Transcript antimalarial-m

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)
Quinine
effective against all four species of malaria and chloroquine-resistant
P.falciparum
for the treatment of chloroquine-sensitive or chloroquine-resistant
P.falciparum)
rapidly acting and highly effective blood schizontocide
should not be used routinely prophylaxis (to avoid emergence of
resistance)
mechanism is not known
Toxicity - 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 chloroquineresistant 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.