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Malaria 2003
 

Malaria 2003

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Malaria 2003 Malaria 2003 Presentation Transcript

  •  
  • Malaria
    • Types
    • Lifecycle
    • Drugs-classification
    • Individual drugs
    • Dosage regimen
    • Chemo-prophylaxis
    • Newer anti-malarials
    • Vaccine
    • Devastating parasitic infection
    • Attacks-500 million
    • Mortality –2 million[1million children].
    • Except N.America, Europe, Russia
  • 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
    • Types
    • P.vivax - Benign tertian
    • P.Falciparum - Malignant tertian
    • P.ovale -Benign tertian
    • P.Malariae -Benign Quartan
  • Transmission
    • “ Bite of Infected Female Anopheles Mosquito”
    • Blood transfusion
    • Congenital
    • Sharing needles
  • Life Cycle
  • 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 +
  • Erythrocytic Phase
    • Most of the drugs act in this stage
    • Leads to clinical cure
    • Most of the drugs do not prevent transmission
    • Chemoprophylaxis
  • 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
  • Classification of Drugs
    • Cinchona alkaloids: Quinine & Quinidine
    • Quinolines:
    • 1. 4-Aminoquinolines- Chloroquine
    • Hydroxychloroquine
    • Amodiaquine
    • Piperaquine
    • 2. 8-Aminoquinolines- Primaquine
    • Tafloquine
    • Bulaquine
  • Classification……
    • Quinolines..
    • 3. Quinoline methane- Mefloquine
    • Halofentrine
    • Lumefantrene
    • Antifolates:
    • 1. Biguanides- Proguanil
    • 2. Diaminopyrimidine- Pyremethamine
    • 3. Sulfonamides- Sulfadoxine
    • Dapsone
  • Classification……
    • Artemisinin compounds : Artesunate
    • Artemether
    • Arteether
    • AMA: Doxycycline, Clindamycin,
    • Others Atovaquone , Pyoronaridine
  • 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 - + + - +
  • 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
  • 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
  • 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.
  • 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.?????
  • Life Cycle And Drugs NONE Pyrimethamine Proguanil Primaquine Most of the drugs Except Primaquine Chloroquine Quinine [not F.P.]
  • 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
  • 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
  • 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
  • Quinine contd…
    • Chloroquine,
    • Amodiaquine,
    • Mefloquine, Lumefantrine
    • Halofantrine & Pyronaridine
    • Have similar MOA
  • Quinine contd…
    • Skeletal muscles: Decreases contractile force & excitability
    • Antagonize physostigmine.
    • Myesthenia gravis?
    • Myotonia congenita?
    • Local-Inflammatory and anesthetic
    • Uterus-Stimulant
  • 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.!
  • Therapeutic uses:
    • Severe and resistant malaria
    • Nocturnal leg cramps
    • Spermicidal-Vaginal creams
    • Sclerosing agent-V.V.
    • Quinidine used as anti-arrhythmic
  • 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
  • Quinine ….Caution
    • Hypersensitivity
    • Hemolysis- discontinued
    • Cardiac arrhythmia, tinitus, optic neuritis
    • Irritant
    • Fairly safe in pregnancy
  • Quinine (DI)
    • Antacids
    • Reduces absorption of digoxin
    • Elevates plasma conc.of Warfarin
    • Enhances effect of NM blockers
    • Acidification of urine ↑ clearance
  • 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
  • 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
    • 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
  • 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
  • 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
  • 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
  • Chloroquine contd…
    • Preperations:
    • Tab, Syp, Injection
    • Oral- Chl.Po 4 ( 250mg salt=150 mg base)
    • Dose
    • Curative:
    • Prophylactic
  • 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]
  • 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
  • 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
  • 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
  • Primaquine contd…
    • Radical cure of P.V. & P.O.
    • Terminal prophylaxis (just before or soon after leaves endemic area)
    • P.jiroveci with clindamycin
  • 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.
  • 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
  • Proguanil(Chloroguanide)
    • Proguanil Cycloguanil (Triazine)
    • Anti-malarial:
    • PF- Primary tissue stage & Erythrocytic forms
    • P.V.- Only erythrocytic stage
  • 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
  • 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]
  • Atovaquone
    • Uses:
    • Treatment and prophylaxis of resistant PF malaria,
    • T.gondii,
    • P.carinii
    • Babesia
    • Proguanil : Atovaquone – 100:250mg
  • 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
  • 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
  • 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.
  • Artemisinin Derivatives…..
    • MOA:
    • I Step
    • Heme iron in parasite
    • Cleaves endoperoxide bridge,
    • II Step
    • Carbon centerd radical is produced
    • Toxic to parasites
  • 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
  • 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.
  • Quinine Vs Artimisinin
    • Quinine DOC in severe/complicated malaria
    • Artimisinin---
    • Faster parasitic clearance
    • Safe, better tolerated
    • Simple dosing schedule
    • High efficacy, low mortality
  • 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.
  • 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
  • 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
    • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • Treatment-Chloroquine Resistant: P.V .[Rare]
    • Quinine 600mg 8 th hrly X 7 days
    • +
    • Doxy 100mg daily X 7 days
    • +
    • Primaquine
  • 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]
  • 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
  • Severe malaria
    • Cerebral malaria :
    • Severe anemia
    • Renal failure
    • Pulmonary edema
    • Shock
    • Metabolic acidosis
    • Hemoglobinuria, jaundice
    • Hyperpyrexia
    • Hyperparasitemia
  • Severe
    • The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
  • 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
  • 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
  • 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
  • Malaria Vaccine
    • Reduce severity and complications of malaria
    • Tried in children less than 5yrs, in Africa
    • Reduces mortality and morbidity
  • 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
  • Other drugs
    • Halofentrene
    • } Drug resistant
    • Lumefentrene
    • Bulaquine……Primaquine
    • Amodiaquine…..Chloroquine
    • Dapsone….With pyremethamine
    • Fosmidomycin-apicoplast inhibitor
  • 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