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

-

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