It is practical to consider antimalarials by chemical structure since this is associated with important properties of each drug, such as mechanism of action.
Quinine and related agents Quinine has a long history stretching from
Peru, and the discovery of the
cinchona tree, and the potential uses of its bark, to the current day and a collection of derivatives that are still frequently used in the prevention and treatment of malaria. Quinine is an
alkaloid that acts as a blood
schizonticidal and weak
gametocide against
Plasmodium vivax and
Plasmodium malariae. As an alkaloid, it is accumulated in the food
vacuoles of
Plasmodium species, especially
Plasmodium falciparum. It acts by inhibiting the
hemozoin biocrystallization, thus facilitating an aggregation of
cytotoxic heme. Quinine is less effective and more toxic as a blood schizonticidal agent than
chloroquine; however, it is still very effective and widely used in the treatment of acute cases of severe
P. falciparum. It is especially useful in areas where there is known to be a high level of resistance to chloroquine,
mefloquine, and
sulfa drug combinations with
pyrimethamine. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is
endemic. The treatment regimen of quinine is complex and is determined largely by the parasite's level of resistance and the reason for drug therapy (i.e. acute treatment or prophylaxis). The
World Health Organization recommendation for quinine is 20 mg/kg the first dose and 10 mg/kg every eight hours for five days where parasites are sensitive to quinine, combined with
doxycycline,
tetracycline or
clindamycin. Doses can be given by oral,
intravenous or
intramuscular routes. The suggested course of action is determined by the need for therapy and the available resources (i.e. sterilised needles for IV or IM injections). Use of quinine is characterised by a frequently experienced syndrome called
cinchonism.
Tinnitus (a hearing impairment), rashes,
vertigo, nausea, vomiting and abdominal pain are the most common symptoms. Neurological effects are experienced in some cases due to the drug's
neurotoxic properties. These actions are mediated through the interactions of quinine causing a decrease in the excitability of the
motor neuron end plates. This often results in functional impairment of the
eighth cranial nerve, resulting in confusion,
delirium and coma. Quinine can cause
hypoglycaemia through its action of stimulating
insulin secretion; this occurs in therapeutic doses and therefore it is advised that glucose levels are monitored in all patients every 4–6 hours. This effect can be exaggerated in pregnancy and therefore additional care in administering and monitoring the dosage is essential. Repeated or over-dosage can result in
kidney failure and death through depression of the
respiratory system.
Quinimax and
quinidine are the two most commonly used alkaloids related to quinine in the treatment or prevention of malaria. Quinimax is a combination of four alkaloids (quinine, quinidine, cinchonine and cinchonidine). This combination has been shown in several studies to be more effective than quinine, supposedly due to a synergistic action among the four cinchona derivatives. Quinidine is a direct derivative of quinine. It is a
distereoisomer, thus having similar anti-malarial properties to the parent compound. Quinidine is recommended only for the treatment of severe cases of malaria.
Warburg's tincture was a
febrifuge developed by
Carl Warburg in 1834, which included quinine as a key ingredient. In the 19th-century it was a well-known anti-malarial drug. Although originally sold as a secret medicine, Warburg's tincture was highly regarded by many eminent medical professionals who considered it as being superior to quinine (e.g. Surgeon-General W. C. Maclean, Professor of Military Medicine at British Army Medical School, Netley). Warburg's tincture appeared in
Martindale: The complete drug reference from 1883 until about 1920. The formula was published in
The Lancet 1875.
Chloroquine Chloroquine was, until recently, the most widely used anti-malarial. It was the original prototype from which most methods of treatment are derived. It is also the least expensive, best tested and safest of all available drugs. The emergence of drug-resistant parasitic strains is rapidly decreasing its effectiveness; however, it is still the first-line drug of choice in most
sub-Saharan African countries. It is now suggested that it is used in combination with other antimalarial drugs to extend its effective usage. Popular drugs based on chloroquine phosphate (also called nivaquine) are Chloroquine FNA, Resochin and Dawaquin. Chloroquine is a
4-aminoquinolone compound with a complicated and still unclear mechanism of action. It is believed to reach high concentrations in the vacuoles of the parasite, which, due to its alkaline nature, raises the internal
pH. It controls the conversion of toxic
heme to hemozoin by inhibiting the biocrystallization of hemozoin, thus poisoning the parasite through excess levels of toxicity. Other potential mechanisms through which it may act include interfering with the biosynthesis of parasitic
nucleic acids and the formation of a chloroquine-haem or chloroquine-
DNA complex. The most significant level of activity found is against all forms of the
schizonts (with the obvious exception of chloroquine-resistant
P. falciparum and
P. vivax strains) and the
gametocytes of
P. vivax,
P. malariae,
P. ovale as well as the immature gametocytes of
P. falciparum. Chloroquine also has a significant
anti-pyretic and
anti-inflammatory effect when used to treat
P. vivax infections, and thus it may still remain useful even when resistance is more widespread. According to a report on the Science and Development Network website's sub-Saharan Africa section, there is very little drug resistance among children infected with malaria on the island of Madagascar, but what drug resistance there is exists against chloroquinine. Children and adults should receive 25 mg of chloroquine per kg given over three days. A
pharmacokinetically superior regime, recommended by the WHO, involves giving an initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg, then 5 mg/kg on the following two days. For
chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into six daily doses is advised. Chloroquine is only recommended as a
prophylactic drug in regions only affected by
P. vivax and sensitive
P. falciparum strains. Chloroquine has been used in the treatment of malaria for many years and no
abortifacient or
teratogenic effects have been reported during this time; therefore, it is considered very safe to use during pregnancy. However,
itching can occur at intolerable level and chloroquinine can be a provocation factor of
psoriasis.
Hydroxychloroquine Hydroxychloroquine was derived in the 1950s by adding a
hydroxy group to existing chloroquine, making it more tolerable than chloroquine by itself.
Amodiaquine Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to chloroquine. Amodiaquine has tended to be administered in areas of chloroquine resistance while some patients prefer its tendency to cause less itching than chloroquine. Amodiaquine is now available in a combined formulation with
artesunate (
ASAQ) and is among the artemisinin-combination therapies recommended by the World Health Organization. Combination with sulfadoxine=pyrimethamine is not recommended. The drug should be given in doses between 25 mg/kg and 35 mg/kg over three days in a similar method to that used in chloroquine administration. Adverse reactions are generally similar in severity and type to that seen in chloroquine treatment. In addition,
bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded. Some blood and
hepatic disorders have also been seen in a small number of patients. It acts by inhibiting
dihydrofolate reductase in the parasite thus preventing the biosynthesis of
purines and
pyrimidines, thereby halting the processes of
DNA replication,
cell division and reproduction. It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only used in concert with a
sulfonamide The pharmacokinetic profile of the drugs indicates that a half dose, twice daily maintains the
plasma levels with a greater level of consistency, thus giving a greater level of protection. The proguanil- chloroquine combination does not provide effective protection against resistant strains of
P. falciparum. There are very few side effects to proguanil, with slight hair loss and mouth ulcers being occasionally reported following prophylactic use.
Atovaquone Atovaquone is available in combination with proguanil under the name
Malarone, albeit at a price higher than Lariam. It is commonly used in
prophylaxis by travelers and used to treat falciparum malaria in developed countries. A liquid oral suspension of atovaquone is available under the name Mepron.
Primaquine Primaquine is a highly active 8-aminoquinolone that is effective against
P. falcipraum gametocytes but also acts on merozoites in the bloodstream and on hypnozoites, the dormant hepatic forms of
P. vivax and
P. ovale. It is the only known drug to cure both relapsing malaria infections and acute cases. The mechanism of action is not fully understood but it is thought to block oxidative metabolism in Plasmodia. It can also be combined with methylene blue. For the prevention of relapse in
P. vivax and
P. ovale 0.15 mg/kg should be given for 14 days. As a gametocytocidal drug in
P. falciparum infections a single dose of 0.75 mg/kg repeated seven days later is sufficient. This treatment method is only used in conjunction with another effective blood schizonticidal drug. There are few significant side effects although it has been shown that primaquine may cause
anorexia, nausea, vomiting, cramps, chest weakness,
anaemia, some suppression of
myeloid activity and abdominal pains. In cases of over-dosage
granulocytopenia may occur.
Artemisinin and derivatives Artemisinin (
qinghaosu) is a chemical that has been used in the treatment of fevers for over 1,000 years. It is derived from the plant
Artemisia annua, with the first documentation as a successful therapeutic agent in the treatment of malaria is in 340 AD by
Ge Hong in his book
Zhou Hou Bei Ji Fang (
A Handbook of Prescriptions for Emergencies). Ge Hong extracted the artemesinin using a simple
macerate, and this method is still in use today. The active compound was first isolated in 1971 and named artemisinin. •
Artemisinin has a very rapid action and the vast majority of acute patients treated show significant improvement within 1–3 days of receiving treatment. It has demonstrated the fastest clearance of all anti-malarials currently used and acts primarily on the
trophozoite phase, thus preventing progression of the disease. Semi-synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier to use than the parent compound and are converted rapidly once in the body to the active compound dihydroartemesinin. On the first day of treatment 20 mg/kg is often given, and the dose then reduced to 10 mg/kg per day for the six following days. Few side effects are associated with artemesinin use. However, headaches, nausea, vomiting, abnormal bleeding, dark urine, itching and some
drug fever have been reported by a small number of patients. Some cardiac changes were reported during a clinical trial, notably non specific ST changes and a first degree
atrioventricular block (these disappeared when the patients recovered from the malarial fever). •
Artemether is a
methyl ether derivative of dihydroartemesinin. It is similar to artemesinin in mode of action but demonstrates a reduced ability as a hypnozoiticidal compound, instead acting more significantly to decrease gametocyte carriage. Similar restrictions are in place, as with artemesinin, to prevent the development of resistance, therefore it is only used in combination therapy for severe acute cases of drug-resistant
P. falciparum. It should be administered in a 7-day course with 4 mg/kg given per day for three days, followed by 1.6 mg/kg for three days. Side effects of the drug are few but include potential
neurotoxicity developing if high doses are given. •
Artesunate is a
hemisuccinate derivative of the active metabolite dihydroartemisin. Currently it is the most frequently used of all the artemesinin-type drugs. Its only effect is mediated through a reduction in the gametocyte transmission. It is used in combination therapy and is effective in cases of uncomplicated
P. falciparum. The dosage recommended by the WHO is a five or seven day course (depending on the predicted adherence level) of 4 mg/kg for three days (usually given in combination with mefloquine) followed by 2 mg/kg for the remaining two or four days. In large studies carried out on over 10,000 patients in Thailand no adverse effects have been shown. •
Dihydroartemisinin is the active metabolite to which artemesinin is reduced. It is the most effective artemesinin compound and the least stable. It has a strong blood schizonticidal action and reduces gametocyte transmission. It is used for therapeutic treatment of cases of resistant and uncomplicated
P. falciparum. 4 mg/kg doses are recommended on the first day of therapy followed by 2 mg/kg for six days. As with artesunate, no side effects to treatment have thus far been recorded. •
Arteether is an
ethyl ether derivative of dihydroartemisinin. It is used in combination therapy for cases of uncomplicated resistant
P. falciparum. The recommended dosage is 150 mg/kg per day for three days given by IM injections. With the exception of a small number of cases demonstrating neurotoxicity following
parenteral administration no side effects have been recorded.
Halofantrine Halofantrine is a relatively new drug developed by the
Walter Reed Army Institute of Research in the 1960s. It is a
phenanthrene methanol, chemically related to quinine and acts acting as a blood schizonticide effective against all
Plasmodium parasites. Its mechanism of action is similar to other anti-malarials. Cytotoxic complexes are formed with
ferritoporphyrin XI that cause plasmodial membrane damage. Despite being effective against drug resistant parasites, halofantrine is not commonly used in the treatment (prophylactic or therapeutic) of malaria due to its high cost. It has very variable bioavailability and has been shown to have potentially high levels of
cardiotoxicity. It is still a useful drug and can be used in patients that are known to be free of heart disease and that have severe and resistant forms of acute malaria. A popular drug based on halofantrine is Halfan. The level of governmental control and the prescription-only basis on which it can be used contributes to the cost, thus halofantrine is not frequently used. A dose of 8 mg/kg of halofantrine is advised to be given in three doses at six-hour intervals for the duration of the clinical episode. It is not recommended for children under 10 kg despite data supporting the use and demonstrating that it is well tolerated. The most frequently experienced side-effects include nausea, abdominal pain, diarrhea, and itch. Severe
ventricular dysrhythmias, occasionally causing death are seen when high doses are administered. This is due to
prolongation of the QTc interval. Halofantrine is not recommended for use in pregnancy and lactation, in small children, or in patients that have taken mefloquine previously.
Lumefantrine Lumefantrine is a relative of halofantrine that is used in some combination antimalarial regimens.
Doxycycline Probably one of the more prevalent antimalarial drugs prescribed, due to its relative effectiveness and cheapness,
doxycycline is a
tetracycline compound derived from
oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to be developed and are still used widely in many types of infection. It is a
bacteriostatic agent that acts to inhibit the process of
protein synthesis by binding to the
30S ribosomal subunit thus preventing the 50s and 30s units from bonding. Doxycycline is used primarily for
chemoprophylaxis in areas where chloroquine resistance exists. It can also be used in combination with quinine to treat resistant cases of
P. falciparum but has a very slow action in acute malaria, and should not be used as monotherapy. When treating acute cases and given in combination with quinine; 100 mg of doxycycline should be given per day for seven days. In prophylactic therapy, 100 mg (adult dose) of doxycycline should be given every day during exposure to malaria. The most commonly experienced side effects are permanent
enamel hypoplasia (although this is only relevant during the period of tooth development during the first decade of life), transient depression of bone growth, gastrointestinal disturbances and some increased levels of
photosensitivity. Due to its effect of bone and tooth growth it is not used in children under 8, pregnant or lactating women and those with a known hepatic dysfunction. Tetracycline is only used in combination for the treatment of acute cases of
P. falciparum infections. This is due to its slow onset. Unlike doxycycline it is not used in chemoprophylaxis. For tetracycline, 250 mg is the recommended adult dosage (it should not be used in children) for five or seven days depending on the level of adherence and compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences with the process of
ossification and depression of bone growth are known to occur. The majority of side effects associated with doxycycline are also experienced.
Clindamycin Clindamycin is a derivative of
lincomycin, with a slow action against blood schizonticides. It is only used in combination with quinine in the treatment of acute cases of resistant
P. falciparum infections and not as a prophylactic. Being more toxic than the other antibiotic alternatives, it is used only in cases where the Tetracyclines are contraindicated (for example in children). Clindamycin should be given in conjunction with quinine as a 300 mg dose (in adults) four times a day for five days. The only side effects recorded in patients taking clindamycin are nausea, vomiting and abdominal pains and cramps. However these can be alleviated by consuming large quantities of water and food when taking the drug.
Pseudomembranous colitis (caused by
Clostridioides difficile) has also developed in some patients; this condition may be fatal in a small number of cases.
Microtubule Inhibitors Some microtubule inhibitors, including vinblastine and taxol, are highly potent against malarial parasites, disrupting microtubular structures, at the cost of high mammalian toxicity. Very low cytotoxicity can be found in
dinitroaniline or phosphorothioamidate herbicides retaining moderate anti-malarial activity.
Trifluralin accumulates in parasite-infected erythrocytes to ~300 times the external concentration, though derivative molecules with better solubility may be wanted to make administration practical. ==Resistance==