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Drugs for Malaria
Malaria is caused by four protozoan parasites and is treated with several classes of antimalarial drugs. Chloroquine was formerly widely used but resistance emerged. Artemisinin derivatives like artesunate are now usually given in combination therapies due to their rapid action against the parasite and ability to prevent resistance when paired with other drugs. Tu Youyou received a Nobel Prize for discovering artemisinin from traditional Chinese medicine.
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Drugs for Malaria
- 1. Malaria and DrugsFor Malaria Malaria is a protozoal disease, caused by: 1. Plasmodium vivax 2. Plasmodium malariae 3. Plasmodium ovale 4. Plasmodium falciparum Most of the serious complications and death occur due to Plasmodium falciparum. Antimalarial drugs are used for the prophylaxis, treatment and prevention of relapses of malaria.
- 2. British Doctor Ronald Ross receivedthe Nobel Prize for Physiology or Medicine in 1902 for his work on Malaria.
- 3. Chinese traditional medicine researcher Tu Youyou received the NobelPrize for Physiology or Medicine in 2015 for her work on the antimalarial drug artemisin.
- 4. Symptoms of Malaria: •Fever • Shivering • Pain in the joints • Repeated vomiting • Generalized convulsion
- 5. Life Cycle ofPlasmodium
- 6. Class Examples 4-Aminoquinolines Chloroquine(CQ), Amodiaquine (AQ), Piperaquine Quinoline-methanol Mefloquine Cinchona alkaloid Quinine, Quinidine Biguanide Proguanil Diaminopyrimidine Pyrimethamine 8-Aminoquinoline Primaquine, Tafenoquine Sulfonamides and sulfone Sulfadoxine, Sulfamethopyrazine, Dapsone Antibiotics Tetracycline, Doxycycline, Clindamycin Sesquiterpine lactones Artesunate, Artemether, Arteether, Arterolane Amino alcohols Halofantrine, Lumefantrine Naphthyridine Pyronaridine Naphthoquinone Atovaquone Antimalarial Drugs
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- 10. CHLOROQUINE (CQ) Chloroquine isa rapidly acting erythrocytic schizontocide against all species of plasmodium; controls most clinical attacks in 1–2 days with disappearance of parasites from peripheral blood in 1–3 days. Mechanism of Action Chloroquine accumulates in food vacuoles, specifically binds to heme, preventing its polymerization to hemozoin. The increased pH and the accumulation of heme result in oxidative damage to the membranes, leading to lysis of both the parasite and the red blood cell. Heme CQ Hemozoin
- 12. Indication • Malaria • Rheumatoidarthritis • Extraintestinal amoebiasis Contraindication and Precaution • Contraindicated in patients with hypersensitivity, retinal damage. • Precaution should be taken by patients with hepatic or renal impairment, G6PD deficiency, epilepsy etc. Adverse Effects • GI disturbance, aplastic anaemia, dizziness, psychosis, alopecia, ratinopathy, hypokalaemia, headache etc. Dose • Adult: 600 mg stat, then 300 mg 6-8 hr on day 1 & 300mg on day 2 & 3. • Child: initially 10mg base/kg, followed by 5mg base/kg after 6 hrs. single doses of 5 mg base/kg on day 2 and 3. • Prphylaxic dose: 300 mg once a week.
- 13. PRIMAQUINE Primaquine eradicates primaryexoerythrocytic forms of P. falciparum and P. vivax and the secondary exoerythrocytic forms of recurring malarias (P. vivax & P. ovale). It has marked effect on primary as well as tissue phase of malarial parasite and highly active against gametocytes and hypnozoites. Mechanism of Action • It acts by interfering with a part of the parasite electron transport chain (mitochondria) that is responsible for supplying it with energy. • It acts as an antagonist of Ferriprotoporphyrin IX. • It prevent relapse of vivex & ovale malarias following treatment with a blood schizontocide.
- 14. Indication • Used inthe treatmentof vivax or ovale malaria. Contraindication and Precautions • Contraindicated in patients with agranulocytopenia. • Precaution should be taken by patients with G6PD deficiency. Adverse Effects • Nausea, Epigastric distress, vomiting, abdominal cramps, methaemoglobinemia etc. Dose • Adult: 15 mg daily for 14 days, increased to higher doses or longer coarse if resistance in P. vivax occurs. • Child: 0.5 mg/kg once daily for 14 days.
- 15. MEFLOQUINE (MQ) Mefloquine isa fast acting erythrocytic schizontocide but has prolonged absorption time. It is effective against CQ-sensitive as well as resistant plasmodia. It controls fever and eliminates circulating parasites in infections caused by P. falciparum or P. vivax Mechanism of Action: • Mefloquine accumulates in infected RBCs binds to haeme and damages the parasite membranes. • It produces swelling of P. falciparum food vacules and may form toxic complexes with free heme that damage membranes and interact with other plasmodial components. Indication: • Reserved for prevention and treatment of drug resistant P.falciparum and P. vivax • Used in combination with artemisinin • Chemoprophylaxis- travellers spending long duration in endemic regions
- 16. Adverse Effects: • Bittertaste, dizziness, nausea, vomiting, diarrhoea, abdominal pain • Sinus bradycardia and QT prolongation • Neuropsychiatric reactions • Rarely haematological, hepatic and cutaneous toxicity can occur Contraindication and Precautions: • Contraindicated in patients treated with quinine before 12 hr and patients with history of psychiatric illness, seizure and hepatic disorder. • Precaution should be taken by patients with epilepsy and children bellow 3 months or 5 kg. Dose • Adult: 20-25 mg/kg as a single dose or in two to three divided dose (Max. 1.5 gm/dose) • Child: 25 mg/kg BID.
- 17. QUININE & QUINIDINE •Quinine and its stereoisomer, Quinidine, are erythrocytic schizontocide for all species of plasmodia. But is less effective and more toxic than chloroquine. Mechanism of Action • They interfere with heme polymerization, resulting in death of the erythrocytic form of the plasmodial parasite. Contraindication and Precausions • Contraindicated in patients with atrial fibrillation (irregular heart beat that can lead to cloting, stroke &heart fail), atrial flutter (abnormal heart rhythm). • Precaution should be taken by patients with myathenia gravis (neuromuscular disease that leads to fluctuating muscle weakness and fatigue).
- 18. Indication • Uncomplicated resistantfalciparum malaria • Complicated and severe malaria including cerebral malaria • Nocturnal muscle cramps Adverse Effects • The major adverse effect of quinine is cinchonism, a syndrome causing nausea, vomiting, tinnitus, and vertigo. • Other side effects including, hypoglycaemia, hypotension, hypersensitivity, respiratory depression, sinus tracycardia, visual disturbance, black water fever, etc. Dose • Adult and child: 10 mg/kg, IV or PO
- 19. Antifolates/Antimetabolites • Sulfadoxine • Dapsone •Pyrimethamine • Proguanil MOA: These drugs inhibit enzyme dihydrofolate reductase (DHFR) & other enzymes for folate synthesis and affect protozoal DNA synthesis.
- 21. Antibiotics • Doxycycline • Tetracycline •Clindamycin • Slow acting erythrocytic schizontocides • Active against all plasmodial species, including CQ, MQ and S/P resistant P. falciparum Mechansim of Action: • Delayed death mechanism resulting from their inhibition of protein translation in the parasite • Used in combination with quinine or artesunate for uncomplicated and severe falciparum malaria Adverse Drug Reactions • Discolouration of bones and teeth • Not to be given to pregnant women or to children < 8 yrs (Clindamycin used) • Photosensitivity reactions
- 22. Amino Alcohols • Halofantrine •Lumefantrine • Halofantrine is blood schizontocide effective against P. falciparum resistant to CQ and S/P, as well as against P. vivax. • It possess Cardiac toxicity so limited use! • Not to be used for chemoprophylaxis • ADR- abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritis, elevated liver enzyme • Contraindicated in pregnancy, patients with cardiac conduction defects and who have recently taken mefloquine • Lumefantrine is used in combination with artemisinin derivative as first line therapy for uncomplicated falciparum malaria
- 23. Artemisinin & itsderivatives Artemisinin is the active compound of the plant Artemisia annua (तििेपािी) used in Chinese traditional medicine as ‘Quinghaosu’ discovered by Tu Youyou. It is a sesquiterpine lactone endoperoxide active against P. falciparum resistant to all other antimalarial drugs as well as other malarial species. Potent and rapid blood schizontocide action is exerted eliciting quicker parasitic clearance. Artesunate oral, i.m. or i.v. route Artemether oral or i.m. route α/β Arteether i.m. 150mg daily for 3 days Arterolane oral; combined with Piperaquine
- 25. Mechanism of Action: •Artemisinin is metabolised into dihydroartemisinin which interacts with ferriprotoporphyrin IX and generates toxic substances that acts against erythrocytic stage of plasmodium. • The endoperoxide bridge in artemisinin interact with haeme in the parasite. Ferrous iron-mediated cleavage of the bridge releases a highly reactive free radical species that binds to membrane proteins, causes lipid peroxidation, damages endoplasmic reticulum, and ultimately results in lysis of the parasite. • It has potent schizontocidal action and are lethal to early stage malarial gametes. Indication: • ACT-Standard of Care for uncomplicated malaria • Complicated falciparum malaria • Severe malaria
- 27. Adverse Drug Reactions •Nausea, vomiting, diarrhea, dizziness • Rare serious toxicities:- decreased reticulocyte and neutrophil counts, increased transaminase levels, allergic reactions • Recommended not to be used for children </= 5kgs or during the first trimester of pregnancy Contraindication and Precautions • Contraindicated in hypersensitivity. • Precaution should be taken by patients with hepatic impairment, pregnant and lactating mothers.
- 28. Artemisinin Based CombinationTherapy (ACT) WHO has recommended that all cases of acute uncomplicated falciparum malaria should be treated only by combining one of the artemisinin compounds with another effective erythrocytic schizontocide. Because artemisinins are short acting drugs, artemisinin is usually combined with a long acting drug. Advantages of ACT over other antimalarials are: 1. Rapid clinical and parasitological cure. 2. High cure rates (>95%) and low recrudescence rate. 3. Absence of parasite resistance (the components prevent development of resistance to each other). 4. Good tolerability profile.
- 30. FOR Reference SeeK.D.T THANK YOU!