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Malaria 2003

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    • 1.  
    • 2. Malaria
      • Types
      • Lifecycle
      • Drugs-classification
      • Individual drugs
      • Dosage regimen
      • Chemo-prophylaxis
      • Newer anti-malarials
      • Vaccine
    • 3.
      • Devastating parasitic infection
      • Attacks-500 million
      • Mortality –2 million[1million children].
      • Except N.America, Europe, Russia
    • 4. Chloroquine resistant-PF Chloroquine sensitive-PF Malaria Endemic Areas Mexico, Central America west of Panama canal, Carribean, South America, middle east Resistant PV Indonesia,Papua New Guinea, Burma
    • 5.
      • Types
      • P.vivax - Benign tertian
      • P.Falciparum - Malignant tertian
      • P.ovale -Benign tertian
      • P.Malariae -Benign Quartan
    • 6. Transmission
      • “ Bite of Infected Female Anopheles Mosquito”
      • Blood transfusion
      • Congenital
      • Sharing needles
    • 7. Life Cycle
    • 8. Hepatic Stage
      • P.F and P.M No persistent tissue phase
      • No Hypnozoites
      • No relapse
      • No Radical cure required
      • P.V and P.O.- Persistent tissue phase +
    • 9. Erythrocytic Phase
      • Most of the drugs act in this stage
      • Leads to clinical cure
      • Most of the drugs do not prevent transmission
      • Chemoprophylaxis
    • 10. Why P.F. Serious?
      • P.Palciparum
      • Produces
      • Leads to
      • 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
    • 11. Classification of Drugs
      • Cinchona alkaloids: Quinine & Quinidine
      • Quinolines:
      • 1. 4-Aminoquinolines- Chloroquine
      • Hydroxychloroquine
      • Amodiaquine
      • Piperaquine
      • 2. 8-Aminoquinolines- Primaquine
      • Tafloquine
      • Bulaquine
    • 12. Classification……
      • Quinolines..
      • 3. Quinoline methane- Mefloquine
      • Halofentrine
      • Lumefantrene
      • Antifolates:
      • 1. Biguanides- Proguanil
      • 2. Diaminopyrimidine- Pyremethamine
      • 3. Sulfonamides- Sulfadoxine
      • Dapsone
    • 13. Classification……
      • Artemisinin compounds : Artesunate
      • Artemether
      • Arteether
      • AMA: Doxycycline, Clindamycin,
      • Others Atovaquone , Pyoronaridine
    • 14. Spor Liver RBC forms Class I P.E Hypno Asex Gam Chloroquine - - - + ( ±) Mefloquine - - - + - Quinine - - - + ( ±) Pyrimethamine+ Sulfadoxin - ± - + _ T.C - - - ± - Class II Atovaquone+Proguanil - [+] - + - Class III Primaquine - + + - +
    • 15. Lesson!
      • No drug acts on Sporo
      • None very effective against both liver & RBC stages
      • True prevention not possible, only suppress symptomatic malaria.
      • Complete cure requires more than one drug
    • 16. Clinical utility
      • Class I:
      • Liver and sexual forms- No action.
      • Active against RBC stage Only
      • Hence- used in the tt and prevention of clinical malaria
      • Prophylaxis-Takes several weeks to exhaust liver stages
    • 17. Clinical utility……
      • Class II: Act against early Liver & RBC forms, Reduces period of post exposure in prophylaxis
      • Class III: Unique! Radical cure, No place in Symptomatic treatment.
    • 18. Use and Classification
      • Causal prophylactics-
      • Target early liver forms
      • Eg.?????????
      • Terminal prophylaxis and radical cure-
      • Target hypnozoites
      • Eg.????????
      • Suppressive prophylactics and clinical cure-
      • Target asexual RBC forms
      • Eg.?????
    • 19. Life Cycle And Drugs NONE Pyrimethamine Proguanil Primaquine Most of the drugs Except Primaquine Chloroquine Quinine [not F.P.]
    • 20. Quinine
      • Holy bark, Cardinal’s bark, Jesuit’s
      • Quinine & Quinidine-Alkaloids from Cinchona bark. Cheapest source
      • H/O 350 yrs.
      • Even today d.o.c severe and resistant malaria
    • 21. Quinine contd…
      • Anti-malarial action :
      • Active against asexual erythrocytic forms
      • Against gametocytes of P.V & P.M(Not P.F.)
      • More toxic, less effective than chloroquine(If suceptible to both)
      • Chlo. & MDR strains respond.
      • Parenteral treatment
    • 22. Quinine contd…
      • Anti-malarial action ( M.O.A.)
      • Asexual parasites digest Hb in ACIDIC food vacuoles
      • Quinine(Alkaline) Concentrated in vacuoles
      • Raises pH ‘ALKALINE‘
      • Free radicals and heme generated
      • These Toxic sub. sequestered by parasite as non toxic hemozoin
      • Prevents hemozoin formation
      • May also bind to heme- Toxic
    • 23. Quinine contd…
      • Chloroquine,
      • Amodiaquine,
      • Mefloquine, Lumefantrine
      • Halofantrine & Pyronaridine
      • Have similar MOA
    • 24. Quinine contd…
      • Skeletal muscles: Decreases contractile force & excitability
      • Antagonize physostigmine.
      • Myesthenia gravis?
      • Myotonia congenita?
      • Local-Inflammatory and anesthetic
      • Uterus-Stimulant
    • 25. Quinine contd…
      • PK: well absorbed from GIT, i.m.
      • Metabolized by CYP3A4
      • Acidic urine ↑ excretion
      • α 1-acid glycoprotein in malaria protects from toxicity of high plasma concn.!
    • 26. Therapeutic uses:
      • Severe and resistant malaria
      • Nocturnal leg cramps
      • Spermicidal-Vaginal creams
      • Sclerosing agent-V.V.
      • Quinidine used as anti-arrhythmic
    • 27. Quinine ….ADE
      • Fatal dose 2-8g.
      • Cinchonism : Tinitus, high tone deafness, visual disturb., nausea, vomiting
      • Hypoglycemia
      • Cardiac: Arrhythmia, AV block, Hypotension more with quinidine
      • Blackwater fever : Hypersensitivity:
      • “ Hemolysis-hemoglobinemia -hemoglobinuria” Anuria Renal failure and death.
      • Purpura
    • 28. Quinine ….Caution
      • Hypersensitivity
      • Hemolysis- discontinued
      • Cardiac arrhythmia, tinitus, optic neuritis
      • Irritant
      • Fairly safe in pregnancy
    • 29. Quinine (DI)
      • Antacids
      • Reduces absorption of digoxin
      • Elevates plasma conc.of Warfarin
      • Enhances effect of NM blockers
      • Acidification of urine ↑ clearance
    • 30. Chloroquine
      • Anti-malarial spectrum:
      • Erythrocytic forms of all species, Gametocyte of all except P.F,
      • No activity against tissue forms
      • MOA: As before
      • Resistance: Resistant strains concentrate chloroquine less in vacuoles.
      • Crt-Chloroquine resistant transporter and Pfmdr transporters
    • 31. Chloroquine contd… PK:
      • Well absorbed by oral , s.c, i.m.
      • Extensively sequestrated in tissues-Large V (100L/k.g)
      • Loading dose is required-Wide dist.
      • Half life-1 week
      • Slow IV-slow dist.
      • Oral-PK of absorption and dist. matched
    • 32.
      • Clinical cure & Chemoprophy.(Sensitive strains)
      • Hepatic amoebiasis
      • RA
      • Discoid lupus,SLE
      • Lepra reaction, Sarcoidosis
      • Photosensitivity reaction
      • Porphyria cutanea tarda
      • Chikengunya? [HCQ]
      Chloroquine- Uses With other agents
    • 33. Chloroquine contd… ADE:
      • Remarkably safe in th. doses. Safety margin is narrow
      • Parenteral - Rapid infusion ->
      • Arrhythhmia, Hypotension, arrest.
      • More than 5g fatal
      • Oral - GIT, headache, VISUAL disturbances, blurring, rashes
    • 34. Chloroquine contd… ADE :
      • Chronic therapy : Accumulates in melanin rich tissues( ↑ 250mg/day)
      • Irreversible retinopathy, ototoxicity [Total cumulative dose of more than 1G/Kg]
      • Discolouration of nail bed& m.m., bleaching of hair
      • Myopathy, neuropathy, neuropschiatric, cardiopathy
      • Optho and Neuro exam PERIODICALLY
    • 35. Chloroquine contd… ADE :
      • Caution:
      • Not used with Mefloquine (Siezures)
      • Cautiously in liver disease renal failure, G6PD def
      • CI- Epilepsy, myesthenia gravis,
      • Opposes anticonvulsants, arrhythmogenic with halofentrine and amiodarone
    • 36. Chloroquine contd…
      • Preperations:
      • Tab, Syp, Injection
      • Oral- Chl.Po 4 ( 250mg salt=150 mg base)
      • Dose
      • Curative:
      • Prophylactic
    • 37. Mefloquine
      • Antimalarial action- Against blood schizonts
      • MOA : Exactly not known. Similar to chloroquine
      • PK : Slow oral absorption. Food ?. Excretion fecal
      • No parenteral (Local reaction)
      • t 1/2 -2-3 weeks –enterohepatic circulation
      • Uses : Prophy. & Tt of drug resistant malaria[With Artimisinin]
    • 38. Mefloquine ADE contd…
      • Vomiting( repeat if within 1 h.)
      • CNS- seizures, confusion or decreased sensorium, acute psychosis, and disabling vertigo.[reversible]
      • CI: Pregnancy(avoided for 3 mo. After stopping), Epilepsy, psychotics, pilots
      • H/O ADE to other quinolines
    • 39. Mefloquine Caution contd…
      • Pregnancy
      • CI with Halofantrine or within 2 months of mefloquine
      • Compromizes typhoid vaccine
      • Not with drugs which affect cardiac conduction
      • CI in jobs require motor coordination
    • 40. Primaquine
      • History : Lead to Identification of G6PD def.
      • Antimalarial action :
      • Effective against tissue forms[Bothe] and gametocytes.
      • Not against erythrocytic forms
      • Moa: Not known[Metabolites are toxic to parasites ?]
      • PK : only oral. Parenteral cause Hypotension
    • 41. Primaquine contd…
      • Radical cure of P.V. & P.O.
      • Terminal prophylaxis (just before or soon after leaves endemic area)
      • P.jiroveci with clindamycin
    • 42. Primaquine contd…
      • ADE : Hemolysis in G-6-PD def., anemia, methemoglobinemia
      • G-6-PD Def-200 million
      • India-Tirbals-Jharkhand, AP, MP, Assam
      • Spot tests available
      • Passage of dark urine-Stop
      • Pregnancy-Fetus deficient in G6PD
      • Risk is more with RA, SLE
      • Offers protection against severe malaria
      • More than 30mg/day repeated blood counts/urine for Hb.
    • 43. G6PD Glucose Glucose-6-Phospate 6-Phoshogluconate Hexokinase NADP NADPH GSSG GSH Defeciency GSH DEF. Hemolysis No protection For RBC’s Against Oxidative substances Hemolysis
    • 44. Proguanil(Chloroguanide)
      • Proguanil Cycloguanil (Triazine)
      • Anti-malarial:
      • PF- Primary tissue stage & Erythrocytic forms
      • P.V.- Only erythrocytic stage
    • 45. Proguanil(Chloroguanide)
      • MOA:
      • Inhibits DHFR
      • Proguanil-intrinsic antimalarial activity
      • Accentuates action of Atovaquane
      • Therapeutic use : In combination with atovaquone-against resistant strains- prophylactic and curative (uncomplicated )
      • Safe in pregnancy
    • 46. Atovaquone
      • Antiparasitic effect:
      • RBC forms of plasmodia, Early liver forms of FP, T.Gondii, P.Carinii, Babesia
      • MOA: Inhibits ATP and pyrimidine synthesis, collapse of mitochondrial membrane potential[Potentiated by Proguanil]
      • Resistance: Common when used alone
      • PK: Absorption increased by fatty food. 94% excreted unchanged in bile [E.H.circculation]
    • 47. Atovaquone
      • Uses:
      • Treatment and prophylaxis of resistant PF malaria,
      • T.gondii,
      • P.carinii
      • Babesia
      • Proguanil : Atovaquone – 100:250mg
    • 48. Pyrimethamine
      • Antiprotozoal action:
      • RBC forms –plasmodia, Pre-erythrocytic
      • T.Gondii [with S.D, high doses with Leucovorin]
      • MOA: DHFR inhibitor
      • Use:
      • Along with ( 25 : 500 ) sulfadoxine (folate synthetase inhibitor). Synergistic
      • Not for prophylaxis
      • Only tt of resistant strains of P.F. With sulfadiazine for T.Gondii.
      • Toxicity: due to Sulfa
    • 49. Artemisinin Derivatives
      • Sesquiterpine Lactone Endoperoxide derived from weed ARTIMISIA ANNUA (QING HAO)
      • Used by Chinese for 2000 yrs.
      • Derivatives:
      • 1. Artesunate
      • 2. Artemether
      • 3. Arteether
      • 4. Dihydroartimisinin
    • 50. Artemisinin Derivatives…..
      • Anti-malarial action :
      • 1.Only against RBC forms and gametocytes
      • 2.Not against tissue forms
      • 3.Short acting, Recrudescence high, therapy prolonged even after disappearance of parasites from blood.
    • 51. Artemisinin Derivatives…..
      • MOA:
      • I Step
      • Heme iron in parasite
      • Cleaves endoperoxide bridge,
      • II Step
      • Carbon centerd radical is produced
      • Toxic to parasites
    • 52. Artimisinin
      • PK
      • Oral, i.v., Rectal-routes
      • Induce their own CYP450
      • Resistance
      • No resistance
      • Resistance to Chlo. Paradoxically increases sensitivity to Artimisinin
      • ADE:
      • Allergic
      • Embryotoxic in animals, Cardiotoxic
    • 53. Artemisinin Derivatives….
      • Therapeutic uses:
      • Oral: Uncomplicated Chloroquine/MDR malaria
      • Parenteral: Severe complicated F.P.Malaria
      • Not for prophylaxis, or P.V. or chloroquine sensitive F.P.
      • Only with combinations-longer acting drug.
    • 54. Quinine Vs Artimisinin
      • Quinine DOC in severe/complicated malaria
      • Artimisinin---
      • Faster parasitic clearance
      • Safe, better tolerated
      • Simple dosing schedule
      • High efficacy, low mortality
    • 55. ACT-Artemisinin based Combination Therapy
      • To exhaust parasite burden
      • Short acting high efficacy drug to quickly kill 95% of parasites
      • Long acting drug for 7 days[Small parasite load, reduced chances of selecting mutants
      • ACT is the choice. Why?
      • Rapid clinical, parasitological cure
      • Low recrudescence
      • No resistance(Combination prevents)
      • Good tolerability
      • Combination regimens: Ref.KDT 6 th Ed.
    • 56. Chemoprophylaxis Type Drug Before Entering After Leaving Chloroquine Sensitive Chloroquine po 4 500mg once a week 1-2weeks 4 weeks Resistant strains Pro+Ato(Malarone) 1tab/d 1-2 days 7 days Mefloquine 250mg/week 1-2 weeks 4 weeks Doxycycline 100mg 1Tab o.d. 1 day before 4 weeks
    • 57. Chemoprophylaxis: Indications
      • Special risk groups:
      • Non-immune travellers
      • Non-immune persons living in endemic areas
      • Pregnancy- After 1 trimester (Chloroquine, Proguanil, Quinine)
      • Terminal prophylaxis -Primaquine 30mg/day during last 14 days of chloroquine prophylaxis Or Chloro500+Prim45mg/week X 8 weeks
    • 58.
      • Standby Tt.[?Presumptive Tt.]:
      • Travellers within 24 h of symptoms[Presumed as malaria]
      • No chlo. prophylaxis ->Chlo or Meflo
      • Chlo ->Meflo or quinine
      • Meflo ->Quinine
      • Doxy ->Meflo
      • Malarone ->Doxy+Quinine
    • 59. Prophylaxis in Pregnancy
      • Travellers
      • Avoid travel[Pregnant or likely to become pregnant!!]
      • Chlo or Proguanil+F.A
      • Or Meflo in II, III trimester
      • Doxy, Ato, Prim. CI.
      • 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
    • 60. Treatment Guidelines
      • Malaria-Med.emergency
      • Clinical exp is the guide
      • Chloroquine d.o.c for sensitive strains
      • Oral route preferred, chlo.can be given iv with precautions
      • 48-72 h-clinical improvement.
      • Parasites cleared within 7 days
      • If not-drug resistance
      • In Chlo. Resistance- d.o.c is quinine/Artimisinin
      • MDR-quinine & antifolates,T.c
      • Iv until tolerates oral route
    • 61. Guidelines….
      • Children are small adults! Reduced dose, No TC
      • Ato-Pro. Only for more than 11 kg.
      • Pregnancy-Chlo, proguanil
      • Quinine with precautions for hpoglycemia
      • Antifolates, TC, artemisinin, atovaquone, primaquine avoided
      • Mefloquine if necessary
      • Lactating mother- all except ato-prog., tested for G6PD if primaquin to be used
    • 62. Severe malaria Oral not possible Any species Non-Falciparum Falciparum P.Vivax Chlo Resistant F.P. Chlo Sensitive F.P. Chlo Resistant P.Vivax Chlo Sensitive Primaquine for Radical cure
    • 63. Treatment-Chloroquine sensitive: P.V .
      • Chloroquine po 4 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.
    • 64. Treatment-Chloroquine Resistant: P.V .[Rare]
      • Quinine 600mg 8 th hrly X 7 days
      • +
      • Doxy 100mg daily X 7 days
      • +
      • Primaquine
    • 65. Treatment-Chloroquine Sensitive: FP .[Rare]
      • Chloroquine:[250mg]
      • 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]
    • 66. Treatment-Chloroquine Resistant: FP
      • Artesunate 100mg BDx3days
      • +
      • Sulfadoxine/Pyrimethamine 3 tab single dose
      • OR
      • Mefloquine 750mg on ii day-500mg on iii day.
      • (Sulfadoxine500/Pyrimethamine25)
      • Artemether 80mg
      • + Lumefantrine 480mg BD x 3 days
      • Quinine 600mg 8 th hrly x 7 days
      • + Doxycycline 100mg daily x 7 days
    • 67. Severe malaria
      • Cerebral malaria :
      • Severe anemia
      • Renal failure
      • Pulmonary edema
      • Shock
      • Metabolic acidosis
      • Hemoglobinuria, jaundice
      • Hyperpyrexia
      • Hyperparasitemia
    • 68. Severe
      • The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
    • 69. 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 » 1.6mg/Kg x 7days [change….]
      • Or
      • Arteether: Same as above. But 4 days
      • Or
      • Quinine diHCL:20mg/Kg in 10ml/Kg of dextrose infused 4hrs » 10mg/Kg for 4hrs every 8hrs » Oral quinine10mg/kgx 7days
      • + doxy 100mg od oral or 3day oral ACT or pyrimethamine/Sulfadoxine
    • 70. Treatment-Severe malaria
      • Quinidine gluconate-
      • 10mg/kg in 300ml of N.S over 2-3h (max600mg)
      • 0.02mg/kg/.mt 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
    • 71. Treatment-Chloroquine resistance
      • Quinine 10mg/kg/day tid X 7 days
      • or
      • Mefloquine 750mg, repeat 500mg after 12 h.
      • or
      • Artesunate 100mg bid followed by 100mg od X 5 days [ACT?]
      • or
      • Pro + Ato 4 tab od X 3 days
    • 72. Malaria Vaccine
      • Reduce severity and complications of malaria
      • Tried in children less than 5yrs, in Africa
      • Reduces mortality and morbidity
    • 73. Malaria Vaccine
      • Sporozoite vaccine-Prevents infection-RTS,S/ASO2A
      • Asexual RBC form[Merozoite] Vaccine- Reduces severity-MSP-1
      • Transmission blocking Vaccine-Against sexual forms in mosquito gut
      • Prevents development
      • Vaccines against toxins-Disease attenuation
      • Multiantigen, Multistage vaccine
    • 74. Other drugs
      • Halofentrene
      • } Drug resistant
      • Lumefentrene
      • Bulaquine……Primaquine
      • Amodiaquine…..Chloroquine
      • Dapsone….With pyremethamine
      • Fosmidomycin-apicoplast inhibitor
    • 75. MDR Malaria
      • “ Resistance to more than 3 or more anti-malarials of different chemical classes of which 2 are 4-aminoquinolines and diaminopyrimidine”
      • (Wernsdorfer et al, 1994).
      • Exposure of Plasmodium falciparum to sub-lethal doses of antimalarial drugs