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

based on patient age, severity of illness, and the responsiveness of
P. falciparum to the drug. For example, lower doses are more effective
in treating children in Africa than adults in Southeast Asia
because the pharmacokinetics of quinine differ in the two populations,
as does the susceptibility of P. falciparum to the drug (Krishna
and White, 1996). Dosage regimens for quinidine are similar to those
for quinine, although quinidine binds less to plasma proteins and has
a larger apparent volume of distribution, greater systemic clearance,
and shorter terminal elimination t 1/2
than quinine (Griffith et al.,
2007; Miller et al., 1989). Thompson et al. (2003) suggest that the
dose of quinidine currently recommended by the CDC (10 mg salt/kg
initially, followed by 0.02 mg salt/kg per minute) may be too low and
should be 10 mg salt/kg and 0.02 mg/kg of base/minute (60% of the
salt is base). Clinical data on which to base a firm recommendation
are lacking.
Treatment of Nocturnal Leg Cramps. It is commonly believed that
night cramps might be relieved by quinine taken at bedtime at a dose
of 200-300 mg (available until 1995 in products that did not require
a prescription). Some consider this condition severe. The degree of
symptomatic relief appears to vary substantially between individuals.
In 1995, the FDA issued a ruling that required drug manufacturers
to stop marketing over-the-counter quinine products for
nocturnal leg cramps, stating that data supporting safety and efficacy
of quinine for this indication were inadequate and that risks
outweighed the potential benefits.
Toxicity and Side Effects. The fatal oral dose of quinine
for adults is ~2-8 g. Quinine is associated with a triad of
dose-related toxicities when given at full therapeutic or
excessive doses. These are cinchonism, hypoglycemia,
and hypotension. Mild forms of cinchonism—consisting
of tinnitus, high-tone deafness, visual disturbances,
headache, dysphoria, nausea, vomiting, and postural
hypotension—occur frequently and disappear soon after
the drug is withdrawn. Hypoglycemia is also common,
mostly in the treatment of severe malaria, and can be life
threatening if not treated promptly with intravenous glucose.
Hypotension is rarer but also serious and most often
is associated with excessively rapid intravenous infusions
of quinine or quinidine. Prolonged medication or high
single doses also may produce GI, cardiovascular, and
skin manifestations, as discussed next.
Hearing and vision are particularly affected. Functional
impairment of the eighth nerve results in tinnitus, decreased auditory
acuity, and vertigo. Visual signs consist of blurred vision, disturbed
color perception, photophobia, diplopia, night blindness,
constricted visual fields, scotomata, mydriasis, and even blindness
(Bateman and Dyson, 1986). These visual and auditory effects probably
result from direct neurotoxicity, although secondary vascular
changes may have a role. Marked spastic constriction of the retinal
vessels leads to retinal ischemia, pale optic discs, and retinal edema,
with the potential for severe optic atrophy.
GI symptoms are also prominent in cinchonism. Nausea,
vomiting, abdominal pain, and diarrhea result from the local irritant
action of quinine, but the nausea and emesis also have a central basis.
Cutaneous manifestations may include flushing, sweating, rash, and
angioedema, especially of the face. Quinine and quinidine, even at
therapeutic doses, may cause hyperinsulinemia and severe hypoglycemia
through their powerful stimulatory effect on pancreatic
beta cells. Despite treatment with glucose infusions, this complication
can be serious and possibly life threatening, especially in pregnancy
and prolonged severe infection. Hypoglycemia is seen
occasionally in uninfected patients who take quinine.
Quinine rarely causes cardiac complications unless therapeutic
plasma concentrations are exceeded (Krishna and White, 1996).
QTc prolongation is mild and does not appear to be affected by concurrent
mefloquine treatment. Acute overdosage also may cause serious
and even fatal cardiac dysrhythmias such as sinus arrest,
junctional rhythms, AV block, and ventricular tachycardia and fibrillation
(Bateman and Dyson, 1986). Quinidine is even more cardiotoxic
than quinine. Cardiac monitoring of patients on intravenous
quinidine is advisable where possible.
Severe hemolysis can result from hypersensitivity to these
cinchona alkaloids. Hemoglobinuria and asthma from quinine may
occur more rarely. “Blackwater fever”—the triad of massive hemolysis,
hemoglobinemia, and hemoglobinuria leading to anuria, renal
failure, and in some instances death—is a rare type of hypersensitivity
reaction to quinine therapy that can occur during treatment of
malaria. Quinine may cause milder hemolysis upon occasion, especially
in people with G6PD deficiency. Thrombotic thrombocytopenic
purpura is a rare but clinically significant adverse effect. This
reaction can occur even in response to ingestion of tonic water,
which has ~4% the therapeutic oral dose per 12 oz (“cocktail purpura”).
Other rare adverse effects include hypoprothrombinemia,
leukopenia, and agranulocytosis.
Precautions, Contraindications, and Interactions.
Quinine must be used with considerable caution, if at
all, in patients who manifest hypersensitivity (balanced
against risks primarily of not urgently treating severe
malaria in the absence of other effective antimalarial
drugs). Quinine should be discontinued immediately if
evidence of hemolysis appears.
This drug should be avoided in patients with tinnitus or optic
neuritis. In patients with cardiac dysrhythmias, the administration
of quinine requires the same precautions as for quinidine. Quinine
appears to be safe in pregnancy and is used commonly for the treatment
of pregnancy-associated malaria. However, glucose levels must
be monitored because of the increased risk of hypoglycemia.
Because parenteral solutions of quinine and quinidine are
highly irritating, the drug should not be given subcutaneously.
Concentrated solutions may cause abscesses when injected intramuscularly,
or thrombophlebitis when infused intravenously. Antacids
that contain aluminum can delay absorption of quinine from the GI
tract. Quinine and quinidine can delay the absorption and elevate
plasma levels of digoxin and related cardiac glycosides. Likewise,
these alkaloids may raise plasma levels of warfarin and related anticoagulants.
The action of quinine at neuromuscular junctions
enhances the effect of neuromuscular blocking agents and opposes
the action of acetylcholinesterase inhibitors. Prochlorperazine can
amplify quinine’s cardiotoxicity, as can halofantrine. The renal clearance
of quinine can be decreased by cimetidine and increased by
urine acidification and by rifampin.
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CHAPTER 49
CHEMOTHERAPY OF MALARIA