Artemether
Molecular weight: 298.4
Artemether is the methyl ether of dihydroartemisinin. It is more lipid soluble than artemisinin or artesunate. It can
be given as an oil-based intramuscular injection or orally. It is also coformulated
with lumefantrine (previously referred to as
benflumetol) for combination therapy.
Formulations
intramuscular injection containing 80 mg of
artemether in 1 ml for adults or 40 mg of artemether in 1 ml for paediatric use.
In a coformulation with lumefantrine:artemether and 120 mg of lumefantrine.
Pharmacokinetics
Peak plasma concentrations occur around 2–3 h after oral administration. Following
intramuscular injection, absorption is very variable, especially in children with poor
peripheral perfusion: peak plasma concentrations generally occur after around 6 h
but absorption is slow and erratic and times to peak can be 18 h or longer in some
cases. Artemether is metabolized to dihydroartemisinin, the active metabolite.
After intramuscular administration, artemether predominates, whereas after oral
administration dihydroartemisinin predominates. Biotransformation is mediated via
the cytochrome P450 enzyme CYP3A4. Autoinduction of metabolism is less than with
artemisinin. Artemether is 95% bound to plasma proteins. The elimination half-life is
approximately 1 h, but following intramuscular administration the elimination phase
is prolonged because of continued absorption. No dose modifications are necessary in
renal or hepatic impairment.
Toxicity
In all species of animals tested, intramuscular artemether and artemotil cause an
unusual selective pattern of neuronal damage to certain brain stem nuclei. Neurotoxicity
in experimental animals is related to the sustained blood concentrations that follow
intramuscular administration, since it is much less frequent when the same doses
are given orally, or with similar doses of water-soluble drugs such as artesunate. Clinical,
neurophysiological and pathological studies in humans have not shown similar findings
with therapeutic use of these compounds. Toxicity is otherwise similar to that of
artemisinin (see below).
Artemisin Toxicity
Artemisinin and its derivatives are safe and remarkably well tolerated. There have
been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia,
neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities,
including bradycardia and prolongation of the QT interval, although most studies
have not found any electrocardiographic abnormalities. The only potentially serious
adverse effect been reported with this class of drugs is type 1 hypersensitivity reactions
in approximately 1 in 3000 patients. Neurotoxicity has been reported in animal
studies, particularly with very high doses of intramuscular artemotil and artemether, but
has not been substantiated in humans. Similarly, evidence of death of embryos
and morphological abnormalities in early pregnancy have been demonstrated in animal
studies. Artemisinin has not been evaluated in the first trimester of pregnancy so
should be avoided in first trimester patients with uncomplicated malaria until more
information is available.
Drug interactions
None known.
Artesunate
Molecular weight: 384.4
Artesunate is the sodium salt of the
hemisuccinate ester of artemisinin.
It is soluble in water but has poor
stability in aqueous solutions at
neutral or acid pH. In the injectable
form, artesunic acid is drawn up in
sodium bicarbonate to form sodium
artesunate immediately before
injection.
Artesunate can be given orally, rectally or by the intramuscular or intravenous routes.
There are no coformulations currently available.
Formulations
intramuscular or intravenous injection containing 60 mg of anhydrous
artesunaic acid with a separate ampoule of 5% sodium bicarbonate solution.artesunate.
Pharmacokinetics
Artesunate is rapidly absorbed, with peak plasma levels occurring 1.5 h, 2 h and 0.5 h after
oral, rectal and intramuscular administration, respectively. It is almost entirely
converted to dihydroartemisinin, the active metabolite. Elimination of artesunate is
very rapid, and antimalarial activity is determined by dihydroartemisinin elimination
(half-life approximately 45 min). The extent of protein binding is unknown. No dose
modifications are necessary in renal or hepatic impairment.
Toxicity
As for artemisinin.
Drug interactions
None known.
Atovaquone
Molecular weight: 366.8
Atovaquone is a hydroxynaphthoquinone
antiparasitic drug active against all Plasmodium
species. It also inhibits pre-erythrocytic
development in the liver, and oocyst development
in the mosquito. It is combined with proguanil
for the treatment of malaria – with which
it is synergistic. Atovaquone interferes with
cytochrome electron transport.
Formulations
Atovaquone is available for the treatment of malaria in a coformulation with proguanil.atovaquone and 100 mg of proguanil
hydrochloride for adults.atovaquone and 25 mg of proguanil hydrochloride for
paediatric use.
Pharmacokinetics
Atovaquone is poorly absorbed from the gastrointestinal tract but bioavailability following
oral administration can be improved by taking the drug with fatty foods. Bioavailabillity
is reduced in patients with AIDS. Atovaquone is 99% bound to plasma proteins and has
a plasma half-life of around 66–70 h due to enterohepatic recycling. It is excreted almost
exclusively in the faeces as unchanged drug. Plasma concentrations are significantly
reduced in late pregnancy.
Toxicity
Atovaquone is generally very well tolerated. Skin rashes, headache, fever, insomnia,
nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia and, very rarely,
haematological disturbances, such as anaemia and neutropenia, have all been reported.
Drug interactions
Reduced plasma concentrations may occur with concomitant administration
of metoclopramide, tetracycline and possibly also acyclovir, antidiarrhoeal drugs,
benzodiazepines, cephalosporins, laxatives, opioids and paracetamol. Atovaquone
decreases the metabolism of zidovudine and cotrimoxazole. Theoretically, it may displace
other highly protein-bound drugs from plasma-protein binding sites.
Chloroquine
Molecular weight: 436.0
Chloroquine is a 4-aminoquinoline which has been used extensively for the treatment and prevention of malaria. Widespread resistance has now rendered it virtually useless against P. falciparum infections in most parts of the world, although it still maintains considerable efficacy for the treatment of P. vivax, P. ovale and P. malariae infections. As with other 4-aminoquinolines, it does not produce radical cure.
Chloroquine interferes with parasite haem detoxification (1, 2). Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the concentrations of chloroquine at its site of action, the parasite food vacuole.
Formulations
chloroquine base as phosphate or sulfate.
Pharmacokinetics
Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract when taken orally, although peak plasma concentrations can vary considerably.
Absorption is also very rapid following intramuscular and subcutaneous administration. Chloroquine is extensively distributed into body tissues, including the placenta and breast milk, and has an enormous total apparent volume of distribution. The relatively small volume of distribution of the central compartment means that transiently
cardiotoxic levels may occur following intravenous administration unless the rate of parenteral delivery is strictly controlled. Some 60% of chloroquine is bound to plasma
proteins, and the drug is eliminated slowly from the body via the kidneys, with an estimated terminal elimination half-life of 1–2 months. Chloroquine is metabolized
in the liver, mainly to monodesethylchloroquine, which has similar activity against P. falciparum.
Toxicity
Chloroquine has a low safety margin and is very dangerous in overdosage. Larger doses of chloroquine are used for the treatment of rheumatoid arthritis than for malaria, so adverse effects are seen more frequently in patients with the former. The drug is generally well tolerated. The principle limiting adverse effects in practice are the unpleasant taste, which may upset children, and pruritus, which may be severe in dark-skinned patients. Other less common side effects include headache, various skin eruptions and gastrointestinal disturbances, such as nausea, vomiting and diarrhoea. More rarely central nervous system toxicity including, convulsions and mental changes may occur. Chronic use (>5 years continuous use as prophylaxis) may lead to eye disorders, including keratopathy and retinopathy. Other uncommon effects include myopathy, reduced hearing, photosensitivity and loss of hair. Blood disorders, such as aplastic anaemia, are extremely uncommon. Acute overdosage is extremely dangerous and death can occur within a few hours. The patient may progress from feeling dizzy and drowsy with headache and gastrointestinal
upset, to developing sudden visual loss, convulsions, hypokalaemia, hypotension and cardiac arrhythmias. There is no specific treatment, although diazepam and epinephrine (adrenaline) administered together are beneficial.
Drug interactions
Major interactions are very usual. There is a theoretical increased risk of arrhythmias when chloroquine is given with halofantrine or other drugs that prolong the electrocardiograph QT interval; a possible increased risk of convulsions with mefloquine; reduced absorption with antacids; reduced metabolism and clearance with cimetidine; an increased risk of acute dystonic reactions with metronidazole; reduced bioavailability of ampicillin and praziquantel; reduced therapeutic effect of thyroxine; a possible antagonistic effect on the antiepileptic effects of carbamazepine and sodium valproate; and increased plasma concentrations of cyclosporine.
Clindamycin
Molecular weight: 425.0
Clindamycin is a lincosamide antibiotic,
i.e. a chlorinated derivative of lincomycin.
It is very soluble in water. It inhibits
the early stages of protein synthesis
by a mechanism similar to that of the
macrolides. It may be administered
by mouth as capsules containing the
hydrochloride or as oral liquid preparations
containing the palmitate hydrochloride.
Clindamycin is given parenterally as the phosphate either by the intramuscular or the
intravenous route. It is used for the treatment of anaerobic and Gram-positive bacterial
infections, babesiosis, toxoplasmosis and Pneumocystis carinii pneumonia.
Formulations
clindamycin base as
hydrochloride.
Pharmacokinetics
About 90% of a dose is absorbed following oral administration. Food does not impede
absorption but may delay it. Clindamycin phosphate and palmitate hydrochloride are
rapidly hydrolysed to form the free drug. Peak concentrations may be reached within 1 h
in children and 3 h in adults. It is widely distributed, although not into the cerebrospinal
fluid. It crosses the placenta and appears in breast milk. It is 90% bound to plasma proteins
and accumulates in leukocytes, macrophages and bile. The half-life is 2–3 h but this may
be prolonged in neonates and patients with renal impairment. Clindamycin undergoes
metabolism to the active N-demethyl and sulfoxide metabolites, and also some inactive
metabolites. About 10% of a dose is excreted in the urine as active drug or metabolites
and about 4% in the faeces. The remainder is excreted as inactive metabolites. Excretion
is slow and takes place over many days. Clindamycin is not effectively removed from the
body by dialysis.
Toxicity
Diarrhoea occurs in 2–20% of patients. In some, pseudomembranous colitis may develop
during or after treatment, which can be fatal. Other reported gastrointestinal effects
include nausea, vomiting, abdominal pain and an unpleasant taste in the mouth. Around
10% of patients develop a hypersensitivity reaction. This may take the form of skin rash,
urticaria or anaphylaxis. Other adverse effects include leukopenia, agranulocytosis,
eosinophilia, thrombocytopenia, erythema multiforme, polyarthritis, jaundice and
hepatic damage. Some parenteral formulations contain benzyl alcohol, which may cause
fatal “gasping syndrome” in neonates.
Drug interactions
Clindamycin may enhance the effects of drugs with neuromuscular blocking activity
and there is a potential danger of respiratory depression. Additive respiratory depressant
effects may also occur with opioids. Clindamycin may antagonize the activity of
parasympathomimetics.
Doxycycline
Molecular weight: 444.4
Doxycycline is a tetracycline derivative with
uses similar to those of tetracycline. It may be
preferred to tetracycline because of its longer halflife,
more reliable absorption and better safety
profile in patients with renal insufficiency, where
it may be used with caution. It is relatively water
insoluble but very lipid soluble. It may be given
orally or intravenously.
It is available as the hydrochloride salt or phosphate complex, or as a complex prepared
from the hydrochloride and calcium chloride.
Formulations
doxycycline salt as hydrochloride.
Pharmacokinetics
Doxycycline is readily and almost completely absorbed from the gastrointestinal tract
and absorption is not affected significantly by the presence of food. Peak plasma
concentrations occur 2 h after administration. Some 80–95% is protein-bound and halflife
is 10–24 h. It is widely distributed in body tissues and fluids. In patients with
normal renal function, 40% of doxycycline is excreted in the urine, although more if the
urine is alkalinized. It may accumulate in renal failure. However, the majority of the dose
is excreted in the faeces.
Toxicity
As for tetracycline. Gastrointestinal effects are fewer than with tetracycline, although
oesophageal ulceration can still be a problem if insufficient water is taken with tablets
or capsules. There is less accumulation in patients with renal impairment. Doxycycline
should not be given to pregnant or lactating women, or children aged up to 8 years.
Tetracycline toxicityAll the tetracyclines have similar adverse effect profiles. Gastrointestinal effects, such as nausea, vomiting and diarrhoea, are common, especially with higher doses, and are due to mucosal irritation. Dry mouth, glossitis, stomatitis, dysphagia and oesophageal ulceration have also been reported. Overgrowth of Candida and other bacteria occurs, presumably due to disturbances in gastrointestinal flora as a result of incomplete absorption of the drug. This effect is seen less frequently with doxycycline, which is better absorbed. Pseudomembranous colitis, hepatotoxicity and pancreatitis have also been reported. Tetracyclines accumulate in patients with renal impairment and this may renal failure. In contrast doxycycline accumulates less and is preferred in patient with renal impairment. The use of out-of-date tetracycline can result in the development of a reversible Fanconitype syndrome characterized by polyuria and polydipsia with nausea, glycosuria, aminoaciduria, hypophosphataemia, hypokalaemia, and hyperuricaemia with acidosis and proteinuria. These effects have been attributed to the presence of degradation products, in particular anhydroepitetracycline. Tetracyclines are deposited in deciduous and permanent teeth during their formation and cause discoloration and enamel hypoplasia. They are also deposited in calcifying areas in bone and the nails and interfere with bone growth in young infants or pregnant women. Raised intracranial pressure in adults and infants has also been documented. Tetracyclines use in pregnancy has also been associated with acute fatty liver. Tetracyclines should therefore not be given to pregnant or lactating women, or children aged up to 8 years. Hypersensitivity reactions occur, although they are less common than for β-lactam antibiotics. Rashes, fixed drug reactions, drug fever, angioedema, urticaria, pericarditis and asthma have all been reported. Photosensitivity may develop, and, rarely, haemolytic anaemia, eosinophilia, neutropenia and thrombocytopenia. Pre-existing systemic lupus erythematosus may be worsened and tetracyclines are contraindicated in patients with the established disease.
Drug interactions
Doxycycline has a lower affinity for binding with calcium than other tetracyclines, so
may be taken with food or milk. However, antacids and iron may still affect absorption.
Metabolism may be accelerated by drugs that induce hepatic enzymes, such as
carbamazepine, phenytoin, phenobarbital and rifampicin, and by chronic alcohol use.
Lumefantrine (benflumetol)
Molecular weight: 528.9
Lumefantrine belongs to the aryl
aminoalcohol group of antimalarials,
which also includes quinine,
mefloquine and halofantrine. It
has a similar mechanism of action.
Lumefantrine is a racemic fluorine
derivative developed in China. It is
only available in an oral preparation
coformulated with artemether.
This ACT is highly effective against
multidrug resistant P. falciparum.
Formulations
Available only in an oral preparation coformulated with artemether.
artemether and 120 mg of lumefantrine.
Pharmacokinetics
Oral bioavailability is variable and is highly dependant on administration with fatty
foods. Absorption increases by 108% after a meal and is lower in patients with
acute malaria than in convalescing patients. Peak plasma levels occur approximately 10 h
after administration. The terminal elimination half-life is around 3 days.
Toxicity
Despite similarities with the structure and pharmacokinetic properties of halofantrine,
lumefantrine does not significantly prolong the electrocardiographic QT interval, and has
no other significant toxicity (50). In fact the drug seems to be remarkably well tolerated.
Reported side effects are generally mild – nausea, abdominal discomfort, headache and
dizziness – and cannot be distinguished from symptoms of acute malaria.
Drug interactions
The manufacturer of artemether-lumefantrine recommends avoiding the following: grapefruit
juice; antiarrhythmics, such as amiodarone, disopyramide, flecainide, procainamide and
quinidine; antibacterials, such as macrolides and quinolones; all antidepressants; antifungals
such as imidazoles and triazoles; terfenadine; other antimalarials; all antipsychotic drugs;
and beta blockers, such as metoprolol and sotalol. However, there is no evidence that
coadministration with these drugs would be harmful.
Primaquine
Molecular weight: 259.4
Primaquine is an 8-aminoquinoline and is
effective against intrahepatic forms of all types of
malaria parasite. It is used to provide radical cure
of P. vivax and P. ovale malaria, in combination
with a blood schizontocide for the erythrocytic
parasites. Primaquine is also gametocytocidal
against P. falciparum and has significant blood
stages activity against P. vivax (and some against
asexual stages of P. falciparum). The mechanism
of action is unknown.
Formulations
primaquine base as diphosphate.
Pharmacokinetics
Primaquine is readily absorbed from the gastrointestinal tract. Peak plasma concentrations
occur around 1–2 h after administration and then decline, with a reported elimination
half-life of 3–6 h. Primaquine is widely distributed into body tissues. It is rapidly
metabolized in the liver. The major metabolite is carboxyprimaquine, which may
accumulate in the plasma with repeated administration.
Toxicity
The most important adverse effects are haemolytic anaemia in patients with G6PD
deficiency, other defects of the erythrocytic pentose phosphate pathway of glucose
metabolism, or some other types of haemoglobinopathy. In patients with the African
variant of G6PD deficiency, the standard course of primaquine generally produces a
benign self-limiting anaemia. In the Mediterranean and Asian variants, haemolysis may be
much more severe. Therapeutic doses may also cause abdominal pain if administered on
an empty stomach. Larger doses can cause nausea and vomiting. Methaemoglobinaemia
may occur. Other uncommon effects include mild anaemia and leukocytosis.
Overdosage may result in leukopenia, agranulocytosis, gastrointestinal symptoms,
haemolytic anaemia and methaemoglobinaemia with cyanosis.
Drug interactions
Drugs liable to increase the risk of haemolysis or bone marrow suppression should be
avoided.
Proguanil
Molecular weight: 253.7
Proguanil is a biguanide compound that is
metabolized in the body via the polymorphic
cytochrome P450 enzyme CYP2C19
to the active metabolite, cycloguanil.
Approximately 3% of Caucasian and
African populations and 20% of Oriental
people are “poor metabolizers” and have
considerably reduced biotransformation of
proguanil to cycloguanil (55,56).
Cycloguanil inhibits plasmodial dihydrofolate reductase. The parent compound has
weak intrinsic antimalarial activity through an unknown mechanism. It is possibly
active against pre-erythrocytic forms of the parasite and is a slow blood schizontocide.
Proguanil also has sporontocidal activity, rendering the gametocytes non-infective to
the mosquito vector. Proguanil is given as the hydrochloride salt in combination with
atovaquone. It is not used alone for treatment as resistance to proguanil develops very
quickly. Cycloguanil was formerly administered as an oily suspension of the embonate
by intramuscular injection.
Formulations
proguanil hydrochloride containing 87 mg of proguanil base.
In coformulation with atovaquone: atovaquone and 100 mg of proguanil
hydrochloride for adults.atovaquone and 25 mg of proguanil hydrochloride for
paediatric use.
Pharmacokinetics
Proguanil is readily absorbed from the gastrointestinal tract following oral administration.
Peak plasma levels occur at about 4 h, and are reduced in the third trimester of pregnancy.
Around 75% is bound to plasma proteins. Proguanil is metabolized in the liver to the
active antifolate metabolite, cycloguanil, and peak plasma levels of cycloguanil occur
an hour after those of the parent drug. The elimination half-lives of both proguanil
and cycloguanil is approximately 20 h. Elimination is about 50% in the urine, of
which 60% is unchanged drug and 30% cycloguanil, and a further amount is excreted
in the faeces. Small amounts are present in breast milk. The elimination of cycloguanil
is determined by that of the parent compound. The biotransformation of proguanil
to cycloguanil via CYP2C19 is reduced in pregnancy and women taking the oral
contraceptive pill.
Toxicity
Apart from mild gastric intolerance, diarrhoea and occasional aphthous ulceration
and hair loss there are few adverse effects associated with usual doses of proguanil
hydrochloride. Haematological changes (megaloblastic anaemia and pancytopenia)
have been reported in patients with severe renal impairment. Overdosage may produce
epigastric discomfort, vomiting and haematuria. Proguanil should be used cautiously
in patients with renal impairment and the dose reduced according to the degree of
impairment.
Drug interactions
Interactions may occur with concomitant administration of warfarin. Absorption of
proguanil is reduced with concomitant administration of magnesium trisilicate.
Quinine
Molecular weight: 324.4
Quinine is an alkaloid derived from
the bark of the Cinchona tree. Four
antimalarial alkaloids can be derived
from the bark: quinine (the main alkaloid),
quinidine, cinchonine and cinchonidine.
Quinine is the L-stereoisomer of quinidine.
Quinine acts principally on the mature trophozoite stage of parasite development and
does not prevent sequestration or further development of circulating ring stages of
P. falciparum. Like other structurally similar antimalarials, quinine also kills the sexual
stages of P. vivax, P. malariae and P. ovale, but not mature gametocytes of P. falciparum.
It does not kill the pre-erythrocytic stages of malaria parasites. The mechanisms of its
antimalarial actions are thought to involve inhibition of parasite haem detoxification in
the food vacuole, but are not well understood.
Formulations
quinine hydrochloride, quinine dihydrochloride, quinine sulfate and quinine
bisulfate containing 82%, 82%, 82.6% and 59.2% quinine base respectively.quinine hydrochloride, quinine dihydrochloride and quinine
sulfate containing 82%, 82% and 82.6% quinine base respectively.
Pharmacokinetics
The pharmacokinetic properties of quinine are altered significantly by malaria infection,
with reductions in apparent volume of distribution and clearance in proportion to disease
severity. In children under 2 years of age with severe malaria, concentrations
are slightly higher than in older children and adults (63). There is no evidence for
dose-dependent kinetics. Quinine is rapidly and almost completely absorbed from the
gastrointestinal tract and peak plasma concentrations occur 1–3 h after oral administration
of the sulfate or bisulfate (64). It is well absorbed after intramuscular injection in severe
malaria. Plasma-protein binding, mainly to alpha 1-acid glycoprotein, is 70% in
healthy subjects but rises to around 90% in patients with malaria.
Quinine is widely distributed throughout the body including the cerebrospinal fluid (2–7%
of plasma values), breast milk (approximate 30% of maternal plasma concentrations) and
the placenta. Extensive metabolism via the cytochrome P450 enzyme CYP3A4 occurs
in the liver and elimination of more polar metabolites is mainly renal . The initial
metabolite 3-hydroxyquinine contributes approximately 10% of the antimalarial activity
of the parent compound, but may accumulate in renal failure. Excretion is increased
in acid urine. The mean elimination half-life is around 11 h in healthy subjects, 16 h in
uncomplicated malaria and 18 h in severe malaria. Small amounts appear in the bile
and saliva.
Toxicity
Administration of quinine or its salts regularly causes a complex of symptoms known
as cinchonism, which is characterized in its mild form by tinnitus, impaired high tone
hearing, headache, nausea, dizziness and dysphoria, and sometimes disturbed vision. More severe manifestations include vomiting, abdominal pain, diarrhoea and severe
vertigo. Hypersensitivity reactions to quinine range from urticaria, bronchospasm,
flushing of the skin and fever, through antibody-mediated thrombocytopenia and
haemolytic anaemia, to life-threatening haemolytic-uraemic syndrome. Massive
haemolysis with renal failure (“black water fever”) has been linked epidemiologically
and historically to quinine, but its etiology remains uncertain . The most important
adverse effect in the treatment of severe malaria is hyperinsulinaemic hypoglycaemia. This is particularly common in pregnancy (50% of quinine-treated women with
severe malaria in late pregnancy). Intramuscular injections of quinine dihydrochloride
are acidic (pH 2) and cause pain, focal necrosis and in some cases abscess formation, and
in endemic areas are a common cause of sciatic nerve palsy. Hypotension and cardiac
arrest may result from rapid intravenous injection. Intravenous quinine should be given
only by infusion, never injection. Quinine causes an approximately 10% prolongation of
the electrocardiograph QT interval – mainly as a result of slight QRS widening. The
effect on ventricular repolarization is much less than that with quinidine. Quinine has
been used as an abortifacient, but there is no evidence that it causes abortion, premature
labour or fetal abnormalities in therapeutic use.
Overdosage of quinine may cause oculotoxicity, including blindness from direct retinal
toxicity, and cardiotoxicity, and can be fatal. Cardiotoxic effects are less frequent
than those of quinidine and include conduction disturbances, arrhythmias, angina,
hypotension leading to cardiac arrest and circulatory failure. Treatment is largely
supportive, with attention being given to maintenance of blood pressure, glucose, and
renal function and to treating arrhythmias.
Drug interactions
There is a theoretical concern that drugs that may prolong the QT interval should
not be given with quinine, although whether or not quinine increases the risk of
iatrogenic ventricular tachyarrhythmia has not been established. Antiarrhythmics,
such as flecainide and amiodarone, should probably be avoided. There might be an
increased risk of ventricular arrhythmias with antihistamines such as terfenadine, and
with antipsychotic drugs such as pimozide and thioridazine. Halofantrine, which causes
marked QT prolongation, should be avoided but combination with other antimalarials,
such as lumefantrine and mefloquine is safe. Quinine increases the plasma concentration
of digoxin. Cimetidine inhibits quinine metabolism, causing increased quinine levels and
rifampicin increases metabolic clearance leading to low plasma concentrations and an
increased therapeutic failure rate (77).