Antimalarial drugs
Malaria: is an acute infectious disease caused by four species of the
protozoal genus Plasmodium (P. falciparum infection , Plasmodium vivax
, Plasmodium ovale and malariae)
Life cycle of the malarial parasite
1-When an infected mosquito bites, it injects Plasmodium sporozoites
into the bloodstream .
2- The sporozoites migrate through the blood to the liver, where they
form cyst-like structures containing thousands of merozoites (schizonts) .
3- Upon release, each merozoite invades a red blood cell, becoming a
trophozoite and using hemoglobin as a nutrient.
4-The trophozoites multiply and become merozoites. Eventually, the
infected cell ruptures, releasing heme and merozoites that can enter other
erythrocytes.
5-Alternatively, released merozoites can become gametocytes, which are
picked up by mosquitoes from the blood they ingest.
6-The cycle thus begins again, when the gametocytes becoming
sporozoites in the insect.
The effectiveness of a drug treatment is related to the particular
species of infecting plasmodium and the stage of its life cycle that is
targeted.
In P falciparum and P malariae infection, only one cycle of liver cell
invasion and multiplication occurs, and liver infection ceases
spontaneously in less than 4 weeks. Thus, treatment that eliminates
erythrocytic parasites will cure these infections.
In P vivax and P ovale infections, a dormant hepatic stage, the
hypnozoite, is not eradicated by most drugs, and subsequent relapses can
therefore occur after therapy directed against erythrocytic parasites.
Eradication of both erythrocytic and hepatic parasites is required to cure
these infections.
Drugs is classified into 3 types:
1-Drugs that eliminate developing or dormant liver forms are called
tissue schizonticides.e.g. primaquine
2- those that act on erythrocytic parasites are blood schizonticides.e. g.
chloroquine, mefloquine,quinine and pyrimethamine
3-those that kill sexual stages and prevent transmission to mosquitoes are
gametocides e.g. quinine,chloroquine and primaquine
No one available agent can reliably effect a radical cure, ie, eliminate
both hepatic and erythrocytic stages.
Few available agents are causal prophylactic drugs, ie, capable of
preventing erythrocytic infection.
However, all effective chemoprophylactic agents kill erythrocytic
parasites before they increase sufficiently in number to cause clinical
disease.
Tissue schizonticide: Primaquine
Clinical indications:
1-eradicates primary exoerythrocytic forms of P. falciparum and P.
vivax.
2- eradicates secondary exoerythrocytic forms of recurring malarias
(P. vivax and P. ovale),so primaquine is the only agent that can lead to
radical cures of the P. vivax and P. ovale malarias, which may remain
in the liver in the exoerythrocytic form after the erythrocytic form of
the disease is eliminated.
3-The sexual (gametocytic) forms of all four plasmodia are destroyed
in the plasma or are prevented from maturing later in the mosquito,
thus interrupting the transmission of the disease.
Note: Primaquine is not effective against the erythrocytic stage of
malaria and, therefore, is often used in conjunction with a blood
schizonticide, such as chloroquine, quinine, mefloquine, or
pyrimethamine.
Mechanism of action:
This is not completely understood. Metabolites of primaquine are
believed to act as oxidants that are responsible for the schizonticidal
action.
Adverse effects:
Primaquine has a low incidence of adverse effects, except for druginduced hemolytic anemia in patients with genetically low levels of
glucose-6-phosphate dehydrogenase..
Blood schizonticide:
1.Chloroquine
Clinical indications:
1-Chloroquine has been the mainstay of antimalarial therapy, and it is the
drug of choice in the treatment of erythrocytic forms of plasmodia.,
except in resistant strains.
2- Chloroquine is also effective in the treatment of gametocytes.
Mechanism of action:
1-Damage to parasite mediated by accumulated heme.
2-Alkinization of food vacuole.
3-Decreased DNA synthesis.
Adverse effects:
1-Side effects are minimal at the low doses used in the chemo
suppression of malaria.
.2- At higher doses, many more toxic effects occur, such as
gastrointestinal upset, pruritus, headaches, and blurring of vision .
Note: An ophthalmologic examination should be routinely performed.
3-Chloroquine should be used cautiously in patients with hepatic
dysfunction or severe gastrointestinal problems or in patients with
neurologic or blood disorders.
4-Chloroquine can cause electrocardiographic changes, because it has
a quinidine-like effect.
Resistance:
Resistance of plasmodia to available drugs has become a serious
medical problem throughout Africa, Asia, and most areas of Central
and South America. Chloroquine-resistant P. falciparum exhibit
multigenic alterations that confer a high level of resistance.
Note: When a chloroquine-resistant organism is encountered, therapy
usually consists of an orally administered combination of quinine,
pyrimethamine, and a sulfonamide, such as sulfadoxine.
2. mefloquine
Clinical indication:
Mefloquine is used for infections caused by multidrug-resistant forms
of P. falciparum.
Mechanism of action: remains to be determined, but like quinine, it can
apparently damage the parasite's membrane.
Adverse reactions;
at high doses range from nausea, vomiting, and dizziness to
disorientation, hallucinations, and depression.
2-Electrocardiographic abnormalities and cardiac arrest are possible if
mefloquine is taken concurrently with quinine or quinidine.
3.Quinine and quinidine
Clinical indications:
These drugs are reserved for severe infestations and for malarial strains
that are resistant to other agents, such as chloroquine.
Mechanisim of action:
Quinine
and its stereoisomer, quinidine , interfere with heme
polymerization, resulting in death of the erythrocytic form of the
plasmodial parasite.
Adverse effect :
1-Cinchonism a syndrome causing nausea, vomiting, tinnitus, and
vertigo. These effects are reversible and are not considered to be reasons
for suspending therapy.
2-However, quinine treatment should be suspended if a positive Coombs'
test for hemolytic anemia occurs.
Drug interactions
include potentiation of neuromuscular-blocking agents and elevation of
digoxin levels if taken concurrently with quinine.
Blood schizonticide and sporontocide:
Pyrimethamine
1-The antifolate agent pyrimethamine is frequently employed to effect a
radical cure as a blood schizonticide.
2-It also acts as a strong sporonticide in the mosquito's gut when the
mosquito ingests it with the blood of the human host.
Mechanisim of action:
Pyrimethamine inhibits plasmodial dihydrofolate reductase at much lower
concentrations than those needed to inhibit the mammalian enzyme.
Clinical indications;
1-Pyrimethamine alone is effective against P. falciparum.(treatment of
acute attack and prophylaxis).
2- In combination with a sulfonamide sulfadoxine(fansider), is also used
against P. malariae .It cause megaloblastic anemia.
Exercise one: match anti-malarial drugs with side effect?
1-quinidine
haemolytic anemia in patient with G-6-P-D deficiency.
2-Pyrimethamine
disorientation, hallucinations, and depression.
3- mefloquine.
Cinchonism a syndrome
4-Primaquine
blurring of vision
.
5-Chloroquine
megaloblastic anemia
Exercise two: match anti-malarial drugs with site of action?
1-quinidine
tissue schizonticides
2-Pyrimethamine
blood schizonticides
3- mefloquine.
gametocides
4-Primaquine
Blood schizonticide and sporontocide
5-Chloroquine
Exercise three: match anti-malarial drugs with mechanism
of action?
1-quinidine
inhibit plasmodial dihydrofolate reductase
2-Pyrimethamine
Damage to parasite mediated by accumulated heme.
3- mefloquine.
act as oxidants that are responsible for the
schizonticidal action.
4-Primaquine
damage the parasite's membrane.
5-Chloroquine
interfere with heme polymerization