1. MANAGEMENTOF CHLOROQUINE RESISTANT MALARIA Dr.HARMANJIT SINGH JR- PHARMACOLOGY GMC , PATIALA

2. CONTENTS Introduction Life cycle Anti malarial drugs Treatment (Chloroquine sensitive & Resistant both) Anti malarial vaccine Summary 2

4. Caused by : Plasmodium.

5. Four species : P.vivax,

6. P.falciparum,

8. In 2010, more than 100 countries were considered malarious.

9. Malaria kills more than 1 million children a year in the developing world

11. Malaria Endemic Areas Chloroquine resistant-PF Chloroquine sensitive-PF Mexico, Central America west of Panama canal, Carribean, South America, middle east Resistant PV Indonesia,Papua New Guinea, Burma

12. DRUG RESISTANT MALARIA Definition: Drug resistance is the ability of the parasite species to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance. MDR Malaria Resistance to 3 or more anti-malarials of different chemical classes of which two are 4-aminoquinolines and diaminopyrimidine” 7

13. Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials The important factors that are associated with resistance are: 1. Longer half-life. 2. Single mutation for resistance. 3. Poor compliance 4. Host immunity. 5. Number of people using these drugs. Although chloroquine resistant strains of P. vivax have been described, drug resistance poses a serious clinical problem only with P. falciparum: >70% of cases 8

14. Global Scenario of Drug Resistant Malaria P. falciparum resistance 􀁺 Chloroquine resistant strains are found now in nearly all areas of chloroquine use including South America, Central America, east of the Panama Canal, the Western Pacific, East Asia P. vivax resistance 􀁺 Recent reports from Indonesia (Irian Jaya, Sumatra) and Papua, New Guinea indicate high levels of P. vivaxschizonts resistant to chloroquine. Decreased susceptibility may also be appearing in the Solomon Islands, Myanmar, Brazil, Colombia. P. ovale and P. malariae resistance 􀁺 P. ovale and P. malariae forms have not shown resistance to chloroquine 9

15. MECHANISM Resistant strains are able to efflux the drug by an active pump mechanism and, thereby rendering the drug ineffective. Resistant strains concentrate chloroquine less in vacuoles. Crt-Chloroquine resistant transporter and Pfmdr transporters : mutations There is an increase in the surface area of the resistant parasites, permitting more efficient pinocytosis. Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented. Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (e.g. verapamil), have not shown any benefit 10

16. Types of Drug Resistance 􀁺 In defining criteria for resistance to the aminoquinolineantimalarial drugs, the WHO has described three grades of resistance following treatment 􀁺 (Low grade) R1 : Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance. 􀁺 (High grade) R2 : Reduction of parasitaemia by > 75% at 48 hours but failure to clear parasites within 7 days. 􀁺 R3 : Parasitaemia does not fall by >75% within 48 hours. 11

17. Indian Scenario of Drug Resistant Malaria P. falciparum >> P. vivax Incidence being 5% to full dose chloroquine The first confirmed report of chloroquine resistance in P. falciparum was reported in Diphuarea of Karbianglong district of Assam in 1973. Resurgence of P. falciparum resistant to chloroquine has been noticed in several regions of India, more in North Eastern parts of the country KEM hospital in Mumbai, confirmed the existence of chloroquine resistance in P. falciparum cases in Mumbai However for all practical purposes, drug resistant malaria in the Indian context means malaria caused by strains of P. falciparum which are resistant to chloroquine. 12

19. Vigorous Shivering, Rigor

21. Dry Burning Skin

22. Throbbing Headache

24. Declining Temperature

25. Exhausted, Weak

26. Lasts 2-4 Hours13

27. Why P.F. Serious? Binds-RBCs all ages Alters surface Grows in low o2 Micro-vascular blocks Cytokine release Endotoxin release High parasitemia Cerebral malaria Hypoglycemia Shock, Multi organ failure Death P.Palciparum Produces Leads to

28. Diagnosis Thick Smear : Rapid Diagnosis Thin: Species identification Rapid diagnostic test Antibody detection test- RIA - ELISA 15

29. 1. Chemical classification . 4-aminoquinolines: - Chloroquine, amodiaquine, Piperaquine 8-aminoquinolines: - Primaquine , Bulaquine Folate synthesis inhibitors: - Sulphonamides like Sulphadoxine , Dapsone - Biguanides like proguanil and chloroproguanil -Diaminopyrimidine like pyrimethamine CINCHONA ALKALOIDS : Quinine , Quinidine AMINO ALCOHOLS : - Lumefantrine , Halofantrine - 16

30. Antimicrobials: Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones ,FOSMIDOMYCIN Peroxides: Artemisinin(Qinghaosu) derivatives and analogues - artemether, arteether, artesunate, artelinic acid Naphthoquinones: Atovaquone Iron chelating agents: Desferrioxamine Chemical classification 17

32. Slow acting :-

33. Proguanil, sulphonamides , tetracyclines , pyrimethamine18

34. According To Mode Of Action FOR PREVENTION OF TRNSMISSION MODE : GAMETOCIDES ( kill Gametes ) DRUGS : - Primaquine : for all species - Artemisinin : for all - Quinine : For vivax - Chloroquine : for vivax FOR RADICAL CURE MODE : Exo-erythrocyticSchizonticides (killExo-erythrocytic forms i.e. Hypnozoites) DRUGS : - Primaquine 19

35. Site of action 20

37. Chloroquine ADRs:Nausea, vomiting, Blurring of vision ,Headache, Confusion, seizures Hemolysis: G6PD individuals, Impaired hearing Hypotension, ECG changes High dose: Irreversible ototoxicity, retinopathy, myopathy, Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base Dose : 600 mg stat , 300 mg after 8 hours and then for next two days 22

38. Faster acting MOA & resistance similar to chloroquine ADRs Toxic hepatitis Agranulocytosis Dose: 25-35 mg/kg over 3 days Chloroquine resistant: combine Artesunate Amodiaquine 23

39. Mefloquine Erythrocytic schizontocide Rapidly control fever, eliminate circulating parasite Effective: Chloroquine resistant plasmodium MOA:- Inhibits heme polymerization - Forms toxic complexes with free heme Oral absorbed ,Highly protein bound ,Extensive tissues distribution ADRs Nauses, Vomiting, Diarrhoea Neuropsychiatric Arrythmias , Haematological Hepatic toxicity Dose:1250 mg, 750 mg, 500mg 12 hrly 24

40. Quinine Derived from bark of cinchona tree Effective blood schizonticidal Gametocidal: P. vivax Chloroquine resistant MDR FP MOA: same as of chloroquine Oral absorption rapid & complete ,Bound to α1 acid glycoprotein , Metabolized by CYP3A4 ,Excreted in urine t1/2: 10-12 hrs 25

41. Quinine ADRs :Cinchonism:tinnitus,dysphoria, headache, Nausea, vomiting, dizziness, flushing & visual disturbances, GIT: nausea, vomiting, diarrhoea,abdominal pain Hypoglycemia CVS: hypotension, dysrhythmias, VT, fibrillation Hemolysis (G6PD deficiency) Blackwater fever: hemolysis, hemoglobinemia, hemoglobinuria. Dose: Quinine: 600 mg 8 hrly 26

42. Pyrimethamine Erythrocytic schizontocide Resistance develops rapidly if used alone MOA : DHFRase inhibitor Oral: absorption good, slow Concentrated: liver, spleen, kidneys Metabolized: liver ,Excreted: renal & t1/2: 4 days ADRs : Nausea, Rashes, Folate deficiency Dose: sulphadoxine 1500 mg + pyrimethamine 75 mg 27

43. Proguanil Erythrocyte schizontocide Cyclic triazine metabolite: cycloguanil MOA: DHFRase Inhibitor Slowly, adequately absorbed ,Partly metabolized Excreted in urine & t1/2 is 20 hrs. ADRs : Vomiting, Abdominal pain ,Haematuria Dose: 200-300 mg/day for 4wks 28

44. Primaquine Radical cure of relapsing cases Preerythrocytic Gametocytes & hypnozoites MOA : - Interferes electron transport of parasite Readily absorbed orally, oxidized in liver t1/2: 3-6 hrs ,excreted in urine ADRs : Abdominal pain, GI upset Hemolysis in G6PD deficiency, methaemoglobinaemia Dose: 15 mg/day for 2wks 29

45. Sulphonamides Blood schizonticides Given in combination MOA: inhibit folatesynthetase Oral: Rapidly absorbed ,Metabolized by acetylation in liver ,Excreted by kidneys Dose : (Chloroquine resistant P.falciparum) sulphadoxine 1500 mg + pyrimethamine 75 mg 30

46. Tetracyclines Week erythrocytic schizonticidal Use with Quinine, S/P Multidrug resistant cases . 31

47. FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the nonmevalonate pathway fosmidomycin blocks the biosynthesis of isopentenyldiphosphate and the subsequent development of isoprenoids in P. falciparum . In contrast, isoprenoids are derived from an alternative pathway, known as the mevalonate pathway, in mammals . Hence, fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids, which are essential for cellular function, 32

48. Artemether, Artesunate, Arteether Blood schizonticidal Duration of action short, recrudescence rate high Combine with a long acting drug Artemisinin derivatives 33

49. MOA Endoperoxide bridge interact haeme of parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite Artemisinin derivatives 34

50. PKs Artemisinin derivatives 35

51. ADRs: Nausea, Vomiting Abnormal bleeding ST segment changes, QT prolongation Artemisinin derivatives 36

52. Artesunate-mefloquine 100 mg BD for 3 days + 750 mg 1st day, 500 mg 2nd day Aretemether-lumefantrine 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine 100 mg BD for 3 day + 1500 mg & 75 mg single dose ACT regimens for uncomplicated falciparum malaria 37

53. Halofantrine Blood schizontocide Effective: chloroquine & S/P resistant PKs Oral absorption: low t 1/2: of active metabolite 3 day ADRs Cardiovascular toxicity 38

54. Atovaquone Erythrocytic schizontocide MOA: Mitochondrial electron transport Interferes ATP production PKs : Lipid soluble: absorption slow 99% bound plasma proteins Enterohepatic circulation t1/2: 1.5-3 days Dose:Atovaquone: 250 mg & Proguanil: 100mg for 3 days ADRs Vomiting, diarrhoea Maculopapular rash 39

55. Chemoprophylaxis: Indications Special risk groups: Non-immune travellers Non-immune persons living in endemic areas Pregnancy- After 1st trimester (Chloroquine, Proguanil, Quinine)

56. Chemoprophylaxis

57. Prophylaxis in Pregnancy Travellers Avoid travel[Pregnant or likely to become pregnant!!] Chlo or Proguanil+F.A Or Meflo in II, III trimester Doxy, Atova, Prima : C/ I. Mosquito net Intermittent Preventive Treatment [IPT]: Pregnant in endemic areas Pyr+Sulfa 2-3 doses I dose after quickening-II trimester Further at 1 month intervals

58. Sulfadoxine-pyrimethamine (SP): effective drug for IPT S/P 500 mg of sulfadoxine 25 mg of pyrimethamine Malaria During Pregnancy 43

59. Treatment-Chloroquinesensitive:P.V. Chloroquine po4 1 Tab=250mg salt or 150mg base Clinical cure- 0h - 4Tab stat 6h - 2 Tabs 24h - 2 Tabs 48h - 2 Tabs Radical cure: Primaquine 15mg/d X 14 days. Primaquine C.I in G6PD def.

60. Treatment-ChloroquineResistant:P.V.[Rare] Quinine 600mg 8thhrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days

61. Treatment-ChloroquineSensitive:FP Chloroquine Phoshphate :[250mg] = 150mg Base 0h - 4Tab stat 8h - 2 Tabs 24h - 2 Tabs 48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR Sulfadoxine/Pyrrimethamine 3 Tab + Primaquine[Chlo not tolerated]

62. Treatment-ChloroquineResistant:FP Artesunate 100mg BDx3days + Sulfadoxine/Pyrimethamine 1500/75 mg (3 tab single dose) OR Mefloquine 750mg on 2nd day-500mg on 3rd day. Artemether 80mg + Lumefantrine 480mg BD x 3 days Quinine 600mg 8thhrly x 7 days + Doxycycline 100mg daily x 7 days

63. Severe malaria Cerebral malaria: Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria, jaundice Hyperpyrexia Hyperparasitemia The single most important step in the management of severe malariais IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT

64. Severe and complicated F.P.Malaria Artesunate 2.4mg/Kg i.v or i.m. » 12 hrs » 24 hrs » OD x 7days [Change to oral ACTx3days, if possible] Or Artemether: 3.2mg/Kgi.m on 1st day and then 1.6mg/Kg x 7days [change to oral ACTx3days, if possible ] Or Arteether: Same as above. But 4 days Or Quinine diHCL:20mg/Kg in 10ml/Kg of 5% dextrose infused 4hrs » 10mg/Kg for 4hrs every 8hrs » Oral quinine10mg/kg tds x7days + doxy 100mg od oral or 3day oral ACT or pyrimethamine/Sulfadoxine

65. Treatment-Severe malaria Quinidinegluconate- 10mg/kg in 300ml of N.S over 2-3h (max600mg) ↓ 0.02mg/kg/.min infusion for 24 h ↓ Oral quinine sulfate 600mg tid X 7 days AND Adjunctive therapy oral Doxy 100mg bd or Clindamycin 20mg/kg/day X 7days or Pyr+Sulfa 3 tab on last day of quinine

66. PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in uncomplicated cases. Greater the exposure, higher will be the emergence of resistance. Avoid drugs with longer half-life if possible. Avoid basic antimalarials for non-malarial indications (e.g. Chloroquine for rheumatoid arthritis in a malarial endemic area). Ensure compliance. Monitoring for resistance and early treatment of these cases to prevent their spread. Clear policy of using newer antimalarials. Use of combinations to inhibit emergence of resistance. 51

67. Malaria Vaccine Reduce severity and complications of malaria Tried in children less than 5yrs, in Africa Reduces mortality and morbidity RTS,S/AS01, Phase III Potential targets of the vaccine pre-erythrocytic erythrocytic merozoite gametocyte

68. Newer regimens under development 1.Dihydroartemisinin-Piperaquine 120 mg + 960 mg daily for 3 days 2. Artesunate-amodiaquine 200 mg + 600 mg daily for 3 days 3. Astesunate-pyronaridine 200 mg + 600 mg daily for 3 days 4. Arterolane (RBx 11160)-piperaquine 5. Artesunate-chlorproguanil + Dapsone 6. Fosmidomycin + Clindamycin 53

69. SUMMARY : Drug resistant malaria is a serious problem worldwide P.falciparum should be treated with artemisinin derivatives Chemoprophylaxis should be followed wherever appropriate Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups e.g. travelers For Severe Malaria cases Parenteral therapy should be given Drug combinations should be used 54

70. THANK YOU 55