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

1406 Chemistry. Cinchona contains a mixture of >20 structurally related
alkaloids, the most important of which are quinine and quinidine.
Both compounds contain a quinoline group attached through a secondary
alcohol linkage to a quinuclidine ring (Figure 49–2). A
methoxy side chain is attached to the quinoline ring and a vinyl to the
quinuclidine. They differ only in the steric configuration at two of the
three asymmetrical centers: the carbon bearing the secondary alcohol
group and at the quinuclidine junction. Although quinine and
quinidine have been synthesized, the procedures are complex; hence
they still are obtained from natural sources. Quinidine is both somewhat
more potent as an antimalarial and more toxic than quinine
(Griffith et al., 2007). Structure-activity analysis of the cinchona
alkaloids provided the basis for the discovery of more recent antimalarials
such as mefloquine.
Mechanisms of Action and Parasite Resistance. Quinine
acts against asexual erythrocytic forms and has no significant
effect on hepatic forms of malarial parasites. This
drug is more toxic and less effective than chloroquine
against malarial parasites susceptible to both drugs.
However, quinine, along with its stereoisomer quinidine,
is especially valuable for the parenteral treatment of
severe illness owing to drug-resistant strains of P. falciparum.
Of note, however, some strains from Southeast
Asia and South America have become more resistant to
both agents. Because of its toxicity and short t 1/2
, quinine
is generally not used for chemoprophylaxis.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
The antimalarial mechanism of quinine is thought to share
similarities to chloroquine in being able to bind heme and prevent its
detoxification. The basis of P. falciparum resistance to quinine,
nonetheless, is complex. Patterns of P. falciparum resistance to quinine
correlate in some strains with resistance to chloroquine yet in
others correlate more closely with resistance to mefloquine and halofantrine.
Gene amplification of pfmdr1 in P. falciparum, implicated
in resistance to mefloquine and halofantrine, can contribute to
reduced quinine susceptibility in vitro. Similarly, pfmdr1 point mutations
can also contribute to quinine resistance, in particular the
N1042D mutation (Duraisingh and Cowman, 2005; Sidhu et al.,
2005). Despite their close chemical similarity, quinine and quinidine
sensitivity can also diverge in some strains harboring novel PfCRT
haplotypes (Cooper et al., 2002). Recent evidence suggests that other
transporter genes participate in conferring resistance to quinine,
potentially including the sodium-hydrogen exchanger PfNHE
(Hayton and Su, 2008; Nkrumah et al., 2009).
Action on Skeletal Muscle. Quinine and related cinchona alkaloids
exert effects on skeletal muscle that can have clinical implications.
Quinine increases the tension response to a single maximal stimulus
delivered to muscle directly or through nerves, but it also increases
the refractory period of muscle so that the response to tetanic stimulation
is diminished. The excitability of the motor end-plate region
decreases so that responses to repetitive nerve stimulation and to
acetylcholine are reduced. Thus, quinine can antagonize the actions
of physostigmine on skeletal muscle as effectively as curare. Quinine
may also produce alarming respiratory distress and dysphagia in
patients with myasthenia gravis. The effect on skeletal muscle can be
augmented by concurrent administration of gentamicin. Quinine
may also cause symptomatic relief of myotonia congenita. This disease
is the pharmacological antithesis of myasthenia gravis, such
that drugs effective in one syndrome aggravate the other.
Absorption, Fate, and Excretion. Quinine is readily absorbed when
given orally or intramuscularly. In the former case, absorption occurs
mainly from the upper small intestine and is >80% complete, even
in patients with marked diarrhea. After an oral dose, plasma levels
reach a maximum in 3-8 hours and, after distributing into an apparent
volume of ~1.5 L/kg in healthy individuals, decline with a t 1/2
of
~11 hours. The pharmacokinetics of quinine may change according
to the severity of malarial infection (Krishna and White, 1996).
Values for both the apparent volume of distribution and the systemic
clearance of quinine decrease, the latter more than the former, such
that the average elimination t 1/2
increases to 18 hours. In patients
with severe infection, standard therapeutic doses may produce peak
plasma levels of quinine as high as 15-20 mg/L without causing
major toxicity. In contrast, levels >10 mg/L can produce severe drug
reactions. The high levels of plasma α 1
-acid glycoprotein produced
in severe malaria may prevent toxicity by binding quinine and
thereby reducing the free fraction of drug. Concentrations of quinine
are lower in erythrocytes (33-40%) and CSF (2-5%) than in
plasma, and the drug readily reaches fetal tissues.
The cinchona alkaloids are metabolized extensively, especially
by hepatic CYP3A4; thus only ~20% of an administered dose
is excreted in an unaltered form in the urine. These drugs do not
accumulate in the body upon continued administration. However,
the major metabolite of quinine, 3-hydroxyquinine, retains some
antimalarial activity and can accumulate and possibly cause toxicity
in patients with renal failure. Renal excretion of quinine itself is
more rapid when the urine is acidic.
Therapeutic Uses. Quinine and quinidine have historically
been treatments of choice for drug-resistant and
severe P. falciparum malaria. However, the advent of
artemisinin therapy is changing this situation because
both oral and intravenous artemisinins have entered clinical
practice (Table 49–3). In severe illness, the prompt
use of loading doses of intravenous quinine (or quinidine,
where intravenous quinine is not available, as is
the case in the U.S.) is imperative and can be lifesaving.
Oral medication to maintain therapeutic concentrations
is then given as soon as tolerated and is continued for
5-7 days. Especially for treatment of infections with
multidrug-resistant strains of P. falciparum, sloweracting
blood schizonticides such as tetracyclines or clindamycin
are given concurrently to enhance quinine
efficacy. Formulations of quinine and quinidine and
specific regimens for their use in the treatment of
P. falciparum malaria are shown in Table 49–3.
In a series of studies over the past two decades, White and
associates designed rational regimens, including the institution of
loading doses, for the use of quinine and quinidine in the treatment
of P. falciparum malaria in Southeast Asia (Krishna and White, 1996).
Between 0.2 and 2.0 mg/L has been estimated as the therapeutic range
for “free” quinine. Regimens needed to achieve this target may vary