Antimalarial drugs

Pharmacology of antimalarial drugs with treatment of malaria. mechanism of action, uses, adverse effects of antimalarial drugs like chloroquine, quinine, artemisinin compounds.

1. Antimalarial Drugs Dr Naser Ashraf Tadvi

2. Plasmodium species which infect humans Plasmodium vivax (tertian): Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartan) Sir Ronald Ross

3. Symptoms of malaria Cold stage: Feeling intense cold and vigorous shivering (15-60 minutes) Hot stage: Intense heat, dry burning skin, throbbing headache (2-6 hours) Sweating stage: Profuse sweating, ↓ Temperature, feeling of exhaustion (2-4 hours)

4. Life cycle of the malarial parasite Sporogeny (sexual) Schizogony (asexual) Man : Intermediate host Mosquito : Definitive host True causal prophylactics Causal prophylactics Supressives Gametocidal Sporonticide

5. Objectives of antimalarial treatment Prevent clinical attack of malaria (Prophylaxis) Treat clinical attack of malaria (Clinical curative) To completely eradicate parasite from patient body (Radical Curative) Cut down human –mosquito transmission (Gametocidal)

6. Classification of antimalarials Therapeutic classification Chemical classification

7. Therapeutic classification Causal prophylaxis: (Tissue schizonticides) Destroy parasite in liver cells and prevent invasion of erythrocytes Primaquine , proguanil Supressives Prophylaxis: Destroy merozoites released from liver Supress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics Chloroquine, proguanil , mefloquine, doxycycline

8. Therapeutic classification Clinical cure: erythrocytic schizonticides used to terminate an episode of malarial fever Fast acting high efficacy Chloroquine, quinine, mefloquine, atovaquone , artemisinin Slow acting low efficacy drugs Proguanil , pyrimethamine , sulfonamides, tetracyclines

9. Therapeutic classification Radical curatives: Eradicate all forms of P.vivax & P.ovale from the body Supressive drugs + hypnozoitocidal drugs For vivax : primaquine 15 mg daily for 14 days Gametocidal: Destroy gametocytes and prevent transmission Primaquine , artemisinin – against all plasmodia Chloroquine, quinine – Pl Vivax Proguanil , pyrimethamine – prevent development of sporozoites

10. Chemical classification 4 aminoquinolines: Chloroquine, Amodiaquine 8 aminoquinolines: Primaquine, Tafenoquine, Bulaquine Quinoline methanol: Mefloquine Cinchona alkaloids: Quinine, Quinidine Biguanides: Proguanil Diaminopyrimidines: Pyrimethamine Sulfonamides: Sulfadoxine , dapsone Tetracyclines: tetracycline, doxycycline Naphthoquinone: Atovaquone Sesquiterpene lactones: Artesunate, artemether, arteether

11. Chloroquine: Synthesized by Germans in 1934 ( resochin ) d & l isomers, d isomer is less toxic High against erythrocytic forms of vivax, ovale , malariae & sensitive strains of falciparum No activity against tissue schizonts

12. Hemoglobin Globin utilized by malarial parasite Heme (highly toxic for malaria parasite) Chloroquine Quinine, (+) Heme Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium) Mechanism of action

13. Mechanism of resistance pfcrt gene : Plasmodium falciparum chloroquine resistant gene identified in membrane of acidic vacuoles of chloroquine resistant falciparum Pumps out chloroquine Pfmdr gene encoded p-glycoprotein: Confers resistance to many antimalarials like quinine, mefloquine

14. Other actions Other parasitic infections: Giardiasis , taeniasis , extrainstestinal amoebiasis Other actions: Cardiac depressant, Direct relaxant effect on vascular smooth muscle antiinflammatory , antihistaminic, local anaesthetic

15. Pharmacokinetics Well absorbed, tmax 2-3 hrs , 50 % protein bound Concentrated in liver , spleen, kidney, lungs , leucocytes Selective accumulation in retina: occular toxicity T1/2 = 3-10 days increases from few days to weeks

16. Adverse drug reactions Nausea, vomiting, anorexia Skin rashes, photoallergy Loss of vision due to retinal damage, corneal deposits Loss of hearing, mental disturbances, Myopathy Graying of hair IV use: hypotension and T wave abnormalities in ECG

17. Dosage 600 mg of base stat 300 mg base after 8 hours 150 mg of base BD for 2 days 200 mg oral tablet of chloroquine phosphate consists of 150 mg base

18. Chloroquine is administered in loading dose in malaria Chloroquine is well absorbed after oral administration. It is extensively tissue bound and sequestrated by tissues particularly liver, spleen, kidney it has got large apparent volume of distribution So it is given in loading dose to rapidly achieve the effective plasma conc.

19. Therapeutic uses Malaria Giardiasis Rheumatoid arthritis Extraintestinal Amoebiasis Discoid Lupus Erythematosus Control manifestation of lepra reaction Infectious mononucleosis Photogenic reactions Clonorchis sinensis

20. Amodiaquine As effective as chloroquine Pharmacological actions similar Chloroquine resistant strains may be effective Adverse events: Itching is most common GIT, headache , photosensitivity, rarely agranulocytosis Not recommended for prophylaxis Dose: 25-35 mg/kg for 3 days

21. Piperaquine High efficacy, slow onset and long acting (t½ = 3-4 weeks) Slower onset due to larger volume of distribution Coformulated with dihydroartemisin More effective in chloroquine resistant falciparum malaria Well tolerated in children

22. Mefloquine Quinoline methanol derivative Rapidly acting erythrocytic schizonticide , slower than chloroquine & quinine Effective against chloroquine sensitive & resistant plasmodia Mechanism of action similar to chloroquine

23. Pharmacokinetics Good but slow oral absorption High protein binding Concentrated in liver, lung, intestine Extensive metabolism in liver, primarily secreted in bile , undergoes enterohepatic circulation Long t1/2 = 2 – 3 weeks

24. Adverse events GIT: bitter taste, nausea, vomiting, abdominal pain , diarrhoea Neuropsychiatric disturbances: anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions CVS: Bradycardia, sinus arhythmia , & QT prolongation Teratogenicity: Avoided in first trimester Miscellaneous: allergic skin reactions, hepatitis

25. Uses Effective drug for MDR falciparum T/t of uncomplicated falciparum in MDR malaria should be used along with artesunate (ACT) Prophylaxis in MDR areas 250 mg per week started 2- 3 weeks before to assess side effects Due to fear of development of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area

26. Quinine Alkaloid obtained from cinchona bark Mechanism of action similar to chloroquine Actions: Antimalarial action All Erythrocytic forms including Pl. Falciparum Gametocidal for vivax and malariae Local irritant Cardiac depressant Analgesic, antipyretic, curaremimetic , uterine stimulant

27. Quinine Uses Malaria: resistant falciparum malaria, Cerebral malarial Myotonia congenita : 300 to 600 mg BD/ TDS Nocturnal muscle cramps: 200 – 300 mg before sleeping Spermicidal in vaginal creams Varicose veins: along with urethane Adverse effects Cinchonism Cardiotoxicity Black water fever Hypoglycemia

28. Primaquine Intermediate metabolites Generates intraparasitic toxic oxidative species Disrupt electron transport in plasmodial mitochondria Primaquine (Mechanism of action)

29. Antimalarial action Liver hypnozoites Weak action against erythrocytic stage of vivax, so used with supressives in radical cure No action against erythrocytic stage of falciparum Has gametocidal action and is most effective antimalarial to prevent transmission disease against all 4 species

30. Adverse effects Gastrointestinal: epigastric distress, abdominal cramps , Hemopoetic: mild anemia, methaemoglobinemia , cyanosis, hemolytic anemia in G6PD deficiency Avoided during pregnancy, G6PD deficient

31. Uses Primary use is radical cure of relapsing malaria 15 mg daily for 14 days with dose of chloroquine Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.

32. Tafenoquine : More active slowly metabolized analog of primaquine , has advantage that it can be given on weekly basis. Bulaquine : Congener of primaquine developed in india Comparable antirelapse activity when used for 5 days Partly metabolized to primaquine Better tolerated in G6PD deficiency

33. Atovaquone Synthetic napthoquinone Rapidly acting erythrocytic schizonticide for P. falciparum & other plasmodia MOA: Collapses mitochondrial membrane & interferes ATP production Proguanil potentiates action of atovaquone and prevents development of resistance Atovaquone 250 mg + proguanil 100 mg 4 tablets daily single dose for 3 days in resistant malaria Also used in P. Jivoreci & Toxoplasma gondii infections

34. Drugs affecting synthesis & utilisation of folate Dihydro folate synthetase Dihydrofolate reductase Sulfadoxine Ѳ Pyrimethamine Proguanil Ѳ

35. Pyrimethamine Diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species. Tasteless so suitable for children Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis. Generally combined with sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack Not recommended for prophylaxis due to severe cutaneous reactions like exfoliative dermatitis & stevenson johnson syndrome.

36. Proguanil Biguanide converted to active compound cycloguanil Act slowly on erythrocytic stage of vivax & falciparum Sporonticidal & also prevents development of gametes Adverse effects: Stomatitis , mouth ulcers, larger doses depression of myocardium , megaloblastic anemia Not a drug for acute attack Causal prophylaxis: 100 – 200 mg daily

37. Halofantrine Quinoline methanol Used in chloroquine resistant malaria since 1980 Erratic bioavailabilty, lethal cardiotoxicity & cross resistance to mefloquine limited its use Now a days used only when no other alternative available Adverse events; Nausea, vomiting, QT prolongation , diarrhoea, itching , rashes

38. Artemisinin derivatives Arteether Artemether Artesunate Qinghaosu ("ching-how-soo") Artemisinin derivatives Dihydroartemisinin

39. Mechanism of action These compounds have presence of endoperoxide bridge which interacts with heme in parasite Heme iron cleaves this endoperoxide bridge There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins

40. Antimalarial action Artemisinin Artemisinin Conventional Treatment

41. Artesunate Water soluble ester of dihydroartemisinin Dose: can be given oral, IM,IV Oral : 100 mg BD Parenteral : 2.4 mg/kg BD Advantages Rapid substantial reduction of the parasite biomass & symptoms Effective action against multi-drug resistant P. falciparum Reduction of gametocyte carriage No documented/ minimal parasite resistance yet Few reported adverse effects.

42. Artemisinin derivatives Artemether: Methyl ether of dihydroartemisinin Dose Oral & IM : 80 mg BD Arteether : Ethyl ether of dihydroartemisinin Therapeutically equivalent to quinine in cerebral malaria A longer t 1/2 & more lipophilic than artemether favour accumulation in brain Dose: 150 mg O.D. intramuscular x 3 days

43. Adverse events GIT: nausea, vomiting, abdominal pain (common) Leucopenia Hypersensitivity: Drug fever, itching ECG changes: ST-T changes, QT prolongation Abnormal bleeding, dark urine Reticulocytopenia

44. Artemisinin based combination therapy (ACT) Artemisinin compounds are shorter acting drugs Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose Indicated by WHO in acute uncomplicated resistant falciparum malaria

45. Why combination therapy Rapid clinical & parasitological cure High cure rates and low relapse rates Absence of resistance Good tolerability profile

46. ACT Regimens in use Artesunate – Sulfadoxine , pyrimethamine : Adopted as first line in india under NMP ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets Artesunate Mefloquine: Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day

47. Artemether & lumefantrine Lumefantrine is highly effective , long acting oral erythrocytic schizonticide related to mefloquine Highly lipophilic onset delayed , peak 6 hrs Available as fixed dose combination 80 mg artemether BD WITH 480 mg lumefantrine BD for 3 days Other ACTs: DHA – Piperaquine , Artesunate - pyronaridine

48. Other ACT regimens for uncomplicated Falciparum malaria Artesunate 100 mg BD + Amodiaquine 300 mg BD X 3 DAYS Dihydroartemisinin 120 mg + Piperaquine 960 mg X 3 days Arterolone 150 mg + piperaquine 750 mg daily X 3 days

49. Management of Malaria

50. Prophylaxis of malaria Indication: Duration :1-2 weeks before to 4 weeks after returning from endemic area Drug regimens: Chloroquine sensitive malaria: 300 mg / week Chloroquine resistant malaria: Mefloquine 250 mg once a week , Doxycycline 100 mg daily , Atovaquone + proguanil daily Drugs not allowed for prophylaxis Quinine , artemisinin compounds Pyrimethamine sulfadoxine Amodiaquine

51. Tab. Chloroquine phosphate 250 mg Contains 150 mg of base Give 4 tablets stat , 2 tablets after 8 hours and , 1 tablet BD for 2 days Patients who cannot take orally 3.5 mg/kg IM every 6 hrs for 3 days Tab primaquine 15 mg OD for 14 days in Plasmodium vivax , ovale Primaqine 45 mg single dose for falciparum after chloroquine (gametocidal) Acute attack of chloroquine sensitive malaria:

52. Treatment of uncomplicated falciparum malaria Pts who can take orally: Artesunate 100 mg BD x 3 days with Sulfadoxine 1500 mg + pyrimethamine 75 mg (Single dose) Any other ACT When should resistance be suspected All patients with complication Any patient who has already received chloroquine last 1 month Hb continues to fall in absence of bleeding & asexual forms persist along with symptoms after 48 hrs of treatment

53. Severe and complicated falciparum malaria Hyperparasitaemia Hyperpyrexia Fluid electrolyte disturbances, acidosis Hypoglycemia Cardiovascular collapse Jaundice, severe anaemia Spontaneous bleeding Pulmonary edema Renal failure Hemoglobinuria , black water fever Cerebral malaria

54. Treatment of severe and complicated falciparum malaria Inj Artesunate 2.4 mg/kg IV/ Im followed by 2.4 mg/kg after 12 and 24 hours and then once daily for 7 days OR Artemether 3.2 mg/kg IM on day 1 then 1.6 mg/kg daily for 7 days OR Arteether 150 mg IM daily for 3 days Switchover to 3 Day oral ACT in between whenever patient can take oral medication Or Inj quinine diHCL 20 mg/ kg diluted in 10 ml/kg 5 % dextrose or DNS intravenously over 4 hours followed by 10 mg/kg maintenance dose every 8 hours till patient can swallow

55. Malaria in children: Quinine parenteral high toxicity / oral well tolerated Primaquine avoided in neonates Mefloquine not used in children below 15 kg weight Acute malaria in pregnant women Chloroqune in usual doses Mefloquine C/I in first trimester Primaquine / tetracycline avoided Anemia: folic acid & iron

56. Practice points Most antimalarials are bitter in taste give along with milk or fruit juice If vomiting occurs within hour of drug repeat full dose, in case of mefloquine repeat half dose If vomiting after 1 hour no need to repeat Postural hypotension : quinine, chloroquine