MALARIA l MAL bad aria air l Causative

MALARIA

l ‘MAL’ – bad ; ‘aria’- air l Causative organism- Plasmodium falciparum. P. ovale, P. vivax, P. malariae l Transmission- bite of female anopheles mosquito

PLASMODIUM LIFE CYCLE

l An infected female anopheles mosquito bites and injects parasites (Sporozoites) into the blood l Sporozoites invade liver cells and multiply

l The parasites burst from the liver cells as merozoites and are released into the blood stream. l Merozoites invade RBCs and multiply again. The RBCs eventually ruptures, allowing daughter merozoites to invade more RBCs. This cycle repeated, causing fever each time the parasite break free and invade.

l Some merozoites differentiated into Gametes. Female Anopheles feeds gametes are taken. They multiply in the stomach wall and migrate to her salivary gland.

Classification l Blood Schizonticides -Those which act on erythrocytic parasites. l Eg: Chloroquine, Mefloquine, Quinine l Tissue Schizonticides -Those which eliminate dormant liver forms. l Eg: Primaquine. l Gametocides -Those which kill sexual stages and prevent transmission to mosquito. l Eg: Primaquine, chloroquine and quinine (vivax)

Chemical Classification 4 – Aminoquinolones Chloroquine, Amodiaquine l Quinoline- Methanol Mefloquine l Acridine derivative Mepacrine l Cinchona alkaloid Quinine l Biguanides Proguanil l Diaminopyrimidines Pyrimethamine l 8 - Aminoquinoline Primaquine, Bulaquine l

l Sulfonamides Sulfadoxine, sulfamethopyrazine l Tetracycline Doxycycline l Sesquiterpine lactones Artesunate, artemether, arteether l Phenanthrene methanol Halofantrine l Napthoquinone Atovaquone

Chloroquine l Rapidly acting erythrocytic schizonticide against all species of plasmodia l Controls clinical attacks in 1 – 2 days l No effect on pre/exo erythrocytic phases of the parasite l does not prevent relapses in vivax and ovale malaria

MOA Gets actively concentrated by intraerythrocytic plasmodia. l Accumalates in the acidic vesicle of the parasite. l Because of its basic nature – it increases the vesicular p. H – interferes with degradation of Hb. l Prevents polymerization to hemozoin (Nontoxic) l Free heme damages the plasmodial membrane l

Resistance l Decreased ability to accumulate Chloroquine by the parasite. l Due to mutation in Chloroquine transporter protein. l Verapamil has shown to restore the concentrating ability.

Other Actions l Effective against – E. histolytica, Giardia lamblia l Antiinflammatory, local irritant, local anaesthetic l Weak smooth muscle relaxant l Antihistaminic l Antiarrhythmic

Kinetics l Good oral absorption. l Gets concentrated in liver, spleen, kidney, lungs, skin, leukocytes. l Selective accumulation in retina Ocular toxicity with prolonged use l t½ = 3 – 10 days l Can persist in the body for months

Adverse Effects l l l Gastrointestinal disturbances, nausea , vomiting Uneasiness, difficulty in sleeping Hypotension, cardiac depression, arrhythmias and CNS toxicity convulsions Loss of vision – due to retinal damage, corneal deposits Loss of hearing, rashes, photoallergy, mental disturbances, myopathy, graying of hair. Can be used in pregnancy

Use 1. Clinical cure and suppressive prophylaxis of all types of malaria Dose: l 600 mg stat Dose l 300 mg 8 hrs later l 300 mg 24 hrs later Parenteral Chloroquine – severe cases of falciparum malaria and in cerebral malaria (second choice to quinine)

Uses 2. Extraintestinal amoebiasis 3. Rheumatoid Arthritishydroxychloroquine (less ocular toxicity) 4. DLE 5. Lepra reactions 6. Photogenic reactions 7. Infections mononucleosis

Quinine l From Cinchona bark l Erythrocytic schizonticide l Effective in terminating acute attack of falciparum malaria. l Does not prevent recrudescence. l Can be taken orally, IV l t½ = 10 – 12 hrs; noncumulative

Other actions l Local anaesthetic l Increases gastric secretion l Weak analgesic l Antipyretic l Decreases excitability of muscle fibre. l Stimulates myometrium l Hypotension, cardiac arrhythmias l Hypoglycemia

Adverse Effects l “Cinchonism” – ringing in the ears. l. Nausea, vomiting, headache, confusion, vertigo, visual defects lreversible l Hypotension, cardiac arrhythmias l Delirium , convulsions l Hemolysis & kidney damage

Uses 1. Uncomplicated Chloroquine resistant malaria 2. Complicated / Cerebral malaria 3. Nocturnal Muscle cramps

Mefloquine l 4 -Quinoline methanol l Erythrocytic schizonticide l Use: chloroquine resistant malaria Dose- 15 mg/kg; 750 mg once followed by 500 mg 6 -8 hrs later -for prophylaxis-250 mg weekly

Adverse effects l Nausea , vomiting, abdominal pain, l Sleep & behavioral disturbances, dizziness, l Seizures , psychosis l Thrombocytopenia l Arrythmia or bradycardia

Artemisinin l Sesquiterpene l Derived lactone from artemisia annua

l 3 semisynthetic derivatives dihydroartemisinin (reduced product) artemether (Oil soluble) artesunate (Water soluble) • Potent , fast acting antimalarial • Suited for treatment of severe P. falciparum malaria and drug resistant infections

l Active against erythrocytic stages of P. vivax and falciparum l Slight gametocidal activity

MOA l Heme iron catalyzes cleavage of endoperoxide bridge l Followed by rearrangement to produce carbon centered free radical l Alkylates and damages the macrmolecules in the parasite

l Route of administration Oral- dihydroartemisinin, artemether, artesunate IM-artesunate, artemether IV-artesunate Rectal-artesunate l USES- severe P. falciparum malaria

l Adverse effects l Neurological l Changes l changes in reticulocyte , neutrophil counts QT prolongation

l Dose l artesunate (oral) - 100 mg BD on 1 st day 100 mg OD -5 days IV/IM - 120 mg on 1 st day; later 60 mg -4 days l artemether IM – 80 mg BD on 1 st day, 80 mg OD - 4 days Recrudescence can be prevented by combining with mefloquine

l Malaria in pregnancy Chloroquine Proguanil Mefloquine

REGIMENS FOR CHEMOPROPHYLAXIS A. Prophylaxis for infection with all species : - Chloroquine Phosphate tablet (300 mg base) One tablet weekly starting 1 week before entering endemic area. Continuing for four weeks after leaving.

B. Prophylaxis for Infection with multi drug resistant strains: Mefloquine Hydrochloride tablet – 250 mg 1 tablet weekly starting 1 week before entering endemic area and ending 4 weeks after leaving. OR - Doxycycline capsule – 100 mg – 1 capsule daily starting 1 day prior to travel to an endemic area and 4 weeks after leaving OR -malarone – 1 tablet per day 1 -2 days prior to travel to an endemic area and 7 days after leaving OR Primaquine 30 mg daily several days before to 7 days later

TREATMENT REGIMENS OF MALARIAL INFECTION A. Infection with all species - Chloroquine Phosphate Tab. 0. 5 g (300 mg base) 2 tablets initially followed by 1 tablet at 6, 24 and 48 hours for Falciparum. B. Infection with P. vivax, P. ovale - chloroquine (as above) + primaquine (15 mg) per day for 14 days

B. Infection for Chloroquine Resistant Infection l Quinine 650 mg TID daily for 3 -7 days + Doxycycline 100 mg BD for 7 days OR Clindamycin 600 mg BD for 7 days OR Fansidar 3 tabs once

- Mefloquine Hydrochloride 750 mg to start followed by 500 mg after 12 hour. OR - Artesunate 4 mg/Kg on first day followed by 2 mg/Kg for next four days plus Mefloquine base 25 mg/Kg on second day. OR Malarone 4 tablets daily for 3 days OR Halofantrine 500 mg 6 hrly for 3 doses ; repeat in 1 week

C. Treatment for severe infection with Falciparum - Quinine gluconate I. V 10 mg/Kg in 300 ml of Normal saline infused 1 to 2 hours. - Quinine Sulphate tablet 650 mg 8 th hourly – 7 days