The malaria parasite has caused untold grief throughout human history. The name originated from Italian mal aria (bad air) because the ancient Romans believed the disease was caused by the decay in marshes and swamps and was carried by the malodorous “foul” air emanating from these areas.10 In the 1880s, both the Plasmodium protozoa as well as its mosquito vector were identified.10 Today, 40% of the world’s population lives in areas where malaria is endemic. More than 500 million people develop acute malaria infection, and an estimated one million die from the infection each year.2,10,46 Most of these deaths are from Plasmodium falciparum infections of young children in Africa.5 To put this into perspective, it is estimated that two children die from malaria every minute worldwide.55 Included among those at risk of becoming infected are 50 million travelers from industrialized countries who visit the developing countries each year. Despite using prophylactic medications, 30,000 of these travelers will acquire malaria.101
Malaria is an infection of protozoan parasites in the Plasmodium genus with a unique lifecycle involving the Anopheles mosquito as vector. Today malaria is primarily endemic in tropical and subtropical areas worldwide. It was once endemic in temperate areas, including Western Europe and the United States, but economic development and improvements in public health hastened its retreat.45 Malaria was fully eradicated from the United States between 1947 and 1951 due in large part to the powerful insecticidal effects of dichloro-diphenyl-trichloroethane (DDT).45 The emergence of DDT-resistant Anopheles mosquitoes and chloroquine resistant Plasmodium spp have impeded eradication in other parts of the world.45
Malaria has a unique lifecycle (Fig. 59–1) beginning with inoculation of sporozoites from an infected female Anopheles saliva. The sporozoites travel to the liver, where they invade the host’s hepatocytes and undergo asexual division (asexual exoerythrocytic cycle), ultimately causing rupture of the infected hepatocyte (tissue schizont) and release of thousands of merozoites into the blood stream.9 The tissue phase is complete at this point with the exception ofPlasmodium vivax and Plasmodium ovale, which can remain dormant in liver cells (hypnozoites), causing recurrent infections years later. The erythrocytic cycle begins when merozoites penetrate erythrocytes (trophozoites), undergoing additional cycles of asexual division (erythrocytic schizont), leading to cell rupture and the release of a new wave of merozoites to infect additional erythrocytes. This erythrocytic cycle is responsible for the clinical manifestations of malaria. Some erythrocytic merozoites differentiate into sexual forms (macrogametocytes, female and microgametocytes, male). Ingestion of both sexual forms by the female Anopheles during a blood meal allows fertilization and zygote formation in the mosquito midgut epithelium (sporogenic cycle), ultimately leading to rupture of an oocyst and release of sporozoites that migrate to the salivary glands, awaiting injection into another victim.123
Life cycle stages during which antimalarials exert their effects.
Five Plasmodium spp cause malaria in humans (Table 59–1). The majority of cases worldwide are caused by P. falciparum and P. vivax, with P. falciparum responsible for the overwhelming majority of deaths.77 Traditional teaching highlights the synchronization of blood parasite cycles causing a somewhat predictable fever periodicity, described as tertian or quartan fever depending on the causative organism. These classic periodic fevers are rarely observed in Western countries because symptomatic cases are diagnosed earlier than in the past.9 The routine use of antipyretics may also contribute to atypical presentations.
TABLE 59–1.Plasmodium spp Affecting Humans |Favorite Table|Download (.pdf) TABLE 59–1. Plasmodium spp Affecting Humans
|Species ||Distribution ||Fever Cycle (days) ||RBC Preference ||Parasitemia Levels ||Comments |
|P. falciparum ||Widespread throughout tropics ||2 or less(sub-tertian) ||All ages ||Can be high ||Most fatalities |
|P. knowlesi ||Malaysia and neighboring coun-tries ||1 ||All ages ||Can be high ||Zoonosis (primary host Macaque monkey) se-vere disease |
|P. malariae ||Patchy worldwide ||3-4 (quartan) ||Old ||Low ||Chronic infections, late recrudescence |
|P. ovale ||Africa ||2-3 (tertian) ||Young ||Low ||Relapses/hepatic hyp-nozoites |
|P. vivax ||Predominantly Asia ||2-3 (tertian) ||Young ||Low ||Relapses/hepatic hyp-nozoites |
Unlike the other forms of human malaria, lasmodium knowlesi is a true zoonosis, the natural host being macaques (Macaca spp) and related monkey species. Natural transmission of a nonhuman Plasmodium spp to humans was thought to be rare, but increasing numbers of P. knowlesi malarial infections have been reported in and around Malaysia, Indonesia, and Southeast Asia, causing scientists to include this agent as a potential human pathogen.55
It is somewhat ironic that despite sophisticated drug development methods and advanced technology of the 21st century, the most widely used old treatments (quinine and its derivatives) and the best new regimens (artemisinins) have both been used for centuries as ancient herbal remedies derived from plants.
The bark of the cinchona tree, the first effective remedy for malaria, was introduced to Europeans more than 350 years ago.117 The toxicity of its active ingredient, quinine, was noted from the inception of its use. Pharmaceutical advances occurred, funded largely by the US military during World War II, yielding 4-aminoquinolines, 8-aminoquinolines, and novel antifolates. To combat emerging strains of drug resistant P. falciparum that developed during the Vietnam conflict, alternate quinine derivatives (amino alcohols) were developed.112,117 Other drugs used to treat malaria include the folate inhibitors, selected antibiotics, the sulfonamide sulfadoxine, the tetracyclines, and the macrolides (Chap. 57).
With the introduction of each new drug, resistance developed, particularly in Oceania, Southeast Asia, and Africa.112,117 In some places, quinine is again the first-line therapy for malaria.62 In the past 2 decades, the search for active xenobiotics has returned to a natural product, the Chinese herb qinghaosu. The active metabolite, dihydroartemisinin, is common to all the endoperoxidases. These drugs are primarily used as part of an artemisinin-based combination therapy (ACT), which is recommended by the World Health Organization (WHO) as the preferred treatment of malaria in drug-resistant areas.2,10 With increased leisure travel, a greater number of North Americans are taking prophylactic medications with potential toxicity.
This chapter highlights the toxicity of the most commonly used antimalarials using the structural and mechanistic classification outlined in Table 59–2.
TABLE 59–2.Antimalarial Classification and Mechanisms |Favorite Table|Download (.pdf) TABLE 59–2. Antimalarial Classification and Mechanisms
|Class ||Examples ||Antimalarial Mechanism ||Lifecycle Stage Effect |
|Amino alcohols || |
|Inhibit heme digestion ||Erythrocytic cyclea |
|4-aminoquinolines || |
|Inhibit heme digestion ||Erythrocytic cyclea |
|8-aminoquinolines || |
|Oxidant stress || |
|Endoperoxides || |
oxidant stress likely contributes
|Erythrocytic cyclea |
|Antifolates || |
|Inhibit dihydrofolate reductase || |
(All growing stages)
|Antibiotics || |
|Inhibit dihydropteroate synthetase ||Erythrocytic cyclea |
| || |
Inhibit protein synthesis
| || |
|Napthoquinones ||Atovaquone ||Inhibit mitochondrial respiration ||Mosquito sporogonic cyclec |
Unlike humans, who detoxify heme through the use of heme oxygenase producing the bile pigment biliverdin, Plasmodium spp convert heme to the nontoxic relatively inert compound hemozoin. Amino alcohols and 4-aminoquinolines concentrate in parasite food vacuoles, where they inhibit the ability of the parasite to detoxify hemozoin, leading to accumulation of toxic heme byproducts and parasite death.94,123 In resistant parasites, these antimalarials fail to concentrate in food vacuoles because of increased drug efflux. This resistance is thought to be conferred through amplification of a transmembrane pump. Interestingly, tricyclic antidepressants, phenothiazines, and calcium channel blockers have been shown to reverse resistance in experimental models.94
The therapeutic benefits of the bark of the cinchona tree have been known for centuries. As early as 1633, cinchona bark was used for its antipyretic and analgesic effects,76 and in the 1800s, it was used for the treatment of “rebellious palpitations.”117 Quinine, the primary alkaloid in cinchona bark, was the first effective treatment for malaria. Additionally, because of a reported curarelike action, quinine has also been used as a treatment for muscle cramps. Because of its extremely bitter taste similar to that of heroin, quinine is used as an adulterant in drugs of abuse. Small quantities of quinine can be also found in some tonic waters.
High doses of quinine and other cinchona alkaloids are oxytocic, potentially leading to abortion or premature labor in pregnant women. Because of this, quinine has been used as an abortifacient (Chap. 21).78 Chloroquine continues to be used for this purpose in some parts of the developing world.12,95 Neither is safe for this purpose because of their narrow toxic-to-therapeutic ratio.
Pharmacokinetics and Toxicokinetics.
See Table 59–3 for the pharmacokinetic properties of quinine. Quinine and quinidine are optical isomers and share similar pharmacologic effects as class IA antidysrhythmics and antimalarials. Both are extensively metabolized in the liver, kidneys, and muscles to a variety of hydroxylated metabolites. Quinine undergoes transplacental distribution and is secreted in breast milk.
TABLE 59–3.Pharmacokinetic Properties of Antimalarials |Favorite Table|Download (.pdf) TABLE 59–3. Pharmacokinetic Properties of Antimalarials
|Antimalarial ||Bioavailability (%) ||Time to Peak Hours (oral) ||Protein Bound (%) ||Volume of Distribution (L/kg) ||Half-Life ||Urinary Excretion (%) ||Comments |
|Artemisinin ||Limited ||— ||Large ||— ||2–5 h ||— ||Metabolism largely through cytochrome P450 system. |
|Chloroquine ||80 ||2–5 ||50–65 ||>100 ||40–55 d ||55 ||— |
|Dapsone ||90 ||3–6 ||70–80 ||0.5–1 ||21–30 h ||20 ||— |
|Halofantrine ||Low, varies ||4–7 ||— ||>100 ||1–6 d ||— ||Active metabolite. |
|Mefloquine ||>85 ||8–24 ||98 ||15–40 ||15–27 d ||<1 ||Hepatic metabolism. Inactive metabolite. ||Primaquine |
|74 ||1–3 ||— ||2.9 ||5–7 h ||4 || |
Metabolites primarily responsible for therapeutic and toxic effects.
|Pyrimethamine ||>95 ||2–6 ||87 ||3 ||3–4 d ||16–32 ||— |
|Quinine ||76 ||1–3 ||93 ||1.8–4.6 ||9–15 h ||20 ||Protein binding increased in alkaline environments. Urinary excretion increased with acidic urine. |
Quinine overdose affects multiple organ systems through a number of different pathophysiologic mechanisms. Studies evaluating mechanisms of toxicity have focused on those organ systems primarily affected. Outcomes appear to be most closely related to the degree of cardiovascular dysfunction.42
Quinine and quinidine share anti- and prodysrhythmic effects primarily from an inhibiting effect on the cardiac sodium channels and potassium channels (Chaps. 16 and 64).43 Blockade of the sodium channel in the inactivated state decreases inotropy, slows the rate of depolarization, slows conduction, and increases action potential duration. Inhibition of this rapid inward sodium current is increased at higher heart rates (called use-dependent blockade), leading to a rate-dependent widening of the QRS complex.117,126
Inhibition of the potassium channels suppresses the repolarizing delayed rectifier potassium current, particularly the rapidly activating component,126 leading to prolongation of the QT interval. The resultant increase in the effective refractory period is also rate dependent, causing greater repolarization delay at slower heart rates and predisposing to torsade de pointes. As a result, syncope and sudden dysrhythmogenic death may occur. An additional α-adrenergic antagonist effect contributes to the syncope and hypotension occurring in quinine toxicity.
Inhibition of the adenosine triphosphate (ATP)–sensitive potassium channels of pancreatic β cells results in the release of insulin, similar to the action of sulfonylureas (Chap. 53).32 Patients at increased risk of quinine induced hyperinsulinemia include those patients receiving high dose intravenous (IV) quinine, intentional overdose, and patients with other metabolic stresses (eg, concurrent malaria, pregnancy, malnutrition, and ethanol consumption).21,63,86,90,114
The mechanism of quinine induced inhibition of hearing appears to be multifactorial.112 Microstructural lengthening of the outer hair cells of the cochlea and organ of Corti occurs.48 Additionally, vasoconstriction and local prostaglandin inhibition within the organ of Corti may contribute to decreased hearing.112 Inhibition of the potassium channel may impair hearing and produce vertigo because it is known that the homozygous absence of gene products that form part of some potassium channels (Jervell and Lange-Nielson syndrome) causes deafness and prolonged QT intervals (Chaps. 16 and 26).111
Although older theories suggested that quinine caused retinal ischemia, the preponderance of evidence points to a direct toxic effect on the retina.49 Electroretinographic studies demonstrate a rapid and direct effect on the retina (decreased potentials) within minutes after doses of quinine.44 These early retinographic changes, as well as histologic lesions in photoreceptor and ganglion cell layers, provide evidence of direct damage.44 Changes in the electrooculogram suggest changes in the retinal pigment epithelium and parallel changes in visual acuity. In contrast, no electrophysiologic, angiographic, or morphologic experimental evidence for retinal ischemia has been found.49 Quinine may also antagonize cholinergic neurotransmission in the inner synaptic layer.
Quinine has direct irritant effects on the gastrointestinal (GI) tract and stimulates the brainstem center responsible for nausea and emesis.117
Quinine overdose typically leads to GI complaints, tinnitus, and visual symptoms within hours, but the time course varies with the formulation ingested, coingestants, patient characteristics, and other case-specific details. Significant overdose is heralded by cardiovascular and central nervous system (CNS) toxicity. Death can occur within hours to days, usually from a combination of shock, ventricular dysrhythmias, respiratory arrest, or acute kidney failure (AKI).
Patients receiving even therapeutic doses often experience a syndrome known as “cinchonism,” which typically includes GI complaints, headache, vasodilation, tinnitus, and decreased hearing acuity.76,117 Vertigo, syncope, dystonia, tachycardia, diarrhea, and abdominal pain are also described.51,67,86
Quinine toxicity is closely correlated with total serum concentrations, but only the non protein bound portion is likely responsible for toxic effects. However, because free and total quinine concentrations vary widely from person to person,39 a single quinine concentration may not always correlate with clinical toxicity. In general, serum concentrations greater than 5 μg/mL may cause cinchonism, greater than 10 μg/mL visual impairment, greater than 15 μg/mL cardiac dysrhythmias, and greater than 22 μg/mL death.8 Similar concentrations in individuals who are severely ill with malaria do not necessarily result in as severe toxicity because of the increase α1-acid glycoprotein and consequent reduction in free fraction of quinine present.102,106
The margin between therapeutic and toxic dosing of quinine is very small. It is not surprising that patients taking therapeutic doses frequently develop toxicity because the recommended range of serum quinine concentrations for treatment of falciparum malaria is 5 to 15 μg/mL, well above the concentration reported to cause cinchonism.
The average oral lethal dose of quinine is 8 g, although a dose as small as 1.5 g is reported to cause death.40,51 Delirium, coma, and seizures are less common, usually occurring only after severe overdoses.17
Cardiovascular manifestations of quinine use are related to myocardial drug concentrations.15 They manifest on the electrocardiogram (ECG) as prolongation of the PR interval; prolongation of the QRS complex, QT interval, and ST depression with or without T wave inversion also occur.11 Patients may develop complete heart block or dysrhythmias.15 Patients taking high doses of quinine must be monitored for torsade de pointes, ventricular tachycardia, and ventricular fibrillation. Quinine toxicity can also result in significant hypotension.
Although not commonly reported, mild hyperinsulinemia and resultant hypoglycemia can occur in cases of oral quinine overdose.17,21,42,63,105,128,129 Hypoglycemia with elevated serum insulin concentrations after therapeutic dosing was documented in case reports complicated by severe congestive heart failure and significant ethanol consumption. Hypoglycemia is also noted in healthy patients after overdose.63
Eighth cranial nerve dysfunction results in tinnitus and deafness. The decreased acuity is not usually clinically apparent, although the patient recognizes tinnitus.99 These findings usually resolve within 48 to 72 hours, and permanent hearing impairment is unlikely.
Ophthalmic presentations include blurred vision, visual field constriction, tunnel vision, diplopia, altered color perception, mydriasis, photophobia, scotomata, and sometimes complete blindness.17,36,44 The onset of blindness is invariably delayed and usually follows the onset of other manifestations by at least 6 hours. The pupillary dilation that occurs is usually nonreactive and correlates with the severity of visual loss. Funduscopic examination findings may be normal but usually demonstrate extreme arteriolar constriction associated with retinal edema. Normal arteriolar caliber may be initially present, but funduscopic manifestations such as vessel attenuation and disc pallor may develop as clinical improvement occurs. Improvement in vision can occur rapidly but is usually slow, occurring over a period of months after a severe exposure. Initially, improvement occurs centrally and is followed later by improvement in peripheral vision. The pupils may remain dilated even after return to normal vision.40 Patients with the greatest exposure may develop optic atrophy.
Hypokalemia is often described in the setting of quinine poisoning,105 although the mechanism is unclear. An intracellular shift of potassium rather than a true potassium deficit is the predominant theory behind the hypokalemia associated with chloroquine,71,73 and the mechanism may be similar with quinine.
A number of hypersensitivity reactions are described. These are the result of antiquinine or antiquinine-hapten antibodies cross-reacting with a variety of membrane glycoproteins.18,57 Asthma and dermatologic manifestations, including urticaria, photosensitivity dermatitis, cutaneous vasculitis, lichen planus, and angioedema, also occur.114
Hematologic manifestations of hypersensitivity are rare, but include thrombocytopenia (Chap. 22), agranulocytosis, microangiopathic hemolytic anemia, and disseminated intravascular coagulation (DIC), which can lead to jaundice, hemoglobinuria, and renal failure.51,57 Hemolysis may also occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immunogenic drug platelet complex interactions can occur even after low doses of quinine, such as those in tonic drinks. This self-limited interaction has previously been termed “cocktail purpura.”76,117
A hepatitis hypersensitivity reaction,38 acute respiratory distress syndrome (ARDS), and a sepsislike syndrome are also reported.60
Urine thin-layer chromatography is sensitive enough to confirm the presence of quinine even after the ingestion of tonic water.129 Quinine immunoassay techniques are also available. Quantitative serum testing is not rapidly or widely available.
Patients frequently vomit spontaneously. Emetics should not be used in the absence of vomiting because seizures, dysrhythmias, and hypotension can occur rapidly. Orogastric lavage should only be considered for patients with recent, substantial (potentially life-threatening) ingestions with no spontaneous emesis. Activated charcoal effectively adsorbs quinine and may additionally decrease serum concentrations by altering enteroenteric circulation.3,66
Expectant treatment should be initiated, including oxygen, cardiac and hemodynamic monitoring, IV fluid resuscitation, and frequent ECG and blood glucose measurements.
Extracorporeal membrane oxygenation was used in one case of severe quinidine poisoning with bradydysrhythmias and refractory hypotension to stabilize the cardiovascular system while a quinidine-activated charcoal bezoar was removed and the patient metabolized the remaining quinidine.115 A similar approach should be considered for intractable quinine toxicity.
A conduction delay manifested by a QRS duration of more than 100 msec should be treated with sodium bicarbonate alkalinization to achieve a serum pH of 7.45 to 7.50, as would be done in patients with cardiotoxicity associated with cyclic antidepressant overdoses (Antidotes in Depth: A5). Protein binding is increased in the setting of alkalemia, decreasing the cardiotoxic manifestations of quinine. Thus, serum alkalinization with sodium bicarbonate is a logical therapeutic intervention. Sodium bicarbonate therapy is successful in case reports15,42,76 but has not been specifically studied. Hypertonic sodium bicarbonate may result in or worsen existing hypokalemia, potentially exacerbating the effect of potassium channel blockade.
Potassium supplementation for quinine-induced hypokalemia is controversial because experimental data from the 1960s suggest that hypokalemia is protective against cardiotoxicity and prolongs survival.20,71,105 Because hypokalemia can also lead to lethal dysrhythmias, supplementation for hypokalemia is presently recommended.
The QT interval should be carefully monitored for prolongation. If necessary, interventions for torsade de pointes, including magnesium administration, potassium supplementation, and overdrive pacing, should be initiated (Chap. 17).
Class IA, IC, or III antidysrhythmics and other xenobiotics with sodium channel or potassium channel blocking activity should not be used to treat quinine-overdosed patients because they may exacerbate quinine-induced conduction disturbances or dysrhythmias. The Class IB antidysrhythmics, such as lidocaine, have been used with reported success, but no clinical trials have been performed (Chap. 64).
Hypotension refractory to IV crystalloid boluses should be treated with vasopressors. Although not directly studied, direct acting vasopressors such as epinephrine, norepinephrine, and phenylephrine are recommended. An intraaortic balloon pump was successfully used for the treatment of refractory hypotension in one case report.105
Funduscopic examination, visual field examination, and color testing may be appropriate bedside diagnostic studies. Electroretinography, electrooculography, visual-evoked potentials, and dark adaptation may be helpful in assessing the injury but are not practical because they require equipment that is not portable or readily available in most clinical settings. There is no specific, effective treatment for quinine retinal toxicity,44,47 although hyperbaric oxygen (HBO) was used in three patients who recovered vision, but the role of HBO in that recovery was not established.44,129
A low serum glucose concentration should be supported with an adequate infusion of dextrose. Serum potassium concentration and the QT interval should be monitored during correction and maintenance. Octreotide was successfully used to correct quinine induced hyperinsulinemia in adult malaria victims.89,90 In volunteers, quinine induced hyperinsulinemia was suppressed within 15 minutes after a 100 μg intramuscular dose of octreotide (Antidotes in Depth: A13).89 Octreotide should be used for cases of refractory hypoglycemia in a fashion similar to that recommended in sulfonylurea toxicity, which is 50 μg (1 μg/kg in children) subcutaneously every 6 hours (Chap. 53).
The effect of multiple-dose activated charcoal (MDAC) on quinine elimination was studied in an experimental human model and in symptomatic patients.92 In these patients, MDAC decreased the half-life of quinine from approximately 8 hours to about 4.5 hours and increased clearance by 56%.92 Although numerous studies show that activated charcoal decreases quinine half-life,13,66,92 evidence of clinical benefit is lacking. Nevertheless, because ophthalmic, CNS, and cardiovascular toxicity are related to serum concentration, it is prudent to reduce concentrations as quickly as practicable; thus, activated charcoal (0.5 g/kg) should be administered every 2 to 4 hours for about four doses unless contraindications exist.
There is conflicting evidence about a benefit of urinary acidification in enhancing clearance.13,102 But because of the increased potential for cardiotoxicity associated with acidification, this technique is never recommended.
Because quinine has a relatively large volume of distribution and is highly protein bound, hemoperfusion, hemodialysis, and exchange transfusion have only a limited effect on drug removal.13,17,102,117 Although the blood compartment can be cleared with these techniques, total body clearance is only marginally altered. After rapid tissue distribution occurs, there is little impact on the total body burden because of the large volume of distribution and extensive protein binding.
Pharmacokinetics and Toxicodynamics.
See Table 59–3 for the pharmacokinetic properties of mefloquine.
Common side effects with prophylactic and therapeutic dosing include nausea, vomiting, and diarrhea.83 These side effects are noted particularly in the extremes of age and with high therapeutic dosing. Similar symptoms should be expected in acute overdose.114,125
Mefloquine has a mild cardiodepressant effect—less than that of quinine or quinidine—which is not clinically significant in prophylactic dosing or with therapeutic administration. Bradycardia is commonly reported.25,67,83 With prophylactic use, neither the PR interval nor the QRS complex is prolonged, but QT prolongation is reported.34,67 Reports of torsade de pointes are rare, but the increase in QT and risk of torsade de pointes are increased when mefloquine is used concurrently with quinine; chloroquine; or, most particularly, with halofantrine.67,83,84,126 The long half-life of mefloquine means that particular care must be taken with therapeutic use of other antimalarials when breakthrough malaria occurs during mefloquine prophylaxis or within 28 days of mefloquine therapy to avoid potential drug–drug interactions. This risk may increase with acute overdose, although there is little clinical experience.
Mefloquine commonly has neuropsychiatric side effects. During prophylactic use, 10% to 40% of patients experience insomnia and bizarre or vivid dreams and complain of dizziness, headache, fatigue, mood alteration, and vertigo.103,122 Only 2% to 10% of these complications necessitate the traveler to seek medical advice or change normal activities.25,50,113 Predisposing factors include a past history of neuropsychiatric disorders, recent prior exposure to mefloquine (within 2 months), previous mefloquine-related neuropsychiatric adverse effects, and previous treatment with psychotropics.114 Women appear to be more likely than men to experience neuropsychiatric adverse effects.114,122
The risk of serious neuropsychiatric adverse effects (convulsions, altered mental status, inability to ambulate because of vertigo or ataxia, psychosis, or acute neurosis) during prophylaxis is estimated to be one in 10,600 but is reported to be as high as one in 200 with therapeutic dosing.33,114 Seizures occur rarely with prophylaxis and therapeutic use.91,100 In many of these cases, there is a history of previous seizures, seizures in a first-degree relative or other seizure risk factors. Other neuropsychiatric symptoms include dysphoria, altered consciousness, encephalopathy, anxiety, depression, giddiness, and agitated delirium with psychosis. Although there is a suggestion that the severity of neuropsychiatric events is dose dependent, there does not seem to be a correlation with serum or tissue concentrations.57 In one case report, the severe neuropsychiatric manifestations of mefloquine were reversed with physostigmine, leading the authors to suggest a possible central anticholinergic mechanism.110 Physostigmine is not recommended as a routine treatment for mefloquine neuropsychiatric side effects. A self-resolving postmalaria neurologic syndrome including confusion, seizures, or tremor is associated with therapeutic use of mefloquine for severe malaria.81,100
The effect of mefloquine on the pancreatic potassium channel is much less than that of quinine, resulting in only a mild increase in insulin secretion.32,34 Symptomatic hypoglycemia has not been reported as an effect of mefloquine alone in healthy individuals, but has occurred with concomitant use of ethanol and in a severely malnourished patient with acquired immune deficiency syndrome (AIDS).11,34,67 In overdose, particularly when accompanied by ethanol use or starvation, hypoglycemia can be severe.
Rare events such as hypersensitivity reactions reported with prophylaxis include urticaria, alopecia, erythema multiforme, toxic epidermal necrolysis, myalgias, mouth ulcers, neutropenia, and thrombocytopenia.72,83,103,108 It is unclear which, if any, would be significant after overdose. ARDS was linked to therapeutic dosing in one case.119
In therapeutic use, mefloquine is associated with an increased incidence of stillbirth compared with quinine and a group of other antimalarials.85 Mefloquine was not, however, linked to an increased incidence of abortion, low birth weight, mental retardation, or congenital malformations. The implications of overdose in the absence of malaria are unknown, but fetal monitoring should be instituted.
The consequences of excessive dosing and overdose are not only severe but also prolonged and potentially permanent. Mefloquine overdose led to acute hearing loss and gradual resolution of acute symptoms over one year in one case and persistent symptoms even after one year in another.65 After ingesting 5.25 g of mefloquine over 6 days, a man had prolonged prothrombin time resolving in 5 days and weakness persisting for 2 months after resolution of the acute symptoms.19 A fourth case involved coingestion of 2.5 times the usual therapeutic doses of mefloquine, chloroquine, and sulfadoxine–pyrimethamine over 3 days. The man had encephalopathy which had not resolved 8 months later.23
In overdose, treatment is primarily supportive with monitoring for potential adverse effects. Decontamination with activated charcoal is indicated if the patient presents soon after the ingestion. Specific monitoring for ECG abnormalities, hypoglycemia, and liver injury should be provided. Patients should also be followed for CNS and cranial nerve complications.
In two patients with kidney failure who received mefloquine, prophylactic hemodialysis did not remove mefloquine.30 Given the large volume of distribution and high degree of protein binding of mefloquine, extracorporeal elimination techniques are unlikely to be effective.
Because of erratic absorption, the potential for lethal cardiotoxicity, and concern for cross resistance with mefloquine, halofantrine is not presently recommended for malaria prophylaxis by the WHO.2,114
Pharmacokinetics and Toxicodynamics.
See Table 59–3 for the pharmacokinetic properties of halofantrine.22
The primary toxicity from therapeutic and supratherapeutic doses is prolongation of the QT interval and the risk of torsade de pointes and ventricular fibrillation.84,116 Palpitations, hypotension, and syncope may occur. First degree atrioventricular (AV) block is common, but bradycardia is rare.84 Dysrhythmias are also likely in the context of combined overdose or combined or serial therapeutic use with other xenobiotics that cause QT interval prolongation, particularly mefloquine.56 Because the QT interval duration is directly related to the serum halofantrine concentration, dysrhythmias should be expected in overdose.25,84,114 Fifty percent of children receiving a therapeutic course of halofantrine will have a QT interval greater than 440 msec.109
Other side effects, including nausea, vomiting, diarrhea, abdominal cramps, headache, and lightheadedness, which frequently occur in therapeutic use, are also expected in overdose.67 Less frequently described side effects include pruritus, myalgias, and rigors. Seizures, minimal liver enzyme abnormalities, and hemolysis are described.67,75,120 Whether these manifestations are related to halofantrine or to the underlying malaria is not clear.
Management of patients with halofantrine overdose should focus on decontamination, supportive care, monitoring for QT interval prolongation, and treatment of any associated dysrhythmias.
Lumefantrine is structurally similar to halofantrine. It is primarily used as a partner drug in the artemisinin based combination therapy artemether plus lumefantrine.
Little toxicity of lumefantrine alone or in combination is reported.127 Studies do not show QT interval prolongation or evidence of cardiac toxicity related to lumefantrine.37 Cough and angioedema were described in one case.61 As in the case of all antimalarials, it is difficult to differentiate drug related adverse events from those of malaria, comorbid diseases, or other ingested drugs, which confounds the study of potential complications.
The structurally related compounds chloroquine and amodiaquine were once used extensively for malaria prophylaxis. However, with the development of resistance, they are now used in fewer geographic regions. Amodiaquine is associated with a higher incidence of hepatic toxicity and agranulocytosis. In general, these xenobiotics have low toxicity when used in therapeutic doses. Because of its low toxicity, chloroquine remains the first line drug for malaria prophylaxis and treatment in areas where Plasmodium spp remain sensitive.
Hydroxychloroquine is similar to chloroquine in therapeutic, pharmacokinetic, and toxicologic properties.70 The side effect profiles of the two are slightly different, favoring chloroquine use for malarial prophylaxis and hydroxychloroquine use as an antiinflammatory agent.67,117 Hydroxychloroquine is used in the treatment of rheumatic diseases such as rheumatoid arthritis and lupus erythematosus. In animal studies, chloroquine is two to three times more toxic than hydroxychloroquine.53
Piperaquine is structurally similar to chloroquine but is primarily used in conjunction with artemisinin compounds as a component of an ACT.
The 4-aminoquinolines interfere with the digestion of heme and hemozoin formation in a manner similar to that of the amino alcohols.35
Chloroquine and Hydroxychloroquine
Pharmacokinetics and Toxicodynamics.
See Table 59–3 for the pharmacokinetic properties of chloroquine. Oral chloroquine is rapidly and completely absorbed and is ultimately sequestered in many organs, particularly the kidney, liver, lung, and erythrocytes.16,48
Chloroquine is slowly distributed from the blood compartment to the larger central compartment, leading to transiently high whole blood concentrations shortly after ingestion.95,107 It is the initial high blood concentrations that are thought to be responsible for the rapid development of profound cardiorespiratory collapse typical of chloroquine toxicity. These whole blood chloroquine concentrations correlate with death.29
With structural similarity to quinine, the pathophysiologic mechanisms of chloroquine and hydroxychloroquine are also similar. Most notably, sodium and potassium channel blockade are the proposed primary mechanisms of cardiovascular toxicity.126
Although less common in quinine toxicity, hypokalemia is extremely common in chloroquine overdose. The mechanism appears to be a shift of potassium from the extracellular to the intracellular space and not a true potassium deficit.71,95,105
Similar to quinine, chloroquine has a small toxic-to-therapeutic margin. Severe chloroquine poisoning is usually associated with ingestions of 5 g or more in adults, systolic blood pressure less than 80 mm Hg, QRS duration of more than 120 msec, ventricular fibrillation, hypokalemia, and serum chloroquinine concentrations exceeding 25 µmol/L (8 µg/mL).27,97
Symptoms usually occur within 1 to 3 hours of ingestion.97 The range of symptoms associated with chloroquine toxicity is similar to that of quinine, but the frequencies of various manifestations differ, and other features such as cinchonism are uncommon. Nausea, vomiting, diarrhea, and abdominal pain occur less commonly than with quinine.51,67 In contrast, respiratory depression is common, and apnea, hypotension, and cardiovascular compromise can be precipitous.51
The cardiovascular effects of chloroquine and hydroxychloroquine are similar to those of quinine, including QRS prolongation, AV block, ST and T wave depression, increased U waves, and QT interval prolongation. Hypotension is more prominent in chloroquine toxicity than with quinine.51
Significant hypokalemia in chloroquine toxicity is invariably associated with cardiac manifestations.28,51 In fact, the extent of hypokalemia is a good indicator of the severity of chloroquine overdose.27
Neurologic manifestations include CNS depression, dizziness, headache, and convulsions.47 Rarely, dystonic reactions occur.87 Transient parkinsonism is also reported after excessive dosing.87
Ophthalmic manifestations are infrequent in acute chloroquine toxicity and transient in nature.51,67 More severe and irreversible vision and hearing changes are described in association with the chronic use of chloroquine and hydroxychloroquine as antiinflammatory agents.67,79 Myopathy, neuropathy, and cardiomyopathy also occur when used for that purpose.10,124 Dermatologic findings and hypersensitivity reactions are similar to those associated with quinine.34 Likewise, red blood cell (RBC) oxidant stress from chloroquine may result in hemolysis in patients with G6PD deficiency (Chap. 22).
Acute hydroxychloroquine toxicity is similar to chloroquine toxicity.53 Side effects from therapeutic doses include nausea and abdominal pain; hemolysis in G6PD deficient patients; and, rarely, retinal damage, sensorineural deafness, and hypoglycemia.52,104 Hypersensitivity reactions, including myocarditis and hepatitis, are described.41,69
Aggressive supportive care should be initiated, including oxygen, cardiac and hemodynamic monitoring, and large bore IV access, and serial blood glucose concentrations should be obtained. Orogastric lavage could be considered for life-threatening ingestions presenting early, but there is little evidence of efficacy. Activated charcoal adsorbs chloroquine well, binding 95% to 99% when administered within 5 minutes of ingestion.59 The frequent development of precipitous cardiovascular and CNS toxicity should be considered before initiating any type of GI decontamination.
Early aggressive management of severe chloroquine toxicity decreases the mortality rate.97 This includes early endotracheal intubation and mechanical ventilation. Evidence suggests that barbiturates may not be desirable for induction in patients with chloroquine overdose. When thiopental was used to facilitate intubation, its use immediately preceded sudden cardiac arrest in seven of 25 patients after chloroquine overdose.29 An adequate FiO2, tidal volume, and ventilatory rate should be ensured.
Although theoretically any direct acting vasopressor would be beneficial in the setting of hypotension not responsive to fluid resuscitation, epinephrine is the vasopressor most extensively studied and is considered the vasopressor of choice. High doses of epinephrine were used in the original studies describing the benefits of early mechanical ventilation and the administration of diazepam and epinephrine in chloroquine poisoning.97,98 The epinephrine doses used in these studies are still recommended today.97,98 The recommended dose is 0.25 μg/kg/min, increasing by 0.25 μg/kg/min until an adequate systolic blood pressure (greater than 90 mm Hg) is achieved.31,73,97,98 Clinicians should be mindful that high doses of epinephrine could exacerbate preexisting hypokalemia.
The use of diazepam to augment the treatment of dysrhythmias and hypotension is a unique use of this drug. Initial observations with regard to patients with mixed overdoses of chloroquine and diazepam suggested less cardiovascular toxicity and a potential benefit of high dose diazepam.27,71 Animal and human studies that followed also showed a potential benefit.31,97,98 When early mechanical ventilation was combined with the administration of high-dose diazepam and epinephrine in patients severely poisoned by chloroquine, a dramatic improvement in survival compared with historical control participants (91% versus 9% survival) occurred.97 Studies in moderately poisoned patients failed to show similar benefit,27 and a rat model failed to show an inotropic effect. Although the definitive study has yet to be done, high-dose diazepam therapy (2 mg/kg IV over 30 minutes followed by 1 to 2 mg/kg/d for 2–4 days) seems warranted for serious toxicity. Diazepam or an equivalent benzodiazepine should also be used to treat seizures and for sedation.
The mechanism for a potential benefit of diazepam is unclear, but multiple theories have been postulated: (1) a central antagonistic effect, (2) an anticonvulsant effect, (3) an antidysrhythmic effect by an electrophysiologic action inverse to chloroquine, (4) a pharmacokinetic interaction between diazepam and chloroquine, and (5) a decrease in chloroquine-induced vasodilation71,95,97,98 (Antidotes in Depth: A23).
The use of sodium bicarbonate for correction of QRS prolongation is also controversial. Although alkalinization would be expected to counteract the effects of sodium channel blockade, it could also exacerbate preexisting hypokalemia. Although case reports describe the successful use of sodium bicarbonate in conjunction with xenobiotics for massive hydroxychloroquine overdose, no clinical trials have been performed.64,130 Before using sodium bicarbonate in the setting of chloroquine toxicity, clinicians should consider the overall clinical status of the patient, including the suspected degree of cardiac toxicity and severity of hypokalemia.
Hypokalemia in the setting of chloroquine overdose correlates with the severity of the toxicity.27,71 Potassium replacement in this setting is, again, controversial because it has not been shown that potassium supplementation will improve cardiac toxicity. In fact, several reports suggest a possible protective effect of hypokalemia in acute chloroquine toxicity.27,71,95 This should be balanced against the fact that severe hypokalemia can itself result in lethal dysrhythmias and data suggesting severe hypokalemia (less than 1.9 mEq/L) is associated with severe, life-threatening ingestion.25,51,71,107 Hypokalemia could not be directly attributed as the cause of death in most cases, however.27 Based on the available evidence, potassium replacement for significant hypokalemia seems warranted, but it is essential to anticipate rebound hyperkalemia as chloroquine toxicity resolves and redistribution of intracellular potassium occurs. Cases of hyperkalemia related complications are reported after aggressive potassium supplementation.53,64,71
Because chloroquine and hydroxychloroquine have high volumes of distribution and significant protein binding, enhanced elimination procedures are not beneficial.16,51
Piperaquine was used extensively in China and Indonesia as an antimalarial until the development of piperaquine resistant strains led to the use of better alternatives. Piperaquine has since undergone a rediscovery as a viable combination with atremisinin derivatives in ACT DP (dihydroartemisinin-piperaquine) therapy. Animal studies show piperaquine to be substantially less toxic than chloroquine. Cardiovascular toxicity with piperaquine requires cumulative doses five times higher than that of chloroquine. Hepatotoxicity occurs after chronic exposure in animals. In a human study, no significant changes in ECG or in serum glucose concentration, and no postural hypotension occurred after therapeutic doses of DP.
Patients with overdose should be managed with supportive measures and expectant observation, including cardiovascular and CNS monitoring.
Reports of amodiaquine toxicity suggest that involuntary movements, muscle stiffness, dysarthria, syncope, and seizures may occur.6,51 Amodiaquine is associated with hypersensitivity hepatitis and neutropenia in prophylactic use but not therapeutic use.21 There is no overdose experience reported.
Primaquine and its related compounds are the only drugs licensed for the prevention of P. ovale and P. vivax relapse caused by hepatic hypnozoites.77 Studies using primaquine in the early 1950s led to the discovery of G6PD deficiency after those with the disease developed hemolysis when administered the drug.14 G6PD deficiency actually offers some protection against malaria because the erythrocytes of those with the disease rupture under the increased oxidative stress of the parasite’s metabolism before completion of the erythrocytic cycle.
The antimalarial action of primaquine is poorly understood but thought to be related to increasing the oxidative stress of erythrocytes,123 obstructing proper parasitic development.
Pharmacokinetics and Toxicodynamics.
See Table 59–3 for the pharmacokinetic properties of primaquine.
Primaquine blocks sodium channels both in vitro and animal models.51,126 Significant cardiovascular toxicity has not been reported, although experience with primaquine overdose is limited primarily to case reports.
The predominant clinical toxicity of primaquine relates to its ability to cause RBC oxidant stress and resultant hemolysis or methemoglobinemia. Methemoglobinemia and hemolysis can even occur in normal individuals given high doses as well as those with G6PD deficiency.67,114
The major complication of primaquine in therapeutic use is hemolysis in G6PD deficient individuals.32 Primaquine is contraindicated in pregnant women because of the risk of methemoglobinemia or hemolysis in the fetus. Reversible bone marrow suppression can occur.
Gastrointestinal irritation is common and dose related.
The extent of hemolysis in G6PD deficient individuals depends on the extent of enzyme activity, those with greater enzyme activity having less severe hemolysis than those with less enzyme activity (Chap. 22). Other variables include the dose of primaquine and comorbid conditions, such as infection, liver disease, and administration of other drugs with hemolytic activity.
Overdose with primaquine is rarely reported, and unintentional overdoses have led to methemoglobinemia requiring IV methylene blue.114 Acute liver failure has occurred after unintentional overdose, and fatal hepatotoxicity is described in animal models.65
Therapy should be directed at minimizing absorption with appropriate decontamination and diagnosing and then treating significant methemoglobinemia or hemolysis. Because of structural similarities with other quinolone antimalarials and animal model evidence of sodium channel blockade, cardiovascular toxicity should be anticipated with continuous monitoring and resuscitative interventions initiated as needed.
Activated charcoal would be expected to bind primaquine quite successfully if given early (Antidotes in Depth: A1). Methylene blue (Chap. 127 and Antidotes in Depth: A42) should be administered for patients who are symptomatic with methemoglobinemia. Treatment of hemolysis necessitates avoiding further exposure to primaquine and possibly exchange transfusion in severe cases. Adequate hydration should be ensured to protect against hemoglobin-induced AKI. Urinary alkalinization with sodium bicarbonate is controversial in this setting but may have some benefit (Antidotes in Depth: A5).
Although no clinical studies have been performed, the large volume of distribution of primaquine makes it an unlikely candidate for benefit from extracorporeal removal.
Artemisinin and Derivatives
The medicinal value of natural artemisinin, the active ingredient of Artemisia annua (sweet wormwood or quinghao), has been known for thousands of years. Its antimalarial properties were first recognized by Chinese herbalists in 340 a.d., but the primary active component of qinghaosu, now known as artemisinin, was not isolated until 1974.10,117 Artemisinin and its semisynthetic derivatives, artesunate, artemether, arteether, and dihydroartemisinin, are the most potent and rapidly acting of all antimalarials. They were introduced in the 1980s in China for the treatment of malaria, and since then millions of doses have been used in Asia and Africa. Because of their extremely short half-lives, the artemisinins are now used in combination with drugs with longer half-lives to delay or prevent the emergence of resistance. ACTs are currently recommended by the WHO for the treatment of uncomplicated malaria1,10 but have not been licensed for use in the United States. Only four ACTs are currently recommended by the WHO. These include artesunate plus mefloquine, artesunate plus pyrimethamine–sulfadoxine, artesunate plus amodiaquine, and artemether plus lumefantrine.
The artemesinins have a unique structure containing a 1,2,4-trioxane ring. The endoperoxide linkage within this ring is cleaved when it comes into contact with ferrous iron, releasing free radicals that destroy the parasite.4 Artemisinin is the only known natural product to contain a 1,2,4-trioxane ring, and although chemical synthesis is possible, thus far it has not been financially advantageous.
Pharmacokinetics and Toxicodynamics.
See Table 59–3 for the pharmacokinetic properties of artemisinin. Similar to its proposed efficacy, the toxicity of artemisinin is thought to be a result of the ability of the trioxane molecular core to form intracellular free radicals, particularly in the presence of heme. In animals, damage to brainstem nuclei is consistently produced after prolonged, high-dose, and parenteral administration.114 Sustained CNS exposure from slowly absorbed or eliminated artemisinins is considered markedly more neurotoxic than intermittent brief exposure that occurs after oral dosing.114 Embryonic loss is also observed in animals.114
In contrast to the experience with animals, the experience of more than 8000 human study participants shows that these drugs have a very low incidence of side effects.114 Uncommon side effects include nausea, vomiting, abdominal pain, diarrhea, and dizziness.
Prospective studies have failed to identify adverse neurologic outcomes.58,114 Rare reports of adverse CNS effects during therapeutic use suggest the possibility of CNS depression, seizures, or cerebellar symptoms after intentional self poisoning. In children with cerebral malaria, a higher incidence of seizures and a delay to recovery from coma were noted in a comparison with quinine.121 No neurologic difference was noted in long-term follow up. In an artemether–quinine comparative trial of adults with severe malaria, recovery from coma was also prolonged in the artemether group.118 Rare patients receiving an artemisinin derivative in two other studies experienced transient dizziness or cerebellar signs.74,93 Most recovered within days. One patient in each study had prolonged symptoms lasting 1 month and 4 months, respectively, but both ultimately recovered.74,93
When serial ECGs were obtained, a small but statistically significant decrease in heart rate was noted coincident with peak drug concentrations.74 In one therapeutic trial, 7% of adult patients receiving artemether had an asymptomatic QT interval prolongation of at least 25%.118 Changes in the QRS are not reported.
Although uncommon, neutropenia, reticulocytopenia, anemia, eosinophilia, and elevated aminotransferases are reported.114 Acute ACT overdose is rarely reported outside large population-based studies. Morbidity and mortality of overdose are frequently difficult to differentiate from those of the underlying malarial disease and coingestants.
ANTIFOLATES AND ANTIBIOTICS
Proguanil, pyrimethamine, and the antibiotic trimethoprim interfere with malarial folate metabolism by inhibiting dihydrofolate reductase at concentrations far lower than that required to produce comparable inhibition of mammalian enzymes.117 Dapsone and sulfonamide antibiotics also disrupt malarial folate metabolism, but by inhibiting a different enzymatic reaction; dihydropteroate synthase. Slow onset of action and concerns for the development of resistance have led to the use of these antibiotics in synergistic combinations leading to inhibition of folate metabolism at two different sites.
Pharmacokinetics and Toxicodynamics
See Table 59–3 for the pharmacokinetic properties of pyrimethamine and dapsone.
Genetic polymorphism is described in the metabolism of proguanil and dapsone.54,96 This may be the cause of the significant hypersensitivity reactions noted with dapsone.96
The side effects of proguanil during prophylaxis include nausea, diarrhea, and mouth ulcers.67 Because of the interference with folate metabolism, megaloblastic anemia is a rare complication. Megaloblastic bone marrow toxicity is reported in patients with chronic kidney disease (CKD).114 Folate supplementation may be required in pregnancy and CKD to avoid this complication.33 Rarely, neutropenia, thrombocytopenia, rash, and alopecia are also noted.33 In a single case report, hypersensitivity hepatitis was described.33 When used to treat malaria, atovaquone–proguanil causes vomiting, sometimes severe, in a significant portion of patients (15%–45%).114 This combination is also associated with elevated aminotransferases.94 Unintentional or deliberate overdose has caused little serious toxicity.114
Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomiting, a rapid onset of seizures, fever, and tachycardia.7,51 Blindness, deafness, and mental retardation have followed.7,51 Seizures were attributed to sulfadoxine–pyrimethamine in an overdose of 12 tablets over 2 days (the usual dose is three tablets taken once).82 It is unclear whether the chronic neurologic deficits described in case reports are attributable to direct toxicity of pyrimethamine on the CNS or to complications of toxicity such as status epilepticus.7,51 Chronic high dose use may be associated with a megaloblastic anemia, requiring folate replacement.7
The sulfonamides, including the sulfone dapsone, have a long history of causing idiosyncratic reactions, including neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neuropathy, and hepatitis.67,114 The rare occurrence of life-threatening erythema multiforme major and toxic epidermal necrolysis, associated with pyrimethamine–sulfadoxine prophylaxis, has limited the use of this combination for prophylaxis.
Acute ingestion of dapsone may result in nausea, vomiting, and abdominal pain.51 After overdose, dapsone produces RBC oxidant stress, leading to methemoglobinemia and, to a much lesser extent, sulfhemoglobinemia through formation of an active metabolite (Chap. 127).24,68 The onset of hemolysis may be either immediate or delayed. Dapsone, in particular, is known for its tendency to cause prolonged methemoglobinemia. Other symptoms, particularly tachycardia, dyspnea, dizziness, visual hallucinations, seizure, syncope, and coma resulting from end-organ hypoxia, can occur.24,51 Additional effects described in overdose include hepatitis and peripheral neuropathy.51
Folate supplementation should be considered after an overdose of proguanil or pyrimethamine (Antidotes in Depth: A10). Other efforts should include supportive care.
After dapsone ingestion, clinically significant methemoglobinemia should be treated with methylene blue and possibly cimetidine (Chap. 127 and Antidotes in Depth: A42). There is no antidote for sulfhemoglobinemia, but it constitutes an insignificant portion of total hemoglobin. Both hemodialysis and MDAC enhance elimination of dapsone during therapy.80 MDAC is routinely recommended in the treatment of dapsone overdose.68 Required support may include RBC transfusion and urinary alkalinization if hemolysis is extensive (Antidotes in Depth: A5).
Atovaquone inhibits the de novo pyrimidine synthesis that is necessary for protozoal survival and replication but is unnecessary in mammalian cells. Based on its beneficial side effect profile, many North American physicians are switching from mefloquine to atovaquone–proguanil for routine antimalarial prophylaxis for travelers. Atovaquone and proguanil may now be the most common antimalarials used in North America. The price of this combination previously limited its use mainly to travelers from affluent countries.25 The availability to patients from other countries may increase because the generic form of this combination became available in late 2011.
Atovaquone alone, primarily used to treat Pneumocystis jiroveci in patients with AIDS, is relatively well tolerated.88 Side effects include maculopapular rash, erythema multiforme (rarely), GI complaints, and mild aminotransferase elevations. Three cases of 3 to 42 fold overdose or excess dosing have been reported.26 No symptoms occurred in one case (at three times therapeutic serum concentration). Rash occurred in another, and in the third case, methemoglobinemia was attributed to a simultaneous overdose of dapsone.
Malaria is a parasitic infection of human erythrocytes caused by protozoan parasites in the Plasmodium genus with a unique lifecycle involving the Anopheles mosquito as the vector. It is primarily endemic in tropical and subtropical areas worldwide.
The antimalarial properties of quinine have been known for centuries. Therapeutic dosing can result in a unique symptom complex known as “cinchonism.” Significant overdose is heralded by cardiovascular and CNS toxicity.
The development of resistance has limited the use of chloroquine to specific geographic regions harboring susceptible malarial strains. Rapid development of cardiorespiratory collapse is typical of chloroquine toxicity. High dose epinephrine and valium are recommended for the treatment of serious chloroquine toxicity.
Primaquine and dapsone produce significant oxidant stress, resulting in methemoglobinemia and often hemolysis.
Because of their extremely short half-lives, artemisinins are used in combination with drugs with longer half-lives to delay or prevent the emergence of resistance. Little is known of the acute toxicity after overdose of the newest artemisinin based medications.
G. Randall Bond, MD, contributed to this chapter in previous editions.
Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol.
Atremisinin and a new generation of antimalarial drugs. Educ. Chem. 2006;43.
Update: malaria, U.S. Armed Forces, 2011. MSMR. 2012;19:2–6.
et al.: Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose. Ghana Med J.
M: Biology of human malaria plasmodia including Plasmodium knowlesi.Mediterr J Hematol Infect Dis.
PI: Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet.
M: Chloroquine cardiomyopathy with conduction disorders. Heart.
CF: Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol.
et al.: Pharmacokinetics and clinical toxicity of quinine overdosage: lack of efficacy of techniques intended to enhance elimination. Q J Med.
E: Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood.
MJ: Delayed cardiotoxicity following quinine overdose: a case report. J Emerg Med.
J, van Dijk
A: Hemoperfusion is ineffectual in severe chloroquine poisoning. Crit Care Med.
RH: Patients with quinine-induced immune thrombocytopenia have both “drug-dependent” and “drug-specific” antibodies. Blood.
et al.: Accidental mefloquine poisoning. Presse Med.
HR: The effect of serum potassium concentration on quinidine toxicity. J Pharmacol Exp Ther.
PA: Clinical pharmacology and malaria. Ann Trop Med Parasitol.
KL: Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential. Drugs.
et al.: Mefloquine and sulfadoxine/pyrimethamine
overdose in malaria tropica. Wien Klin Wochenschr.
S: Clinical and laboratory parameters in dapsone
acute intoxication. Rev Saude Publica.
S: Assessment of safety of the major antimalarial drugs. Expert Opin Drug Saf.
et al.: Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med.
et al.: Hypokalaemia related to acute chloroquine ingestion. Lancet.
et al.: Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med.
H: Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study. Antimicrob Agents Chemother.
et al.: Experimental assessment of the protective activity of diazepam on the acute toxicity of chloroquine. J Toxicol Clin Toxicol.
TM: Adverse effects of antimalarial prophylactic drugs: an important consideration in the risk-benefit equation. Ann Pharmacother.
et al.: Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial. Br J Clin Pharmacol.
et al.: 4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents. Biomed Pharmacother.
DN: Quinine amblyopia: is current management appropriate?J Toxicol Clin Toxicol.
F, van Vugt
et al.: Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum
malaria. Antimicrob Agents Chemother.
CJ: Quinine levels revisited: the value of routine drug level monitoring for those on parenteral therapy. Acta Trop.
JL: Abnormalities of the pupil and visual-evoked potential in quinine amblyopia. Am J Ophthalmol.
F: Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis. Antemortem diagnosis and successful treatment. Ann Intern Med.
LF: Quinine overdose: review of toxicity and treatment. Clin Cardiol.
SJ: Quinine sulfate. In:Thomas
CC, ed.Toxicology of the Eye, Vol II: Effects on the Eyes and Visual System from Chemicals, Drugs, Metals and Minerals, Plants, Toxins and Venoms.4th ed. Springfield, IL: Charles C. Thomas;1993:1225–1233.
et al.: Malaria: progress, perils, and prospects for eradication. J Clin Invest.
PL: Malaria: burden of disease. Curr Mol Med.
P: The management of quinine-induced blindness. Arch Emerg Med.
et al.: Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol.
NR: Quinine induced blindness. Br J Ophthalmol.
RB: Malaria, mefloquine and the mind. N Z Med J.
F: Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol Adverse Drug Exp.
et al.: Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics.
TS: Review of cases with the emerging fifth human malaria parasite, Plasmodium knowlesi.Clin Infect Dis.
J, Na Bangchang
et al.: Cardiac effect of halofantrine. Lancet.
NJ: Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet.
et al.: Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients. Am J Trop Med Hyg.
PS: Transient pulmonary infiltrates possibly induced by quinine sulfate. Pharmacotherapy.
J: Suspected allergy to artemether-lumefantrine treatment of malaria. J Travel Med.
et al.: UK malaria treatment guidelines. J Infect.
FJ: Quinine-induced hypoglycemia. Ann Intern Med.
DN: Effect of oral activated charcoal on quinine elimination. Br J Clin Pharmacol.
CA: Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis. Lancet.
MG: Chloroquine poisoning. Rapidly fatal without treatment. BMJ.
CB: Ataxia and slurred speech after artesunate treatment for falciparum
malaria. N Engl J Med.
E, Le Metayer
et al.: Cardiac complications of halofantrine: a prospective study of 20 patients. Trans R Soc Trop Med Hyg.
et al.: Death by quinine. Vet Hum Toxicol.
J: Abortifacients: toxidromes, ancient to modern—a case series and review of the literature. Acad Emerg Med.
et al.: The multifocal pattern electroretinogram in chloroquine retinopathy. Ophthalmic Res.
EJ: Acute dapsone
intoxication: clinical findings and effect of oral charcoal and haemodialysis on dapsone
elimination. Acta Med Scand.
et al.: Danger of malaria self-treatment. Acute neurologic toxicity of mefloquine and its combination with pyrimethamine-sulfadoxine. Presse Med.
F, ter Kuile
et al.: Cardiac effects of antimalarial treatment with halofantrine. Lancet.
et al.: The effects of mefloquine treatment in pregnancy. Clin Infect Dis.
JC: High incidence of hypoglycaemia in African patients treated with intravenous quinine for severe malaria. Br Med J (Clin Res Ed).
RK: Chloroquine induced parkinsonism. J Postgrad Med.
et al.: Adverse effects of drugs used in the management of opportunistic infections associated with HIV infection. Drug Saf.
et al.: Hypoglycaemia and counterregulatory hormone responses in severe falciparum
malaria: treatment with Sandostatin. Q J Med.
et al.: Effectiveness of SMS 201-995, a synthetic, long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinaemia. Lancet.
M: Mefloquine-induced grand mal seizure during malaria chemoprophylaxis in a non-epileptic subject. Trans R Soc Trop Med Hyg.
R: Treatment of quinine overdosage with repeated oral charcoal. Br J Clin Pharmacol.
R, van Vugt
et al.: Adverse effects in patients with acute falciparum
malaria treated with artemisinin derivatives. Am J Trop Med Hyg.
F: Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics. Fundam Clin Pharmacol.
S: Chloroquine poisoning: report of two cases. Acta Anaesthesiol Scand.
CK: Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone
: implications for differences in adverse drug reactions. J Pharmacol Exp Ther.
FJ: Treatment of severe chloroquine poisoning. N Engl J Med.
et al.: Protective cardiovascular effects of diazepam in experimental acute chloroquine poisoning. Intensive Care Med.
et al.: Quinine induces reversible high-tone hearing loss. Br J Clin Pharmacol.
et al.: Mefloquine and an acute brain syndrome. Ann Intern Med.
KC: Health advice and immunizations for travelers. N Engl J Med.
FW: Hemodialysis, peritoneal dialysis, plasmapheresis and forced diuresis for the treatment of quinine overdose. Clin Nephrol.
P: Mefloquine for malaria chemoprophylaxis. 1992–1998: a review. J Travel Med.
T: Hypoglycemia induced by hydroxychloroquine
in a type II diabetic treated for polyarthritis. J Rheumatol.
Jr: The management of acute quinidine intoxication. Chest.
et al.: Alpha 1-acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum
malaria. Br J Clin Pharmacol.
MM: Dermatological adverse effects with the antimalarial drug mefloquine: a review of 74 published case reports. Clin Exp Dermatol.
et al.: Comparative cardiac effects of halofantrine and chloroquine plus chlorpheniramine in children with acute uncomplicated falciparum
malaria. Trans R Soc Trop Med Hyg.
A: Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med.
et al.: Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med.
RA: Ototoxicity. Adverse Drug React Toxicol Rev.
V: Medicinal plants and malaria: an historical case study of research at the London School of Hygiene and Tropical Medicine in the twentieth century. Trans R Soc Trop Med Hyg.
et al.: Pediatric ECMO for severe quinidine cardiotoxicity. Pediatr Emerg Care.
et al.: Electrocardiographic changes and halofantrine plasma level during acute falciparum
malaria. Am J Trop Med Hyg.
L: Drugs used in the chemotherapy of protozoal infections: malaria. In:Hardman
L, eds.Goodman & Gilman’s The Pharmacological Basis of Therapeutics.10th ed. New York: McGraw-Hill;2001:1059–1095.
et al.: A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum
malaria. N Engl J Med.
et al.: Pulmonary toxicity with mefloquine. Eur Respir J.
et al.: Halofantrine and acute intravascular haemolysis. Lancet.
et al.: A trial of artemether or quinine in children with cerebral malaria. N Engl J Med.
et al.: Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther.
et al.: Chloroquine myopathy and neuropathy with elevated CSF protein. Neurology.
NJ, van Vugt
F: Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet.
SP: Quinine fatality—case report. Clin Toxicol.
MP: Cinchonism: two case reports and review of acute quinine toxicity and treatment. J Emerg Med.
S: Diazepam for treatment of massive chloroquine intoxication. Resuscitation.