Antimalarial drugs

1. Antimalarial drugs

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

3. Sir Ronald Ross

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. Classification of antimalarial drugs Therapeutic classification Chemical classification

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

7. 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

8. 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

9. Chemical classification 4 aminoquinolines : Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronaridine 8 aminoquinolines : Primaquine , Tafenoquine , Bulaquine Cinchona alkaloids: Quinine, Quinidine Quinoline methanol: Mefloquine Biguanides Proguanil , Chlorproguanil

10. Chemical classification 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 Cl at position 7 confers maximal antimalarial efficacy

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. Pharmacological actions Antimalarial activity: High against erythrocytic forms of vivax , ovale , malariae & sensitive strains of falciparum Gametocytes of vivax No activity against tissue schizonts Resistance develops due to efflux mechanism Other parasitic infections: Giardiasis , taeniasis , extrainstestinal amoebiasis Other actions: Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory , antihistaminic , local anaesthetic

14. Pharmacokinetics Well absorbed, tmax 2-3 hrs , 60 % 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

15. Adverse drug reactions Intolerance: Nausea, vomiting, anorexia skin rashes, angioneurotic edema, photosensitivity, pigmentation, exfoliative dermatititis Long term therapy may cause bleaching of hair Rarely thrombocytopenia, agranulocytosis, pancytopenia

16. Adverse drug reactions Occular toxicity: High dose prolonged therapy Temporary loss of accommodation Lenticular opacities, subcapsular cataract Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. CNS: Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity CVS: ST & T wave abnormalities, abrupt fall in BP & cardiac arrest in children reported

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 Hepatic amoebiasis: Giardiasis Clonorchis sinensis Rheumatoid arthritis Discoid Lupus Erythematosus Control manifestation of lepra reaction Infectious mononucleosis

20. Hydroxy chloroquine: Less toxic, properties &uses similar Amodiaquine: As effective as chloroquine Pharmacological actions similar Chloroquine resistant strains may be effective Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis Not recommended for prophylaxis Pyronaridine: effective in resistant cases

21. Quinine 1820 Pelletier & caventou isolated quinine from cinchona bark. Mechanism of action: Similar to chloroquine

22. Pharmacological actions Antimalarial action: Erythrocytic forms of all malarial parasites including resistant falciparum strains . Gametocidal for vivax & malariae Local irritant effect: Local pain sterile abcess . 3. Cardiovascular: depresses myocardium, ↓ excitability, ↓ conductivity, ↑ refractory period, profound hypotension IV. 4. Miscellaneous actions: Mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curaremimitic effect

23. Pharmacokinetics Administered orally is completely absorbed Tmax = 1-3 hrs , crosses placental barrier Metabolized in liver degradation products excreted in urine t ½ = 10 hrs

24. Adverse drug reactions Cinchonism : Tinnitus, nausea & vomiting Headache mental confusion, vertigo, difficulty in hearing & visual disturbances Diarrhoea , flushing & marked perspiration Still higher doses , exagerated symptoms with delirium , fever, tachypnoea, respiratory depression , cyanosis.

25. Adverse drug reactions Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses Cardiovascular toxicity: cardiac arrest, hypotension ,fatal arrhytmias Black water fever: Hypoglycemia:

26. Uses Malaria: uncomplicated 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 causes thrombosis & fibrosis of varicose vein mass

27. Primaquine : Mechanism of action: Interferes with oxygen transport system

28. 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

29. Pharmacokinetics Readily absorbed, t1/2 = 3-6 hrs Oxidised in liver excreted in urine

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

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

35. Adverse events GIT: bitter in 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 & blood dyscrasias

36. 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 asses side effects Due to fear of development of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area

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 C/I: along with quinine, chloroquine, antidepressants, antipsychotics .

38. Atovaquone Synthetic napthoquinone Rapidly acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia MOA: Collapses mitochondrial membrane & interferes ATP production Proguanil potentiates action of atovaquone and prevents development of resistance Also used in P. Jivoreci & Toxoplasma gondii infections

39. Dihydrofolate reductase inhibitors Proguanil : Biguanide converted to cycloguanil active compound Act slowly on erythrocytic stage of vivax & falciparum 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

40. Pyrimethamine Diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species. Tasteless so suitable for children Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis.

41. Sulfadoxine-pyrimethamine Sequential blockade sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack Not recommended for prophylaxis Use: single dose treatment of uncomplicated chloroquine resistant falciparum malaria patients intolerant to chloroquine First choice treatment for toxoplasmosis

42. Artemisinin Artemisinin is the active principle of the plant artimisia annua Sesquiterpine lactone derivative Most potent and rapid acting blood schizonticides Short duration of action high recrudescence rate Poorly soluble in water & oil

43. Artemisinin derivatives Artesunate Artemether Arteether

44. PLANT- ARTEMISIA ANNUA

45. Mechanism of action These compounds have presence of endoperoxide bridge Endoperoxide bridge 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

46. Antimalarial action Artemisinin Artemisinin Conventional Treatment

47. Artesunate Water soluble ester of dihydroartemisinin Dose: can be given oral, IM,IV, rectal Oral 100 mg BD on day 1 50 mg BD day 2 to day 5 Parenteral 120 mg on day 1 (2.4 mg/kg BD ) 60 mg OD ( 2.4 mg/kg) for 7 days

48. Artemether Methyl ether of dihydroartemisinin Dose: Oral & IM 80 mg BD on day 1 (3.2 mg/kg) 80 mg OD (1.6 mg/kg) for 7 days

49. Arteether Ethyl ether of dihydroartemisinin Therapeutically equivalent to quinine in cerebral malaria A longer t 1/2 & more lipophilic than artemether favouring accumulation in brain Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days

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

51. Artemisinin based combination therapy (ACT) Artemisinin compunds 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

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

53. 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: By combining artesunate further spread of mefloquine resistance can be prevented Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day

54. 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

55. Tetracyclines Slow but potent action on erythrocytic stage of all MP & Pre- erythrocytic stage of falciparum Always used in combination with quinine or S-P for treatment of chloroquine resistant malaria

56. Management of Malaria

57. 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

58. Drugs not allowed for prophylaxis Quinine , artemisinin compounds Shorter acting, higher toxicity Pyrimethamine sulfadoxine Amodiaquine

59. 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:

60. Acute attack of chloroquine resistant malaria Pts who can take orally: 3 tablets of ( Pyrimethamine + sulfadoxine ) single dose followed by quinine 600 mg TDS for 2 days or Tab Quinine 600 mg TDS X 3 days with Cap doxycycline 100 mg BD for 7 days or Quinine 3 days with mefloquine or ( Atovaquone 250 mg + proguanil 100 mg) 4 tab(Single dose ) for 3 days or artesunate 100 mg BD x 3 days with Sulfadoxine -pyrimethamine or mefloquine

61. Pts who cannot take orally Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline over 4 hrs then 10 mg/kg in dextrose saline over 2 hrs every 8 hrly till patient is able to swallow Then quinine 600 mg TDS for 7 days & tetracycline/ doxycycline Or artemether / arteether injection

62. When should resistance be suspected All pts with complication Any pt 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

63. 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

64. Treatment of severe and complicated falciparum malaria Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4 mg/kg 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 3.2 mg/kg IM on day1, followed by 1.6 mg/kg daily for next 4 days Switchover to 3 Day oral ACT in between whenever patient can take oral medication

65. OR Quinine: 20 mg quinine salt/kg on admission ( i.v . infusion in 5% dextrose/dextrose saline over a period of 4 hours) followed by maintenance dose of 10 mg/kg body weight 8 hourly. When ever patient can swallow orally switch over to oral quinine 10 mg/kg 8 hrly and complete 7 days course

66. 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

67. 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