ANTI MALARIA

Department of Pharmacology

LEARNING OBJECTIVES

Student should be able to

Explain

MALARIA

Malaria is caused by protozoan parasites of the genus Plasmodium, of which 4 species infect man:

P. falciparum P. vivax P. malariae P. ovale

The parasites are transmitted by female mosquitoes of the genus Anopheles while taking a blood meal.

MALARIA CONTROL STRATEGI

Current WHO Global Malaria Control Strategy emphasises:

early diagnosis treatment with effective antimalarials selective use of preventative measures including vector control where it can be sustained.

MALARIA CONTROL STRATEGI-cont

Potential targets for antimalarial therapy must:

constitute essential features of the parasite lifecycle processes in the host to make selectivity between host and parasite possible.

QUININE

Cinchona (Jesuits bark) first brought to Spain in 1639 Quinine, the main alkaloid in the bark of the Cinchona tree was isolated in 1820 Quinidine is also present, but is not used because of its actions on the heart Active against erythrocytic stages of the parasites Its mode of action is not clearly defined but may involve:

Binding to DNA, stopping synthesis of nucleic acids Inhibition of haem digestion

Synthetic Antimalaria

One of the first synthetic antimalarials was PAMAQUINE developed during World War (WW)-1 Pamaquine was active against avian malaria (the model) but not P. falciparum (the major human form) In addition, it was toxic in humans. However, it was found effective against the vivax relapses.

Synthetic Antimalaria

Chloroquine Amodiaquine Mefloquine Pyronaridine Proguanil Sulphonamides/Sulphone Artemisinin Derivatives

Primaquine

Active against liver stages of P. vivax Mechanism of action may involve oxidative stress in the parasite Effective against other stages of the life cycle, but it is too toxic Causes haemolysis and methaemoglobinamia

CHLOROQUINE

Synthesized during WW-II Based on the quinine structure Accumulates in the food vacuole of the parasite Interferes with haem digestion Effective against blood stages Relatively safe Resistance is a problem

Amodiaquine

Developed at the same time as chloroquine Effective against blood stages, even in some chloroquineresistant strains of P. falciparum Has an unacceptable risk of toxicity towards granulocytes and the liver

Mefloquine

Recommended for most risk areas. Minor side effects (nausea, dizziness, difficulty sleeping) do not last long and do not require stopping the drug. Not recommended for use if:

a known allergy to mefloquine a history of epilepsy, severe psychiatric disorders or cardiac conduction abnormalities.

Pyronaridine

Pyronaridine: potential replacement for chloroquine Too expensive Requires new routes for synthesis

Proguanil

It is a prodrug that requires metabolic activation to cycloguanil Effective against erythrocytic and liver stages of P. falciparum Inhibits dihydrofolate reductase and hence DNA synthesis Used as a prophylactic, but is too slow for a cure

Sulphonamides/Sulphone

Sulphones (e.g. Dapsone) and Sulphonamides (e.g. Sulphadoxine) inhibit dihydropteroate synthase

involved in folate, and hence pyrimidine and DNA synthesis

They act too slowly on their own, but act synergistically with proguanil and pyrimethamine because they act at different parts of the same pathway

Always used in combination therapy (Fansidar*)

Artemisinin Derivatives
Artemisinin derivatives are:
Highly effective Rapid have limited toxicity

However, inappropriate use may lead to the development of resistance and untoward toxicity.

THE USE OF MALARIA DRUG

Consider to life-cycle of parasites (Plasmodium) To have selective toxicity between host and parasite Good sensitivity in the various stages

THE FREQUENT DRUG USED

Quinine

Generic quinine ethyl carbonate tablet 100 mg Chloroquine phosphate tablet 250 mg Sulfadoxin 500 mg-pyrimethamine 25 mg

Chloroquine

Sulphonamides/Sulphone

HOW TO USE DRUGS.. QUININE TAB 100 mg

Prevention

1-2 tab ante noctum once/week (as long as out break situation)
3 x 1-2 tab daily 1-2 weeks

Therapy

HOW TO USE DRUGS.. CHLOROQUINE TAB 250 mg

Adult

Prevention

2 tab/week Semi imun (in endemic area) 2 tab /1-2 weeks Semi imun : single dosage 4 tab Non imun : 4 tab2 tab (after 6-8 hours) 2 tab daily for 2 days

Therapy

Child

Prevention

5 mg/kgbb/week ( 1 week before until 4 week after exposure

Therapy

10 mg/kgbb 5 mg/kgbb (after 6 hours) 5 mg/kgbb daily for 2 days

Drug example

Avloclor*, Malarex*, Mexaquin*, Riboquin*

HOW TO USE DRUGS.. Sulfadoxyn 500-Pyrimethamine 25

Adult

Prevention (1-2 DAYS before until 4 week after exposure)

Semi imun (in endemic area) 2-3 tab /4 weeks NON Imun 2 tab /2 weeks
single dosage 2-3 tab

Therapy

Child

Prevention

Semi imune 9-14 th (2 tab), 4-8 th (1 tab), <4 th (1/2 tab) Non Imune 9-14 th (1 tab), 4-8 th (1 tab), <4 th (1/2 tab) 1-2 DAYS before until 4 week after exposure

Therapy

10-14 th (2 tab), 7-9 th (1 tab), 4-6 th (1 tab), <4 th (1/2 tab)

Drug example

Fansidarr*, Plasmodin*, Suldox*

See USalam