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Resistant Malaria

Resistant Malaria. Dept of Medicine,JSS Medical College. Dr. K.A.Sudarshana Murthy & Dr.Ravishankar S.B. Introduction. Resistance was first noted in the early 1960’s in SE Asia & S.America within years of introduction of Chloroquine

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Resistant Malaria

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  1. Resistant Malaria Dept of Medicine,JSS Medical College Dr. K.A.Sudarshana Murthy & Dr.Ravishankar S.B

  2. Introduction • Resistance was first noted in the early 1960’s in SE Asia & S.America within years of introduction of Chloroquine • In India, Chloroquine resistance first reported from Assam - 1973 • Quinine Resistance - Brazil ( 1910) • Proguanil -- Malaya ( 1949 )

  3. Introduction • Pyrimethamine -- Venezuela ( 1962 ) • Mepacrine -- Thailand ( 1980 ) • Sulphadoxine - Pyrimethamine -- SE Asia,Thailand, S.America & S.Africa ( 1980 ) • Mefloquine -- Thai, Cambodia, Myanmar Failure ( 1988 )

  4. What Is Drug Resistance? • The ability of a parasite strain to survive and/or multiply despite administration & absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance of the subject ( WHO 1986)

  5. What Is Drug Resistance? • In clinical Practice its usage indicates resistance of PF against blood schizonticides • Conventionally  4- aminoquinolones • Multidrug Resistance

  6. Mechanism Of Resistance Aminoquinolones, Biguanides & Sulfonamides A. Multiple unlinked mutations encoding for MDR- pump which produces i) active efflux of the drug or ii) increased synthesis of a different haem-polymerase enzyme in the parasite, protecting the parasite from toxic Hb degradation

  7. Mechanism Of Resistance Aminoquinolones, Biguanides & Sulfonamides B. Role of chloroquine resistant gene (within 200 KB segment of chromosome 7 of PF)1. point mutation in DHER gene which reduces the affinity of the enzyme complex of the drug. 2. Use of alternative enzymatic pathway by the parasite 3. PV is intrinsically insensitive 4. Failure to convert Proquanil to active metabolite : Genetic Polymorphism

  8. Antibacterials 1. Active Efflux 2. Ribosomal Alteration Tetracyclines Clindamycins Alteration in the membrane transport of the drug into the parasite Artemesinin Derivatives Mechanism Of Resistance

  9. Chloroquine & Mefloquine resistance is not linked .Evidence shows increseing mefloquine resistance increases Chloroquine sensitivity.

  10. Grading of Resistance Sensitive (S) Clearance of parasitaemia within 7 days without recrudescence Low Grade Resistance (R1) Clearance of parasitaemia followed by recrudescence( 28 Days after the last dose)

  11. Grading of Resistance High Grade ( RII) Greater than 75% but less than 100% of parasites cleared within 7 days High Grade ( RIII) Parasite count does not fall by more than 75%

  12. Quinine  Still remains the Best therapy in all Complicated Malaria  Reports of Quinine resistance are quite rare  Alleged failures  Inadequate Dosage Short Course  Partial decreae in Sensitivity in some localities in Siberia -- Bjorkman et al., 1991.

  13. Quinine Dosage Loading dose 20mg/Kg BW in 500 ml of DNS over 4hrs Maintenance dose 10mg/Kg BW 8th hrly intervals Till patient can take orally ** Dose should be reduced to half or 1/3 after 48 hours ( Cumulative effect) Side Effects Cinchonism, hypoglycemia, Psychosis, Arrythmia, Haemolysis

  14. Quinidine  Superior to Quinine in antimalarial acitivity  Main Drawbacks > Increased Cost Lethal Side-effects Cardiac Arrthymias Hypersensitivity  Should be used only if parenteral Quinine is not available  Loading Dose 15mg/kg BW over 4hrs 7.5 mg/kg BW over 4 hrs repeat every 8hrs

  15. Amodiaquine  Used in Chloroquine failure as primary drug.  More effective in clearing parasitaemia  Pruritis , Toxic Hepatitis , Fatal Agranulocytosis prevents its widespread use.

  16. Mefloquine  First synthetic quinolinemethanol compound  Sensitivity is independent of resistance to 4-aminoquinolones & DHF reductase inhibitors  Blood Schizonticidal with high affinity for erythrocyte membranes - Binds to phospholipids  Single dose advantage - 15mg/kg BW ( Max 1g) Additional 10mg/kg after 8hrs in areas of chloroquine resistance

  17. Mefloquine  Not recommened for children < 5 Kg BW & 3 M pregnancy, epilepsy, psychosis, hypersensitivity Avoid : Patients on beta-blockers Toxic Effects Dizziness, Nausea , Vomiting, Arrythmias Acute Brain Syndrome Fatigue, Asthenia, Seizure , psychosis

  18. Halofantrine  Phenantherne - methanol  Effective aganst MDR- Strains  Schizonticidal against all 4 species  Acts primarily by concentrating & combining with ferriprotoporphyrin-IX in the parasite to form toxic complex that damage bio-membranes  Absorption is unpredictable ( Water insoluble)  Can not be used parentarally

  19. Halofantrine Dosage > 250mg tablets > 2 tablets 6th hrly for 3 doses, not to exceed 1500mg Side Effects> QT prolongation Conduction delay & Arrythymias @ NOT RECOMMENED IN PREGNANCY @ CROSS RESISTANCE WITH MEFLOQUINE

  20. Quinhaosu Also called sweet wormwood. Traditional Chinese Medicine > 2000 yrs Artemesinin Dihydro-artemesinin Artemether Artesunate Arteether

  21. Quinhaosu # Superior to other antimalarial drugs in Complicated & Uncomplicated Malaria # Good oral absorption # Should be used in uncomplicated PF Malaria only if resistance to Mefloquine and/or Quinine ( WHO) # No action on liver stages # Rapid action

  22. Quinhaosu Side Effects Reduction in reticulocyte count Fever, Neurotoxicity in animals “ NOT SAFE IN FIRST TRIMISTER OF PREGNANCY ”

  23. Quinhaosu Artesunate Oral /Parentaral Monotherapy Oral : 10mg/kg over a period of 3- 5 days Parenteral : 2.4mg/kg IV/IM Stat 1.2 mg/kg at 12 & 24 hrs and then daily

  24. Quinhaosu Artesunate : > Sequential therapy with Mefloquine > More efective & low incidence of side effects > Useful in endemic & MDR areas Artemether : Oral > Same as Artesunate paranteral > 3.2 mg/kg IM stat 1.6mg/kg/day for 4 days

  25. Tetracycline & Clindamycin • Used in combination with Quinine • Enhances the efficiency in drug resistant Malaria • Avoided in pregnancy & children • Dosage : • Tetracycline : 1-2 G /day for 3- 7 days • Clindamycin: 20mg/ kg / day for 3 - 7 days

  26. precautions  Quinine should not be used for 7 days if the patient was given Mefloquine  Mefloquine should not be administered for 12 hours after the last dose of Quinine  One should watch for Hypoglycemia during Quinine & Chloroquine therapy

  27. Newer Drugs • WR - 33O63  80% cure rate in MDR Strain • WR - 30090  90% cure rate ( Volunteers) • Cysteine & Aspartate protein inhibitors • Pyronaridine  Similar to Amodiaquine • Azithromycin • Atovoquone  Prompt clinical response but recrudescence; combined with proquanil

  28. Miscellaneous Drugs • Benflumentol • Hydroxypiperaquine • Trioxanes, Tetraxanes, Peroxides. • Hydoxynaphthoquinones • Lead Compounds • Antifungals : Ketacanozole, Ampho-B, Micanozole • Desfuroxamine : Combined with quinine > resolves complications faster.

  29. Drugs reversing Chloroquine Resistance >> > Experimental • Ca-Channel Blockers: Verapamil • Phenothiazines : Desipramine • Taxol : Anticancer drug (Both Chlor & Pyr) • Vitamin E : Deficiency may afford protecton • Penfluridol : Reverses Mefloquine resistance • Erythocyte specific Ab encapsulated in liposomes: to circumvent Chlor-resistance

  30. Concept of Combination Therapy • More Promising than monotherapy • Moe efficacious & retards the resistant strains * Quinine & Tetracyclines/ Clindamycin : More effective than Quinine monotherapy * Sequential Mefloquine & Artemether : Higher overall cure rate * Artesunate & Tetracyclines: 80% cure rates * Pyronaridine + SDX - Pyr or Primaquine Inhibits development of drug resistance.

  31. What the Future May Hold?? • Drug resistance will remain to be a problem world over • Need for flawless Antimalarial agent • Consensus to device effective strategies to combat • the problem • Indiscriminate and irresponsible use of antimalarials • should be stopped • Constant need to upgrade the treatment of Malaria • Newer antimalarials should be under International • & government control

  32. Vaccines Types : 1. Sporozoite Vaccine : Prevent infection and development of liver stages 2. Asexual Stage : Decrease morbidity & mortality 3. Sexual Stage : Expected to block trasmission

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