This page intentionally left blank rr e e t t p p a CChha 9.8 1.4 Pharmacodynamics Antimalarial Agents (Mode of Action of Drugs) Human malaria is caused by four species of Plasmodium namely Plasmodium falciparum, P vivax, P malariae and P ovale P vivax is mainly responsible for most of the infections (70%) which results in benign tertian malaria In P falciparum and P vivax infections, the patient has fever with rigors every third day and termed as tertian The other two, P ovale and P malariae are mild in nature in which fever develops every fourth day and termed as benign quartan Symptoms and complications in P falciparum malaria are more severe than P vivax malaria The antimalarial drugs can be classified as in table 9.8.1 4-AMINOQUINOLINE DERIVATIVES CHLOROQUINE Chloroquine is a 4-aminoquinoline antimalarial agent used for the suppression and clinical cure of malaria It is an excellent erythrocytic schizontocide It does not prevent relapse in P vivax and P ovale malaria It has no effect on pre and exoerythrocytic phase of the parasite It also has antiinflammatory and local irritant properties It probably influences haemoglobin degradation by parasitic lysosomes by raising intravesicular pH in malarial parasite cells It also interferes with synthesis of nucleoproteins by the parasite It is well absorbed (about 90%) from gastrointestinal tract After IM injection absorption is rapid Elimination is very slow and it may persist in tissue for months or years after discontinuation of therapy Adverse reactions include nausea, vomiting, epigastric distress, headache, anorexia, difficulty in accommodation and chronic therapy may cause loss of vision due to retinal damage On prolonged use it may also cause skin rash, photoallergy, myopathy, loss of hearing, greying of hair and mental disturbances Parenteral administration may cause hypotension, arrhythmia and CNS toxicity Therapeutic Uses It is a drug of choice for clinical cure and suppressive prophylaxis of acute malaria but not for the resistant cases of P falciparum It can be safely used in preg- Section 9/ Chemotherapy 350 Table 9.8.1: Classification of antimalarial drugs I 4-aminoquinoline derivative Chloroquine (LARIAGO) Amodiaquine (CAMOQUIN) 8-aminoquinolines Primaquine (MALIRID) III Quinoline-methanol derivatives Mefloquine (MEFLOC) Initially 600 mg, after hr 300 mg followed by 300 mg daily for days, 200-400 mg IM hourly 25-35 mg/kg for days II Bulaquine (AABLAQUIN) IV Acridine derivative Mepacrine (MALADIN) V Cinchona alkaloids Quinine (as sulphate) VI Biguanides Proguanil (Chloroguanide; LAVERAN) VII Diaminopyrimidine & Sulfonamides Pyrimethamine (DARAPRIM) Pyrimethamine 25 mg + sulfadoxine 500 mg (MALARPRIM) Pyrimethamine 25 mg + sulfamethopyrazine 500 mg (METAKELFIN) VIII Artemisinin derivatives Artesunate (FALCIGO) Artether (EMAL) Artemether (LARITHER) nancy Apart from malaria, chloroquine in also used in: • Rheumatoid arthritis 15 mg daily for 14 days 15 mg/kg single dose (for treatment, maximum g); mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance) 125 mg (used with chloroquine 500 mg) 900 mg 1st day, 600 mg on 2nd & 3rd day, 300 mg on 4th, 5th and 6th day in divided doses; 600 mg/wk for prophylaxis 600 mg/day, oral TDS or 10 mg/kg with 5% glucose IV infusion TDS (for cerebral malaria) for days 100 mg daily during exposure and continued for weeks after exposure 25 mg (for prophylaxis) Once a week tablets single dose tablets single dose 100 mg BD on 1st day, followed by 50 mg BD for next four days (for cerebral malaria, chloroquineresistant malaria & P falciparum malaria) 150 mg daily for days IM 160 mg BD on first day and 80 mg OD for next four days orally; 80 mg BD IM on first day and 80 mg OD IM for next four days IM • Lepra reactions • Hepatic amoebic abscess (used along with metronidazole) • Giardiasis AMODIAQUINE • Discoid lupus erythematosus Another 4-aminoquinoline and possesses antimalarial activity similar to that of chloroquine It is useful in uncompli- • Infectious mononucleosis • Taeniasis Antimalarial Agents cated falciparum malaria but is not recommended for prophylaxis 8-AMINOQUINOLINES PRIMAQUINE Primaquine, a 8-aminoquinoline, is a poor erythrocytic schizontocide It is highly effective against gametocytes and exoerythrocytic stages It disrupts the parasites mitochondria and binds to native DNA, resulting in inhibition of gametocytes and exoerythrocytic forms Adverse effects include nausea, vomiting, weakness, abdominal pain and methaemoglobinaemia Haemolytic anaemia in patients with G-6-PD deficiency Passage of dark urine is indication of haemolysis In larger dose it can cause leucopenia It is effective in radical cure of P vivax and P ovale malaria QUINOLINE-METHANOL DERIVATIVES MEFLOQUINE It is a highly effective erythrocytic schizonticide especially against mature trophozoite and schizont forms of malarial parasite It behaves like quinine in many ways but does not inhibit haem polymerase It probably acts by forming toxic complexes with free haem that damages membranes and interacts with other plasmodial components 351 It is absorbed after oral administration and presence of food may enhance the absorption It is extensively metabolised in liver and primarily secreted in bile Adverse reactions include nausea, vomiting, dizziness, diarrhoea, abdominal pain, anxiety disorder, sinus bradycardia, ataxia It is reported that mefloquine is teratogenic in nature so should not be given in first trimester of pregnancy It is used in multiresistant P falciparum malaria It is not useful in complicated/ cerebral malaria BULAQUINE Bulaquine is a mixture of 3{-1-4-6(methoxy-8-quinolinyl) aminopentyl} ethylidenedihydro-2-(3H) furanone and it’s tautomers The exact action is not fully elucidated However, bulaquine inhibits protein synthesis in protozoa and indirectly inhibits polymerisation of amino acids by the plasmodia Treatment prevents emergence of either primary or secondary liver stage parasitaemia and the disease Since bulaquine is a tissue schizontocide it is effective against the dormant hepatic stages of P vivax only It has to be combined with chloroquine which acts on the erythrocytic stage of the plasmodium For convenience bulaquine is available along with chloroquine as an anti-relapse treatment pack It is an erythrocytic schizontocide used in the treatment and prevention of P vivax malaria relapse Section 9/ Chemotherapy 352 ACRIDINE DERIVATIVE MEPACRINE It is an erythrocytic schizontocide related to its ready intercalation into DNA Readily absorbed from the GI tract even in the presence of severe diarrhoea It is widely distributed in the tissues and is eliminated very slowly Adverse effects include nausea, vomiting, epigastric discomfort, skin rash, itching, hypotension, haemolysis, blurred vision, vertigo, tinnitus and cinchonism It is used in the treatment of cerebral falciparum malaria and multidrug resistant strains of cerebral malaria It is also used along with clindamycin in the treatment of babesiosis It is also effective in myotonia congenita and nocturnal muscle cramps Adverse effects include urticaria, exfoliative dermatitis, GI disturbances, dizziness and yellow discoloration of the skin on prolonged use PROGUANIL It is indicated in drug resistant P falciparum malaria and in the treatment of giardiasis It is an effective erythrocytic schizontocide against P falciparum and P vivax but slower acting than chloroquine CINCHONA ALKALOIDS QUININE Quinine is a natural alkaloid obtained from cinchona bark It is erythrocytic schizontocide and is effective against all species of plasmodia It has no effect on preerythrocytic stage and on hypnozoites of relapsing malaria It kills the gametes of P vivax It also has anaesthetic, local irritant action Quinine causes hypotension, cardiac depression (IV injection), stimulates myometrium and rapid IV injection causes hypoglycaemia It is highly concentrated in the acidic food vacuoles of the parasite where it inhibits haem polymerase leading to the accumulation of haem which is cytotoxic BIGUANIDES The active triazine metabolite, inhibits plasmodial dihydrofolate reductase and thus disrupts the synthesis of nucleic acids in the parasite It is slowly but adequately absorbed from the GI tract It is metabolised in the liver to the active metabolite cycloguanil Adverse effects include gastrointestinal disturbances, nausea, vomiting, diarrhoea, abdominal pain and haematuria It is mainly used in prophylaxis of malaria in combination with chloroquine in areas with low chloroquine resistance among P falciparum It can be safely used in pregnancy DIAMINOPYRIMIDINE & SULFONAMIDES PYRIMETHAMINE It is an inhibitor of plasmodial ... mg/wk for prophylaxis 600 mg/day, oral TDS or 10 mg/kg with 5% glucose IV infusion TDS (for cerebral malaria) for days 100 mg daily during exposure and continued for weeks after exposure 25 mg (for. .. followed by 50 mg BD for next four days (for cerebral malaria, chloroquineresistant malaria & P falciparum malaria) 150 mg daily for days IM 160 mg BD on first day and 80 mg OD for next four days... in also used in: • Rheumatoid arthritis 15 mg daily for 14 days 15 mg/kg single dose (for treatment, maximum g); mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance)