Pharmacotherapy of malaria


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Malaria treatment

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Pharmacotherapy of malaria

  1. 1. Pharmacotherapy of Malaria Dr Ritu Budania JR 1, Department of Pharmacology, GMC Nagpur
  2. 2. Malaria  Protozoal disease Plasmodium infected female anopheles mosquito
  3. 3. Tropical ,subtropical countries
  4. 4. WHO estimates  300-500 million cases year  > 1 million death India- NVBDCP- 1.5 million confirmed cases
  5. 5. Pathogenesis 5
  6. 6. Classification of Anti Malarial Agents: 1 – Chemical Structure  4-Aminoquinolines : Chloroquine, Amodiaquine  8-Aminoquinoline: Primaquine, Bulaquine  Cinchona alkaloid : Quinine  Sesquiterpine lactones: Artesunate, Arteether, Artemether  Biguanides: Proguanil  Diaminopyrimidine : Pyremethamine  Quinoline methanol : Mefloquine  Sulfonamides : Sulfadoxine Sulfamethopyrazine  Phenanthrene methanol : Halofantrine  Tetracycline: Doxycycline,  Acridine : Mepacrine  Naphthoquinone Atovaquone 6
  7. 7. Classification- Stage of Parasite affected Stage Drugs Blood schizonticidal drugs Erythrocytic phase Terminates clinical illness Chloroquine, Artemissin, Quinine, Atovaquone, Tissue schizonticidal drugs Tissue form of plasmodium Primaquine, Pyrimethamine Proguanil Tetracycline Gametocidal drugs Destroy sexual forms of parasite Prevent transmission to mosquiotes Primaquine Quinine Hypnozoiticidal Destroy persistent liver stages of P vivax , P ovale Primaquine
  8. 8. Target of Existing therapies Target location Pathway/ mechanism Target molecule Existing therapies Cytosol Folate metabolism DHF reductase Pyrimethamine Proguanil DHP synthetase Sulfadoxine Heme polymerization Hemozoin Aminoquinolines Free radical generation Unknown Artemisinin Electron transport Cyt. c oxidoreductase Atovaquone Food vacuole Mitochondrion 9
  9. 9. Anti- Malarial Drugs
  10. 10. Chloroquine Sulfa/Pyri Quinine Mefloquine Artemissin Efficacy +++ ++ +++ +++ ++++ Onset of action rapid slow rapid rapid fastest Use Chemophrophyla Uncomplicat- Only for xis ed resistant -Treatment of resistant P. Chloroquine P. falciparum falciparum sensitive malaria severe malaria Only for uncomplica ted, resistant P. falciparum -resistant P. falciparum. - life threatening complications of P. falciparum due to its rapid action - severe malaria cerebral malaria
  11. 11. Chloroquine ADR Sulfa -pyr Quinine Mefloquine Artemissin GI ADR IVHypotension ,arrythmias Retinal damage Steven Johnson Megaloblast ic anemia -Cinchonism -Hypoglycemia -Hypotension -Arrhythmias Neuropsychiatric symptoms -Sinus bradycardia Safe A-V block Reticulopenia Transient leucopenia -Allergy to sulfa drugs -Prior hypersensitivit y -Epilepsy -Psychosis -Heart block - -5 % glucose solution -Infusion -Not rapid iv -Not given parenterally Do not kill hypnozoites moderate expensive Contraindic -Psoriasis, ation porphyrias Special points Cost Not given parenterally in children cheap cheap Not given withHalofantrine, Beta blockers expensive
  12. 12. Primaquine • Radical cure • prevents relapse in P vivax and P ovale malaria • Hemolytic anemias- G-6PD status should be evaluated • Not given parenterally- causes hypotension • Contraindicated in Pregnancy and infants 13
  13. 13. Antimalarial Combination Therapy  Simultaneous use of two or more blood schizontocidal drugs with independent modes of action  more effective than monotherapy  Higher cure rates  reduce the development of resistance  decrease transmission of drug-resistant parasites. 14
  14. 14. Combination therapies recommended by WHO • Artemether – Lumefanterine • Artesunate- Amodiaquine • Artesunate – Mefloquine • Artesunate- SP • Quinine - Tetracyclines/ Clindamycin Oral Artemissin monotherapy is banned in India -never orally as monotherapy for uncomplicated malaria .
  15. 15. Guidelines for treatment of Malaria -2011
  16. 16. Early diagnosis and treatment of cases of malaria aims at: • Complete cure • Prevention of progression of uncomplicated malaria to severe disease • Prevention of deaths • Interruption of transmission • Minimizing risk of selection and spread of drug resistant parasites
  17. 17. Treatment of P. vivax Malaria • Chloroquine 25 mg/kg for 3 days • Primaquine 0.25 mg/kg for 14 days
  18. 18. Treatment of P. falciparum cases • Artemisinin based Combination Therapy (ACT) Artesunate 4 mg/kg for 3 days Sulfadoxine (25 mg/kg body weight)Pyrimethamine (1.25 mg/kg body weight) on Day 0 • Primaquine 0.75mg/kg on Day 2
  19. 19. Treatment of malaria in pregnancy  P. falciparum: • 1st Trimester: Quinine • 2nd & 3rd Trimester: ACT  P vivax: Chloroquine Note: Primaquine is contraindicated in pregnant woman 20
  20. 20. Treatment based on clinical criteria without laboratory confirmation • Suspected cases – “clinical malaria” Chloroquine 25 mg/kg for 3 days • Once the parasitological diagnosis is available, appropriate treatment as per the species
  21. 21. General recommendations for the management of uncomplicated malaria • Avoid starting treatment on an empty stomach. • if vomiting occurs within 30 minute- repeat the dose . • Ask the patient to report back- if there is no improvement after 48 hours or if the situation deteriorates.
  22. 22. Treatment of severe malaria • Impaired consciousness/coma • Repeated generalized convulsions • Renal failure (Serum Creatinine >3 mg/dl) • Jaundice (Serum Bilirubin >3 mg/dl) • Severe anaemia (Hb <5 g/dl) • Pulmonary oedema/acute respiratory distress syndrome • Hypoglycaemia (Plasma Glucose <40 mg/dl) • Metabolic acidosis • Circulatory collapse/shock (Systolic BP <80 mm Hg, <50 mm Hg in children) • Abnormal bleeding and Disseminated intravascular coagu- lation (DIC) • Haemoglobinuria • Hyperpyrexia (Temperature >106 F or >42C) • Hyperparasitaemia 23
  23. 23.  Medical emergency  Parenteral treatment  Parenteral Artemisinin derivatives or Quinine should be used irrespective of chloroquine sensitivity. Artesunate 2.4 mg/kg i.v. or i.m. at admission 12 & 24hr , then once a day or Artemether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day; or Quinine 20 mg /kg on admission (i.v. infusion in 5 % dextrose over 4 hours) then maintenance dose 10 mg/kg every 8 hrly . Arteether 150 mg daily i.m. for 3 days in adults only (not recommended for children). Parenteral treatment should be given for minimum of 24 hours once started
  24. 24. • Patients receiving parenteral Quinine should receiveoral Quinine 10 mg/kg three times a day to complete a course of 7 days Doxycycline 3 mg/ kg per day for 7 days. • Doxycycline is contraindicated in pregnant women and children under 8 years of age • Instead, Clindamycin 10 mg/kg 12 hourly for 7 days should be used
  25. 25. Chemoprophylaxis • Non immune travellers • Army units • Migrant workers
  26. 26. Chemoprophylaxis • Short-term chemoprophylaxis (less than 6 weeks) Doxycycline: 100 mg daily in adults 1.5 mg/kg for children> 8 years old The drug should be started 2 days before travel and continued for 4 weeks after leaving the malarious area. • Long-term chemoprophylaxis (more than 6 weeks) Mefloquine: 5 mg/kg (up to 250 mg) weekly administered two weeks before, during and four weeks after leaving the area. 27
  27. 27. Malaria Vaccine Is Malaria vaccine feasible? Current clinical studies have shown that new candidate vaccines can induce complete protection against malaria infection. Complete protection against malaria can be induced by infecting volunteers with irradiated malaria parasites. People living in endemic areas who have been multiply exposed to malaria develop immunity against severe malaria disease. Antibodies purified from life-long residents of endemic areas can be transferred into other individuals and can confer some protection against the effects of malaria infection.
  28. 28. Leading transmission blocking antigens (Sexual Stage) Antigen Strengths Weakness Pfs25/Pvs25 Pfs28/Pvs28 - Both antigens cloned and expressed - induces complete transmission-blocking in model systems Not expressed in the vertebrate host, not subject to natural boosting following vaccination Pfs48/45 -Monoclonal antibodies completely block transmission -Expressed on the gametocyte so boosting of antibody response a possibility. Pfs230 -Monoclonal antibodies completely block transmission -compliment mediated antiparasite activity -Expressed on the gametocyte ------------------ A very large molecule, so unclear which part/s to make. These antigen vaccines are currently in phase I/Preclinical stage.
  29. 29. New Malarial Vaccines Status Parasite stage Vaccine Stage of Development Pre Erythrocytic Stage CSP C-ter peptide + Montanide ISA 720 Phase Ib ICC-1132: Hybrid CSP multiepitope-HBc VLPs Phase II RTS,S: Hybrid P. falciparum CSP -HBsAg particles + AS02 adjuvant Phase IIb DNA vaccines (including MuStDO-5: CSP/LSA-1/ LSA-3/EXP1/TRAP) Phase I Live recombinant FPV- or MVA-CSP + LSA-1 epitope Phase Ib Live recombinant MVA-multiepitope string + TRAP Phase Ib LSA-3 (long peptides; lipopeptide; recombinant) Phase Ia
  30. 30. New Malarial Vaccines Status Parasite stage Vaccine Stage of Development Blood Stage PfCP 2.9: MSP-1-AMA-1 fusion protein (yeast) + Montanide ISA 720 Phase I MSP-3 long peptides Phase Ib GLURP long peptide Phase I MSP-3-GLURP hybrid long peptide + Montanide ISA 720 Phase I Combination B: MSP-1, -2, RESA + Montanide Phase II SE36 Phase I MSP-4, -5 Preclinical
  31. 31. Drugs reversing Chloroquine Resistance >> > Experimental • Ca-Channel Blockers: Verapamil • Vitamin E : Deficiency may afford protecton • Penfluridol : Reverses Mefloquine resistance
  32. 32. Summary • • • • • Antigen variability- vaccine development Resistance in plasmodium Insecticide resistance Judicious use of Anti malarials Early diagnosis and treatment
  33. 33. References • Goodman & Gilman’s 12th edition • K.D.Tripathi 6th edition • KK Sharma 2nd edition • Basic & clinical Pharmacology Katzung • Guidelines for diagnosis and treatment of Malaria 2011 National Vector Borne Disease Control Programme, National Institute of Malaria Research