In this essay we will discuss about the drugs used for the treatment of malaria.
1. Quinine:
It is an alkaloid obtained from the bark of the Cinchona tree and remains the best drug for all complicated malaria, especially chloroquine resistant P. falciparum infection.
Pharmacokinetics:
Quinine is well absorbed orally, about 70% is bound to plasma proteins and CSF penetration is poor. It is mainly metabolized in the liver and excretion is complete within 24 hours.
Pharmacological actions:
Quinine suppresses the multiplication of the plasmodium in the blood stream. It does not have any action on exo-erythrocytic stage of malarial life cycle and relapses (symptoms) may occur, when quinine is stopped. Quinine has no action on gametes and does not prevent transmission of the infection.
Quinine has a number of other actions, which are responsible for the adverse effects seen with the drug. It is a cardiac depressant (action similar to quinidine), causes contraction of the uterus, decreases the excitability and contractility of the skeletal muscles and releases insulin.
Therapeutic uses:
Quinine is not suitable for the prophylaxis of malaria. It is used for the treatment of falciparum malaria or if the infective species is not known or if the infection is mixed. It is given in dosage of 600 mg of quinine sulfate every 8 hourly for 7 days, followed by fansidar (combination of pyrimethamine 25 mg and sulfadoxine 500 mg), 3 tablets as a single dose. Doxicycline 200 mg daily for 7 days is an alternative to fansidar.
In cerebral malaria, quinine dihydrochloride is given by intravenous infusion in a loading dose of 20 mg/kg in 500 ml dextrose saline, followed by a maintenance dose of 10 mg/kg at 8 hourly intervals in IV. drip until the patient can take it orally. Quinine in dosage of 200-300 mg at bed time is used for nocturnal leg cramps.
Adverse effects:
Cinchonism, hypoglycemia, giddiness, psychosis, visual disturbances, nausea and vomiting are common. Cardiac arrhythmia, hemolysis and renal failure may occur. It should not be given in hemoglobinuria and optic neuritis.
Antiarrhythmics, antihistaminics, antipsychotics and cisapride increase the risk of ventricular arrhythmias.
2. Mefloquine:
Mefloquine is a synthetic quinoline methanol compound. Its antimalarial action is similar to quinine.
Pharmacokinetics:
Mefloquine is well absorbed orally and is highly bound to plasma proteins. It is concentrated in many organs including lungs, liver and intestines. It undergoes extensive enterohepatic circulation and is primarily secreted in the bile.
Therapeutic uses:
Mefloquine has the advantage of being given in a single dose of 1 g. It is used for chemoprophylaxis of malaria, treatment of uncomplicated falciparum malaria and chloroquine resistant P. vivax malaria.
Adverse effects:
Dizziness, nausea and vomiting are common. Arrhythmia and acute brain syndrome consisting of fatigue, asthenia, convulsions and psychosis may occur. Mefloquine should not be given during first trimester of pregnancy and breast-feeding and in patients with history of neuropsychiatric disorders including depression or convulsions or hypersensitivity to quinine. Concomitant use of beta blockers, calcium channel blockers and cardiac glycosides increases the risk of bradycardia.
3. Halofantrine:
Halofantrine is a synthetic phenanthrene methanol compound, which is not suitable for the prophylaxis of malaria. It is effective in P. falciparum malaria, but owing to its side effects, it is seldom used.
Adverse effects:
The most serious toxic effect is ventricular arrhythmia. Others include GIT disturbances and hypersensitivity reactions. It should not be used in cardiac disease associated with prolonged QT interval and with drugs that induce arrhythmia.
4. Chloroquine:
Chloroquine is an 4-aminoquinoline, which is a very useful drug to treat malaria, but resistant strains of P. falciparum are common. It is effective against all forms of the plasmodia in the blood stream, but has no effect on the exo-erythrocytic stages and the gametes. Chloroquine has number of other actions, which include anti-inflammatory, local anesthetic, antihistaminic and antiarrhythmic properties.
Pharmacokinetics:
Chloroquine is rapidly absorbed orally and is stored in various organs of the body. Its selective accumulation in retina is responsible for the ocular toxicity seen with prolonged therapy. It is partly metabolized and partly excreted in urine.
Therapeutic uses:
Chloroquine is no longer recommended for the treatment of falciparum malaria owing to widespread resistance. It is the drug of choice for chemoprophylaxis and clinical cure of benign malaria caused by P. vivcix and less commonly by P. ovale and P. malariae. In an acute attack of malaria, an initial dose of 600 mg of chloroquine (of base) is followed by 300 mg after 6 hours and then 300 mg daily for 2 days. For prophylaxis 300 mg chloroquine base is given weekly. Chloroquine sulphate 300 mg contains 225 mg of chloroquine base. Other uses of chloroquine include rheumatoid arthritis, lupus erythematosus and hepatic amoebiasis.
Adverse effects:
These are generally uncommon with doses employed for malaria. Chloroquine is liable to cause GIT disturbances, headache, convulsions, visual disturbances, skin rashes and rarely bone marrow depression. Other side effects like retinal damage, keratopathy, ototoxicity, blood disorders, mental changes, myopathy, exfoliative dermatitis and hepatic damage are not usually associated with malaria prophylaxis or treatment.
5. Proguanil (Paludrine):
Paludrine is effective against the blood stream asexual phase of Plasmodia and also has some action against gametocytes. It is rarely used in malaria, because most of the plasmodia have developed resistance, and is very slow in its antimalarial action.
Paludrine is also not suitable for chemoprophylaxis of malaria, because of need of daily dosing and its doubtful efficacy. It is rapidly absorbed from GIT and is rapidly excreted within 24 hours. Toxicity is very low and includes mild gastric intolerance and diarrhea, occasional mouth ulcers and skin reactions.
6. Artemisinin:
Artesunate and artemether are two currently used derivatives of Chinese antimalarial drug aetemisinin. These derivatives are the most rapidly acting and potent of all antimalarial drugs. They are used for the treatment of uncomplicated P. falciparum malaria in areas, where resistance to mefloquine and/or quinine has been demonstrated. They can be given orally or parenterally.
In endemic and multi-drug resistant areas, artesunate in combination with mefloquine is more effective and is associated with lower incidence of side effects. Artemisinin derivatives do not have any apparent local or systemic effects and need to be given only once a day for 5 days.
7. Pyrimethamine:
The antimalarial action of pyrimethamine resembles paludrine. Owing to slow onset of action and emergence of resistant strains, it should not be used alone and is used in combination, e.g. pyrimethamine and sulfadoxine (fansidar) or pyrimethamine and dapsone (maloprim). Pyremethamine along with sulfadiazine is the treatment of choice for toxoplasmic encephalitis in patients with AIDS.
8. Fansidar:
It is used as an adjunct to quinine in the treatment of resistant P. falciparum malaria. It should not be used for prophylaxis, because long term use leads to serious toxicity, leading to pulmonary infiltrates, e.g. eosinophilic or allergic alveolitis. The drug should be discontinued, if there is cough or shortness of breath.
9. Maloprim:
It has a very limited use in the prophylaxis of falciparum malaria, because of serious toxic effects like blood disorders, psychosis, jaundice and pneumonia. It is not suitable for the treatment of malaria. Fansidar and maloprim are contraindicated in sulfonamide allergy.
10. Doxycycline:
Doxycycline is effective against resistant P. falciparum and has been used in doses of 10-200 mg daily as an adjunct to quinine.
11. Primaquine:
Primaquine is an 8-aminoquinoline and is the only antimalarial, which is effective against the exo-erythrocyte stage and the gametocytes. The only indication of primaquine is to achieve a radical cure of benign tertian malaria due to P. vivax and P. ovale, where resting forms of parasites exist in the liver and give rise to relapses. It is given in adult dose of 15 mg daily for 14-21 days following chloroquine treatment.
Primaquine may cause nausea vomiting and abdominal pain. The serious, though less common, side effect is methemoglobinemia and haemolytic anemia, especially in G6PD deficiency. It should be avoided in pregnancy, as fetus is G6PD deficient.