Antimalarial Drugs

Mother Nature gave us the cinchona alkaloids and qinghaosu. World War II led to the introduction of chloroquine, chloroguanide (proguanil), and eventually amodiaquine and pyrimethamine. The war in Vietnam brought mefloquine and halofantrine. These drugs are all we have available now to treat malaria. It is difficult to see where the next generation of antimalarial drugs will come from….there is little pharmaceutical industry interest in developing new antimalarial drugs; the risks are great, but the returns on investment are low….If drug resistance in P. falciparum continues to increase at the current rate, malaria may become untreatable in parts of Southeast Asia by the beginning of the next millennium.

White NJ. The treatment of malaria. NEJM. 12.9.1996;335:11:800-806

The effectiveness of early diagnosis and prompt treatment as the principal technical components of the global strategy to control malaria is highly dependent on the efficacy, safety, availability, affordability and acceptability of antimalarial drugs. The effective antimalarial therapy not only reduces the mortality and morbidity of malaria, but also reduces the risk of resistance to antimalarial drugs. Therefore, antimalaria chemotherapy is the KEYSTONE of malaria control efforts. On the other hand, not many new drugs have been developed to tackle malaria (Nature, Oct 3, 2002; 419:426); of the 1223 new drugs registered between 1975 and 1996, only 3 were antimalarials! Hence the need for a rational antimalaria treatment policy.

Classification

Anti malarial drugs can be classified according to anti malarial activity and according to structure.

1. According to anti malarial activity:

  1. Tissue schizonticides for causal prophylaxis: These drugs act on the primary tissue forms of the plasmodia which after growth within the liver, initiate the erythrocytic stage. By blocking this stage, further development of the infection can be theoretically prevented. Pyrimethamine and Primaquine have this activity. However since it is impossible to predict the infection before clinical symptoms begin, this mode of therapy is more theoretical than practical.
  2. Tissue schizonticides for preventing relapse: These drugs act on the hypnozoites of P. vivax and P. ovale in the liver that cause relapse of symptoms on reactivation. Primaquine is the prototype drug; pyrimethamine also has such activity.
  3. Blood schizonticides: These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs in anti malarial chemotherapy. These include chloroquine, quinine, mefloquine, halofantrine, pyrimethamine, sulfadoxine, sulfones, tetracyclines etc.
  4. Gametocytocides: These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection to the mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae, but not against P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum.
  5. Sporontocides: These drugs prevent the development of oocysts in the mosquito and thus ablate the transmission. Primaquine and chloroguanide have this action.

Thus in effect, treatment of malaria would include a blood schizonticide, a gametocytocide and a tissue schizonticide (in case of P. vivax and P. ovale). A combination of chloroquine and primaquine is thus needed in ALL cases of malaria.

2. According to the structure:

  1. Aryl amino alcohols: Quinine, quinidine (cinchona alkaloids), mefloquine, halofantrine.
  2. 4-aminoquinolines: Chloroquine, amodiaquine.
  3. 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
  4. 8-aminoquinolines: Primaquine, WR238, 605
  5. Antimicrobials: Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones
  6. Peroxides: Artemisinin (Qinghaosu) derivatives and analogues – artemether, arteether, artesunate, artelinic acid
  7. Naphthoquinones: Atovaquone
  8. Iron chelating agents: Desferrioxamine

The Artemisinin Derivatives

Artemisinin or Qinghaosu (“ching-how-soo”) is the active principal of the Chinese medicinal herb Artemisia annua. It has been used as treatment of fevers in China for more than 1000 years. The antimalarial value of Artemisia annua was first documented in Zhou Hou Bei Ji Fang (Handbook of prescriptions for emergency treatments) written as early as 340 AD by Ge Hong of the Eastern Jin Dynasty. The active antimalarial constituent of this plant was isolated in 1971 and it was named artemisinin. The WHO accorded high priority to the development of fast acting artemisinin derivatives for the treatment of cerebral malaria as well as for the control of multi-drug resistant P. falciparum malaria. A water soluble ester called artesunate and two oil soluble preparations called artemether and arteether (artemotil) have now been developed.

Anti malarial activity: They act by inhibiting a P falciparum-encoded sarcoplasmic-endoplasmic reticulum calcium ATPase, and not by inhibiting the haem metabolic pathway as previously supposed. Most clinically important artemisinins are metabolised to dihydroartemisinin (elimination half-life of about 45 min), in which form they have comparable antimalarial activity. However, their use in monotherapy is associated with high incidences of recrudescent infection, suggesting that combination with other antimalarials might be necessary for maximum efficacy.

It is the fastest acting anti malarial available. It inhibits the development of the trophozoites and thus prevents progression of the disease. Young circulating parasites are killed before they sequester in the deep microvasculature. These drugs starts acting within 12 hours. These properties of the drug are very useful in managing complicated P. falciparum malaria. These drugs are also effective against the chloroquine resistant strains of P. falciparum.

Artesunate and artemether have been shown to clear parasitaemias more effectively than chloroquine and sulfadoxine/pyrimethamine. Meta analysis of mortality in trials indicated that a patient treated with artemether had at least an equal chance of survival as a patient treated with quinine. It has also been reported that artemisinin drugs cleared parasites faster than quinine in patients with severe malaria but fever clearance was similar. Also, parenteral artemether and artesunate are easier to use than quinine and do not induce hypoglycaemia.

Gametocytocidal action: Artemisinin compounds have been reported to reduce gametocytogenesis, thus reducing transmission of malaria, this fact being specially significant in preventing the spread of resistant strains.

These drugs prevent the gametocyte development by their action on the ring stages and on the early (stage I-III) gametocytes.[2] In studies including over 5000 patients in Thailand, it was shown that gametocyte carriage was significantly less frequent after treatment with artemisinin derivatives than after treatment with mefloquine.

Absorption, fate and excretion: Artemisinin derivatives are absorbed well after intra muscular or oral administration. The drug is fully metabolised and the major metabolite is dihydroartemisinin, which also has anti parasite effects. It is rapidly cleared, predominantly through the bile.

Toxicity:[1] Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents. The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are probably due, in many patients, to acute malaria rather than to the drugs. More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been noted rarely. Two cases of severe allergic reactions to oral artesunate have been reported, with an estimated risk of approximately 1 reaction per 3000 treatments.

Neurotoxicity is the greatest concern regarding artemisinins, since the administration of high doses in laboratory animals has led to severe and irreversible changes in the brain. Extensive studies in many species showed that intramuscular dosing was more toxic than oral dosing and that, by any route, fat-soluble artemisinins were more toxic than artesunate. In humans, an episode of ataxia was reported after treatment with oral artesunate, and one case–control study showed hearing loss after the use of artemether–lumefantrine, but auditory toxic effects were not detected in another case–control study, and reported toxic effects may have been due to underlying malaria or other factors that were independent of artemisinin use. Multiple studies have shown that neurologic findings are fairly common with acute malaria, but there is no convincing evidence of neurotoxic effects resulting from standard oral or intravenous therapy with artemisinins.

Another concern about artemisinins is embryotoxic effects, which have been demonstrated in animals. Studies from Asia and Africa, including treatments during the first trimester, showed similar levels of congenital abnormalities, stillbirths, and abortions in patients who received and those who did not receive artesunate during pregnancy. Limited data are available on the use of intravenous artesunate for severe malaria during pregnancy.

Availability: Artemisinin is available as its derivatives, artemether, artesunate and arteether. The ether derivatives are more soluble in oil and are available as injections for intra muscular use. Artemether is available as injection of 80 mg in 1 ml. Artemether capsules containing 40 mg of the drug are also now available. Arteether is available as injection of 150 mg in 2 ml.

Artesunate is an ester derivative that is more soluble in water. The drug is available as a powder. It should be first dissolved in 1 ml of 5% sodium bicarbonate (usually provided with the vial) and shaken for 2-3 minutes. After it dissolves completely, it is diluted with 5% dextrose or saline (for intravenous use, dilute with 5 ml and for intramuscular use, dilute with 2 ml). Intravenous dose should be injected slowly at a rate of 3-4 ml/minute. It is also available as tablets, each containing 50 mg of the drug.

Dose:[3]

Artemether: Available as 80mg/ml Injection and 40mg per capsule

Injection: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg daily until oral therapy.

Oral: 4mg/kg on first day followed by 2mg/kg.

Arteether (Artemotil): Available as 150mg per 2 ml ampoule

Dose: 3 mg/kg once a day for 3 days, as deep intra muscular injection.

Artesunate: In India it is available as 50mg tablets and 60mg/ml injection. In China it is also available as 100mg suppository and in Switzerland is available as 200mg rectocap

Oral: 4 mg/kg.

Parenteral: Loading dose of 2.4 mg/kg followed by 2.4mg/kg after 12 hours, 24 hours and once daily thereafter.

Artesunate dosages need not be changed because of hepatic or renal failure or concomitant or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine. There are no known interactions between artesunate and other drugs.[1]

See Rectal artemisinins rapidly eliminate malarial parasites [Full text, Report, Report]

See Artemisinin based combinations

Resistance: The short half-lives of artemisinins limit the possibility of selection for resistance. Nonetheless, recent heavy use of artemisinins, including monotherapy, has created selective pressure.[1] Resistance to artesunate has been recently reported from Cambodia.[4] Some parasites isolated from French Guiana and Senegal recently showed diminished in vitro sensitivity to artemether, and the efficacies of artemisinin-based combination agents have apparently decreased along the Thailand–Cambodia border. However, at present, the likelihood of true artemisinin resistance in malaria parasites is low, and this concern should not prevent the use of intravenous artesunate to treat severe malaria.[1]

Sources:

  1. Rosenthal PJ. Artesunate for the Treatment of Severe Falciparum Malaria. NEJM. 2008;358(17):1829-1836 Available at http://content.nejm.org/cgi/content/full/358/17/1829
  2. Mehra N, Bhasin VK. In vitro gametocytocidal activity of artemisinin and its derivatives on Plasmodium falciparum. Jpn J Med Sci Biol. 1993 Feb;46(1):37-43.
  3. Day N, Dondorp AM. The Management of Patients with Severe Malaria. Am. J. Trop. Med. Hyg. 2007;77(Suppl 6):29–35 Available at http://www.ajtmh.org/cgi/reprint/77/6_Suppl/29
  4. Fears of new malaria drug resistance. Available at http://news.bbc.co.uk/1/hi/world/asia-pacific/8072742.stm

Chloroquine

Chloroquine is the prototype anti malarial drug, most widely used to treat all types of malarial infections. It is also the cheapest, time tested and safe anti malarial agent.

Mechanism of action: The mechanism of action of chloroquine is unclear. Being alkaline, the drug reaches high concentration within the food vacuoles of the parasite and raises its pH. It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. It may also interfere with the biosynthesis of nucleic acids. Other mechanisms suggested include formation of drug-heme complex, intercalation of the drug with the parasitic DNA etc.

Absorption, fate and excretion: 90% of the drug is absorbed from G.I.T and rapidly absorbed from intra muscular and subcutaneous sites. It has a large distribution volume due to extensive sequestration in tissues of liver, spleen, kidney, lung etc. Hence the need for a larger loading dose. Therapeutic blood levels persist for 6-10 days and elimination half-life is 1-2 months. Half of the drug is excreted unchanged by the kidneys, remaining is converted to active metabolites in the liver.

Anti malarial activity: It is highly effective against erythrocytic forms of P. vivax, P. ovale and P. malariae, sensitive strains of P. falciparum and gametocytes of P. vivax. It rapidly controls acute attack of malaria with most patients becoming afebrile within 24-48 hours. It is more effective and safer than quinine for sensitive cases.

Adverse effects: Chloroquine is a relatively safer anti malarial. At therapeutic doses, it can cause dizziness, headache, diplopia, disturbed visual accomodation, dysphagia, nausea, malaise, and pruritus of palms, soles and scalp. It can also cause visual hallucinations, confusion, and occasionally frank psychosis. These side effects do not warrant stoppage of treatment. It can exacerbate epilepsy. When used as prophylactic at 300 mg of the base/ week, it can cause retinal toxicity after 3-6 years (i.e. after 50-100 g of chloroquine). Intra muscular injections of chloroquine can cause hypotension and cardiac arrest, particularly in children.

Contra indications: Chloroquine should be used with caution in patients with hepatic disease, (even though it is not hepatotoxic per se, it is distributed widely in the liver and is converted to active metabolites there; hence the caution), severe gastro intestinal, neurological or blood disorders. The drug should be discontinued in the event of such problems during therapy.

It should not be co-administered with gold salts and phenyl butazone, because all the three can cause dermatitis.

Chloroquine may interfere with the antibody response to human diploid cell rabies vaccine.

Availability: Chloroquine is available as Chloroquine phosphate tablets; each 250-mg tablet contains 150 mg of the base. Chloroquine hydrochloride injection contains 40 mg of the base per ml.

Dose: Oral- 10mg/kg stat., then three doses of 5 mg/kg, over 36-48 hours.

Age in years Dose of chloroquine (as base)
(Each 250 mg tablet contains 150 mg base and each 5 ml of suspension contains 50 mg base)
1st dose 2nd dose 3rd dose 4th dose
0-1 75 mg 37.5 mg 37.5 mg 37.5 mg
1-5 150 mg 75 mg 75 mg 75 mg
5-9 300 mg 150 mg 150 mg 150 mg
9-14 450 mg 225 mg 225 mg 225 mg
>14 600 mg 300 mg 300 mg 300 mg

Dose of parenteral chloroquine:

Intra venous infusion 10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by 15 mg / kg (max.900mg) over 24 hours.
Intra muscular or sub cutaneous injections 3.5 mg of base/ kg (max.200 mg) every 6 hours or 2.5 mg of base/ kg (max.150mg) every 4 hours. (Intramuscular injection can cause fatal hypotension, especially in children).

Quinine

Quinine is the chief alkaloid of cinchona bark (known as ‘Fever Bark’), a tree found in South America. It has a colourful history of more than 350 years. Calancha, an Augustinian monk of Lima, first wrote about the curative properties of cinchona powder in “fevers and tertians” as early as in 1633. By 1640, the bark had already found its way into Europe, thanks to the Jesuit fathers (hence the name ‘Jesuit’s bark’). Eminent philosopher Cardinal de Lugo popularised the bark in Rome (hence it is also called Cardinal’s bark). In 1820, Pelletier and Caventou isolated quinine and cinchonine from cinchona. Even today, quinine is obtained entirely from the natural sources due the difficulties in synthesising the complex molecule.

Mechanism of action: Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. 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.

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.

Absorption, fate and excretion: Quinine is readily absorbed when given orally or intramuscularly. Peak plasma concentrations are achieved within 1 – 3 hours after oral dose and plasma half-life is about 11 hours. In acute malaria, the volume of distribution of quinine contracts and clearance is reduced, and the elimination half-life increases in proportion to the severity of the illness. Therefore, maintenance dose of the drug may have to be reduced if the treatment is continued for more than 48 hours. The drug is extensively metabolised in the liver and only 10% is excreted unchanged in the urine. There is no cumulative toxicity on continued administration.

Adverse effects: 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 colour 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 are 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 in pregnancy or on repeated use. Hypoprothrombinemia, agranulocytosis are also reported.

Quinine has little effect on the heart in therapeutic doses and hence regular cardiac monitoring is not needed. However it can cause hypotension in the event of overdose.

Quinine reduces the excitability of the motor end plate and thus antagonises the actions of physostigmine. It can cause respiratory distress and dysphagia in patients of myasthenia gravis.

Quinine stimulates insulin secretion and in therapeutic doses it can cause hypoglycemia. This can be more severe in patients with severe infection and in pregnancy. Hypoglycemia in malaria may go unnoticed and could even cause death. Therefore, it is advisable to monitor blood glucose levels at least once in 4-6 hours while quinine is administered, especially in severe infection and in pregnancy. Quinine induced hypoglycemia can recur even after administration of 25% or 50% dextrose. In such situations, maintenance with a 10% dextrose infusion is advisable. Resistant hypoglycemia due to quinine can be managed with Injection Octreotide, 50 microgram subcutaneously, every 6 to 8 hours.

Contraindications: Hypersensitivity in the form of rashes, angioedema, visual and auditory symptoms are indications for stopping the treatment. It is contraindicated in patients with tinnitus and optic neuritis. It should be used with caution in patients with atrial fibrillation. Hemolysis is indication for immediately stopping the drug. It is also contraindicated in patients suffering from myasthenia gravis.

Availability: It is available as tablets and capsules containing 300 or 600 mg of the base. It is also available as injections, containing 300mg /ml.

Dose:

Oral: 10 mg/kg 8 hourly for 4 days and 5 mg/kg 8 hourly for 3 days.

Intra venous: 20 mg of salt/kg in 10 ml/kg isotonic saline or 5% dextrose over 4 hours, then 10 mg of salt/kg in saline or dextrose over 4 hours, every 8 hours until patient is able to take orally or for 5-7 days.

Intra muscular: 20 mg/kg stat, followed by 10 mg/kg 8 hourly by deep intra muscular injections for 5-7 days

Quinidine: The anti-arrhythmic drug related to quinine can also be used in the treatment of severe P. falciparum malaria. Dose is 10 mg of base / kg by infusion over 1-2 hours, followed by 0.02 mg/kg/min with ECG monitoring.

Chloroguanide (Proguanil)

More popularly known as proguanil, this drug was developed by British antimalarial research in 1945. It is a biguanide derivative that is converted to an active metabolite called cycloguanil pamoate. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

Chloroguanide is slowly but adequately absorbed from the gastrointestinal tract. Peak plasma levels are attained within 5 hours and elimination half-time is about 16-20 hours.

Chloroguanide is available as tablets, each containing 100 mg of the drug. The dose for prophylaxis is 100-200 mg daily.

Chloroguanide along with chloroquine is used as prophylaxis effective against P. falciparum malaria.

At the prophylactic doses, it produces occasional nausea and diarrhoea. It is otherwise a safe drug and can be used in pregnancy.

Sulfadoxine+Pyrimethamine

Pyrimethamine and sulphadoxine are very useful adjuncts in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. It is now used in combination with artesunate for the treatment of P. falciparum malaria. It is also used in intermittent treatment in pregnancy (IPTp)

Anti malarial activity: Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are so essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

Sulfadoxine inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydropteroic acid. The combination of pyrimethamine and sulfa thus offers two step synergistic blockade of plasmodial division.

Absorption, fate and excretion: Pyrimethamine is slowly but completely absorbed after oral administration and is eliminated slowly with a plasma half-life of about 80-95 hours. Suppressive drug levels may be found in the plasma for up to 2 weeks. The drug is excreted in breast milk.

Sulfonamides are rapidly absorbed from the gut and are bound to plasma proteins. They are metabolised in the liver and are excreted in the urine. They pass through the placenta freely. Sulfadoxine is a long acting sulfonamide with a half-life of 7-9 days.

Toxicity and contraindications: Pyrimethamine can cause occasional skin rashes and depression of hematopoiesis. Excessive doses can produce megaloblastic anemia.

Sulfonamides can cause numerous adverse effects. Agranulocytosis; aplastic anemia; hypersensitivity reactions like rashes, fixed drug eruptions, erythema multiforme of the Steven Johnson type, exfoliative dermatitis, serum sickness; liver dysfunction; anorexia, vomiting and acute hemolytic anemia can also occur. The drug is contraindicated in patients with known hypersensitivity to sulfa, infants below 2 months of age, patients with advanced renal disease and first and last trimesters of pregnancy.

Availability: Pyrimethamine and sulphadoxine is no longer used as a single drug, but only in combination with artesunate.

Halofantrine

Halofantrine was developed in the 1960s by the Walter Reed Army Institute of Research. It is a phenanthrene methanol structurally related to quinine. Its mechanism of action may be similar to that of chloroquine, quinine, and mefloquine; by forming toxic complexes with ferritoporphyrin IX that damage the membrane of the parasite. This synthetic anti malarial is effective against multi drug resistant (including mefloquine resistant) P. falciparum malaria.

Its bioavailability is low and variable (may be doubled if taken with a fatty meal). The peak plasma concentration is achieved in 4-8 hours after the oral dose. The elimination half-life is 1-3 days for the parent drug and 3-7 days for the active metabolite.

Halofantrine is no more used in the treatment of chloroquine resistant and multi-drug resistant, uncomplicated P. falciparum malaria.

Dose: For adults, three tablets of 500 mg each, 6 hours apart. For children, three doses of 8 mg/kg of the salt 6 hours apart. Treatment should be repeated after 7 days.

Side effects include abdominal pain, diarrhoea, prolongation of QTC interval and arrhythmias that could be fatal. It is contraindicated in patients with prolonged QTC interval (congenital, electrolyte disorders, myocardial disease). However, it appears less toxic than quinine and mefloquine. It is also contraindicated in pregnancy and lactation, infants, and patients who have received mefloquine in the preceding 3 weeks.

Mefloquine

Mefloquine was born during the Vietnam war, as a result of research into newer anti malarials, to protect the American soldiers from the multi drug resistant falciparum malaria. Nothing much has happened after that and hence this ‘new’ drug should be restricted for use against multi drug resistant falciparum only.

Anti malarial activity: Mefloquine has been found to produce swelling of the P. falciparum food vacuoles. It may act by forming toxic complexes with free heme that damage membranes and interact with other plasmodial components. It is effective against the blood forms of falciparum malaria, including the chloroquine resistant types.

Absorption, fate and excretion: Mefloquine is available for oral administration only because parenteral preparations cause severe local reactions. It is absorbed rapidly and is extensively bound to plasma proteins. Elimination half-life is about 2-3 weeks. It is mainly excreted in the faeces.

Toxicity: It is generally well tolerated in therapeutic doses up to 1500 mg. Nausea, vomiting, abdominal pain and dizziness can occur in doses exceeding 1 g. Less frequently it can cause nightmares, sleeping disturbances, dizziness, ataxia, sinus bradycardia, sinus arrhythmia, postural hypotension, and an ‘acute brain syndrome’ consisting of fatigue, asthenia, seizures and psychosis. Mefloquine should be used with caution in patients with heart block, patients taking beta blockers, patients with history of epilepsy and psychiatric disease. It should be avoided in first trimester of pregnancy and pregnancy should be avoided within 3 months of taking the drug.

Contraindications: It should not be used for prophylaxis in pregnancy, particularly during the first trimester. It is contraindicated in patients with history of seizures, severe neuropsychiatric disturbances, or adverse reactions to quinoline antimalarials like chloroquine and quinine. It should not be used concomitantly with these drugs for increased risk of cardiotoxicity and risk of convulsions. Mefloquine is reported to increase the risk of seizures in patients taking valproate. It may compromise adequate immunisation by live typhoid vaccine. Patients taking mefloquine should refrain from driving or operating machinery.

Availability: It is available as 250 mg tablets and in combikits with artesunate.

Dose: 15 mg/kg in a single dose. If the dose exceeds 1000 mg, the second dose can be given after 4-8 hours to minimise gastric irritation. Total dose should not exceed 1500 mg.

Atovaquone

A synthetic hydroxynaphthoquinone developed in the early 1980s, atovaquone has been found to be useful against the Plasmodia (as well as Toxoplasma and Pneumocystis carinii). It has a highly lipophilic molecule that supposedly interferes with the mitochondrial electron transport and thereby ATP and pyrimidine biosynthesis and in Plasmodia, it is found to target cytochrome bc1 complex and disrupt the membrane potential. Its bio-availability after oral administration is poor and may be increased by a fatty meal. It has a long half-life of 2-3 days and it undergoes entero-hepatic circulation. It is available as 750 mg tablets. It may cause rash, fever, vomiting, diarrhoea and head ache. Safety in pregnancy, lactation, children, and elderly is yet to be established.

Atovaquone plus Proguanil: A fixed dose combination of atovaquone and proguanil hydrochloride (Malarone™) is now approved for both treatment and prophylaxis of malaria. It is available as 250 mg atovaquone + 100 mg proguanil per tablet for adults and 62.5 mg atovaquone + 25 mg proguanil per tablet for children.

It has been shown to be highly efficacious in the treatment of uncomplicated malaria caused by Plasmodium falciparum, including malaria that has been acquired in areas with chloroquine-resistant or multidrug-resistant strains. The daily dose should be taken at the same time each day with food or milk.

For details: http://www.cdc.gov/travel/diseases/malaria/malarone.htm

Pyronaridine: Structurally, it resembles amodiaquine and has been found to be highly effective against chloroquine resistant strains in China.

Piperaquine: Its activity is similar to that of chloroquine. A combination with artimisinin is undergoing studies.

WR-288, 605: It is 7.4 times more active than primaquine as a tissue schizonticidal drug. It has lesser toxicity, good oral bio-availability and longer half-life.

Lumefantrine is an aryl alcohol related to quinine, mefloquine and halofantrine that is devoid of cardiac toxicity of halofantrine. It is being tried in combination with artemether.

Other Drugs with Antimalarial Activity:

Many drugs have been tested for their potential anti malarial effects. Research into newer anti malarials being scanty, such attempts might throw up one or two candidates for use in malaria, however, these drugs are yet to find a place in standard anti malarial regimen. Clindamycin, fluoroquinolones like ciprofloxacin and Norfloxacin, azithromycin etc. have been found to be effective against malarial parasites. Atovaquone; Desferrioxamine; Pyronaridine; Piperaquine; WR-288, 605; and 566C80 are drugs undergoing trials.

Tetracyclines

One among the first antibiotics to come into use in human beings, these drugs have stood the test of time and are continuing to be useful in treating a broad range of infections, including malaria.

Mechanism of action: Tetracyclines are bacteriostatic agents, supposedly acting by inhibiting protein synthesis by binding to the 30s ribosome subunit. They are effective against a wide range of organisms, including aerobic and anaerobic gram positive and gram negative bacteria, Rickettsia, Coxiella burnetii, Mycoplasma, Ureaplasma, Chlamydia, Legionella, Spirochaetes, Brucella, Helicobacter pylori, Yersinia, some atypical mycobacteria and Plasmodia.

Absorption, fate and excretion: These drugs are incompletely absorbed form the gut after oral administration and the absorption may be hampered by antacids containing aluminium hydroxide; calcium, magnesium and zinc salts and bismuth subsalicylate. They distribute widely in the tissues and accumulate in liver, spleen, bone marrow, bone, dentine and enamel of un-erupted teeth. The drug is mainly excreted through the kidney 9except minocycline) and that may be hampered in renal failure.

Adverse effects: Gastrointestinal irritation, nausea, vomiting, diarrhoea, photosensitivity, hepato-toxicity, aggravation of uremia, hypersensitivity reactions, staining of the teeth if used in young children and pregnant women etc.

Use in malaria: These anti microbials are useful in the treatment of drug resistant P. falciparum malaria. They act relatively slowly and hence should always be combined with a faster acting drug like quinine. They are contraindicated in children below the age of 8 years and in pregnant women because of their adverse effects on bones and teeth.

Both tetracycline and doxycycline are equally effective. Tetracycline is given at a dose of 250 mg every 6 hours for 7-10 days. Dose of doxycycline is 100 mg twice daily for 7-10 days.

Doxyxycline is also used for short term prophylaxis against P. falciparum malaria at 100mg once daily.

Clindamycin: It acts by inhibiting the protein synthesis by binding to the 50s subunit of ribosomes. It can be used for drug resistant malaria along with quinine at a dose of 10 mg/kg 8 hourly for 5 days. Adverse effects include pseudomembrane colitis and skin rashes. In one study, a cure rate of only 50% was observed. (Hall et al, P. falciparum malaria semiresistant to clindamycin. Br. Med. J., 1975, 2:12-14; Seaberg et al. Clindamycin activity against chloroquine resistant P. falciparum. Antimicrob. agents Chemothera., 1984, 150:904-911)

Fluoroquinolones: Both ciprofloxacin and norfloxacin have been found to have anti malarial activity both in vitro and in vivo. However, results are not consistent.

Azithromycin: Azithromycin is found to have anti malarial activity and has been found to be useful as a causal prophylactic agent. It was found to be effective at the dose of 300 mg stat, followed by 250 mg daily for 7 days as a prophylactic agent against chloroquine resistant P. falciparum infection.

Quick comparison between blood schizonticidal drugs

 ChloroquinePyr./Sulpha.QuinineMefloquineArtemisinin
Efficacy+++++++++++++++++
Onset of actionRapidSlowRapidRapidFastest
UsePrototype drug, first choice for all casesOnly for uncomplicated, resistant P. falciparumOnly for resistant P. falciparumOnly for uncomplicated, multi drug resistant P. falciparumReserved for drug resistant P. falciparum. However, it may be considered in life threatening complications of P. falciparum due to its rapid action
Use in severe P. falciparum malariaParenteral preparation can be used in areas with sensitive strainsNot useful in acute illness; can be co- prescribed with other parenteral antimalarialsDrug of choice for severe malaria; it was the only parenteral drug available for a long time until parenteral chloroquine and artemisinin arrivedNot to be used in acute illness; can be co-prescribed with artemisinin after acute phase is over.Useful in severe malaria; may be more effective and better tolerated than quinine.
Toxicity++++++++++++
Contra indicationsAlmost none, only advanced liver diseaseAllergy to sulphaPrior hypersensitive reactionsEpilepsy, psychosis, heart block, u00df blocker useNone
Use in pregnancyYesOnly in 2nd trimester if warrantedOnly if warranted, watch for hypoglycemiaNot in first trimesterYes, if the situation demands
CostCheapestCheapModerateExpensiveExpensive
The Salt-Base Table
Drug Salt Base
Chloroquine sulphate 136 mg 100 mg
Chloroquine diphosphate 250 mg 150 mg
Quinine sulphate 362 mg 300 mg
Quinine bisulphate 508 mg 300 mg
Quinine hydrochloride 405 mg 300 mg
Mefloquine hydrochloride 274 mg 250 mg
Primaquine 26.3 mg 15 mg

©malariasite.com ©BS Kakkilaya | Last Updated: Mar 10, 2015

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One Response to Antimalarial Drugs

  1. Petr Roberts says:

    Served in Viet Nam, 1971-72, US Army Transportation Corps, base camp 10 km from Port of Qui Nhon. Our unit (27th Trans Bat.) had to convoy all materiel from the port to Central Highlands (Pleiku and beyond) and along the coast to Tuy Hoa. Because of our extended geographic routes we had to take two types of antimalarials, one a large pill (1/day), and one small one (1/wk), supposedly to protect us against both the “Lowland Malaria” and the other to protect us against the “Highland Malaria”. I assume the former was caused by Plasmodium falciparum and the latter was Plasmodium vivax. Is this correct? I also assume that the larger daily pill was chloroquine-primaquine, would that be correct? What would the smaller weekly pill have been?
    Thanks.

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