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4-aminoquinolines (chloroquine, amodiaquine)

CHLOROQUINE

Chloroquine is a 4-aminoquinoline first synthesized in 1934 but subsequently discovered independently as a result of antimalarial research in 1943. It is related chemically to other quinolones which are also antiparasitic. Amodiaquine is a closely related analog.

Chloroquine and amodiaquine both act as blood schizontocides. They are thought to act by being concentrated in the parasite's lysosomes (food vacuoles) where hemoglobin is digested. There they inhibit the polymerization of hemin, which is toxic to the parasite, into insoluble, and nontoxic, hemozoin (malaria pigment). The accumulating hemin acts to kill the parasite.

Chloroquine acts against the red cell forms of P. vivax, P. ovale and P. malariae forms as well as against P.

falciparum, which is chloroquine sensitive. It is also gametocytocidal against the first three forms. It has no activity against latent tissue forms of P. vivax or P. ovale.

Chloroquine has also been used to treat hepatic amebae as well as inflammatory diseases with an autoimmune element.

One resistant strain of P. falciparum transports chloroquine out of its food vacuole more rapidly than do susceptible strains. Calcium channel blockers (e.g. verapamil and nifedipine) suppress the efflux of chloroquine and, if given together with chloroquine, could theoretically allow effective therapy against chloroquine-resistant strains. Recent attempts to demonstrate the genetic basis of resistance have not been completely successful, suggesting that multiple mechanisms of resistance may be occur.

Chloroquine is the most widely prescribed antimalarial drug in the tropics. If the plasmodium is susceptible, chloroquine is invaluable for curative use because it acts rapidly. It is also useful in suppressive prophylaxis.

Chloroquine is rapidly absorbed orally, and therapeutic blood concentrations are reached within 2-3 hours. It is slowly eliminated from the body, with the kidney being the main route of elimination. Chloroquine is excreted unchanged (about 50%) or metabolized in the liver, mostly by oxidation via CYPs.

Adverse effects of chloroquine include nausea, vomiting, headache, uneasiness, restlessness, blurred vision, hypotension and pruritus. It is considered to be relatively safe for use in pregnancy.

AMODIAQUINE

Amodiaquine is similar to chloroquine in many ways, but it appears to retain some activity against chloroquine-resistant strains of P. falciparum. However, this advantage is usually short-lived. With sustained amodiaquine administration one of its metabolites, a quinoneimine, produces toxic hepatitis and potentially lethal agranulocytosis.

The use of amodiaquine is now discouraged.

Arylaminoalcohols

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The quinoline methanols (quinine, quinidine and mefloquine) and the phenanthrene methanol (halofantrine) are all blood schizontocides that act only on the blood stages of the malaria plasmodium when the plasmodium is engaged in digesting hemoglobin. They are used to treat acute disease because of their rapid actions.

Quinine, in the form of cinchona bark, has a long (350-year) recorded history. It is an alkaloid extracted from the bark of the cinchona tree found originally in South America. In its crude form, as infusions of the bark, it was introduced to Europe many centuries ago for the treatment of fevers. Only much later was it discovered to be a specific therapy for malaria. Despite its long history, it remains the drug of choice for the treatment of severe and complicated malaria.

Its mechanism of action is as a weak base that inhibits the detoxifying polymerization of heme. Quinine is a

schizontocide and has little effect on other forms except for being gametocytocidal for P. malariae and P. vivax. Thus it is not used for prophylaxis. Quinine has a number of other pharmacological actions. Thus, it has ion channel blocking actions which it shares with quinidine (the D enantiomer of quninine) which is used as an antiarrhythmic. It also acts on skeletal muscle to reduce its excitability; hence its use at low doses to reduce leg cramps.

Quinine's main use in malaria is by i.v. administration as a suppressive and cure in chloroquine-resistant infections.

Oral treatment follows initial i.v. treatment. It should always be given as a controlled infusion. Quinine is considered to be relatively safe in pregnancy.

Mild adverse responses to quinine are common with controlled i.v. infusions. At high doses a triad of adverse effects are seen, notably the condition known as cinchonism, hypoglycemia and hypotension. Symptoms of cinchonism include tinnitus, hearing loss, nausea, vomiting, uneasiness, restlessness and blurring of vision. Hypoglycemia is the most serious frequent adverse effect. Quinine and its isomer quinidine are ion channel blocking drugs. By virtue of such actions, particularly on the cardiac potassium ion channel responsible for the current known as IKr, it can induce cardiac arrhythmias.

Mefloquine, which is chemically similar in structure to quinine, is a long-acting blood schizontocide that is effective in the treatment of all malarial species, including multidrug-resistant P. falciparum. It can also be used for suppressive prophylaxis.

Mefloquine is only available in tablet form. The adverse effects of mefloquine include nausea, vomiting, abdominal colic, sinus bradycardia, sinus arrhythmia and postural hypotension. Serious, but relatively rare, adverse effects are acute psychosis and a transient encephalopathy with convulsions. It has been suggested that mefloquine may cause fetal abnormalities when taken during the first trimester of pregnancy.

Halofantrine is another synthetic antimalarial drug that is active against multiresistant P. falciparum. Its oral

bioavailability is poor and variable, but bioavailability can be increased if the drug is taken with a fatty meal. There is no parenteral preparation.

Halofantrine is usually well tolerated, with minor and reversible adverse events such as nausea, abdominal pain and diarrhea. However, it has been shown to prolong the QTc interval of the ECG when given at standard doses, and there have been rare reports of serious, sometimes fatal, ventricular arrhythmias (i.e. torsades de pointes, see Ch.

13).

Antifolates

See also Antibiotics below.

The sulfonamides (sulfadoxine, sulfalene and co-trimoxazole), a sulfone (dapsone), the biguanides (proguanil and chlorproguanil) and a diaminopyridine (pyrimethamine) are drugs that inhibit folate metabolism in parasites. They can be divided into two types:

 Type 1, sulfonamides and dapsone compete for the enzyme DHPS, found only in plasmodium.

 Type 2, biguanides and diaminopyrimidines, specifically inhibit a form of DHFR found only in malarial plasmodium (Fig. 6.25).

Since both type 1 and type 2 antifolates inhibit all of the growing stages of the plasmodium, they are used for both prophylaxis and treatment. They also act as sporontocides since they prevent the growth of sporogonic stages in mosquitoes. Mixtures of type 1 and type 2 antifolates are used in the treatment of chloroquine-resistant P. falciparum.

Sulfadoxine has a long half-life of 120-200 hours. It is less effective against P. vivax than against P. falciparum. It is synergistic in combination with pyrimethamine at a ratio of 20:1, although as a combination it acts only on the late red blood stages. It seems to have a slower onset of antimalarial action than chloroquine. This combination may cause systemic vasculitis, Stevens-Johnson syndrome, or toxic epidermal necrosis in patients who are hypersensitive to sulfonamides, and should preferably not be given in late pregnancy, during lactation, or to newborn infants because of the theoretical risk of provoking kernicterus.

Sulfalene has a half-life of 65 hours and it is often used in combination with pyrimethamine.

Dapsone has a half-life of 25 hours. It is mainly used in combination with pyrimethamine, and the prophylactic drug maloprim.

Co-trimoxazole (trimethoprim and sulfamethoxazole) is an antibacterial combination with antimalarial activity.

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Figure 6.25 Sites of action of antifolate drugs. Synthesis of DNA from guanosine triphosphate (GTP) by malaria parasites. The enzymes indicated with a dagger have been detected in malaria parasites, the others are presumptive. (GTPCase, GTP

cyclohydrolase; PABA, para-aminobenzoic acid) (Adapted from Warhurst DC. Parasitology Today 1986; 2: 58-59.)

Proguanil (and its analog chlorproguanil, which has a considerably longer half-life) are metabolized in the liver into its active metabolites. The parent compounds are biguanides that are rearranged into the active metabolites cycloguanil and chlorcycloguanil, respectively. These metabolites are inhibitors of DHFR. There appear to be two groups of metabolizers of these drugs. Thus, metabolism by the hepatic enzyme CYP2C19 is either extensive or poor. Poor metabolizers represent 3-6% of Europeans and Africans, and 13-23% of Asians. An unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals, exhibiting poor metabolism of proguanil, was reported on the islands of Vanuatu in eastern Melanesia. A study in Vanuatu also suggested that the parent compound proguanil has significant activity against falciparum and vivax malaria independent of the metabolite cycloguanil.

Proguanil has a half-life of 11-20 hours. It has a slow schizontocidal action on the red blood cell forms of plasmodium, but is highly effective against the exo-red blood cell forms in the liver and has sporontocidal effects on P. falciparum.

Because of its safety, proguanil (200 mg/day) is widely prescribed in combination with chloroquine (300 mg/week) as a causal prophylactic drug. This combination can be used in pregnancy. Proguanil given alone is no longer

recommended for the treatment of malaria, but recently there has been renewed interest in its use in combination with sulfones, sulfonamides, or atovaquone. It is not available in the USA.

Pyrimethamine has a half-life of 95 hours. It is used only in combination with sulfonamides or sulfones for treatment and prophylaxis since resistance to this drug is now widespread.

Unfortunately, P. falciparum seems to undergo spontaneous mutations of its dhfr gene, usually as a result of drug exposure. This gene conveys resistance to pyrimethamine and/or cycloguanil. Resistance to sulfadoxine is the result of point mutations on this gene. Both pyrimethamine and sulfadoxine are eliminated from the body slowly and, after a standard combination dose, plasma concentrations are initially high enough to kill most P. falciparum strains.

Unfortunately, thereafter, drug concentrations fall slowly, and only sensitive strains are killed, thus providing a powerful selection pressure for emergence of resistant strains.

8-aminoquinolines

Primaquine, an 8-aminoquinoline, is chemically related to the dye methylene blue shown to be active against malarial parasites over 115 years ago. A variety of antimalarial 8-aminoquinolines were synthesized mainly in the 1940s although newer ones are still appearing (e.g. tafenoquine). Primaquine is particularly active against the nongrowing stages of plasmodium (i.e. gametocytes and hypnozoites). It is currently the only drug available as a gametocytocide for P. falciparum and as a hypnozoitocide (antirelapse) for P. vivax and P. ovale.

Primaquine is given orally since the parenteral route causes severe hypotension. Bioavailability is high. It crosses the placenta, and is excreted in breast milk. Therefore, it is not be used during pregnancy or lactation. It is rapidly

metabolized to various metabolites, some of which may be antimalarial.

A single dose of 30-45 mg is adequate for eliminating gametocytes of P. falciparum, but 15 mg is given daily for 14 days to kill the hypnozoites and achieve a radical cure of P. vivax and P. ovale malaria.

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Primaquine is generally well tolerated when given orally, especially in whites. It can cause a limited degree of epigastric distress. More seriously, it can cause methemoglobinemia. The most serious side effect is acute intravascular hemolysis in those with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. There is an X-chromosome linked hereditary defect of this red blood cell enzyme in some humans which is more common in some geographical groups. However, severe hemolysis is unusual.

Tafenoquine, a congener of primaquine, is being introduced. It has a better therapeutic index than primaquine and much slower elimination (a half-life of about 14 days). The former property might make tafenoquine a safer drug, but its therapeutic role has yet to be established.

Antibiotics

These drugs (i.e. tetracycline, doxycycline, clindamycin, see Drugs and Bacteria in this chapter, above) have a slow onset of action but marked effect on the red blood cell stages of malaria. They are all inhibitors of plasmodium ribosomal protein synthesis:

 Tetracycline has proved to be a useful addition to quinine in the treatment of multidrug-resistant P. falciparum.

 Doxycycline is used as a suppressive prophylactic, especially in areas where mefloquine resistance is now common (such as Thailand and Cambodia), but may have a photosensitizing effect in some individuals.

Tetracyclines should not be used in pregnant or lactating women or in children under 8 years of age because tetracyclines may produce ossification disorders of developing bones and teeth.

Clindamycin is a synthetic derivative of lincomycin and has proved effective in the treatment of uncomplicated falciparum malaria. It may also be used for treatment in combination with quinine.

ARTEMISININ AND ITS DERIVATIVES

Artemisinin (quinghaosu) is a sesquiterpene lactone extracted from the herb Artemisia annua (sweet wormwood). It has been used in China as an antipyretic for over 2000 years. The active component was isolated and characterized in 1971. Its peroxide (trioxane) structure is responsible for its antimalarial activity. It has been used in oral and

suppository forms and several semisynthetic derivatives have been developed. Artemisinin derivatives in common use include artemether, artesunate and dihydroartemisinine (the latter being the principal metabolite of artemether and artesunate).

Clinical trials of artemisinin and its derivatives (artemether, which is administered as an intramuscular preparation, and artesunate, which is available as an oral and i.v. preparation) show that they are rapidly acting blood schizontocides against plasmodium including multiresistant strains of P. falciparum. However, recrudescences are common. These drugs have an important potential in the treatment of severe and complicated malaria, including cerebral malaria. In Thailand, artesunate tablets combined with mefloquine proved more effective for the treatment of multiresistant P.

falciparum than artesunate or mefloquine alone. Artemisinin and its derivatives have a significant effect on

gametocytogenesis. Studies on the Thailand and Myanmar border suggest that artemisinin-based drugs may reduce transmission and, consequently, the spread of resistant strains. Artemisinin derivatives are now among the most promising drugs for malaria chemotherapy because of their different molecular structure, rapid onset of action and relatively safe profile.

Antiparasitic actions of antimalarial drugs

 4-aminoquinolines such as chloroquine are concentrated in the parasite's lysosomes where hemoglobin is being digested

 Arylaminoalcohols such as quinine and mefloquine act on parasites digesting hemoglobin

 Antifolate drugs such as sulfadoxine, pyrimethamine and proguanil affect parasite folate metabolism

 Antibiotics such as tetracycline inhibit parasite ribosomal protein synthesis

 Primaquine is particularly active against the non-growing stages (i.e. gametocytes and hypnozoites)

 Artemisinin and its derivatives have a peroxide (trioxane) configuration that is responsible for their action

Serious adverse effects of antimalarial drugs

 Chloroquine and proguanil: mainly mild adverse effects; may be relatively safe in pregnancy

 Amodiaquine: lethal agranulocytosis

 Quinine: hypoglycemia; appropriate in pregnancy with severe malaria

 Mefloquine: acute psychosis and a transient encephalopathy with convulsions

 Halofantrine: prolongation of the QT interval of the ECG

 Sulfadoxine and pyrimethamine: Stevens-Johnson syndrome

 Primaquine: acute intravascular hemolysis in people with glucose-6-phosphate dehydrogenase deficiency

 Tetracycline: affects development of bones and teeth in children under 8 years of age

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New antimalarial drugs

ARTEMETHER-LUMEFANTRINE

During treatment of malaria with two different drugs, the chance of a mutant strain resistant to both drugs emerging can be calculated from the product of the individual per-parasite mutation rates. Artemisinin derivatives reduce the plasmodium biomass by around 4 log units (10 000-fold) for each asexual cycle. This rapid reduction has a major theoretical role when artemisinin derivatives are combined with other antimalarial drugs since the parasite population available to develop mutations to the second drug is markedly reduced.

Lumefantrine is a slowly eliminated antimalarial drug given as an oral solution in linoleic acid. However, there is marked variation in its bioavailability. A fixed-ratio combination of lumefantrine with artemether is available for the treatment of uncomplicated P. falciparum infections.

ATOVAQUONE-PROGUANIL

The antimalarial potential of the naphthoquinones was discovered in the mid-1940s. The most interesting compound in this group is hydroxynaphthoquinone (atovaquone), which kills resistant P. falciparum parasites. Atovaquone alone has an unacceptably high recrudescence rate, but its fixed-ratio combination with proguanil may prevent this.

CHLORPROGUANIL-DAPSONE

This represents a new use for two old drugs and is one of the possible alternatives to the sulfadoxine-pyrimethamine combination. The former combination is eliminated more rapidly than the latter, offering the possibility of lower risk of emerging resistant strains. Furthermore, chlorproguanil-dapsone retains activity against plasmodium with mutations in their dhfr gene at positions 108, 51 and 59. This combination is effective for uncomplicated malaria in Africa.

PYRONARIDINE

Pyronaridine, a mannich base, is structurally related to amodiaquine, but it may have a different mechanism of action and differing adverse effects. The current oral formulation is effective against multiresistant P. falciparum and is well tolerated, but its oral bioavailability is low.

The main adverse effects of pyronaridine include headache, dizziness, gastrointestinal disorders and transient electrocardiographic changes.

Resistance of parasites to antimalarial drugs

Resitant strains of P. falciparum were first noted for chloroquine in 1959 in Thailand and in Colombia in 1960. The subsequent rapid worldwide spread of chloroquine-resistant falciparum strains is a serious problem. This problem has been further complicated by an increased prevalence of plasmodium resistant to the combination of sulfadoxine-pyrimethamine and quinine.

Figure 6.26 The response of malaria parasites to chloroquine. The diagram shows degrees of response ranging from sensitivity to the highest resistance (RIII). (Adapted from WHO Technical Report Series No. 529, WHO Scientific Group, 1973.) There are also mefloquine-resistant strains of P. falciparum in South East Asia and in some African countries.

However, despite the extensive spread of chloroquine-resistant strains of P. falciparum, and the recent emergence of chloroquine-resistant P. vivax in Papua New Guinea, chloroquine is still the most widely used antimalarial drug in the world, which indicates the great need for alternative antimalarials.

The resistance of parasites to antimalarial drugs ranges from a minimal loss of effect, detected only by delayed recrudescence, to a high level of resistance, where the drug has no suppressive effect. In 1967 the WHO proposed a resistance grading system based on the response of P. falciparum parasites to normally recommended doses of chloroquine (Fig. 6.26). This grading system is also used for other blood schizontocides and other species of malaria affecting humans.