Download Antimalarial Drug Toxicity: A Review

Review
Chemotherapy 2007;53:385–391
DOI: 10.1159/000109767
Received: October 26, 2004
Accepted after revision: August 7, 2006
Published online: October 12, 2007
Antimalarial Drug Toxicity: A Review
Hussien O. AlKadi
Faculty of Medicine and Health Sciences, Sana’a University, Sana’a, Yemen
Key Words
Antimalarial drugs Toxicity
Introduction
Abstract
Antimalarial drug toxicity is viewed differently depending
upon whether the clinical indication is for malaria treatment
or prophylaxis. In the treatment of Plasmodium falciparum
malaria, which has a high mortality if untreated, a greater risk
of adverse reactions to antimalarial drugs is inevitable. As
chloroquine resistance has become widespread, alternative
agents may be used in treatment regimens, however, the
toxicity of these antimalarial agents should be considered.
Quinine is the mainstay for treating severe malaria due to its
rare cardiovascular or CNS toxicity, but its hypoglycemic effect may be problematic. Mefloquine can cause dose-related serious neuropsychiatric toxicity and pyrimethaminedapsone is associated with agranulocytosis, especially if the
recommended dose is exceeded. Pyrimethamine-sulfadoxine and amodiaquine are associated with a relatively high
incidence of potentially fatal reactions, and are no longer
recommended for prophylaxis. Atovaquone/proguanil is an
antimalarial combination with good efficacy and tolerability
as prophylaxis and for treatment. The artemisinin derivatives
have remarkable efficacy and an excellent safety record. Prescribing in pregnancy is a particular problem for clinicians
because the risk-benefit ratio is often very unclear.
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Malaria, caused mostly by Plasmodium falciparum
and P. vivax, remains one of the most important infectious diseases in the world. The current approaches to
curtail this disease include vector control, vaccination,
immunotherapy, malaria prevention during pregnancy
and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and
creating a barrier between the human host and mosquitoes. One of the most important current approaches to
develop new drugs involves the synthesis of chemical libraries and their evaluation against most validated biochemical targets of malarial parasites.
Avenues of research for the development of new antimalarials include lipid metabolism, degradation of hemoglobin and proteins, interaction with molecule transport, iron metabolism, apicoplasty, and signal transduction. Throughout the course of evolution, microorganisms have thwarted traps set by the environment including those designed by man.
P. falciparum, which is responsible for causing severe
forms of the disease, is also adept at developing resistance
to drugs thereby decreasing their efficacy in treatment
over a period of time. Antimalarial drug toxicity is one
side of the risk-benefit equation and is viewed differently
depending upon whether the clinical indication for drug
administration is malaria treatment or prophylaxis. Research that leads to drug registration tends to omit two
important groups who are particularly vulnerable to malaria – very young children and pregnant women. Prescribing in pregnancy is a particular problem for cliniProf. Hussien AlKadi
Faculty of Medicine, Sana’a University
PO Box 13276, Sana’a (Yemen)
Tel +967 1 205 335
E-Mail [email protected]
cians because the risk-benefit ratio is often very unclear
[1]. In the prevention of malaria in travelers, a careful
risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of
harm from the prophylactic agent. The therapeutic ratios
for some antimalarials are narrow, and toxicity is frequent when recommended treatment dosages are exceeded; parenteral administration above the recommended
dose range is especially associated with the hazards of
cardiac and neurological toxicity [2]. The purpose of this
review is to update physicians on the toxicity associated
with antimalarial drugs.
Toxicity
All drugs cause toxicity. Type A adverse effects (AEs)
result from excessive responses to a drug; these AEs are
predictable from the known effects of the drug and are
dose or concentration related. In contrast, type B AEs are
not predictable from the known effects of the drug; there
may be an immunological basis to the AE, and there is
often no clear relationship with the dose or concentration
of drug. Furthermore, certain patient groups are at particular risk of severe AEs – including the elderly, the very
young, glucose-6-phosphate dehydrogenase (G6PD)-deficient people and HIV-positive people – and these may
not be well represented in submissions to regulatory authorities [3, 4]. Toxicity may range from mild to serious
and from reversible to irreversible [3]. Adequate clinical
response is defined as rare toxicities, e.g. those which
occur in !1% of patients using the agent, uncommon in
1–10%, and common in 110%.
Toxicity of Antimalarial Drugs
All drugs used for malaria therapy or prophylaxis have
common AEs, in addition to rare, mild-to-severe and/or
sometimes fatal AEs [5].
Chloroquine
Chloroquine is effective against P. vivax, P. ovale, P.
malariae, and drug-sensitive P. falciparum. It is used for
treatment or as prophylaxis. Chloroquine is usually well
tolerated. Mild side effects, such as nausea and headache,
may occur. Africans rather than African-Canadians may
experience generalized pruritus, which is not indicative
of drug allergy. Fehintola et al. [6] observed an incidence
of 24.7% of chloroquine-induced pruritus in African
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Chemotherapy 2007;53:385–391
children. Ademowo and Sodeinde [7] recorded a higher
incidence of 41.3%, but patient age ranged from 1 to 33
years. Chloroquine-induced pruritus is thought to involve a complex interaction between the host, the parasite
and the drug. Some genetic markers, notably hemoglobin
genotype and G6PD, have been found to be associated
with chloroquine-induced pruritus. Retinal toxic effects,
which may occur with long-term daily doses of chloroquine (1100 g total dose) used in the treatment of other
diseases, are extremely unlikely with chloroquine given
as weekly chemoprophylaxis. Chloroquine may worsen
psoriasis and, rarely, is associated with seizures and psychosis. Acute toxicity is most frequently encountered
when therapeutic or high doses are administered too rapidly by parenteral routes. Cardiovascular effects include
hypotension, vasodilatation, suppressed myocardial
function, cardiac arrhythmias, and cardiac arrest. Confusion, convulsions and coma indicate central nervous
dysfunction. Chloroquine doses of more than 5 g given
parenterally are usually fatal [8]. Parenteral administration can cause hypotension, cardiac depression and arrhythmias. A number of case reports in the medical literature have suggested an association between seizures
and parenteral chloroquine, both at therapeutic concentrations and overdose. Seizures may occur within a few
hours of overdose or between 1 day and several weeks after the start of therapy [9]. Chloroquine is contraindicated in individuals with a history of epilepsy or generalized psoriasis.
Primaquine
Primaquine is often administered for the hypnozoite
stage of P. vivax and P. ovale to prevent relapse and after
departure from a malaria-risk area for prophylaxis. Therapeutic or higher doses of primaquine can cause hemolytic anemia or fatal hemolysis in G6PD-deficient persons. In Arab populations living in malaria-risk areas,
more than 30% of the patients will show evidence of this
deficiency in general, with an incidence of about 10–20%.
In patients having the sickle cell trait, G6PD deficiency is
more commonly seen. Large doses cause epigastric distress and mild-to-moderate abdominal distress. Mild
anemia, cyanosis (methemoglobinemia), and leukocytosis are less common. High doses (60–240 mg of primaquine daily) accentuate the abdominal symptoms and
cause methemoglobinemia in most subjects and leukopenia in some. Methemoglobinemia can occur even with
common doses of primaquine and can be severe in persons with congenital deficiency of nicotinamide adenine
dinucleotide methemoglobin reductase [10]. GranulocyAlKadi
topenia and granulocytosis are rare complications of
therapy and usually associated with overdosing. Hypertension, arrhythmia and symptoms involving the central
nervous system including depression and confusion are
further rare complications [11].
cant association. However, the long-term safety (13
months) of doxycycline has not been established. Adjustment of the doxycycline dosage may be necessary with
either a twice daily dosing schedule (100 mg b.i.d.) or
200 mg daily [14].
Mefloquine
Mefloquine is structurally similar to quinine. It is
used for treatment or prophylaxis of drug-resistant malaria. It may have cardiac depressant effects and antifibrillary activity, and may result in marked gastrointestinal or CNS AEs and is, therefore, not recommended as
first-line treatment; nausea, strange dreams, seizures
(rare), and psychosis may also occur [12]. Severe CNS
events requiring hospitalization (e.g. seizures and hallucinations) occur in 1:10,000 patients taking mefloquine
as chemoprophylaxis. However, milder CNS events (e.g.
dizziness, headache, insomnia, and vivid dreams) are
more frequently observed, occurring in up to 25% of patients. The higher incidence of AEs observed when the
drug is used at the higher doses needed for malaria treatment implies a dose effect [13]. It is contraindicated in
hypersensitivity; epilepsy or seizure disorder; severe psychiatric disorder, and in patients with a diagnosis or treatment for irregular heartbeat.
Proguanil
Proguanil marketed in combination with atovaquone
is used for both the treatment of uncomplicated P. falciparum and prophylaxis of mild chloroquine-resistant
malaria. The most common AEs reported in 110% of patients taking atovaquone/proguanil for treatment of malaria are abdominal pain, nausea, vomiting, and headache in adults, and vomiting in children; for prophylaxis
of malaria AEs include headache and abdominal pain
and vomiting in children. It is well tolerated, and although oral aphthous ulcerations are not uncommon,
they are rarely severe enough to warrant discontinuing
this medication. Proguanil is considered safe during
pregnancy and breastfeeding, but insufficient drug is excreted in the milk to protect a breastfed infant [15].
Amodiaquine
Amodiaquine is thought to have the same mechanism
of action as its analogue chloroquine. Hepatitis and agranulocytosis were seen in patients taking amodiaquine for
prophylaxis, and the drug is no longer recommended for
this indication. Amodiaquine-quinoneimine can be generated from amodiaquine both spontaneously, when the
drugs is in aqueous solution, and as a result of enzyme activity. The quinoneimine is highly reactive and haptenates
proteins, generating antigen to which an immune response
may be mounted. Repeated exposure to this antigen may
be important in the generation of organ damage [3].
Doxycycline
Doxycycline is used as part of combination therapy or
as prophylaxis of malaria. Photosensitivity may occur
with prolonged exposure to sunlight or tanning equipment. In renal impairment, dose reductions are indicated. Doxycycline may cause gastrointestinal upset and
rarely esophageal ulceration. It is photosensitizing and
may make the skin more susceptible to sunburns. Although tetracyclines and other antibiotics have been cited as a cause of oral contraceptive failure [8, 14], a recent
case-control analysis failed to demonstrate any signifiAntimalarial Drug Toxicity
Diaminopyrimidines (Antifolates)
Pyrimethamine-sulfadoxine can be used to treat malaria. It is no longer considered a first-line agent for prophylaxis because of the AE profile. Co-trimoxazole can
be used in combination with rifampicin and isoniazid in
resistant P. falciparum [16]. Antimalarial doses of pyrimethamine alone cause little toxicity except occasional
skin rashes and decreased hematopoiesis. Excessive doses
produce megaloblastic anemia, resembling folate deficiency, that responds readily to drug withdrawal or treatment with folinic acid. It causes severe to even fetal cutaneous reactions, such as erythema multiforme, StevensJohnson syndrome, and toxic epidermal necrolysis,
dermatitis, serum sickness-type reactions, and hepatitis.
Toxic sulfamethoxazole metabolites may elicit hypersensitivity reactions. Trimethoprim can inhibit renal creatinine secretion, leading to high serum creatinine levels.
Trimethoprim also inhibits dihydrofolate reductase,
causing decreased dopamine production, which may lead
to parkinsonian symptoms [17]. The drug is contraindicated in persons with a history of intolerance to sulfonamides and in infants ^2 months [18].
Quinine
Quinine sulfate is used for malaria treatment only, has
no role in prophylaxis and is used with a second agent in
drug-resistant P. falciparum. Hemolytic anemia may occur in patients with G6PD deficiency.
Chemotherapy 2007;53:385–391
387
Quinine is associated with a triad of dose-related toxicities when it is given at full therapeutic or excessive doses, e.g. cinchonism, hypoglycemia, and hypotension.
Quinine has an -adrenergic blocking effect, and hypotension may occur as a result of vasodilation, myocardial
depression, or dysrhythmia [19]. Mild forms of cinchonism, e.g. tinnitus, high-tone deafness, visual disturbances, headache, dysphoria, nausea, vomiting, and postural hypertension, occur frequently and disappear soon
after the drug is withdrawn. Hypoglycemia is also common [20]. Symptoms appear when the total plasma concentration of quinine is about 5 mg/l, i.e. at the lower
limit of the therapeutic range of the drug, which is 5–
15 mg/l. Dose-related cardiovascular, gastrointestinal
and central nervous system effects may arise following
excessive infusion or from accumulation following oral
administration. Severe hypotension may develop if the
drug is injected too rapidly. A single dose of quinine of
13 g is capable of causing serious and potentially fatal intoxication in adults, preceded by central nervous system
involvement and seizures. Much smaller doses can be lethal in children. Dysrhythmias, hypotension and cardiac
arrest can result from the cardiotoxic action, and visual
disorders may be severe, leading to blindness in rare cases. Plasma concentrations 15 g/ml cause cinchonism,
110 g/ml visual impairment, 115 g/ml cardiac arrhythmias, and 122.2 g/ml death [21].
Artemisinin and Its Derivates
Artemether-lumefantrine, a new fixed-dose oral antimalarial drug which combines the fast onset of action of
artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in
the treatment of acute uncomplicated P. falciparum malaria. The most commonly reported AEs following artemether-lumefantrine therapy are abdominal pain, anorexia, nausea, vomiting, diarrhea and CNS involvement
(headache and dizziness). Pruritus and rash were reported by !2% of patients. Artemether-lumefantrine can thus
be expected to show, both in children and in adults, a favorable safety profile for the treatment of acute, uncomplicated, P. falciparum malaria; it could as well be an alternative treatment option for travelers to endemic countries. Oral artesunate and artemether alone were very well
tolerated. There was no difference in the incidence of possible AEs between the two drugs, and no evidence that
either derivative caused allergic, neurologic or psychiatric
reactions, or cardiovascular or dermatologic toxicity [22].
Piperaquine has a mode of action similar to quinine and
is used in combination with artemisinin.
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Atovaquone
Atovaquone causes few side effects that required withdrawal of therapy. The most common reactions are rash,
fever, vomiting, diarrhea, abdominal pain, and headache.
Patients treated with atovaquone only occasionally exhibit abnormalities in serum transaminase and amylase
levels. Atovaquone/proguanil should not be used in infants !11 kg, pregnant women, women breast-feeding infants !11 kg, or patients with severe renal impairment
(creatinine clearance !30 ml/min). Apparently, a few
acute AEs are caused, but more clinical evaluation of the
drug is needed, especially to detect possible rare, unusual, or long-term toxicity [23].
Toxicity of Antimalarial Drugs
Cardiovascular Toxicity
Chloroquine has three main cardiovascular effects:
membrane stabilization, direct negative inotropic effects,
and direct arterial vasodilation. The data also suggest a
role for nitric oxide and histamine release in mediating
this response leading to hypotension/postural hypotension. These effects are manifested as rhythm and
conductance disturbances, myocardiopathy, or vasoplegic shocks. Quinine and halofantrine are capable of prolonging the QT interval. Quinine prolongs the QT interval at standard doses, similar to halofantrine. Halofantrine induces a dose-related prolongation of the QT
interval whereas mefloquine has no effect on the QT interval. However, the risk of significant QT prolongation
was greater if halofantrine was given as a re-treatment
following mefloquine failure than as primary treatment.
Cardiotoxicity of antimalarials is increased in patients
with acute renal failure, especially after 3 days of treatment. This is partly because the degree of QT prolongation is dependent on the plasma concentration of halofantrine. The frequency of QT interval prolongations following artemether-lumefantrine treatment was similar
to or lower than that observed with chloroquine, mefloquine, or artesunate + mefloquine; these changes were
considerably less frequent than with quinine or halofantrine [24, 25].
Ocular Toxicity
Ocular toxicity caused by antimalarials was first described in the literature as early as 1957. As antimalarials
were also found to be effective in the treatment of rheumatoid diseases apart from the treatment and prophylaxis of malaria, the risk of ocular toxicity is increased.
AlKadi
The incidence of early retinopathy in ophthalmologically
unmonitored patients was estimated by Bernstein [26] to
be 10% for chloroquine and 3–4% for hydroxychloroquine. Advanced retinopathy had an incidence of 0.5%.
These risks might be reduced substantially by regular observation and testing [27]. The major toxicity of antimalarial agents is retinal damage (rare), which can lead to
visual impairment. The major risk factor for retinal toxicity appears to be the combination of cumulative doses
1800 g and age 170 years (presumably due to the increased prevalence of macular disease in the elderly). In
the absence of risk factors, it is recommended that an
ophthalmologic examination and central field testing be
performed every 6–12 months. The central 10° of the visual field is the initial site of antimalarial retinal toxicity.
There is a higher risk of visual loss when plasma concentrations of quinine exceed 15 mg/l at any stage of overdosage. Blurred vision may proceed to complete blindness
within a few hours. As vision is lost, the pupils become
dilated and unresponsive to light. Initially, only narrowing of the retinal arterioles may be seen on fundoscopy
but after 3 days retinal edema may appear [28]. Hirst
et al. [29] reported that a 34-year-old man treated with
1250 g of amodiaquine hydrochloride during 1 year was
noted to have diffuse conjunctival and corneal changes
and also demonstrated abnormal results in retinal function tests.
Myopathy
Factors increasing the risk of muscle disorders may
depend on concomitant disease (diabetes, hypothyroidism, renal and hepatic disease), advanced age and dose.
Myopathy has rarely been reported with these agents
[30]. Clinicians should be aware that treatment may lead
to neuromyopathy as well as irreversible retinopathy with
chronic use. Usually patients complain of muscle weakness with or without muscle pain. Peripheral sensory abnormalities, such as lack of deep tendon reflexes, may be
noted on examination. Muscle enzymes are normal or
slightly elevated. In cases suspected of drug-induced
myopathy, plasma concentrations of cellular contents
released from damaged muscle are assessed. These laboratory parameters include creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, aldolase myoglobin, and potassium and
phosphorus, both of which increase with muscle injury.
Serum creatine kinase is considered to be the most sensitive indicator, but its lack of specificity is a major limitation. In the presence of drug-induced myopathy, serum
creatine kinase may be normal, slightly elevated, or as
Antimalarial Drug Toxicity
high as 10–20 times the upper normal limit [31]. Myopathy and cardiomyopathy are thought to be caused by
damage to the mitochondria in muscle cells.
Neurotoxicity
Serial audiometry was performed in 10 patients receiving quinine treatment for acute P. falciparum malaria. Quinine reduced high-tone auditory responses.
Tinnitus was reported in 7 patients after plasma concentrations 15 mg/ml, but the high-tone loss resolved
completely after treatment was completed. Neuropsychiatric AEs of mefloquine range from anxiety and paranoia
to depression, hallucinations, psychotic behavior and
possibly suicide [32]. A number of case reports in the
medical literature have suggested an association between
seizures and parenteral chloroquine, both at therapeutic
concentrations and overdosage. Seizures may occur within a few hours of overdosage or between 1 day and several weeks after the start of therapy. Seizures complicate
the clinical course of 130% of patients admitted to hospital for cerebral malaria and are associated with an increased risk of death and neurological sequelae. There are
many explanations for seizures in malaria. Due to high
tissue binding, the concentration of chloroquine within
the brain is approximately 4 times that of plasma, and
experimental evidence suggests that chloroquine may
precipitate seizures by attenuation of -amino butyric
acid pathways (GABAergic mechanism) and enhancement of dopaminergic neurotransmission [33, 34]. Auditory deficits inclue transient tinnitus and eighth bilateral
nerve damage after overdose. Deafness and mutism occurred in a 14-year-old child who ingested approximately 6.5–7.8 g of quinine sulfate. Symptoms lasted for approximately 3 days. Benign intracranial hypertension is
a rare but potentially serious condition. It has been documented in association with a variety of drugs, particularly tetracyclines [35, 36].
Hepatotoxicity
Amodiaquine can cause AEs including liver damage.
The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine-quinoneimine, which can bind to cellular macromolecules
and initiate hypersensitivity reactions. Since hepatitis
and agranulocytosis occurred in prophylactically treated
patients, it is no longer recommended as prophylactic
treatment of malaria. Repeated exposure to the quinoneimine-generated antigen may be important in the generation of organ damage [37]. Mainra and Card [38] reported on a 24-year-old woman with severe liver failure
Chemotherapy 2007;53:385–391
389
following trimethoprim-sulfamethoxazole treatment,
demonstrating the possible severity of the drug hypersensitivity syndrome associated with trimethoprim-sulfamethoxazole. The abrupt onset of hepatic failure, 5 days
after the start of doxycycline, and the rapid normalization after drug discontinuation leads to suspect a causal
relationship between doxycycline and liver insufficiency
[39]. Williams [40] found significant changes in the proportions of plasma proteins in malarious birds 8 days after infection; albumin and 2-globulin were reduced,
while 1- and 2-globulin were increased. Those changes
coincided with significant increases in the plasma concentrations of total protein and enzymes (aspartate aminotransferase, glutamate dehydrogenase and -glutamyltransferase), and a decrease in creatinine. A prospective study done in 216 children with complicated P.
falciparum malaria showed hepatopathy in 33.3% of cases, with a higher incidence in children aged 15 years. Bilirubin and alanine aminotransferase were moderately
raised in most cases [40].
Pregnancy
The US Centers for Disease Control and Prevention
consider that chloroquine is safe throughout pregnancy,
and mefloquine is safe in the second and third trimesters,
with limited data suggesting safety in the first trimester
[41]. Malaria often occurs in chloroquine-resistant regions, thus the pregnant traveler cannot generally choose
chloroquine. Effectively, she has the choice of mefloquine
in the second and third trimester, and nothing for the first
trimester. The data suggest that mefloquine may lead to
stillbirths if administered in the first trimester [42]. Published data on 607 pregnancies in which artemisinin compounds were given during the 2nd or 3rd trimesters indicate no evidence of treatment-related, adverse pregnancy
outcomes. Similar data show normal outcomes in 124
pregnancies exposed to artemisinin compounds in the
1st trimester. Artemisinin compounds cannot be recommended for treatment of malaria in the first trimester. Because the safety data are limited, artemisinin compounds
should only be used in the second and third trimester.
Artesunate-atovaquone-proguanil is a well-tolerated, effective, practical, but expensive treatment for multidrugresistant P. falciparum malaria during the second or third
trimester of pregnancy [43]. Very small amounts of antimalarial drugs are have been discovered in the breast
milk, but the amount of drug transferred is not thought
to be harmful to the infant. Because the quantity of antimalarials transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require treatment or chemoprophylaxis should obtain the
recommended antimalarial dosages.
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