Malaria

MALARIA

1. Pharmacotherapy of Malaria Dr. Prerna Singh Junior Resident Department of Pharmacology JNMC, AMU

2. INTRODUCTION Cause: Plasmodium 6 species: P falciparum (Severe) P. vivax P. ovale curtisi P. ovale wallikeri P. malariae P. knowlesi (Monkey parasite) Transmission: female anopheles mosquito: Sporozoites

3. Merozoites: RBC Hypnozoites: latent (vivax and ovale ) Gametocytes: infective to mosquito

4. introduction Africans resistant to Vivax: WHY? Duffy negative phenotype Recrudescence vs recurrence

5. Classification Agents not effective against primary or latent liver stage: Artemisinin Chloroquine Mefloquine Quinine Quinidine Pyrimethamine Sulfadoxine Tetracycline Agents targeting both erythrocytic form and primary liver stage of falciparum Atovaquone Proguanil Agent effective against primary and latent liver stage and also gametocytes Primaquine Taefnoquine

6. Antimalarial NO ANTIMALARIAL KILLS SPOROZOITES Cant prevent infection Can only prevent development of symptomatic malaria by targeting asexual exo -erythrocytic forms

7. Artemisinin and its derivatives Dihydro-artemisinin(oral) Artemether(oral/ IM/ Rectal) Artesunate (oral/IV/IM/Rectal) Not effective against primary or latent liver stage Some activity against gametocytes

8. Artemisinin and its derivatives Uses: First line antimalarial Treatment of severe P. falciparum and asexual erythrocytic stage of vivax ACT: to avoid emergence of resistance (delayed parasite clearance time) Reason: mutation in Pfk13 gene encoding kechl 13 protein( how? UK) Resistance of non falciparum species to artemisinin- not reported

9. Artemisinin and its derivatives Mechanism of action: cleavage of endoperoxide bridge – generation of reactive oxygen species - oxidative stress- protein damage via alkylation ADME: oral/IM/IV/Rectal Bioavailability (Oral) : 30% Plasma protein bound: 40- 80% Half life: 1-2 hr - NOT for prophylaxis Induce their own metabolism via CYP2B6, CYP3A4

10. Artemisinin and its derivatives Side effect: GI side effect Neutropenia Hemolysis Anaphylaxis Urticaria Fever Not indicated in pregnancy and Children <5 YR age (increased embryo lethality in rats)

11. ACT PARTNER DRUGS Artemether-Lumefantrine, Artesunate -Mefloquine Dihydroartemisinin -Piperaquine Artesunate - Sulfadoxine -Pyrimethamine Artesunate -Amodiaquine

12. LUMEFANTRINE First line of treatment Large volume of distribution Half life 4-5 days Fatty meal increase absorption No major side effect Artemether-lumefantrine (1.5/9 mg/kg bid for 3 days with food)

13. AMODIAQUINE Half life: 3 hr Metabolite half life: 9- 18 days Side effect: Agranulocytosis Hepatitis Artesunate (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)

14. PIPERAQUINE Half life: 21- 28 days(longest among partner drugs) Resistance seen in some places: mutation in Pfk13 gene No major side effect DHA-piperaquine 4/18 mg/kg qd for 3 days in persons weighing ≥25 kg)

15. Other antimalarial drugs

16. ATOVAQUONE 250 mg atovaquone and 100 mg proguanil hydrochloride * 3days FDC for prophylaxis, uncomplicated falciparum, resistant falciparum Vivax malaria: but may reoccur- No activity against hypnozoites

17. ATOVAQUONE Mechanism of action: inhibits electron transport, inhibits regeneration of ubiquinone Not toxic to human: structural differences in the amino terminal regions of plasmodial and human cytochrome b

18. ATOVAQUONE ADME : Slow and variable oral absorption (fatty meal) 99% plasma protein bound Enterohepatic circulation Excreted in bile and feces Half life – 2-3 days No major side effect Rarely elevation of transaminases or amylase

19. Diaminopyrimidines Sulfadoxine and pyrimethamine: was primary treatment for falciparum Artesunate (4 mg/kg qd for 3 days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single dose No longer recommended

20. Diaminopyrimidines Mechanism of action: inhibit folate biosynthesis- schizontocide No activity against hepatic form, hypnozoites, gametocytes- increased transmission Dihydropteroate synthase and inhibited by sulfonamides Reduction of dihydrofolate to tetrahydrofolate, which is catalyzed by dihydrofolate reductase and inhibited by pyrimethamine

21. Diaminopyrimidines ADME : 90% Plasma protein bound Half life pyrimethamine: 85-100 hr Supressive concentration last for 2 wk Enter milk : contraindicated in lactation Teratogenic in animal : contraindicated in pregnancy

22. Diaminopyrimidines Side effect: minimal Pyrimethamine- megaloblastic anemia Sulfonamide : Fatal cutaneous reaction Resistance : mutation in DHF reductase

23. PROGUANIL Mechanism of action: inhibit dihydrofolate reductase- thymidylate synthetase Required for purine and pyrimidine synthesis Active against primary liver stage and asexual blood cell stage No activity against latent stage and gametocyte (may recur)

24. PROGUANIL Uses: chemoprophylaxis(100mg) along with atovaquone(250 mg)* 3 days May be used for treatment in resistant cases Side effect: no severe side effect, nausea, diarrhea, abdominal pain

25. proguanil ADME: HALF LIFE 180-200hr Metabolized by CYP2C19 - active cycloguanil and inactive 4- chlorophenyl biguanide Resistance due to non conversion to active metabolite Excreted in urine Concentration in RBC is 3 times higher than plasma

26. Chloroquine DOC for treatment and prophylaxis(if sensitive) Mechanism of action: Inhibit heme polymerase- free heme is toxic No action on liver stage Given with primaquine to eliminate hepatic forms

27. CHLOROQUINE Resistance: mutation in pfcrt gene- encodes a transporter which resides membrane of site of action of chloroquine Pfmdr 1 – p. falciparum multidrug resistance associated protein

28. chloroquine ADME : well absorbed Oral/IM/ SC/ IV SLOW INFUSION TO AVOID TOXICITY Converted to active metabolite by CYP- desethylchloroquine and bisdesethylchloroquine . High volume of distribution half life 1-2 months 60% plasma protein bound Excreted in kidney Inhibit CYP2D6- DIGOXIN TOXICITY

29. CHLOROQUINE Dose Prophylaxis in chloroquine sensitive area- 300 mg oral once a wk Start 2 wk before travel and upto 4 wk after return Treatment of falciparum and vivax in sensitive areas: 600 mg base 300 mg at 6, 4, 48 hr TO PREVENT REPLPSE : GIVEN ALONG WITH PRIMAQUINE Other uses: hepatic amebiasis

30. chloroquine Narrow safety margin GI upset Pruritus, rash Postural hypotension Arrythmias Retinopathy, ototoxic – irreversible Myopathy Overdose: convulsion coma confusion AVOID with mefloquine- seizure precipitate C/I IN G6PD deficiency, psoriasis

31. Quinine and quinidine Uncomplicated falciparum- parenteral treatment of severe illness, resistant cases Quinidine is more potent and more toxic (cardiotoxic) No activity against hepatic form Mechanism same as chloroquine Not for prophylaxis- short half life and toxic Resistance : transporter genes involved

32. Quinine and quinidine ADME: Oral/IM- Good absorption SC- irritating and not given IM concentrated may cause abscess Thrombophlebitis - IV

33. Quinine and quinidine Half life- 11- 13 hr Increase in malaria - high levels of plasma α1- acid glycoprotein produced in severe malaria may prevent toxicity by binding quinine and thereby reducing the free fraction of drug Metabolized by CYP 3A4 Excreted in urine

34. Quinine and quinidine Side effect : Triad of cinchonism , hypoglycaemia(stimulate beta cell), and hypotension(alpha blockage) Cinchonism - tinnitus, high-tone deafness, visual disturbances, headache, dysphoria, nausea, vomiting, and postural hypotension

35. Quinine and quinidine Side effect: Cutaneous- flushing rash angioedema Rarely cardiac arrhythmias – potassium channel blockage, Qunidine more cardiotoxic Hemolysis in G6PD Deficient Blackwater fever-triad of massive hemolysis , hemoglobinemia , and hemoglobinuria

36. Quinine and quinidine Safe in pregnancy Quinine inhibit Tat2p transporter Transport tryptophan - precursor of of 5HT Inhibit 5HT biosynthesis- inhibit tryptophan hydroxylase

37. MEFLOQUINE Drug resistant falciparum Not first line agent Mechanism- same as chloroquine Given with artesunate to prevent resistance Artesunate (4 mg/kg qd for 3 days) plus mefloquine (24–25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3) Oral Parental: local reaction

38. Mefloquine Enterohepatic circulation- rise biphasic Half life: 13-24 days Highly plasma protein bound- 98% CYP3A4 Fecal excretion

39. mefloquine Side effect: Neuropsychiatric reaction- black box warning Full dose repeated if vomiting occurs Teratogenic in rodents Avoid pregnancy for 3 month after use- long half life

40. Primaquine Act on liver stage – prevent and cure relapsing malaria Gametocidal USE : p rophylaxis and radical cure of vivax and ovale Given with blood schizonticide - chloroquine Screen G6PD deficiency Half life – 7 hr Metabolised by CYP2D6 Induce CYP1A2 Mild side effect- abdominal distress Not safe in pregnancy

41. TAFENOQUINE Mechanism side effect same as primaquine Different ADME Half life- 14 days

42. SULFONAMIDE AND SULFONES Inhibit dihydropteroate synthase Mutation – resistance Blood schizonticide – falciparum and ovale

43. Tetracyclin clindamycin doxycycline Schizonticide - weak activity Chloroquine resistant falciparum and vivax Containdicated in pregnancy and children Doxycycline -100 mg oral BD 7 DAYS Clindamycin- 20 mg base/kg/d orally divided 3 times daily × 7 d Tetracycline: 250mg qid 7days Side effect- Doxycycline: esophagitis- prevent by taking with large amount of fluid Clindamycin- no major side effect, renal failure in impaired renal function

44. treatment Radical cure: eliminate hepatic and erythrocytic form Causal prophylaxis: prevent erythrocytic infection

45. treatment Aims Causation Therapy Drugs To alleviate symptoms Symptoms are caused by blood forms of the parasite Blood schizonticidal drugs Chloroquine, quinine, artemisinin combinations To prevent relapses Relapses are due to hypnozoites of P. vivax/ P. ovale Tissue schizonticidal drugs Primaquine To prevent spread Spread is through the gametocytes Gametocytocidal drugs Primaquine for P. falciparum, Chloroquine for all other

46. treatment

47. prophylaxis Atovaquone /proguanil Chloroquine in sensitive area Mefloquine Doxycycline in chloroquine and mefloquine resistance Primaquine

48. prevention Insecticide treated nets Insecticide RTS,S/AS01 ( Mosquirix TM) Genetically engineered vaccine Vaccine target against P.falciparum It is a fusion protein of malaria antigen with Hepatitis B antigen. Vaccine targeting placental malaria: against VAR2CSA – UNDER RESEARCH

49. TAKE HOME MESSAGE Chloroquine sensitive falciparum Chloroquine Chloroquine resistant falciparum ACT Vivax malaria Chloroquine with primaquine Severe malaria IV Artesunate First trimester pregnancy (falciparum) Quinine with clindamycin Second and third trimester pregnancy ( falciparum) ACT Pregnancy vivax malaria Weekly chloroquine (Primaquine contraindicated) Prophylaxis (travel <6 week) Doxycycline Prophylaxis (travel >6 week) Mefloquine

50. New drugs TE3 A prodrug of bis -ammonium compound. Inhibit phosphatidylcholine synthesis → Heme detoxification hampered FOSMIDOMYCIN - Inhibit lipid and haem synthesis of plasmodium ARTEROLANE and TRIOCXOLANE - free radical damage ARTEMISONE a drug in Phase II trials, is 10 times more potent than artesunate SPIROINDOLONES Phase II trials ALBITIAZOLIUM inhibiting the transport of choline into the parasite- PHASE 2 SEVUPARIN To prevent vasoocclusion , antiadhesive Actelion reported ACT-213615  - fast-acting against all asexual erythrocytic stages

51. THANK YOU!

52. Severe malaria

53. Merozoites: RBC Hypnozoites: latent (vivax and ovale ) Gametocytes: infective to mosquito