The Causative Agents Of Malaria Biology Essay

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The causative agents of malaria are plasmodia, unicellular organisms belonging to the order hemosporidia class protozoa. The infective form, the sporozoite, is inoculated into skin capillaries when infected female Anopheles mosquitoes , it sucks blood from humans. The sporozoites invade liver parenchymal cells where they develop into primary tissue schizonts. After multiple fission, these schizonts produce numerous merozoites that enter the blood. The preerythrocytic stage is symptom free. In blood, the parasite enters erythrocytes (erythrocytic stage) where it again multiplies by schizogony, resulting in the formation of more merozoites. Rupture of the infected erythrocytes releases the merozoites and pyrogens (Price et al, 2007). A fever attack ensues and more erythrocytes are infected. The generation period for the next crop of merozoites determines the interval between fever attacks. With Plasmodium vivax and P. ovale, there can be a parallel multiplication in the liver (paraerythrocytic stage). Moreover, some sporozoites may become dormant in the liver as "hypnozoites" before entering schizogony. When the sexual forms (gametocytes) are ingested by a feeding mosquito, they can initiate the sexual reproductive stage of the cycle that results in a new generation of transmittable sporozoites. Different antimalarials selectively kill the parasite's different developmental forms. The mechanism of action is known for some of them: pyrimethamine and dapsone inhibit dihydrofolate reductase ,as does chlorguanide (proguanil) via its active metabolite(Muller et al, 2011). The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid . Chloroquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. Antimalarial drug choice takes into account tolerability and plasmodial resistance. Tolerability. The first available antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated. Plasmodium (P.) falciparum, responsible for the most dangerous form of malaria, is particularly prone to develop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine and sulfadoxine( Hastings, 2006).

This essay will focus on particular drugs which is quinine sulphate and their structure , formation, mode of action and their side effects.

Quinine sulphate (Quinine)

The discovery of quinine is considered the most serendipitous medical discovery of the 17th century(Toovey, 2004)and malaria treatment with quinine marked the first successful use of a chemical compound to treat an infectious disease Quinine, as a component( figure 1) of the bark of the cinchona (quina-quina) tree, was used to treat malaria from as early as the 1600s, when it was referred to as the "Jesuits' bark," "cardinal's bark," or "sacred bark." These names stem from its use in 1630 by Jesuit missionaries in South America, though a legend suggests earlier use by the native population[(Rocco and Fiametta ,2004). According to this legend, an Indian with a high fever was lost in an Andean jungle. Thirsty, he drank from a pool of stagnant water and found that it tasted bitter. Realizing that the water had been contaminated by the surrounding quina-quina trees he thought he was poisoned. Surprisingly, his fever soon abated, and he shared this accidental discovery with fellow villagers, who thereafter used extracts from the quina-quina bark to treat fever . The legend of quinine's discovery accepted in Europe differs though, and involves the Spanish Countess of Chinchon who, while in Peru, contracted a fever that was cured by the bark of a tree. Returning to Spain with the bark, she introduced quinine to Europe in 1638 and, in 1742, botanist Carl Linnaeus called the tree "Cinchona" in her honour . Before 1820, the bark of the cinchona tree was first dried, ground to a fine powder, and then mixed into a liquid (commonly wine) before being drunk. In 1820, quinine was extracted from the bark, isolated and named by Pierre Joseph Pelletier and Joseph Caventou. Purified quinine then replaced the bark as the standard treatment for malaria (Loren and Humphery, 2000). Quinine and other cinchona alkaloids including quinidine, cinchonine and cinchonidine are all effective against malaria. The efficacies of these four alkaloids were evaluated in one of the earliest clinical trials, conducted from 1866 to 1868 in 3600 patients using prepared sulfates of the alkaloids. With the main outcome measure of "cessation of febrile paroxysms", all four alkaloids were found to be comparable, with cure rates of >98%. However, after 1890 quinine became the predominantly used alkaloid, mainly due to a change in supply from South American to Javan cinchona bark, which contained a higher proportion of quinine (Aftalion and Fred, 2001). Quinine remained the mainstay of malaria treatment until the 1920s, when more effective synthetic anti-materials became available.

http://www.malariajournal.com/content/figures/1475-2875-2-25-5-l.jpg

Figure 1; shows quinine structure .

The properties of quinine sulphate

Quinine is a cinchona alkaloid that belongs to the aryl amino alcohol group of drugs. It is an extremely basic compound and is, therefore, always presented as a salt (Yakoub et al, 1995). Various preparations exist, including the hydrochloride, dihydrochloride, sulphate, bisulphate, and gluconate salts; of these the dihydrochloride is the most widely used. Quinine has rapid schizonticidal action against intra-erythrocytic malaria parasites. It is also gametocytocidal for Plasmodium vivax and Plasmodium malariae, but not for Plasmodium falciparum. Quinine also has analgesic, but not antipyretic properties. Quinine is a cinchona alkaloid that belongs to the aryl amino alcohol group of drugs. It is an extremely basic compound and is, therefore, always presented as a salt (Yakoub et al, 1995). Various preparations exist, including the hydrochloride, dihydrochloride, sulphate, bisulphate, and gluconate salts; of these the dihydrochloride is the most widely used. Quinine has rapid schizonticidal action against intra-erythrocytic malaria parasites. It is also gametocytocidal for Plasmodium vivax and Plasmodium malariae, but not for Plasmodium falciparum. Quinine also has analgesic, but not antipyretic properties.. Quinine is rapidly absorbed both orally and parenterally, reaching peak concentrations within 1-3 hours(Salako, and Sowunmi,1992). It is distributed throughout the body fluids and is highly protein bound, mainly to alpha-1 acid glycoprotein. The binding capacity in plasma is concentration dependent, but also depends on the levels of alpha-1 acid glycoprotein, which therefore makes comparisons between different studies difficult(Mihaly,1987) . Quinine has a low therapeutic index, and adverse effects with its use are substantial (WHO,2000).

Using of quinine sulphate

Quinine sulphate (quinine) was originally developed as an antimalarial but has been used in the United Kingdom for many years as a treatment for nocturnal leg cramps. Muscle cramps are a common symptom, affecting patients with and without diabetes(Parisiet al, 2003) . A study of over 65-year-olds reported that 50% of outpatients complained of frequent nocturnal muscle cramps. Muscle cramps are defined as involuntary, generally painful contractions of a muscle or muscle group and can be frequent, severe and disabling. They are caused by ectopic discharges from nerves and - although thought to be exacerbated by metabolic disorders, neuropathic conditions, pregnancy, hypomagnesaemia, hypocalcaemia, hypothyroidism, renal and liver dysfunction - are most commonly idiopathic. A number of drugs commonly used in diabetes such as lipid lowering agents, diuretics, beta-blockers and insulin are also thought to increase risk of cramps. Patients with diabetic neuropathy can experience muscle cramps, along with other symptoms of pain and altered sensation. Symptoms of neuropathy in patients with diabetes are a therapeutic challenge and treatment often involves multiple therapies. When, as is usually the case, the etiology of nocturnal muscle cramps is unknown, treatment is symptomatic (Miller et al, 2005). Many non-pharmacological treatments including stretching, massage and walking have been tried with little evidence of benefit. Pharmacological treatments with calcium-channel blockers or vitamin E have been used but quinine has historically been the treatment of choice in the UK.

Quinine sulphate is used in the management of malaria

Quinine remains an important anti-malarial drug, almost 400 years after Jesuit priests first documented its effectiveness. The 2010 World Health Organization (WHO) guidelines recommend a combination of quinine plus doxycycline, tetracycline or clindamycin as second line treatment for uncomplicated malaria (to be used when the first-line drug fails or is not available) and quinine plus clindamycin for treatment of malaria in the first trimester of pregnancy (WHO,2010). Based on recent trials, intravenous artesunate should be used for the treatment of severe falciparum malaria in adults (Dondrop et al,2005) and children in preference to quinine. By 2009, 31 African countries recommended quinine as second-line treatment for uncomplicated malaria, 38 as a first - line treatment of severe malaria and 32 for treatment of malaria in the first trimester of pregnancy (WHO, 2009). In most of Africa, quinine is still used as monotherapy, contrary to the WHO recommendations (2009,2010); the reason for this practice may be the higher costs of quinine antibiotic combinations. Quinine continues to play a significant role in the management of malaria in sub- Saharan Africa and other malaria endemic areas, and its use in routine practice may not be restricted to the stated WHO recommendations. In Cameroon, even one year after the introduction of artemisinin-based combination therapy (ACT), quinine continued to be used as first-line therapy, with 45% of adults receiving oral quinine for uncomplicated malaria ( Sayang et al, 2009). Recent surveillance data from sentinel sites in Uganda showed that quinine was prescribed for up to 90% of children < 5 years with uncomplicated malaria (UMSP, 2010). The use of quinine for uncomplicated malaria cases should have decreased due to toxicities, poor compliance and the implementation of newer and better tolerated therapies such as ACT. However, the limited availability of ACT and the increasing resistance to chloroquine and antifolates have actually increased its use in recent times (Yeka et al, 2009). Therefore, studies evaluating the role of quinine in the management of malaria have been reviewed.

The mode of actions of quinine sulphate

Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. Vivax and P. Malaria. Because it is a weak base, it is concentrated in the food vacuoles of P. Falciparum. It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. (Figure 2). As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.

The mechanisms of resistance of Quinine sulphate

Parasite drug resistance is probably the greatest problem faced by malaria control programs worldwide and is an important public health concern. Over the years, malaria parasites have developed resistance to a number of commonly used anti-malarial drugs. However the development of resistance to quinine has been slow. Although its use started in the 17th century, resistance to quinine was first reported in 1910 (Peters,1982). Resistance to quinine is usually low grade, with the drug retaining some activity but having its action delayed or diminished. Diminished sensitivity of P. falciparum to quinine has been widely documented in Asia and South America ( Mayxay, et al,2007) but it seems relatively uncommon in Africa where conflicting results of no resistance (Tinto et al, 2006) or varying degrees of resistance (Pradines et al, 1998) have been reported. A recent study from Thailand showed significant reductions in efficacy of quinine, artemisinin and mefloquine when compared to previous reports from the same area, suggesting a further increase in drug resistance in this region (Huttinger et al, 2010). No convincing evidence of high grade quinine resistance in the treatment of severe malaria has been reported. Findings from a recent systematic review of about 435 clinical trials published between 1966 and 2002 showed that the recrudescence rates for quinine reported over these past 30 years remained roughly constant (Myint et al, 2004)These findings are encouraging and may suggest that the efficacy of quinine has been preserved.

The side effects of Quinine sulphate

Quinine is a potentially toxic drug. The typical syndrome of quinine side effects is called as cinchonism and it can be mild in usual therapeutic dosage or could be severe in larger doses. Mild cinchonism consists of ringing in the ears, headache, nausea and disturbed vision. Functional impairment of the eighth nerve results in tinnitus, decreased auditory acuity and vertigo. Visual symptoms consist of blurred vision, disturbed color perception, photophobia, diplopia, night blindness, and rarely, even blindness. These changes are due to direct neurotoxicity, although vascular changes may contribute to the problem. Gastrointestinal symptoms like nausea, vomiting, abdominal pain and diarrhoea may be seen. Rashes, sweating, angioedema can occur. Excitement, confusion, delirium is also seen in some patients. Coma, respiratory arrest, hypotension, and death can occur with over dosage. Quinine can also cause renal failure. Massive hemolysis and hemoglobinuria can occur, especially during pregnancy or with repeated use. Hypoprothrombinemia, agranulocytosis are also reported.

Conclusion

In the near future, quinine will continue to play a significant role in the management of malaria, particularly in the role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but this remains a promising intervention given the limited availability of rectal artemisinin preparations in resource limited settings. The continued use of quinine in the management of uncomplicated malaria is a concern. Clearly, the seven day duration of therapy and thrice daily administration of quinine presents a major challenge to completion of therapy, leading to sub-optimal treatment outcomes. In these situations, ACT is a better option given the simplicity of dosing and shorter treatment duration. However, because of the frequent ACT stock outs, the rapid withdrawal of quinine as a treatment option for uncomplicated malaria cases is risky. The best approach would be, besides improving the supply system, to maintain quinine as a fallback drug in case of ACT stock-outs.

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