Antimalarial drugs

Malaria is cause by four species of protozoa:

Plasmodium malariae.
P. falciparum.
P. vivax.
P. ovale (rare).
The plasmodium transmitted to human by the
bite of an infected female anopheles mosquito.


Malaria transmission life cycle:
Sporozoites tissue schizonts (in liver)
merozoites infect RBC (blood schizonts)
rupture of RBC (clinical attack) new
crops of merozoites
Sexual form: some merozoites
differentiate into male & female
gametocytes ingested by a mosquito
where they form Sporozoites human
P. malariae & p. falciparum have one cycle
of liver invasion and end by the 4th week
i.e. no relapse occurs.
P.ovale & p. vivax have dormant stages
(hypnozoites) in the liver. These
hypnozoites may rupture months or years
later causing relapse of the attacks.
Blood Schizonticides

Chloroquine (4- aminoquinoline derivative)
Mechanism of action:
Inhibits synthesis of DNA and RNA in the
plasmodium.
Increases pH of the vacules in the parasite, so
prevent its utilization of erythrocyte hemoglobin.
Uses:
Acute attack 600 mg base (4 tab.) then 300 mg
after 6 h. then 150 mg bid for two more days.
Add 100 mg proguanil/ day (2 tab.) in
chloroquine-resistant area.
Chemoprophylaxis:
300 mg base (2 tab.) / week,
one week before entering the endemic
area
& 4 weeks after leaving.
Other uses:
Amebic liver abscess (as chloroquine is
concentrated in the liver).
Anti-inflammatory in autoimmune diseases e.g.
rheumatoid arthritis (unknown mechanism).
A/E: GIT upset, rash, headache, peripheral
neuritis, cardiac depressant, retinal damage
(dont use chloroquin> 5 years without regular
ophthalmic examination), toxic psychosis and
precipitates porphyria.


Quinine:
Mechanism of action:
Inhibits DNA strand separation.
Inhibits transcription and protein synthesis.
Uses:
Chloroquine-resistant P. falciparum (orally).
Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it
could repeated at an intervals of 8-12 h. until patient can
take the drug orally.
A/E:
Cinchonism i.e. headache, dizziness, & tinnitus.
Inhibits cardiac conductivity, hemolysis in G-6-P D and
black water fever (intravascular hemolysis).
Quinidine:
It is the dextro-isomer of quinine.
It is used when quinine is not available.
Mefloquine:
Its mechanism of action is unknown.
Uses:
treatment & prophylaxis of chloroquine-resistant
P. falciparum.
A/E: GIT upset, headache, dizziness, syncope,
extrasystoles & seizures.
Halofantrine:
Unknown mechanism of action.
Used only by oral route in P. falciparum
cerebral malaria.
No parenteral preparation.
Not used for prophylaxis.
Not used during pregnancy unless benefit
outweighs the risk.
Qinghaosu (Artemisinin):
It is a Chinese herbal medicine was used as antipyretic.
It is a blood schizonticide against all types of malaria
including chloroquine-resistant p. falciparum.
Unknown mechanism of action.
Uses:
P. falciparum cerebral malaria (oral & parenteral).
Not used prophylactically.
Not used in pregnancy as it is emberytoxic in rats.

Antifolates (sulfonamides & sulfones):
Synergistic blockade of folic acid synthesis
Sulfonamide inhibits dihydropteroate
synthetase, so inhibits folic acid synthesis.
Pyrimethamine and proguanil inhibit
dihydrofolate reductase, so inhibit
tetrahydrofolate (folinic acid synthesis).

Fansidar:
It is a combination of sulfadoxin and pyrimethamine.
It is used in chloroquine-resistant p. falciparum.
Not used for prophylaxis as it causes agranulocytosis &
Stevens-Johnson syndrome.
A.E:
Sulfonamide: rashes, kidney damage, hemolysis & GIT
upset.
Pyrimethamine: folic acid deficiency, agranulocytosis &
Stevens-Johnson syndrome.
Disadvantages: slow blood schizonticide activity, drug
resistance & numerous & serious adverse effects.
C/I: pregnancy & nursing women, G-6-PD, renal
impairment & children under 2 months of age.

Atovaquone:
Unknown mechanism of action.
Used alone for treatment of pneumocytosis and
toxoplasmosis in patients with AIDS.
Atovaquone + proguanil (malarone) for
treatment & prophylaxis of chloroquine-resistant
P. falciparum.
A/E: fever, rashes, cough, nausea, vomiting,
diarrhea, headache & insomnia.
Tissue Schizonticide

Primaquine (8- aminoquinoline derivative):
It is a tissue schizonticide.
It has a cellular oxidant activity and possibly interferes
with mitochondria function.
Gametocide, so inhibits infection transmission by
mosquito.
Uses:
Eradication of liver stages (hypnozoites) of P.vivax & P.
ovale, after standard chloroquine therapy to prevent
relapse.
It should not be given if there is risk of reinfection.
A/E: GIT upset, pruritis, headache, methemoglobinemia,
hemolysis especially in G-6-PD.


Treatment of malaria

P. vivax, P. ovale & P. malariae:
Chloroquine
NB: It is also allowed in pregnancy.
P. Falciparum (most cases are chloroquine-resistant):
Quinine 600 mg salt/8h till patient become better and
blood is free of parasites (usually in 3-5 days).
Followed by a single dose of fansidar (3 tablets).
In pregnancy 7-day course of quinine alone should
be given.
Alternative therapy
Mefloquine 20 mg base/kg up to a maximum of
1.5 g in two divided doses 8 hours apart.
Mefloquine is contraindicated in pregnancy.
Cerebral malaria:
Quinine 10 mg/kg i.v infusion over 4 h. could be
repeated at intervals of 8-12 h. until patient can
take drug orally.
Or Halofantrine: orally only
Or Qinghaosu (Artemisinin): oral & i.v

Chemoprophylaxis of malaria

Chloroquine-sensitive area:
Chloroquine 150 mg base ( 2 tab/week)
Chloroquine-resistant area:
Chloroquine ( 2 tab/week) plus proguanil
100 mg (one or two tab/ day)
or
Mefloquine 250 mg (one tab./ week)