Antimalarial agents
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This document discusses various antimalarial agents used to treat malaria infections caused by Plasmodium parasites. It describes the mechanisms of action and side effects of different drug classes, including aminoquinolines like chloroquine; quinoline-methanols like mefloquine; artemisinin derivatives like artesunate; antifolates like pyrimethamine; and antibiotics used in combination therapy like doxycycline. The document also covers parasite life cycles, drug resistance mechanisms, and how various drugs target different parasite stages to achieve treatment and prevention of malaria.
Antimalarial agents
- 1. Antimalarial Agents Saifuddin Lala MBA PHARMA 9426786383 1
- 2. Introduction Malaria is a protozoal disease, caused by Plasmodium vivax Plasmodium malariae Plasmodium ovale Plasmodium falciparum Most of the serious complications and death occur due to Plasmodium falciparum. 2
- 4. Types of malaria Benign tertian • P vivax and P ovale • with a fever every 2nd day Benign quartan • P malariae • with a fever every 3rd day Malignant tertian • P falciparum • This type of malaria is more dangerous because of the complications 4
- 5. symptoms of malaria Fever Shivering pain in the joints Repeated vomiting Generalized convulsion 5
- 6. Life cycle of the malarial parasite 6
- 7. Classification 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine Quinoline-methanol: Mefloquine Cinchona alkaloid: Quinine, Quinidine Biguanides: Proguanil, Cholrproguanil 7
- 8. Diaminopyrimidines: Pyrimethamine 8-Aminoquinoline: Primaquine, Bulaquine Sulfonamides and sulfone: Sulfadoxine, Sulfamethopyrazine, Dapsone Tetracyclines : Tetracycline, Doxycycline 8
- 9. Sesquiterpine lactones: Artesunate, Artemether, Arteether Amino alcohols: Halofantrine, Lumefantrine Mannich base: Pyronaridine Naphthoquinone : Atovaquone 9
- 10. Antimalarial therapy and the parasite life cycle Drugs used to treat acute attack • Blood schizonticidal agents • Quinine,mefloquine,atovaquone,Pyrimethamine,art emether,artesunate Drugs that effect a radical cure Drugs used for chemoprophylaxis • Tissue schinzonticidal • Primaquine and tafenoquine • Kill the sporozoites • Chloroquine,mefloquine,proquanil,pyrimethamine 10
- 11. Malarial Parasite Developmental Stages Targeted by Antimalarial Drugs 11
- 12. Inhibition of haem polymerase Haemoglobin convert into haem Haem is free and toxic Haem Polymerase Haemozoin Parasite Inhibition of haem polymerase cause toxicity and death of the parasite 12
- 13. Chloroquine 4-Aminoquinoline derivatives Uncharged at neutral pH Diffuse freely into lysosome of parasite At acid pH of lysosome, it converted to a protonated, membrane impermeable form and is ‘trapped’ inside the parasite. At high conc. It inhibits protein RNA and DNA synthesis. 13
- 14. Choroquine Drug Mechanism of Action Uses Chloroquine phosphate (ARALEN) concentrating in parasite food vacuoles Acute malarial Pruritus,Diarrhea, attack Loss of appetite, Nausea, Suppressive Stomach cramps, prophylaxis Vomiting ,Retinopathy Tablet250mg, 500mg preventing the polymerization of the hemoglobin breakdown product heme, into hemozoin, Adverse Effect Half-life- 3-5 days parasite toxicity due Metabolise via to the buildup of free CYPs heme Other formulation hydroxychloroquine sulfate (Rx) - Plaquenil Use for treatment purpose 14
- 15. Resistance Plsmodium falciparum is now resistant to chloroquine in most of the part. Resistance appears to result from enhanced efflux of the drug from parasitic vesicles as result from enhanced efflux of the drug from parasitic vesicles as a mutation in plsmodium transporter genes. (pfcrt gene) 15
- 16. Contraindications & Cautions Chloroquine is contraindicated in patients with psoriasis or porphyria, in whom it may precipitate acute attacks of these diseases. It should generally not be used in those with retinal or visual field abnormalities or myopathy. Chloroquine should be used with caution in patients with a history of liver disease or neurologic or hematologic disorders. The antidiarrheal agent kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be coadministered with the drug. 16
- 17. Quinoline-Methanols derivatives Drug Mechanism of action Quinine sulfate Same as Qaulaquine(oral) Chloroquine 8-14 hr IV Inhibition of haem Metabolise via polymerase CYP3A4 Contra indication Uses Adverse Effects Treatment of severe falciparum malaria Cinchonism, sinus arrhythmia, atrioventricular block, prolonged QT interval, ventricular tachycardia, hypoglycemia Combine with tetracycline, doxycycline, or clindamycin Digoxin therapy, warfarin therapy, patients with tinnitus or optic neuritis. Resistance- pfmdr1 point mutations can contribute to quinine resistance, in particular the N1042D mutation. The mechanism is same as chloroquine. 17
- 18. Quinidine Drug Mechanism of action Uses Adverse Effects Quinidine gluconate (IV) Same as Chloroquine Severe malaria, Patient unable to take oral medication Combine with tetracycline, doxycycline, or clindamycin Cinchonism, tachycardia, prolongation of QT intervals, Ventricular arrhythmias, hypotension, hypoglycemia Inhibition of haem polymerase 18
- 19. Mefloquine Drug Mechanism of action Uses Adverse Effects Mefloquine (LARIAM) Same as Chloroquine Chemoprophylaxis and treatment Half life – 30 days Inhibition of haem polymerase Contraindication- nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrohea, abdominal pain, headache, rash, and dizziness, seizures and psychosis CYP3A4 patients with a history of seizures, depression, bipolar disorder and other severe neuropsychiatric conditions, 19
- 20. Inhibit electron transfer chain 8-aminoquinoline More active against liver hynozoites (Tafenoquine , Etaquine and Primaquine) Use to Prevent the transmission of disease. Active against P.vivax and P.ovale 20
- 21. Mechanism of action Primaquine may be converted to electrophilic intermediates that act as oxidation-reduction mediators. Such activity could contribute to antimalarial effects by generating reactive oxygen species or by interfering with mitochondrial electron transport in the parasite 21
- 22. Primaquine Drug Mechanism of action Uses Adverse Effects Primaquine Inhibits electron transport chain in Plasmodium active against hepatic stages of all human malaria parasites. active against the hypnozoite stages of P vivax and P ovale. For presumptive antirelapse therapy GI disturbances, methemoglobine mia, hemolysis in persons with G6PD deficiency Halflife- 7 hr metabolized by CYP1A2 Prophylaxis for shortduration travel to areas with principally Radical cure of P. vivax and P. ovale (to eliminate hypnozoites) Bind with acute-phase reactant protein α1-glycoprotein in liver 22
- 23. G6pd defficiency X chromosome linked genetic metabolic condition-glucose 6-phosphate dehydrogenase- in red cell Red cell can’t regenerate the NADPH Primaquine oxidative metabolites derivative of primaquine decrease the concentration of NADPH metabolic function of red cell impaired and heamolysis occur… 23
- 24. Hydroxynaphthaoquinone Drugs Inhibit electron transfer chain Atavaquone is used for treatment of malaria and can prevent its development Resistance to atavaquone is rapid and result from a single point mutation in the gene of cytochrome b. 24
- 25. Atovaquone Drug Mechanism of Uses action Adverse Effects Atovaquone Mepron tablet 250mg oral suspension 750mg/5mL Inhibits electron transport chain in Plasmodium Abdominal pain Cough Depression Diarrhea Dyspnea Fever Headache Infection Insomnia Treatment of acute attack of malaria 25
- 26. Atovaquone-proguanil Drug Mechanism of action Uses Adverse Effects Atovaquoneproguanil MALARONE (oral) tablet 250mg/100mg Atovaquone: Selective Treatment of inhibitor of parasite acute attack of mitochondrial electron malaria transport Proguanil: Primary effect through metabolite cycloguanil, a dihydrofolate reductase inhibitor in malaria parasite, which leads to disruption of deoxythymidylate synthesis Abdominal pain Transaminase increases Headache Vomiting Nausea Half-life: Atovaquone, 2-3 days; proguanil, 12-21 hr 26
- 27. Inhibit DNA replication transcription The quinghaousu based compound are derivative from the herb quin hao. Artimisinin generate carbon centered free radical by breaking down ferrrous porphyrin IX This radical cause alkylation of protein or damage the cell membrane 27
- 28. Artesunate Drug Mechanism of action Artesunate (IV) 60mg/vial may inhibit DNA Treatment of acute replication & attack of malaria transcription Cerebral malaria Half-Life: 40-50 min Uses Adverse Effects Cardiotoxicity (high doses) Neurotoxicity observed in animal studies Drug induced fever Skin rash 28
- 29. Artemether-lumefantrine Drug Artemetherlumefantrine (COARTEM) Mechanism of action Both artemether and lumentantrine inhibit nucleic tablet acid and protein 20mg/120mg synthesis Metabolism via Half-Life: lumefantrine: artemether 2 hr; CYP2D6 lumefantrine 3-6 artemether: days CYP3A4 Uses Adverse Effects Treatment of acute attack of malaria Abdominal pain Anorexia Arthralgia Chills Dizziness Fatigue Headache Myalgia Cerebral malaria 29
- 30. Drugs affecting synthesis and utilization of folate PABA Dihydropteroate synthetase Folate Dihydrofolate reductase Tetrahydrofalate Synthesis of thymidylate DNA synthesis 30
- 31. Proguanil Drug Mechanism of action Uses Adverse Effects Proguanil Paludrine tablet 26.3mg inhibit plasmodial dihydrofolate reductase Treatment of acute attack of malaria Abdominal pain Hemolytic anemia in G6PD deficiency Nausea Vomiting Half-life, Elimination: 3.79.6 hr 31
- 32. Pyrimethamine Drug Mechanism of action Uses Adverse Effects Pyrimethamine Daraprim Folic acid antagonist Treatment of acute attack of malaria Abdominal cramps Abnormal skin pigmentation Anaphylaxis Anorexia Arrhythmias (large doses) Atrophic glossitis Depression Fever Insomnia Lightheadedness Malaise Seizures tablet 25mg Half life: 96 hr 32
- 33. Pyrimethamine/sulfadoxine Drug Mechanism of action Uses Adverse Effects pyrimethamine/s ulfadoxine (Rx) – Fansidar Folic acid antagonists Treatment of acute attack of malaria Agranulocytosis Anemias Insomnia Lightheadedness Malaise Seizures Abnormal skin pigmentation Dermatitis tablet 25mg/500mg Pyrimethamine: 96 hr Sulfadoxine: ~200 hr 33
- 34. Antibiotics Doxycline and tetracycline used in acute attack of malaria and chemopropylaxis purpose. Sometimes given in combination with other drug. Clindamycin is also used. 34
- 35. Tetracycline Drug Mechanism of Uses action Adverse Effects Doxycycline Doryx (oral or IV) Tetracycline Inhibit the protein synthesis by compettition with tRNA for A site Nausea, vomiting, diarrhea, abdominal pain, dizziness, photosensitivity, headache,staining of teeth Tetracycline (oral or IV) Oral quinine and Doxycycline for acute attacks Oral chloroquine and Doxycycline for chemoprophylaxis 35
- 36. Clindamycin Drug Mechanism of Uses amalctosobion Adverse Effects Clindamycin (oral or IV) Inhibit the ribosomal translocation Diarrhea, nausea, rash Treatment of malaria Always use in combination with quinine-quinidine 36
- 37. 4-Aminoquinolone derivatives Pyronaridine, a chloroquine relative, is being used in combination with artesunate as a promising new artemisinin- based combination therapy. Pyronaridine-artesunate has been studied in Phase II and Phase III clinical trials, and has been shown to be effective against uncomplicated P. falciparum and blood stage P. vivax. Pyronaridine-artesunate is available as Pyramax® tablets and pediatric granule formulations,and manufacture of this compound is being undertaken by Shin Poong Pharmaceuticals. 37
- 38. 8-Aminoquinolone derivatives Tafenoquine is a lead candidate drug aimed at a radical cure of P. vivax, and is being studied in a Phase II/III. A fixed dose artemisinin combination therapy, artesunate-amodiaquine (Coarsucam) has been approved by WHO and developed by Sanofi- Aventis. 38
- 39. Artemisinin derivatives The endoperoxide feature of artemisinins, which confers antimalarial activity, is shared by ozonide OZ439, a synthetic endoperoxide. OZ439 carries the hope of providing a single dose oral cure in humans when used in combination. OZ439 is a rapidly acting agent against asexual stage parasites.This drug is currently undergoing Phase IIa trials. 39
- 40. Newer target TE3, a prodrug of a bis-ammonium compound that acts on phospholipid metabolism through the inhibition of de novo phosphatidylcholine synthesis, combined with a putative activity on heme detoxification. This new class of compounds has shown potent in vivo antimalarial activity in the primatemodel Aotus and is not cross resistance in vitro with known antimalarials. 40
- 41. osmidomycin osmidomycin, which inhibits the 1desoxy-D-xylulose-5-phosphate reductoisomerase in the mevalonateindependent pathway of isoprenoid synthesis in the apicoplast. The apicoplast, a specialized parasite organelle of algal origin, appears to be important for lipid and heme biosynthesis. 41
- 42. References 1) Rang H P. Dale M M. How drugs act: molecular aspects, Pharmacology, Fifth edition. Elsevier publishers. P.703-709 2) Katzung B., Masters S., Trevor A., Basic and clinical pharmacology, New york: Mc Graw Hill Medical Publisher;2009;p.699-705 3) Seth S., Seth V., Textbook of pharmacology ,New Delhi: Elsevier, publisher;2009;p.VIII.63 42
- 43. 4) Hobbs C., Duffy P., Drugs for malaria: something old, something new, something borrowed, F1000 Biology Reports 2011, 3(24),1-9 43
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