DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 49–1
Malarial Parasite Developmental Stages Targeted by Antimalarial Drugs
EFFECT OF DRUG ON PARASITE VIABILITY
LIVER STAGES
BLOOD STAGES
GROUP DRUGS SPOROZOITE PRIMARY HYPNOZOITE ASEXUAL GAMETOCYTE
1 Artemisinins − − − + +
Chloroquine − − − + +/−
Mefloquine − − − + −
Quinine/Quinidine − − − + +/−
Pyrimethamine − − − + −
Sulfadoxine − − − + −
Tetracycline − − − + −
2 Atovaquone/ − + − + +/−
Proguanil
3 Primaquine − + + − +
−, no activity; +/−, low to moderate activity; +, important activity.
of agents (artemisinins, chloroquine, mefloquine, quinine
and quinidine, pyrimethamine, sulfadoxine, and
tetracycline) are not reliably effective against primary
or latent liver stages. Instead, their action is directed
against the asexual blood stages responsible for disease.
These drugs will treat, or prevent, clinically symptomatic
malaria. When used as chemoprophylaxis, these
drugs must continue to be taken for several weeks
after exposure, until parasites complete their intrahepatic
stage of development and become susceptible to
therapy.
The spectrum is somewhat expanded for a second
category of drugs (typified by atovaquone and proguanil),
which target not only the asexual erythrocytic forms but
also the primary liver stages of P. falciparum. This additional
activity shortens to several days the required period
for postexposure chemoprophylaxis.
The third category, currently comprised solely of
primaquine, is effective against primary and latent liver
stages as well as gametocytes. Primaquine has no place
in the treatment of symptomatic malaria but rather is
used most commonly to eradicate the intrahepatic hypnozoites
of P. vivax and P. ovale that are responsible for
relapsing infections. Primaquine also has anti-gametocytic
activity.
Aside from their antiparasitic activity, the utility
of antimalarials for chemoprophylaxis or therapy
depends on their pharmacokinetics and their safety.
Thus quinine and primaquine, which have significant
toxicity and relatively short half-lives, generally are
reserved for the treatment of established infection and
are not used for chemoprophylaxis in a healthy traveler.
In contrast, chloroquine is relatively free from toxicity
and has a long t 1/2
that is convenient for chemoprophylactic
dosing (in those few areas still reporting chloroquine-sensitive
malaria).
Regimens currently recommended for chemoprophylaxis
in travelers are given in Table 49–2,
whereas regimens for the treatment and presumptive
self-treatment (based on symptom presentation) of
malaria in travelers are provided in Table 49–3 and
Table 49–4, respectively. Individual agents are discussed
in greater detail later in this chapter, listed
alphabetically.
ARTEMISININ AND DERIVATIVES
History. Artemisinin is a sesquiterpene lactone endoperoxide
derived from qing hao (Artemisia annua), also called sweet
wormwood or annual wormwood. The Chinese have ascribed
medicinal value to this plant for >2000 years (White, 2008). As
early as 340 A.D., Ge Hong prescribed tea made from qing hao as
a remedy for fevers, and in 1596, Li Shizhen recommended it to
relieve malarial symptoms. By 1972, Chinese scientists had identified
the major antimalarial ingredient, qinghaosu, now known as
artemisinin.
Chemistry. The structures of artemisinin and its three major semisynthetic
derivatives in clinical use, dihydroartemisinin, artemether,
and artesunate, are as follows: