Download - Pharmacotherapy of malaria
Pharmacotherapy of Malaria
Dr Ritu Budania JR 1, Department of Pharmacology, GMC Nagpur
Malaria Protozoal disease Plasmodium infected female anopheles mosquito
Tropical ,subtropical countries
WHO estimates 300-500 million cases year > 1 million death
India- NVBDCP- 1.5 million confirmed cases
Pathogenesis
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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
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Classification- Stage of Parasite affectedStage Drugs
Blood schizonticidal drugs Erythrocytic phaseTerminates clinical illness
Chloroquine, Artemissin, Quinine, Atovaquone,
Tissue schizonticidal drugs Tissue form of plasmodium Primaquine, Pyrimethamine Proguanil Tetracycline
Gametocidal drugs Destroy sexual forms of parasitePrevent transmission to mosquiotes
PrimaquineQuinine
Hypnozoiticidal Destroy persistent liver stages of P vivax , P ovale
Primaquine
Target of Existing therapiesTargetlocation
Pathway/ mechanism
Target molecule
Existing therapies
Cytosol Folate metabolism
DHF reductase
DHP synthetase
Pyrimethamine Proguanil
SulfadoxineFood vacuole Heme
polymerization
Free radical generation
Hemozoin
Unknown
Aminoquinolines
Artemisinin
Mitochondrion Electron transport Cyt. c oxidoreductase
Atovaquone
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Anti- Malarial Drugs
Chloroquine Sulfa/Pyri Quinine Mefloquine Artemissin
Efficacy +++ ++ +++ +++ ++++
Onset of action
rapid slow rapid rapid fastest
Use Chemophrophylaxis
-Treatment of Chloroquine
sensitive malaria
Uncomplicat-ed resistantP. falciparum
Only for resistantP. falciparum
severe malaria cerebral malaria
Only for uncomplicated, resistantP. falciparum
-resistantP. falciparum.
- life threatening complications of P. falciparum due to
its rapid action
- severe malaria
Chloroquine Sulfa -pyr Quinine Mefloquine Artemissin
ADR GI ADRIV-Hypotension,arrythmiasRetinal damage
Steven Johnson Megaloblastic anemia
-Cinchonism-Hypoglycemia-Hypotension-Arrhythmias
Neuropsychiatric symptoms-Sinus bradycardia
SafeA-V blockReticulopeniaTransient leucopenia
Contraindication
-Psoriasis,porphyrias
-Allergy to sulfa drugs
-Prior hypersensitivity
-Epilepsy-Psychosis-Heart block
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Special points
Not given parenterally in children
-5 % glucose solution-Infusion -Not rapid iv
-Not given parenterally
Not given with-Halofantrine,Beta blockers
Do not kill hypnozoites
Cost cheap cheap moderate expensive expensive
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
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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.
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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.
Guidelines for treatment of Malaria -2011
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
Treatment of P. vivax Malaria• Chloroquine 25 mg/kg for 3 days • Primaquine 0.25 mg/kg for 14 days
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
Treatment of malaria in pregnancy P. falciparum:• 1st Trimester: Quinine• 2nd & 3rd Trimester: ACT
P vivax: Chloroquine Note: Primaquine is contraindicated in pregnant woman
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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
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.
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
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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
• Patients receiving parenteral Quinine should receive-
oral 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
Chemoprophylaxis• Non immune travellers• Army units• Migrant workers
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.
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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.
Leading transmission blocking antigens(Sexual Stage)
Antigen Strengths Weakness
Pfs25/Pvs25Pfs28/Pvs28
- Both antigenscloned and expressed - induces completetransmission-blocking in model systems
Not expressed in the vertebrate host,not subject to natural boosting followingvaccination
Pfs48/45 -Monoclonal antibodies completely block transmission-Expressed on the gametocyte so boosting of antibody response a possibility.
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Pfs230 -Monoclonal antibodiescompletely 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.
New Malarial Vaccines Status
Parasite stage
Vaccine Stage of Development
PreErythrocytic 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-multiepitopestring + TRAP
Phase Ib
LSA-3 (long peptides; lipopeptide; recombinant)
Phase Ia
New Malarial Vaccines Status
Parasite stage
Vaccine Stage of Development
Blood Stage PfCP 2.9: MSP-1-AMA-1 fusionprotein (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
Drugs reversing Chloroquine Resistance >> > Experimental
• Ca-Channel Blockers: Verapamil
• Vitamin E : Deficiency may afford protecton
• Penfluridol : Reverses Mefloquine resistance
Summary• Antigen variability- vaccine development• Resistance in plasmodium• Insecticide resistance• Judicious use of Anti malarials• Early diagnosis and treatment
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