MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA

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MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA

  1. 1. MANAGEMENTOF CHLOROQUINE RESISTANT MALARIA<br />Dr.HARMANJIT SINGH <br /> JR- PHARMACOLOGY<br /> GMC , PATIALA <br />
  2. 2. CONTENTS<br />Introduction <br />Life cycle<br />Anti malarial drugs<br /> Treatment (Chloroquine sensitive & Resistant both)<br />Anti malarial vaccine<br />Summary <br />2<br />
  3. 3. MALARIA <br /><ul><li>Malaria was once considered to arise from marshy land (hence the name 'mal aria'-bad or poisonous air)
  4. 4. Caused by : Plasmodium.
  5. 5. Four species : P.vivax,
  6. 6. P.falciparum,
  7. 7. P.ovale</li></ul>P.malariae. <br /> The insect vector : female Anopheles mosquito<br /><ul><li>Breeds in stagnant water.</li></li></ul><li>MALARIA<br /><ul><li>Malaria remains the world’s most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year.
  8. 8. In 2010, more than 100 countries were considered malarious.
  9. 9. Malaria kills more than 1 million children a year in the developing world
  10. 10. In malaria endemic areas - Children under age of 5 years - greater risk of dying</li></li></ul><li>
  11. 11. Malaria Endemic Areas<br />Chloroquine resistant-PF<br />Chloroquine sensitive-PF<br />Mexico, Central America west of Panama canal,<br />Carribean, South America, middle east<br />Resistant PV<br />Indonesia,Papua New Guinea, Burma<br />
  12. 12. DRUG RESISTANT MALARIA<br />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.<br />MDR Malaria<br />Resistance to 3 or more anti-malarials of different chemical classes of which two are <br /> 4-aminoquinolines and diaminopyrimidine”<br />7<br />
  13. 13. Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials<br />The important factors that are associated with resistance are:<br /> 1. Longer half-life. 2. Single mutation for resistance. 3. Poor compliance 4. Host immunity. 5. Number of people using these drugs.<br /> Although chloroquine resistant strains of P. vivax have been described, drug resistance poses a serious clinical problem only with P. falciparum: >70% of cases<br />8<br />
  14. 14. Global Scenario of Drug Resistant Malaria<br />P. falciparum resistance<br />􀁺 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<br />P. vivax resistance<br />􀁺 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.<br />P. ovale and P. malariae resistance<br />􀁺 P. ovale and P. malariae forms have not shown resistance to chloroquine<br />9<br />
  15. 15. MECHANISM <br />Resistant strains are able to efflux the drug by an active pump mechanism and, thereby rendering the drug ineffective. <br />Resistant strains concentrate chloroquine less in vacuoles.<br />Crt-Chloroquine resistant transporter and Pfmdr transporters : mutations <br />There is an increase in the surface area of the resistant parasites, permitting more efficient pinocytosis.<br /> Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented.<br />Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (e.g. verapamil), have not shown any benefit<br />10<br />
  16. 16. Types of Drug Resistance<br />􀁺 In defining criteria for resistance to the aminoquinolineantimalarial drugs, the WHO has described three grades of resistance following treatment<br />􀁺 (Low grade) R1 : Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance.<br />􀁺 (High grade) R2 : Reduction of parasitaemia by > 75% at 48 hours but failure to clear parasites<br />within 7 days.<br />􀁺 R3 : Parasitaemia does not fall by >75% within 48 hours.<br />11<br />
  17. 17. Indian Scenario of Drug Resistant Malaria<br />P. falciparum >> P. vivax<br />Incidence being 5% to full dose chloroquine<br />The first confirmed report of chloroquine resistance in P. falciparum was reported in Diphuarea of Karbianglong district of Assam in 1973.<br />Resurgence of P. falciparum resistant to chloroquine has been noticed in several regions of India, more in North Eastern parts of the country<br /> KEM hospital in Mumbai, confirmed the existence of chloroquine resistance in P. falciparum cases in Mumbai<br />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.<br />12<br />
  18. 18. Clinical features <br />Cold Stage<br /><ul><li>Feeling of Intense Cold
  19. 19. Vigorous Shivering, Rigor
  20. 20. Lasts 15-60 Min</li></ul>Hot Stage<br /><ul><li>Intense Heat
  21. 21. Dry Burning Skin
  22. 22. Throbbing Headache
  23. 23. Lasts 2-6 Hours</li></ul>Sweating Stage<br /><ul><li>Profuse Sweating
  24. 24. Declining Temperature
  25. 25. Exhausted, Weak
  26. 26. Lasts 2-4 Hours</li></ul>13<br />
  27. 27. Why P.F. Serious?<br />Binds-RBCs all ages<br />Alters surface<br />Grows in low o2<br />Micro-vascular blocks<br />Cytokine release<br />Endotoxin release<br />High parasitemia<br />Cerebral malaria<br />Hypoglycemia<br />Shock, Multi organ failure<br />Death<br />P.Palciparum<br />Produces<br />Leads to<br />
  28. 28. Diagnosis <br />Thick Smear : Rapid Diagnosis <br />Thin: Species identification<br />Rapid diagnostic test <br />Antibody detection test- RIA - ELISA<br />15<br />
  29. 29. 1. Chemical classification<br />. 4-aminoquinolines:<br /> - Chloroquine, amodiaquine, Piperaquine<br />8-aminoquinolines: - Primaquine , Bulaquine<br />Folate synthesis inhibitors:<br /> - Sulphonamides like Sulphadoxine , Dapsone<br /> - Biguanides like proguanil and chloroproguanil<br /> -Diaminopyrimidine like pyrimethamine<br />CINCHONA ALKALOIDS : Quinine , Quinidine<br />AMINO ALCOHOLS : - Lumefantrine , Halofantrine<br />-<br />16<br />
  30. 30. Antimicrobials: <br />Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones ,FOSMIDOMYCIN<br />Peroxides:<br />Artemisinin(Qinghaosu) derivatives and analogues - artemether, arteether, artesunate, artelinic acid<br />Naphthoquinones:<br />Atovaquone<br /> Iron chelating agents:<br />Desferrioxamine<br />Chemical classification <br />17<br />
  31. 31. 2. According To Mode Of Action<br />FOR CAUSAL PROPHYLAXIS<br />MODE : Pre-erythorcyticSchizonticides ( kill schizonts in the liver ) <br /> DRUGS : <br /> - Primaquine<br /> - Proguanil<br /> - Tetracycline <br />FOR THE TREATMENT OF ACUTE ATTACK<br />MODE : ErythrocyticSchizonticides (kill schizonts in the Blood)<br /> DRUGS : <br /><ul><li>Rapidly acting : - Chloroquine, quinine , atovaquone , artemisinin derivatives, mefloquine
  32. 32. Slow acting :-
  33. 33. Proguanil, sulphonamides , tetracyclines , pyrimethamine</li></ul>18<br />
  34. 34. According To Mode Of Action<br />FOR PREVENTION OF TRNSMISSION <br />MODE : GAMETOCIDES ( kill Gametes ) <br /> DRUGS : <br /> - Primaquine : for all species <br /> - Artemisinin : for all <br /> - Quinine : For vivax<br /> - Chloroquine : for vivax<br />FOR RADICAL CURE <br />MODE : Exo-erythrocyticSchizonticides (killExo-erythrocytic forms i.e. Hypnozoites)<br /> DRUGS : <br />- Primaquine<br />19<br />
  35. 35. Site of action<br />20<br />
  36. 36. CHLOROQUINE<br />Erythrocytic schizontocide: all plasmodial species<br />Gametocytic: not P.falciparum<br />No effect on sporozoites, hypnozoites<br />MOA: Concentrates in parasite food vacuoles, ↑pH<br />Disruption of polymerization of Heme to Hemozoin<br />Heme damage plasmodium membrane<br /><ul><li>Well absorbed: oral, IM, SC .60% PPB</li></ul>Metabolized by liver , t1/2: 3-10 days <br />Excreted by kidney.<br />21<br />
  37. 37. Chloroquine<br />ADRs:Nausea, vomiting, Blurring of vision ,Headache, Confusion, seizures<br />Hemolysis: G6PD individuals, Impaired hearing <br />Hypotension, ECG changes<br />High dose: Irreversible ototoxicity, retinopathy, myopathy, Peripheral neuropathy<br />Chloroquine sulphate (Tab)136 mg = 100 mg Base <br />Chloroquine phosphate (Tab) 250mg=150mg Base <br />Dose : 600 mg stat , 300 mg after 8 hours and then for next two days <br />22<br />
  38. 38. Faster acting <br />MOA & resistance similar to chloroquine<br />ADRs<br />Toxic hepatitis<br />Agranulocytosis <br />Dose: 25-35 mg/kg over 3 days<br />Chloroquine resistant: combine Artesunate<br />Amodiaquine<br />23<br />
  39. 39. Mefloquine <br />Erythrocytic schizontocide<br />Rapidly control fever, eliminate circulating parasite<br />Effective: Chloroquine resistant plasmodium<br />MOA:- Inhibits heme polymerization<br /> - Forms toxic complexes with free heme<br />Oral absorbed ,Highly protein bound ,Extensive tissues distribution <br />ADRs Nauses, Vomiting, Diarrhoea<br />Neuropsychiatric <br />Arrythmias , Haematological<br />Hepatic toxicity<br />Dose:1250 mg, 750 mg, 500mg 12 hrly<br />24<br />
  40. 40. Quinine <br />Derived from bark of cinchona tree<br />Effective blood schizonticidal<br />Gametocidal: P. vivax<br />Chloroquine resistant<br />MDR FP <br />MOA: same as of chloroquine<br />Oral absorption rapid & complete ,Bound to α1 acid glycoprotein , Metabolized by CYP3A4 ,Excreted in urine t1/2: 10-12 hrs<br />25<br />
  41. 41. Quinine<br />ADRs :Cinchonism:tinnitus,dysphoria, headache, Nausea, vomiting, dizziness, flushing & visual disturbances, <br />GIT: nausea, vomiting, diarrhoea,abdominal pain<br />Hypoglycemia<br /> CVS: hypotension, dysrhythmias, VT, fibrillation<br />Hemolysis (G6PD deficiency)<br />Blackwater fever: hemolysis, hemoglobinemia, hemoglobinuria.<br />Dose:<br />Quinine: 600 mg 8 hrly<br />26<br />
  42. 42. Pyrimethamine<br />Erythrocytic schizontocide<br />Resistance develops rapidly if used alone<br />MOA : DHFRase inhibitor <br />Oral: absorption good, slow<br />Concentrated: liver, spleen, kidneys<br />Metabolized: liver ,Excreted: renal & t1/2: 4 days <br />ADRs : Nausea, Rashes, Folate deficiency<br />Dose: sulphadoxine 1500 mg<br /> +<br />pyrimethamine 75 mg<br />27<br />
  43. 43. Proguanil<br />Erythrocyte schizontocide<br />Cyclic triazine metabolite: cycloguanil<br />MOA: DHFRase Inhibitor <br />Slowly, adequately absorbed ,Partly metabolized <br />Excreted in urine & t1/2 is 20 hrs.<br />ADRs : Vomiting, Abdominal pain ,Haematuria<br />Dose: 200-300 mg/day for 4wks<br />28<br />
  44. 44. Primaquine<br />Radical cure of relapsing cases<br />Preerythrocytic Gametocytes & hypnozoites<br />MOA : - Interferes electron transport of parasite <br /> Readily absorbed orally, oxidized in liver<br />t1/2: 3-6 hrs ,excreted in urine <br />ADRs : Abdominal pain, GI upset Hemolysis in G6PD deficiency, methaemoglobinaemia<br />Dose: 15 mg/day for 2wks<br />29<br />
  45. 45. Sulphonamides<br />Blood schizonticides<br />Given in combination <br />MOA: inhibit folatesynthetase<br />Oral: Rapidly absorbed ,Metabolized by acetylation in liver ,Excreted by kidneys <br />Dose : (Chloroquine resistant P.falciparum)<br />sulphadoxine 1500 mg + pyrimethamine 75 mg<br />30<br />
  46. 46. Tetracyclines<br />Week erythrocytic schizonticidal<br />Use with Quinine, S/P<br />Multidrug resistant cases .<br />31<br />
  47. 47. FOSMIDOMYCIN <br />Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the nonmevalonate pathway<br />fosmidomycin blocks the biosynthesis of isopentenyldiphosphate and the subsequent development of isoprenoids in P. falciparum .<br /> In contrast, isoprenoids are derived from an alternative pathway, known as the mevalonate pathway, in mammals . <br />Hence, fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids, which are essential for cellular function, <br />32<br />
  48. 48. Artemether, Artesunate, Arteether<br />Blood schizonticidal<br />Duration of action short, recrudescence rate high<br />Combine with a long acting drug<br />Artemisinin derivatives<br />33<br />
  49. 49. MOA<br />Endoperoxide bridge interact haeme of parasite<br />Release highly reactive free radicals<br />Damage membrane protein<br />Inhibits protein synthesis<br />Lysis of parasite<br />Artemisinin derivatives<br />34<br />
  50. 50. PKs<br />Artemisinin derivatives<br />35<br />
  51. 51. ADRs: <br />Nausea, Vomiting <br />Abnormal bleeding<br />ST segment changes, QT prolongation<br />Artemisinin derivatives<br />36<br />
  52. 52. Artesunate-mefloquine<br />100 mg BD for 3 days + 750 mg 1st day, 500 mg 2nd day<br />Aretemether-lumefantrine<br />80 mg + 480 mg BD for 3 days<br />Artesunate-sulfadoxine+pyrimethamine<br />100 mg BD for 3 day + 1500 mg & 75 mg single dose<br />ACT regimens for uncomplicated falciparum malaria<br />37<br />
  53. 53. Halofantrine<br />Blood schizontocide<br />Effective: chloroquine & S/P resistant <br />PKs<br />Oral absorption: low<br />t 1/2: of active metabolite 3 day<br />ADRs<br />Cardiovascular toxicity<br />38<br />
  54. 54. Atovaquone<br />Erythrocytic schizontocide<br />MOA: Mitochondrial electron transport<br />Interferes ATP production<br />PKs : Lipid soluble: absorption slow<br />99% bound plasma proteins<br />Enterohepatic circulation<br />t1/2: 1.5-3 days<br />Dose:Atovaquone: 250 mg & Proguanil: 100mg for 3 days<br />ADRs<br />Vomiting, diarrhoea<br />Maculopapular rash<br />39<br />
  55. 55. Chemoprophylaxis: Indications<br />Special risk groups:<br />Non-immune travellers<br />Non-immune persons living in endemic areas<br />Pregnancy- After 1st trimester (Chloroquine, Proguanil, Quinine)<br />
  56. 56. Chemoprophylaxis<br />
  57. 57. Prophylaxis in Pregnancy<br />Travellers<br />Avoid travel[Pregnant or likely to become pregnant!!]<br />Chlo or Proguanil+F.A<br />Or Meflo in II, III trimester<br />Doxy, Atova, Prima : C/ I.<br />Mosquito net<br /> Intermittent Preventive Treatment [IPT]:<br />Pregnant in endemic areas<br />Pyr+Sulfa<br />2-3 doses<br />I dose after quickening-II trimester<br />Further at 1 month intervals<br />
  58. 58. Sulfadoxine-pyrimethamine (SP): effective drug for IPT<br />S/P <br />500 mg of sulfadoxine<br />25 mg of pyrimethamine<br />Malaria During Pregnancy<br />43<br />
  59. 59. Treatment-Chloroquinesensitive:P.V.<br />Chloroquine po4 1 Tab=250mg salt or 150mg base<br />Clinical cure- 0h - 4Tab stat<br /> 6h - 2 Tabs<br /> 24h - 2 Tabs<br /> 48h - 2 Tabs<br />Radical cure: Primaquine 15mg/d X 14 days. Primaquine C.I in G6PD def.<br />
  60. 60. Treatment-ChloroquineResistant:P.V.[Rare]<br />Quinine 600mg 8thhrly X 7 days<br />+<br />Doxy 100mg daily X 7 days<br />+<br />Primaquine 15 mg x 14 days<br />
  61. 61. Treatment-ChloroquineSensitive:FP<br />Chloroquine Phoshphate :[250mg] = 150mg Base<br />0h - 4Tab stat<br /> 8h - 2 Tabs<br /> 24h - 2 Tabs<br /> 48h - 2 Tabs<br />+<br />Primaquine 45 mg single dose[gametocidal]<br />OR<br />Sulfadoxine/Pyrrimethamine 3 Tab + Primaquine[Chlo not tolerated]<br />
  62. 62. Treatment-ChloroquineResistant:FP<br />Artesunate 100mg BDx3days + Sulfadoxine/Pyrimethamine 1500/75 mg (3 tab single dose)<br />OR<br />Mefloquine 750mg on 2nd day-500mg on 3rd day.<br />Artemether 80mg + Lumefantrine 480mg BD x 3 days <br />Quinine 600mg 8thhrly x 7 days + Doxycycline 100mg daily x 7 days<br />
  63. 63. Severe malaria<br />Cerebral malaria:<br />Severe anemia<br />Renal failure<br />Pulmonary edema<br />Shock<br />Metabolic acidosis<br />Hemoglobinuria, jaundice<br />Hyperpyrexia<br />Hyperparasitemia<br />The single most important step in the management of severe malariais IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT<br />
  64. 64. Severe and complicated F.P.Malaria<br />Artesunate 2.4mg/Kg i.v or i.m. » 12 hrs » 24 hrs » OD x 7days [Change to oral ACTx3days, if possible]<br />Or<br />Artemether: 3.2mg/Kgi.m on 1st day and then 1.6mg/Kg x 7days [change to oral ACTx3days, if possible ]<br />Or<br />Arteether: Same as above. But 4 days<br />Or<br />Quinine diHCL:20mg/Kg in 10ml/Kg of 5% dextrose infused 4hrs » 10mg/Kg for 4hrs every 8hrs » Oral quinine10mg/kg tds x7days<br />+ doxy 100mg od oral or 3day oral ACT or pyrimethamine/Sulfadoxine<br />
  65. 65. Treatment-Severe malaria<br />Quinidinegluconate-<br />10mg/kg in 300ml of N.S over 2-3h (max600mg)<br />↓<br />0.02mg/kg/.min infusion for 24 h<br />↓<br />Oral quinine sulfate 600mg tid X 7 days<br />AND Adjunctive therapy oral<br />Doxy 100mg bd<br />or <br />Clindamycin 20mg/kg/day X 7days <br />or <br />Pyr+Sulfa 3 tab on last day of quinine<br />
  66. 66. PREVENTION OF RESISTANCE <br />Selection of drugs - Use conventional drugs first in uncomplicated cases. Greater the exposure, higher will be the emergence of resistance.<br />Avoid drugs with longer half-life if possible.<br />Avoid basic antimalarials for non-malarial indications (e.g. Chloroquine for rheumatoid arthritis in a malarial endemic area).<br />Ensure compliance.<br />Monitoring for resistance and early treatment of these cases to prevent their spread.<br />Clear policy of using newer antimalarials.<br />Use of combinations to inhibit emergence of resistance.<br />51<br />
  67. 67. Malaria Vaccine<br />Reduce severity and complications of malaria<br />Tried in children less than 5yrs, in Africa<br />Reduces mortality and morbidity<br /> RTS,S/AS01, <br />Phase III<br />Potential targets of the vaccine<br />pre-erythrocytic<br />erythrocytic<br />merozoite<br />gametocyte<br />
  68. 68. Newer regimens under development<br />1.Dihydroartemisinin-Piperaquine<br />120 mg + 960 mg daily for 3 days<br /> 2. Artesunate-amodiaquine<br />200 mg + 600 mg daily for 3 days<br /> 3. Astesunate-pyronaridine<br />200 mg + 600 mg daily for 3 days<br /> 4. Arterolane (RBx 11160)-piperaquine<br /> 5. Artesunate-chlorproguanil + Dapsone<br /> 6. Fosmidomycin + Clindamycin<br />53<br />
  69. 69. SUMMARY : <br />Drug resistant malaria is a serious problem worldwide <br />P.falciparum should be treated with artemisinin derivatives <br />Chemoprophylaxis should be followed wherever appropriate <br /> Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups e.g. travelers <br /> For Severe Malaria cases Parenteral therapy should be given<br /> Drug combinations should be used <br />54<br />
  70. 70. THANK YOU<br />55<br />

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