ANTIMALARIAL DRUGS. Malarial parasites only four species can infect human Plasmodium malariae, P. ovale, P. vivax, P. falciparum malaria caused by P.

ANTIMALARIAL DRUGS

Malarial parasites

only four species can infect human

Plasmodium malariae, P. ovale, P. vivax, P. falciparum

malaria caused by P. falciparum and P. vivax - the most common forms

P.ovale and P. vivax can cause relapse

P.falciparum causes the most serious complication and death

The parasite life cycle

parasites in the sexual form in human blood

sporozoites that develop in the mosquito

sporozoites multiply in the liver to form tissue schizonts

the parasite escape from liver into blood stream as merozoites

the parasites invade red blood cell, multiply in them to form blood schizonts

they rupture the RBC, releasing a new crop of merozoites

(meanwhile, the gametocytes are released into the circulation, where

they may be taken in by another mosquito)

This cycle may be repeated many times

They cause lysis of RBC, leading to anemia and agglutination of RBC

Lysis of RBC cause paroxysm (chill, fever, malarial rigor)

Types of antimalarial drugs

1.Primary tissue schizontocide - kills schizonts in the liver soon after infection (e.g. primaquine)

2.Blood schizontocide - kills the parasitic form only in the RBC (e.g. chloroquine, quinine)

3.Gametocide - kills gametes in the blood (primaquine)

4.Sporontocide - prevents sporogony and multiplication in the mosquito (pyrimethamine, chloroguanide)

Selection of drugs is based on

1.the severity of the infection

2.the strain of the infecting plasmodium

3.the degree to which the organism is drug-resistant

4.the need of chemophylaxis in endemic area

Chloroquine

a 4-aminoquinoline

effective against all four types of malaria (except chloroquine-resistant P.falciparum)

for acute attack of malaria and for prophylactic use (except against chloroquine-resistant P.falciparum)

mechanism - forms a complex with DNA to prevent its replication or its transcription into RNA

Selective toxicity is due to a drug-concentrating mech. Present in the parasited cells

Drug resistance occur in P.falciparum (decrease in the drug uptake mechanism)

toxicity - low dose (dizziness, headache, itching, skin rash, vomiting, and blurring of vision)

-high dose (respiratory depression, convulsion, cardiac arrest) (can be associated with rash, alopecia, photosensitivity, leukemia, hemolysis especially with those with G-6-PD deficiency, retinal damage (irriversible retinopathy)

Quinineeffective against all four species of malaria and chloroquine-resistant P.falciparumfor the treatment of chloroquine-sensitive or chloroquine-resistant P.falciparum)rapidly acting and highly effective blood schizontocideshould not be used routinely prophylaxis (to avoid emergence of resistance)mechanism is not knownToxicity - overdose cause cinchonism (deafness, ringing in the ears, blurred vision and headache)

-hemolysis

Mefloquine

highly effective against chloroquine-resistant P.falciparum or pyrimethamine-sulfadoxine-resistant P.falciparum

a highly effective blood schizontocide

used for the prevention and treatment of malaria caused by chloroquine-resistant and multidrug-resistant P.falciparum

mechanism - not known

Primaquine

the only drug effective against the hepatic stage of P.vivax, P.ovale, and P.falciparum

for the radical cure of relapsing malaria

has a marked gametocidal effect against all four species of plasmodium

weak or ineffective against the erythrocytic stage of plasmodium (therefore, it’s not good for acute attack)

reserved primarily for the terminal prophylaxis and radical cure of P.vivax and P.ovale (relapsing) malaria

Should be given together with a blood schizontocide such as chloroquine

mechanism - not known

- it may act as oxidant to oxidize membrane protein leading to lysis of cellular membrane

toxicity - hemolysis or methemoglobinemia in patient with G-6-PD deficiency

- at high dose, it may suppress myeloid activity

Antifolate drugs

sulfonamides (sulfadoxine, sulfadiazine), pyrimethamine, chloroguanide (also named proguanil)

all are basically blood schizontocide

chloroguanide has prophylactic and suppressive activity against falciparum and the acute attack of vivax malaria

chloroguanide (not pyrimethamine) has a marked effect on the primary tissue stage of susceptible P.falciparum

pyrimethamine is a slow-acting blood schizontocide with antimalarial effect similar to those chloroguanide

Sulfonamides are slow-acting blood schizontocide that are more active against P.falciparum than P.vivax

choloroguanide, pyrimethamine, and sulfonamides are not effective tissue schizontocides (with the exception of chloroguanide as mentioned above)

mechanism - sulfonamides block folic acid synthesis by inhibiting dihydropteroate synthetase

- pyrimethamine and cycloguanil (active metabolite of

chloroguanide) inhibit the plasmodial dihydrofolate reductase (inhibiting tetrahydrofolate formation)

A combination of pyrimethamine (or chloroguanide) with sulfonamides may have a synergistic antimalarial effect (the most useful --> pyrimethamine-sulfadoxine (Fansidar)

chloroguanide + chloroquine is used as a safe alternative to mefloquine for prophylaxis of chloroquine-resistant falciparum malaria or for the treatment of mixed vivax and falciparum infection (ineffective against multidrug-resistant P.falciparum)

pyrimethamine is always given with a sulfonamides such as sulfadoxine to enhance its antifolate activity

A single antifolate drug should not be used as the sole therapeutic agent for treating acute malarial attack (should be combined with another antimalarial agents, such as chloroquine)First phase of treatment

prompt elimination of the parasitic form responsible for the symptoms (erythrocytic form)

effective drug are chloroguanide, chloroquine, quinine, pyrimethamine

Second phase of treatment

for the suppression of relapse, the gametocides and tissue form of the parasites have to be eliminated

to cure P.falciparum malaria with no latent tissue form --> chloroquine can be used with a duration of therapy of up to 3 months (life span of RBC)

for patients with mixed infection(p.falciparum plus P.vivax or P.ovale) - primaquine should probably be given after chloroquine therapy to avoid relapse due to P.vivax and P. ovale

Drugs used for malaria prophylaxis

chloroquine - drug of choice for P.malariae, P.ovale, P.vivax and choloroquine-sensitive P.falciparum

For cholroquine-resistant P.falciparum - mefloquine or chloroguanide plus choroquine (safe alternative) can be used

Treatment of drug-resistant P.falciparum infection

for the chloroquine-resistant P.falciparum - mefloquine or quinine can be used

for multidrug-resistant P.falciparum - quinine + antifolate (pyrimethamine or sulfadiazine) or tetracycline

References

1.Brenner GM. Pharmacology. Philadelphia: W.B. Saunders Company, 2000.

2.Clive Page, Michael Curtis, Morley Sutter, Michael Walker, and Brian Hoffman. Integrated Pharmacology. 2nd ed, Philadelphia: Mosby, 2002.