MECHANISM OF ANT MALARIAL DRUG

SUMMARY

            Antimalarial drugs are used for treatment and prevention of malaria infection, most antimalarial drugs target and erothrocytic stage of malaria infection which is the base of infection that causes symptomatic illness. The extent of pre-erythrocytic (hepatic stage) activity for most antimalarial drugs is not well characterized, treatment of acute blood stage infection is necessary for malaria caused by all malaria species, In addition for infection due to plasmodium are ovale or plasmodium vivax terminal prophylaxis is required with a drug active against hypozoites (which can remain dormant in the liver for months and occasionally years after the initial infection) The indication availability are relatively cost for the drugs, the mechanism of action, resistance and toxicities of antimalarial drugs and  these agents for prevention and treatment of malaria is discussed in detail, Quinoline Drivative  include chloroquine, Amodiaquine, primaguine and others these drugs have the active against the erythrocytic stage of infection, primaquine also kill in trahaptic forms and genatoycyte the drug act by accumulating in the parasite food vacuole and forming a complex with heme that prevents crystallization in the plasmodium food vacuole, Heme polymerase activity is inhibited resulting in accumulation of cytotoxic free Heme, 4 amminoquinoline chloroquine-chloroquine was the first drugs produce on a large scale for treatment and prevention of malaria infection chloroquine has activity against the blood stages of plasmodium ovale, plasmodium, malariae and susceptible stains of p vivax and p faliciparium  wide spread resistance in most malaria endemic countries has lead to declare in its use for the treatment of p. falciparum although it remains effective for treatment of p ovale, p malariae and in most regions.

INTRODUCTION

Antimalarial drugs treat or prevent malaria, malaria is parasitic infections due to the protozoa, plasmodium which is are responsible for malarial a severe disease that cause abut 225 million cases and 781,000 human death in 2009, despite the efforts developed during the last decade to fight the disease (Alonso et al. 2011). The internation
al funding allocated to anitmalarial strategies has increased regularly since 2003 for about 0.3 billions of 1.7 billion dollars in 2009 (Collier 2009) allowing many countries to undertakes or strengthen effective fights against the parasite the disease and the vector Nonetheless more than half of the world population still lives in area where there is risk of malaria transmission this drugs kill plasmodium or prevent it growth.

Chart 1

LIFE CYCLE OF MOSQUITO

        Diagram of mosquito life cycle the mosquito goes through four separated and distinct stages of it life they are the egg, larva, pupa and adult or image. Each of these stages can be easily recognized by their special appearance. There are four different mosquitoes living in the Bay Area, they are Aedes Anopheles, culex and culiseta egg-Eggs are laid one at a time and the float on the surface of the water. In the case of culex and culista species their eggs are struck together in rafts, of a hundred or more eggs while Anopheles and Aedes species lay their eggs separated. Some lay their eggs in the water while others on damp soil a flooded water, most egg hatch in larvae within 48 hours

Larva   the larva live in the water and come to the surface to breathe though spiracles located on the eight abdominal segment they shed their skin four time growing large after each molting the larva feed on micro-organism and organic matter in the water in the water on the fourth molt the larva changes into a pupa pupa the pupa stages is a resting non-feeding stage, this is the time the mosquito turns into adult it takes about two days before the adult is fully developed when  develop is completely the pupa skin splits and the mosquito emerges as adult Adult-the newly emerged adult rest on the surface of the water for a short time to allow it self to dry and all its part to harden. Also the wings have to spread out and dry properly before it can fly.

CHART 2

FAMILY OF PARASITE THAT CAUSES MALARIA

The difficulty in fighting malaria is that five species of plasmodium namely plasmodium-ovale, plasmodium malariae plasmodium vivax p. faciparum and p. knowsi (until recently considered as a non human)  primate parasite transmitted by over 30 species of Anopheles female mosquito are known to cause human malaria the most virulent plasmodium is responsible for severe clinical malaria and death further more, an increasing prevalence of resistance of vectors  to insecticides are of parasites to a standard antimalarial drugs has been observed for decades.

CHART THREE

ROUTES BY WHICH THESE PARASITE ENTER HUMAN BODY

        After the bite by an infected Anopheles the parasite at the sporozoite stage enter the blood and are carried to the liver where the transverse and invade hapatocytes initiating which is called  hepatic or exoerythrocytic phase, During this asymptomatic periods that last 5-7 days for plasmodium falciparum the sporoziites developed within the hapatocytes and after several rounds of mitosis produce several thoughts of new infective forms called the merozoites that the released into the bloodstream and invade the red blood cello. During this intra erythrocytic cycle which last 48 hour to plasmodium falciparum and causes the malaria.

 why is it than immunity cannot supers it

The immune system that enhance immunity to this infection is by the change in human red blood cell that hinder the malaria parasites ability to invade and replication within this cells host resistance to malaria therefore it involves not only blood cell but also genes such as abnormal hemoglobin, glucose -6- phosphate dylydrogence deficiency and duffty antigen which provide innate resistance but also gene involves immunity such as the major his to capability complex response

CHART FOUR

THE MECHANISM OF RESISTANCE TO ANTIMALARIAL DRUGS IN PLASMODIUM FALA PARUM.

Plasmodium drugs resistance to malaria originates from chromosomal mutation analyses using molecular genetic and bio chemical approaches showed that: (1) Impaired uptake of chloroquine by the parasite vacuole is a common characteristics of resistant strains that phenotype correlates with pfmdrl and pfcrt gene mutedmon (2) one S108N to four (N 511, CS9R, 1164L) point mutation of dihydrofolate reductase,  The enzyme target of antifolinics (pyrimethamine and proguanil gives moderate to high level of resistance to these drugs. Plasmodium falciparum resistance level may differ according to place and time depending malaria transmission and drug pressure coupling in vitro test and using molecular test is essential for the surveillance of replacement drugs, loco cost biochemistry tools are urgently needed for a prospective monitoring of resistance.

CHART FIVE

ANTI MALARIA MEDICATION

Some anti malaria agents are

a.     Quinoline Derivative are aminoquinoline chloroquine  amodiaquinine 4 methanol quinoline, qulnine nad quinodine mefloquine, B Aminoquinonline, pimaquine, limefantrine and humefantrine.

b.     Anitifolates Derivation are sulfadoxine, pyimethamine, Atrovaquine, proquanil, antovaqune, proqunail.

c.      Antimicrobial derivative  are arterisinine Derivative artemisin in base combination therapies investigational drugs are tefenoquine pryranaridine.

Chloroquine

Chloroquine is a synthetic 4 aminoquinoline derivative available as chloroquine was the first drugs produce on a large scale of treatment and prevent of malaria infection chloroquine has activity against the blood stages of plasmodium ovale, p, malariae and susceptible strains of p vivax and p faciparium it is use for their treatment.

 

Pharmacokinetic

Chloroquine can be given orally by 1.m injection or by slow I.V infusion, it is almost completely absorbed for GIT. The drugs is distributed widely is extensively bound to the liver and other body tissues including cornea and R.B.CS it under goes metabolism in the liver. It is mainly excreted in urine (70% the liver as unchanged 30% as metabolites) Initial half life is 3-4 days but as it is slowly released from the tissues the terminal half life may be extended to 1-2 month.

Mechanism of action

        Chloroquine centers the red blood cells accumulates in the food vacuoles of the parasite this accumulation may involve on tapping following protonation specific transport and or binding to a receptor (e.g. home) the major action of chloroquine is to inhibit the formation of hemozion (H₂) from the heme released by the digestion of hemozion (Hb) the free heme then lyses membranes and leads to parasite death. Chloroquine resistance is due to an erythrocyte.

 

Mechanism of action

Decreased accumulation of chloroquine in the food vacuole two different transporters (CRT and MDRI) chloroquine resistance transporter and muti drug resistance, have been implicated. In resistance the functions of these transporters and their exact roles in chloroquine resistance are not known.

Adverse effect or toxicity

1.     Chloroquine is usually well tolerated in the dose used for chemoprophylaxis.

2.     With does used to treat the clinical attack of malaria nausea vomiting dizziness headache urticaria and blurred vision may occur occasionally 3. Larger does sometime may precipitate retinopathies

Interaction

1.     Its use should avoid in patients with retinal and visual field abnormalities.

2.     Ca ²⁺ and mg ²⁺ containing antacids decrease its absorption.

3.     Chloroquine is considered safe in pregnancy and in younger children above 2yers of age.

Anitmalarial drug resistance

The emergence of drug resistance severely limits the arsenal of available drugs against protozoa pathogen parasite has evolved numerous way of over come the toxicity of drugs. Mechanism of 1. Resistance mutation in target gene, 2. Increase production of target decreasing drugs accumulation (including increase in afflux drug in activation)

        Quite of drug resistant involves mutation in the drugs target so that the drug does not bind or inhibit the target as well,

        Drug resistance can developed quickly in situation where a single point mutation can confer. Resistance another mechanism of drug resistance involves expressing higher level of the target this can be accomplished either through increase transcription and translation or gene amplification, this level of drug to non toxic product will result in less drug reaching the target and can also involve the accumulation of mutation in the same or different target which will have the additive or synergistic effect parasite with mutation or genetic polymorphisms with confer a decrease in drugs sensitivity will be selected under drugs pressure. 

REFERENCES

Glaxosmithkline major me prescribing Information (2008)

Gasasira A.F; Kamya M.R. J Achan. J et al; High risk of neutropenia In HIV Infection following treatment with artesunate plus amodiagquine for uncomliclated malaria, In Uganda Clin Infect Dis (2008) PP, 46-985.

Deen JL; Von Seldein. L; Dondor P.A. (2008) therapy of uncomplicated malaria In Children. A review of treatment Principles essential drugs and current recommendation Trop med Int Health.