of malaria do produce symptoms of toxicity because of over dosage or drug reactions consequent upon administration of Antimalarials. Various Antimalarial drugs such as Mefloquine, Halofantrine, Artether, Artemether etc. are known to have caused clinical manifestations such as Neuropsychiatric toxicity, Neurotoxicity, Cardio respiratory collapse and death. The present study reviews the articles stating the clinical findings in the cases of antimalarial drugs toxicity. Keywords: Mefloquine, Halofantrine, Artether, Artemether. Introduction Malaria is a deadly parasitic disease spread by the bite of female anopheles mosquitoes. The disease is endemic mostly in tropical regions receiving high rainfall as the temperature and weather conditions are conducive for the burgeon of mosquitoes. The species of protozoa known to cause harm are plasmodium Falciparum, vivax, Ovale and Malariae. The WHO factsheet on malaria estimates about 3.4 billion population at risk of malaria. In 2012, around 6,27,000 deaths were estimated from this deadly disease. Drug resistance to chloroquine in P. Falciparum was reported in India for the first time from Assam in 1973. Since then the cases of resistance towards malarial drugs have increased manifold causing fatality. Efforts are being taken worldwide to reduce the causation and mortality but the fact remains that this disease affects large mass of population and numbers of poisoning cases are reported due to over dosage or drug reactions consequent upon administration of malaria. The genesis of this review is based on survey was a survey administered in hospitals of Mahamaya Nagar, Uttar Pradesh, India wherein it total number of malaria cases reported, mortality rate, complications due to the disease, were recorded. A total of 100 cases were studied in two hospitals of the district, and ill effects on human physiology were noted. In majority of the cases renal problems, hepatomegaly, muscle cramps was the major finding. Based on these observations, research articles on the toxicity of antimalarial drugs were reviewed, compiled and presented in the table 1. The toxicity of Anti malarial drugs sets an unusual and interesting problem for the clinician as well as the scientists. The Toxic effects associated with Malaria can be due to the disease as well as the prophylaxis. High mortality rate is reported if diseased is not medicated but at the same time threat of toxicity due to drug is also noteworthy. Recurrent inimical effects of antimalarial drugs vary in range. Staining of dentition, disturbances in gastrointestinal tract effect on mental status of a person as psychosis, depression, nausea, allergic reactions, ulceration, and psoriasis are some examples. Grievous effects are cardiac toxicity, toxic effects on neurons, nephrons, muscles, cells that could prove to be virulent. According to chemical structure, Antimalarial Drugs can be classified as i. Aryl amino alcohols: Quinine, quinidine (cinchona alkaloids), mefloquine, and halofantrine. ii. 4-aminoquinolines: Chloroquine, amodiaquine. iii. Folate synthesis inhibitors: Type 1 - competitive inhibitors of dihydropteroate synthase - sulphones, sulphonamides Type 2 - inhibit dihydrofolate reductase - biguanides like proguanil and chloroproguanil; diaminopyrimidine like pyrimethamine iv. 8-aminoquinolines: Primaquine, WR238, 605 v. Antimicrobials: Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones vi. Peroxides: Artemisinin (Qinghaosu) derivatives and analogues - artemether, arteether, artesunate, artelinic acid vii. Naphthoquinones: Atovaquone viii. Iron chelating agents: Desferrioxamine. Toxic effects of various drugs have been listed below in table-2. Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(IVC-2014), 1-4 (2014) Res. J. Recent. Sci. International Science Congress Association 2 Table–1 Cases of Malaria reported in hospital of Mahamaya Nagar, India Name of Hospital Number of cases reported Toxicity K. A. V. Memorial Hospital 63 Spleenomegaly, renal dysfunction, hypotension, hypertension, muscle cramps Khetan Charitable Hospital 37 Drug induced abortion, hepatomegaly, dimness of vision Table-2 Toxicity of various Antimalarials drugs Drugs Half life LD-50 Toxicity Amodiaquine 5.2 ± 1.7 min Mouse = 225mg/kg, intraperitoneal Cardiac arrest, respiratory arrest, broadened QRS Complex, ventricular fibrillation Mouse= 550 mg/kg Oral Lumefantrine 4- 5 days QT Prolongation, Spleenomegaly, hepatomegaly, angiodema Halofantrine 6-10 days Troubled breathing Artemether Artemether, 1.6 +/- 0.7 and 2.2 +/- 1.9 hr Mouse = 895 mg/kg intravenous Mouse = 296 mg/kg intramuscular Rat = 597mg/kg intramuscular Quinacrine 5 -14 days Mouse = 1000 mg/kg Oral Seizures, hypotension, cardiac arrhythmias, and cardiovascular collapse Rat = 900 mg/kg Oral Atovaquone 2.2- 3.2 days 825 mg/kg/day Methamoglobinemia Cardiotoxicity As cardiac system is one of the system that forms bishop tripod of life, so any toxic effect on cardiac system is of paramount importance. Fatal cardiac arrythemias and prolonged qt intervals are some of usual seen effects of the toxicity on cardiac system. The first case of drug associated death was reported in 1993, untill then halofantrine was choice of medical practitioners. After this numerous studies have reported and confirmed fatal arrythemias. Quinidine and halofantrine which are known to induce class III effect of ventricular repolarisation. Being reported to be associated with lethal QT prolongation; cardiovascular collapse. The concern raised out from this almost withdrew halofantrine from market. Almost all the drugs available in market possess side effects which may be minimal to severe in their effect. Mild change in heart rate is known to be induced by amodiaquine, excessive prolongation of QT interval leading to Torsade de Pointes by halofantrine. A research article describes the cellular mechanism associated with therapy which inhibition of ion channel (e.g., human ether-a-go-go related gene channel), which slows down the process of repolarisation and engender environment for arrythemia. A research study conducted on dogs showed that Artemisinin and its derivatives as artemether, artemotil have also been found to be associated with severe effects. A series of electrocardiograms and calculated QT wave interval checkup will help better administration of artesunate with lesser possibility of side effect 10. Neurotoxicity Neurotoxic effects are yet another toxic effect exhibited by the drugs that are used in malaria prophylaxis. The neuropathology exhibited is noteworthy and eventuate in critical parts of brain defiling brain stem nuclei peculiarly those parts which are involved in hearing and balance11, 12. Quinine compounds like chloroquine have been reported to cause retinal dysfunction, seizures and even coma has been reported in some patients13. A Research study of arteether multiple dose conducted on dogs for eight days to study the pharmacokinetics presented clinical neurological effects and progressive cardio respiratory leading to death collapse in five out of six animals. Gait disturbances, loss of spinal reflex, lesser pain response and evident loss in brain stem and reflexes shown by eye are some neurological problems associated with administration of Antimalarial drugs14. Mefloquine is usually found to be generally well tolerated by patients15. Embryotoxicity A Study reported embryo deaths and malformations during organogenesis by administration of artemisinin compounds16. To study embryofetal development test were conducted on (ICH compliant animals) rats and rabbits. The animals were treated with artesunate and combination of drug therapy. The effect behold were sizeable loss of embryo, apparent abortions and resorptions17. Another study aimed to assess fertility and development of embryos showed artemisinin compound to be Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(IVC-2014), 1-4 (2014) Res. J. Recent. Sci. International Science Congress Association 3 toxic to the foetus, retarded ossification and induced septal defects in ventricles of heart18. Conclusion It would rather be inappropriate if one talk about toxicity of antimalarial drugs and restricts the space only for Cardiotoxicity, neurotoxicity or Embryotoxicity. Antimalarial drugs affect the whole human body to a great extent. The toxic effects of drugs used in malaria prophylaxis starts from muscle cramps, seizures, retinal changes, neuropsychiatric disorders, and agranulocytosis and extend up to death. Drugs currently used in the treatment of Malaria are more prone to cause toxic effects that may be fatal. There is an urgent need to discover a drug that would be free from severe toxicity to help fight this giant problem worldwide. A study has suggested that protein of parasite particularly proteases play a prime role in metabolic pathways19. A recently discovered compound from the amino pyridine class, code named MMV390048, had been on headlines few days back and had been known to posses potent activity against multiple points in the lifecycle of malarial parasite's. This novel Antimalarial drug has been tested in vitro and known to posses antiplasmodial activity against chloroquine drug resistant and susceptible strain. Synthesis and structure– activity studies have been identified for number of promising compounds with peculiar antiplasmodial action20. Various numerical algorithms and perturbation methods have been worked out by scientists to find exact solution to non linear problems as malaria21. In 21st century science and technology has grown up to such a extent wherein there is no room for approximation22. References 1.http://www.who.int/malaria/media/world_malaria_report_ (2013)2.Peto T.E.A., Toxicity of Antimalarial drugs, J of Royal Soc. of Med., 1(82), (1989) 3.Alkadi H.O., Antimalarial Drug toxicity : A Review, Chemo J., (2007) 4.Khanna N., Antimicrobial Agents: Antiprotozoal Drugs, Pharmacology,82, (2007)5.Harrison A.C., Bioactivation and detoxification of amodiaquine, Xeno J., 25(2), 199-217 (1995)6.Touze J.E., Heno P., Fourcade I., Deharo J.C., Thomas G., Bohan S., Paule P., Riviere P. and Kouassi E., The Effects of Antimalarial drugs on ventricular repolarization, J. Trop. Med. Hyg., 67(1), 54–60(2002) 7.Kinoshita A., Yamada H., Kotaki H. and Kimura M., Effects of Anti-Malarial drugs on the Electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system, Malar J,. 9, 318 (2010) 8.Bouchaud O., Imbert P., Touze J.E., Dodoo A.N. and Danis M., Legros F., Fatal Cardiotoxicity related to Halofantrine: A review based on a worldwide safety data base, Malar J. 8, 289 (2009) 9.White N. J., Cardiotoxicity of antimalarial drugs, Lanc Infect Dis., 7(8), 549-58 (2007) 10.Traebert M. and Dumotier B., Antimalarial drugs: QT prolongation and cardiac arrhythmias, Expert Opin Drug Saf. , 4(3), 421-31 (2005) 11.Maude R.J., Plewes K, Faiz M.A, Hanson J, Charunwatthana P, Lee S. J. and Tärning J., Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria?, Am J Trop Med Hyg., 80(1), 126-32 (2009)12.Thapa R., Patra V. and Kundu R., Plasmodium vivax cerebral malaria, Indian Pediatr, 44(6), 4334 (2007) 13.Carter J.A., Mung'ala-Odera V., Neville B.G., Murira G., Mturi N. and Musumba C., Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children, J. Neurol Neurosurg Psychiatry, 76(4), 47681 (2005) 14.Winstanley P. and Ward S., Malaria chemotherapy, Adv Parasitol, 61, 47-76 (2006) 15.Genovese R.F., Nguyen H.A. and Mog S.R., Effects of arteether on an auditory radial-arm maze task in rats, Physiol Behav., 73(1-2), 87-91(2001) 16.Brewer T. G., Grate S. J., Peggins J.O., Weina P.J., Petras J.M., Levine B.S., Heiffer M.H. and Schuster B.G., Fatal neurotoxicity of arteether and artemether, Am J Trop Med Hyg. 51(3), 251-9 (1994) 17.Nosten F. and Price R.N., New antimaiarials: a risk-benefit analysis, Drug Saf, 12(4), 264-73 (1995) 18.Clark R.L., Embryotoxicity of the artemisinin antimalarials and potential consequences for use in women in the first trimester, J. Reprod Toxicol., 28(3), 285-96 (2009) 19.Bhatt T.K., Computational Studies on Calpain from Plasmodium Falciparum, Res. J. of Rec. Sc., 1(9), 79-82 (2012) 20.Clark R.L., White T.E., Clode S.A., Gaunt I., Winstanley P. and Ward S.A., Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit, Res. B. Dev. Reprod Toxicol., 71(6), 380-94 (2004) 21.Khan M.A., Islam S., Khan S.A., Zaman G., Muhammad A. and Syed F.S., Application of Homotopy Perturbation Method to Vector Host Epidemic Model with Non-Linear Incidences, Res. J. of Rec. Sc., 2(6), 90-95 (2013) 22.Mac Donald I.,Science and Technology in the 21st Century: Phytomedicine in Focus, Res. J. of Rec. Sc., (2), 1-7 (2012) Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(IVC-2014), 1-4 (2014) Res. J. Recent. Sci. International Science Congress Association 4 23.Schmuck G., Klaus A.M., Krötlinger F. and Langewische F.W., Developmental and reproductive toxicity studies on artemisone, Res. B. Dev.Reprod Toxicol,86(2), 131-43 (2009) 24.Younis Y., J. Med. Chem., 55 (7), 3479–348 (2012) 25.Lalithambika B., Vani C. and Arayil N.T., Biological Control of Dengue Vector using Pseudomonas fluorescens, Res. J. Recent. Sci,. 3(ISC-2013), 344-351 (2014) 26.Ahmed R.R., Ahmad N., Nasir F. and Khoso I., Patients’ Satisfaction and Quality Health Services: An Investigation from Private Hospitals of Karachi, Pakistan, Res. J. Recent. Sci., 3(7), 34-38, (2014)