++
++
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.8 In the 1880s, both the Plasmodium protozoa and its mosquito vector were identified.8 Today, nearly half of the world’s population lives in areas where malaria is endemic. Despite markedly decreased mortality rates over the last 7 years, malaria remains a significant cause of morbidity and mortality worldwide. In 2015, there were 212 million estimated malaria cases, leading to 429,000 deaths.119 Most of these deaths were from Plasmodium falciparum infections of young children and primigravid pregnant women in Africa.15 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, an estimated 30,000 of these travelers will acquire malaria.96
++
Malaria is an infection of protozoan parasites in the Plasmodium genus with a unique life cycle 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 owing 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 has impeded eradication in other parts of the world.45
++
Malaria has a unique life cycle (Fig. 55–1) 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 bloodstream.5 The tissue phase is complete at this point with the exception of Plasmodium 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.115
++
++
Six Plasmodium spp cause malaria in humans (Table 55–1). The majority of cases worldwide are caused by P. falciparum and P. vivax, with P. falciparum responsible for the overwhelming majority of deaths.76 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.5 The routine use of antipyretics probably also contributes to atypical presentations.
++
++
Unlike the other forms of human malaria, Plasmodium 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 are reported in and around Malaysia, Indonesia, and Southeast Asia, causing scientists to include this parasite as a potential human pathogen.54
++
It is somewhat ironic that despite sophisticated drug development methods and advanced technologies 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.114 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.106,114 Other drugs used to treat malaria include the folate inhibitors, selected antibiotics, the sulfonamide sulfadoxine, the tetracyclines, and the macrolides (Chap. 54).
++
With the introduction of each new drug, resistance developed, particularly in Oceania, Southeast Asia, and Africa.106,114 In some instances, quinine is again the first-line therapy for malaria.118 In the past 2 decades, the search for active xenobiotics has returned to a natural product, the Chinese herb qinghaosu. The active metabolite, of which is dihydroartemisinin, is common to all the endoperoxides. 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.8,119 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 55–2.
++
+++
Antimalarial Mechanism
++
Unlike humans, who eliminate heme through the use of heme oxygenase ultimately 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 by-products and parasite death.89,115 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 reverse resistance in experimental models.89
++
++
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,75 and in the 1800s, it was used for the treatment of “rebellious palpitations.” Quinine, the primary alkaloid in cinchona bark, was the first effective treatment for malaria. Additionally, because of a reported curarelike action, quinine is infrequently 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 and bitter lemon drinks.
++
High doses of quinine and other cinchona alkaloids are oxytocic, potentially leading to abortion or premature labor in pregnant women. Because of this, quinine is occasionally used as an abortifacient (Chap. 19).77 Chloroquine continues to be used as an abortifacient in some parts of the developing world.11,90 Neither is safe as an abortifacient because of their narrow toxic-to-therapeutic ratio.
+++
Pharmacokinetics and Toxicokinetics
++
See Table 55–3 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 utilizing cytochrome P450 isoenzymes to a variety of hydroxylated metabolites. As such, quinine could alter the metabolism of other xenobiotics utilizing the same enzyme systems, especially CYP3A4, CYP2D6, and CYP1A2. Quinine is also highly protein bound, primarily to α-1-acid glycoproteins, providing an additional mode for potential drug–drug interactions. Quinidine’s volume of distribution varies from 0.5 L/kg in patients with congestive heart failure to 2 to 3 L/kg in healthy adults, to 3 to 5 L/kg in patients with cirrhosis.111 The widely varied volume of distribution between healthy individuals, those with differing levels of parasitemia, and those with various comorbidities, is a shared property of all antimalarials. Quinine undergoes transplacental distribution and is secreted in breast milk.
++
++
Quinine overdose affects multiple organ systems through a number of different pathophysiologic mechanisms. Outcomes appear to be most closely related to the degree of cardiovascular dysfunction.41
++
Quinine and quinidine share anti- and prodysrhythmic effects primarily from an inhibiting effect on the cardiac sodium channels and potassium channels (Chaps. 15 and 57).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.114,116
++
Inhibition of the potassium channels suppresses the repolarizing delayed rectifier potassium current, particularly the rapidly activating component,116 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 occur. This “quinidine syncope”—ventricular dysrhythmias or fibrillation—was identified more than half a century ago as a therapeutic complication.99 An additional α-adrenergic antagonist effect contributes to the syncope and hypotension occurring in quinine toxicity. Quinidine possesses antimuscarinic activity in therapeutic dosing.57
++
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. 47).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).21,107
++
The mechanism of quinine-induced ototoxicity appears to be multifactorial. 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 contributes to decreased hearing.106 Inhibition of the potassium channel also impairs hearing and produces 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. 15 and 25).105
++
Although older theories suggested that quinine caused retinal ischemia, the preponderance of evidence points to a direct toxic effect on the retina, and possibly the optic nerve fibers.38 Quinine also antagonizes cholinergic neurotransmission in the inner synaptic layer.
++
Quinine has direct irritant effects on the gastrointestinal (GI) tract and stimulates the brain stem center responsible for nausea and emesis.114
+++
Clinical Manifestations
++
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 injury (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.75,114 Vertigo, syncope, dystonia, tachycardia, diarrhea, and abdominal pain are also described.49,63
++
Quinine toxicity is 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,37 a single quinine concentration does not always correlate with clinical toxicity. In general, serum concentrations greater than 5 mcg/mL cause cinchonism, greater than 10 mcg/mL visual impairment, greater than 15 mcg/mL cardiac dysrhythmias, and greater than 22 mcg/mL death.4 Similar concentrations in individuals who are severely ill with malaria do not necessarily result in as severe toxicity because an increase in plasma α1-acid glycoprotein reduces the free fraction of quinine present.97,101
++
The toxic-to-therapeutic ratio 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 mcg/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.39,49 Delirium, coma, and seizures are less common, usually occurring only after severe overdoses.18
++
Cardiovascular manifestations of quinine use are related to myocardial drug concentrations. They manifest on the electrocardiogram (ECG) as prolongation of the PR interval, prolongation of the QRS complex, prolongation of the QT interval, and ST depression with or without T wave inversion. Dysrhythmias and complete heart block are reported.16 Quinine toxicity can also result in significant hypotension.
++
Although not commonly reported, mild hyperinsulinemia and resultant hypoglycemia occur in cases of oral quinine overdose. Hypoglycemia with elevated serum insulin concentrations was documented after therapeutic dosing in case reports complicated by severe congestive heart failure and significant ethanol consumption. Hypoglycemia is also noted in healthy patients after overdose. Hypoglycemia is fairly common in patients with severe malaria treated with quinine, occurring in up to 10% of patients and 50% of pregnant women.107
++
Eighth cranial nerve dysfunction results in tinnitus and deafness. The decreased acuity is not usually clinically apparent, although the patient recognizes tinnitus.95 These findings usually resolve within 48 to 72 hours, and permanent hearing impairment is unlikely.
++
Ophthalmic presentations include blurred vision, visual field constriction, diplopia, altered color perception, mydriasis, photophobia, scotomata, and sometimes complete blindness.18,44 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 are occasionally normal but usually demonstrate extreme arteriolar constriction associated with retinal edema. Normal arteriolar caliber is commonly seen initially, but funduscopic manifestations such as vessel attenuation and disc pallor develop as clinical improvement occurs. Improvement in vision can occur rapidly but is usually slow, occurring over a period of months after a severe toxicity. Initially, improvement occurs centrally and is followed later by improvement in peripheral vision. The pupils occasionally remain dilated even after return to normal vision.39 Patients with the greatest exposure frequently develop optic atrophy.
++
Hypokalemia is often described in the setting of quinine poisoning, 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,65,69 and the mechanism is assumed to be similar with quinine.
++
A number of immune-mediated hypersensitivity reactions are described. These are the result of antiquinine or antiquinine-hapten antibodies cross-reacting with a variety of membrane glycoproteins19,56 dramatically increasing their binding affinity to cell-surface antigens by more than 10,000 times.40 Asthma and dermatologic manifestations, such as urticaria, photosensitivity dermatitis, cutaneous vasculitis, lichen planus, and angioedema, also occur.107
++
Hematologic manifestations of hypersensitivity include thrombocytopenia (Chap. 20), agranulocytosis, microangiopathic hemolytic anemia, and disseminated intravascular coagulation (DIC), which can lead to jaundice, hemoglobinuria, and AKI.49,56 Quinine is recognized as a common cause of drug-induced thrombocytopenia and the most common cause of drug-induced thrombotic microangiopathy syndrome (characteristically microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury). Hemolysis also occurs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Severe multisystem hypersensitivity reactions can occur even after minute doses of quinine, such as those in tonic drinks.40,60 This type of interaction has previously been termed “cocktail purpura.”75,114
++
A hepatitis hypersensitivity reaction, acute respiratory distress syndrome (ARDS), and a sepsislike syndrome are also reported.
++
Urine thin-layer chromatography is sensitive enough to confirm the presence of quinine even after the ingestion of tonic water.120 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 is not routinely recommended except for patients with recent, substantial (potentially life-threatening) ingestions with no spontaneous emesis. Activated charcoal effectively adsorbs quinine and additionally decreases serum concentrations by altering enteroenteric circulation62 but should only be administered in patients with a low risk of aspiration or protected airways.
++
Expectant treatment should be initiated, including oxygen, cardiac and hemodynamic monitoring, IV fluid resuscitation, and frequent ECG and blood glucose measurements. In general, patients should be monitored until vital signs normalize, mental status improves, and laboratory values stabilize. Variables including the amount ingested, patient comorbidities, and coingestions, highlight the importance of individualized care. Asymptomatic patients with suspected overdose should be monitored for 6 to 12 hours depending on variables as above, before medical clearance.
++
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. A similar approach would be reasonable to consider for intractable quinine toxicity.
++
In patients with a conduction delay manifested by a QRS complex of more than 100 milliseconds (ms) we recommend treating 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. Sodium bicarbonate therapy is successful in case reports16,41,75 but has not been specifically studied. Since hypertonic sodium bicarbonate will 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.20,65,100 Because hypokalemia can also lead to lethal dysrhythmias, supplementation for significant hypokalemia (<3.0 mmol/L) is recommended as a reasonable intervention.
++
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. 15 and Antidotes in Depth: A16).
++
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 would be expected to exacerbate quinine-induced conduction disturbances or dysrhythmias. The Class IB antidysrhythmics, such as lidocaine, have been used with reported success,47 but no clinical trials have been performed (Chap. 57).
++
Hypotension refractory to IV crystalloid boluses should be treated with vasopressors. In controlled human studies, epinephrine infusions reverse quinidine’s antidysrhythmic drug effects and prolongation of the ventricular refractory period in a dose-dependent fashion.22,74 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.100
++
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.86 In volunteers, quinine-induced hyperinsulinemia was suppressed within 15 minutes after a 100-mcg intramuscular dose of octreotide (Antidotes in Depth: A9).85 Octreotide should be used for cases of refractory hypoglycemia in a fashion similar to that recommended in sulfonylurea toxicity, which is 50 mcg (1 mcg/kg in children) subcutaneously every 6 hours (Chap. 47).
++
Funduscopic examination, visual field examination, and color testing are appropriate bedside diagnostic studies. Electroretinography, electrooculography, visual-evoked potentials, and dark adaptation are 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.46 Hyperbaric oxygen was used in 3 patients who recovered vision, but since its role in that recovery was not established, it cannot be routinely recommended at this time.120
++
The effect of multiple-dose activated charcoal (MDAC) on quinine elimination was studied in an experimental human model and in symptomatic patients.87 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,13,62,87 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, multiple-dose activated charcoal is recommended unless contraindications exist (Antidotes in Depth: A1).
++
There is conflicting evidence about a benefit of urinary acidification in enhancing clearance. 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.13,18,97,114 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; thus, extracorporeal methods of drug removal are not routinely recommended.
++
+++
Pharmacokinetics and Toxicodynamics
++
See Table 55–3 for the pharmacokinetic properties of mefloquine. Similar to its cousin quinine, mefloquine is hepatically metabolized by cytochrome P450 enzyme systems and excreted primarily in the bile and feces. Some hypothesize that the small, lipophilic structure combined with a long elimination half-life allows mefloquine to easily cross the blood–brain barrier, accumulate in the CNS, and interact with neuronal targets, leading to neurotoxic side effects.67
+++
Clinical Manifestations
++
Common side effects with prophylactic and therapeutic dosing include nausea, vomiting, and diarrhea. These side effects are noted particularly in the extremes of age and with high therapeutic dosing. Similar findings should be expected in acute overdose.107,117
++
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.24,63,80 With prophylactic use, neither the PR interval nor the QRS complex is prolonged, but QT interval prolongation is reported.33,63 Reports of torsade de pointes are rare, but the increase in QT interval and risk of torsade de pointes are increased when mefloquine is used concurrently with quinine, chloroquine, or most particularly, with halofantrine.63,80,81,116 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 would be expected to increase with acute overdose, although there is little clinical experience.
++
Mefloquine is commonly associated with 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.98,113 Only 2% to 10% of these complications necessitate the traveler to seek medical advice or change normal activities.24 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.107 Women appear to be more likely than men to experience neuropsychiatric adverse effects.107,113
++
The risk of serious neuropsychiatric adverse effects (convulsions, altered mental status, inability to ambulate due to vertigo, ataxia, or psychosis) during prophylaxis is estimated to be one in 10,600 but is reported to be as high as one in 200 with therapeutic dosing.31,107 Seizures occur rarely with prophylaxis and therapeutic use. 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.56
++
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.32,33 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).10,33,63 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.81,98,103 It is unclear which, if any, would be significant after overdose. Acute respiratory distress syndrome was linked to therapeutic dosing in one case report.
++
In therapeutic use, mefloquine is associated with an increased incidence of stillbirth compared with quinine and a group of other antimalarials.82 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.
++
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. Pregnant patients should be followed with fetal monitoring. Because of mefloquine’s long half-life and potential for CNS accumulation, observation of asymptomatic patients for at least 24 hours is a reasonable approach. Central nervous system effects usually resolve within a few days, but persistent, permanent, and delayed-onset CNS effects are reported, so observation for full resolution of CNS effects would not be practical.
++
In 2 patients with kidney failure who received mefloquine, prophylactic hemodialysis did not remove mefloquine.28 Given the large volume of distribution and high degree of protein binding of mefloquine, extracorporeal elimination techniques are unlikely to be effective.
++
In one case report, the severe neuropsychiatric manifestations of mefloquine were reversed with physostigmine, leading the authors to suggest a possible central anticholinergic mechanism. Physostigmine is not recommended as a routine treatment for mefloquine neuropsychiatric side effects.
++
++
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 CDC.6
+++
Pharmacokinetics and Toxicodynamics
++
See Table 55–3 for the pharmacokinetic properties of halofantrine.
+++
Clinical Manifestations
++
The primary toxicity from therapeutic and supratherapeutic doses is prolongation of the QT interval and the risk of torsade de pointes and ventricular fibrillation.81,109 Palpitations, hypotension, and syncope occur. First-degree atrioventricular (AV) block is common, but bradycardia is rare.81 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.55 Because the QT interval duration is directly related to the serum halofantrine concentration, dysrhythmias should be expected in overdose.24,81,107 Fifty percent of children receiving a therapeutic course of halofantrine will have a QT interval greater than 440 ms.104
++
Other side effects, including nausea, vomiting, diarrhea, abdominal cramps, headache, and lightheadedness, which frequently occur in therapeutic use, are also expected in overdose.63 Less frequently described side effects include pruritus, myalgias, and rigors. Seizures, minimal liver enzyme abnormalities, and hemolysis are described.63,73 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. Based on rare case reports, non-overdose evidence, and known erratic absorption, observation of asymptomatic overdose patients for 24 hours before medical clearance would be a reasonable approach.
++
++
Lumefantrine is structurally similar to halofantrine. It is primarily used as a partner drug in the artemisinin-based combination therapy (ACT) artemether plus lumefantrine.
++
Little toxicity of lumefantrine alone or in combination is reported. Studies do not show QT interval prolongation or evidence of cardiac toxicity related to lumefantrine.36 Cough and angioedema were described in one case. 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. The side effect profiles of the 2 are slightly different, favoring chloroquine use for malarial prophylaxis and hydroxychloroquine use as an antiinflammatory.63,114 Hydroxychloroquine is used in the treatment of rheumatic diseases such as rheumatoid arthritis and lupus erythematosus. In animal studies, chloroquine is 2 to 3 times more toxic than hydroxychloroquine.52
++
Piperaquine is structurally similar to chloroquine but is primarily used in conjunction with artemisinin compounds as a component of an ACT.
+++
Antimalarial Mechanism
++
The 4-aminoquinolines interfere with the digestion of heme and hemozoin formation in a manner similar to that of the amino alcohols.34
++
++
+++
Pharmacokinetics and Toxicodynamics
++
See Table 55–3 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.17,48
++
Chloroquine is slowly distributed from the blood compartment to the larger central compartment, leading to transiently high whole blood concentrations shortly after ingestion.90,102 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 early whole blood chloroquine concentrations correlate with death27 and are better predictors of cardiovascular symptom severity than serum concentrations.70 Unfortunately chloroquine concentrations are rarely rapidly available and thus unlikely to be useful for early bedside clinical decision making.
++
With structural similarity to quinine, the pathophysiologic mechanisms of chloroquine and hydroxychloroquine are also similar. Most notably, sodium and potassium channel blockade are the likely primary mechanisms of cardiovascular toxicity.116
++
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.65,90,100
+++
Clinical Manifestations
++
Similar to quinine, chloroquine has a narrow toxic-to-therapeutic ratio. Severe chloroquine poisoning is usually associated with ingestions of 5 g or more in adults, systolic blood pressure less than 80 mm Hg, QRS complex duration of more than 120 ms, ventricular fibrillation, hypokalemia, and serum chloroquine concentrations exceeding 25 µmol/L (8 mcg/mL).26,93 Not surprisingly, suspected ingested doses do not always correlate with blood concentrations,71 but the suspected ingested dose still remains a potentially helpful historic predictor of the possibility for severe toxicity.
++
Symptoms usually occur within 1 to 3 hours of ingestion.93 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.49,63 In contrast, respiratory depression is common, and apnea, hypotension, and cardiovascular compromise can be precipitous.49
++
The cardiovascular effects of chloroquine and hydroxychloroquine are similar to those of quinine, including QRS complex 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.49
++
Significant hypokalemia in chloroquine toxicity is invariably associated with cardiac manifestations.49 In fact, the extent of hypokalemia is a good indicator of the severity of chloroquine overdose26 and mortality rate.70
++
Neurologic manifestations include CNS depression, dizziness, headache, and convulsions.46 Rarely, dystonic reactions occur. Transient parkinsonism is also reported after excessive dosing.
++
Ophthalmic manifestations are infrequent in acute chloroquine toxicity and transient in nature.49,63 More severe and irreversible vision and hearing changes are described in association with the chronic use of chloroquine and hydroxychloroquine as antiinflammatories.63,78 Myopathy, neuropathy, and cardiomyopathy also occur when used for that purpose.8 Dermatologic findings and hypersensitivity reactions are similar to those associated with quinine.33 Likewise, red blood cell (RBC) oxidant stress from chloroquine results in hemolysis in patients with G6PD deficiency (Chap. 20).
++
Acute hydroxychloroquine toxicity is similar to chloroquine toxicity.52 Side effects from therapeutic doses include nausea and abdominal pain; hemolysis in G6PD-deficient patients; and, rarely, retinal damage, sensorineural deafness, and hypoglycemia. Hypersensitivity reactions, including myocarditis and hepatitis, are described.
++
Aggressive supportive care is recommended, including oxygen, cardiac and hemodynamic monitoring, and large-bore IV access, and serial blood glucose concentrations. Despite reported rapid absorption, one series reported delayed peak blood concentrations in some patients,70 opening the possibility of a potential benefit for early GI decontamination methods. Orogastric lavage is recommended 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 anticipated before initiating any type of GI decontamination.
++
Early aggressive management of severe chloroquine toxicity decreases the mortality rate.93 This includes early endotracheal intubation and mechanical ventilation. Evidence suggests that barbiturates are not desirable for induction in patients with chloroquine overdose. When thiopental was used to facilitate intubation, its use immediately preceded sudden cardiac arrest in 7 of 25 patients after chloroquine overdose.27 Regardless of induction agent, 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 therefore 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.93,94 The epinephrine doses used in these studies are still recommended today.93,94 The recommended dose is 0.25 mcg/kg/min, increasing by 0.25 mcg/kg/min until an adequate systolic blood pressure (>90 mm Hg) is achieved.30,69,93,94 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.27,65 Animal and human studies that followed also showed a potential benefit.30,93,94 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% vs 9% survival) occurred.93 Studies in moderately poisoned patients failed to show similar benefit,26 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 1–2 mg/kg/day for 2–4 days) is recommended 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 vasodilation65,90,93,94 (Antidotes in Depth: A26).
++
The use of sodium bicarbonate for correction of QRS complex 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. Before using sodium bicarbonate in the setting of chloroquine toxicity, clinicians should evaluate the overall clinical status of the patient, including the suspected degree of cardiac toxicity and severity of hypokalemia. In the setting of normal potassium, sodium bicarbonate is a reasonable intervention to counteract QRS complex prolongation.
++
Hypokalemia in the setting of chloroquine overdose correlates with the severity of the toxicity.26,65 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.26,65,90 This should be balanced against the fact that severe hypokalemia can itself result in lethal dysrhythmias and data suggesting severe hypokalemia (<1.9 mEq/L) is associated with severe, life-threatening ingestion.24,49,65,102 Hypokalemia could not be directly attributed as the cause of death in most cases, however.26 Based on the available evidence, potassium replacement for severe hypokalemia would be a reasonable intervention, 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.52,65
++
Because chloroquine and hydroxychloroquine have high volumes of distribution and significant protein binding, enhanced elimination procedures are not beneficial.17,49 There is limited experience with lipid emulsion therapy in the setting of chloroquine poisoning; thus its use is not recommended (Antidotes in Depth: A23).
++
++
See Table 55–3 for the pharmacokinetic properties of piperaquine.
++
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 artemisinin 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 5 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.
++
++
Amodiaquine has pharmacologic properties similar to others in the 4-aminoquinolone family. It is rapidly absorbed from the GI tract and hepatically metabolized by CYP2C8 into its active antimalarial metabolite, desethylamodiaquine.118
++
Amodiaquine fell out of favor as a prophylactic treatment as a result of serious and sometimes fatal liver and bone marrow toxicity,107 but is still a component of one of 5 ACTs recommended by the WHO for treatment of active malarial infection. Hypersensitivity reactions (hepatitis and neutropenia) described in prophylactic use are uncommon with therapeutic use.21,118 Reports of amodiaquine toxicity suggest that involuntary movements, muscle stiffness, dysarthria, syncope, and seizures can occur.2,49 There is no overdose experience reported. Aggressive symptomatic and supportive care, expectant observation, including cardiovascular and CNS monitoring, should be provided for possible poisoning.
++
++
Primaquine and its related compounds are the only drugs licensed for the prevention of P. ovale and P. vivax relapse caused by hepatic hypnozoites (Fig. 55–1). 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 Glucose-6-phosphate dehydrogenase 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. Primaquine is making a resurgence in some countries for P. falciparum treatment as a gametocytocide to reduce transmission in campaigns to eradicate malaria from these regions.50
+++
Antimalarial Mechanism
++
The antimalarial action of primaquine is poorly understood but thought to be related to increasing the oxidative stress of erythrocytes,115 obstructing proper parasitic development.
+++
Pharmacokinetics and Toxicodynamics
++
See Table 55–3 for the pharmacokinetic properties of primaquine. Metabolism is primarily hepatic, using multiple enzyme systems, with CYP2D6 playing a prominent role.7 The parent compound is metabolized to reactive intermediates that are thought to mediate both its antimalarial and hemolytic effects.
++
Primaquine blocks sodium channels both in vitro and in animal models.49,116 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 occur in normal individuals given high doses as well as those with G6PD deficiency.63,107
++
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.
+++
Clinical Manifestations
++
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. 20). 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 (Chap. 124).107 Acute liver failure has occurred after unintentional overdose, and fatal hepatotoxicity is described in animal models.61
++
Therapy should be directed at minimizing absorption with appropriate decontamination, and diagnosing 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 is a reasonable early intervention (Antidotes in Depth: A1). Methylene blue (Chap. 124 and Antidotes in Depth: A43) is recommended 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 acute kidney injury. Urinary alkalinization with sodium bicarbonate is controversial in this setting but is not routinely recommended because it has not been proven to be superior to aggressive sodium chloride 0.9% hydration alone (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 A.D. 340, but the primary active component of qinghaosu, now known as artemisinin, was not isolated until 1974.8,114 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. Artemisinin-based combination therapies are currently recommended by the WHO for the treatment of uncomplicated malaria118 but only one has been licensed for use in the United States; artemether and lumefantrine. Five artemesin-based combination therapies (ACT) are currently recommended by the WHO. These include artemether plus lumefantrine, artesunate plus mefloquine, artesunate plus pyrimethamine–sulfadoxine, artesunate plus amodiaquine, and dihydroartemisinin and piperaquine.
+++
Antimalarial Mechanism
++
The artemisinins 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.1 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 55–3 for the pharmacokinetic properties of artemisinin. Artemisinin and its derivatives are rapidly metabolized to the primary active metabolite dihydroartemisinin.68 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 brain stem nuclei is consistently produced after prolonged, high-dose, and parenteral administration.107 Sustained CNS exposure from slowly absorbed or eliminated artemisinins is considered markedly more neurotoxic than intermittent brief exposure that occurs after oral dosing. Embryonic loss is also observed in animals.
+++
Clinical Manifestations
++
In contrast to the experience with animals, the general theme throughout the literature suggests that these drugs have a very low incidence of side effects. This is consistent with the belief that long-term, rather than short-term, peak concentrations are primarily responsible for toxicity.35 Uncommon side effects include nausea, vomiting, abdominal pain, diarrhea, and dizziness. Few large-scale trials powered to detect rare but possibly significant toxicity have been performed.
++
Prospective studies have failed to identify adverse neurologic outcomes.58,107 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.112 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.110 Rare patients receiving an artemisinin derivative in 2 other studies experienced transient dizziness or cerebellar signs.88 Most recovered within days. One patient in each study had prolonged symptoms lasting 1 month and 4 months, respectively, but both ultimately recovered.
++
When serial ECGs were obtained, a small but statistically significant decrease in heart rate was noted coincident with peak drug concentrations.72 In one therapeutic trial, 7% of adult patients receiving artemether had an asymptomatic QT interval prolongation of at least 25%.110 Changes in the QRS complex are not reported.
++
Although uncommon, neutropenia, reticulocytopenia, anemia, eosinophilia, and elevated aminotransferases are reported.107 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.
++
++
Atovaquone is a structural analog of ubiquinone, or coenzyme Q, a mitochondrial protein involved in electron transport.9 Atovaquone disrupts the protozoal mitochondrial membrane potential, leading to inhibition of several parasite-specific enzymes, ultimately leading to the inhibition of pyrimidine synthesis, which is necessary for protozoal survival and replication. Based on its beneficial side effect profile, the CDC recommends the combination atovaquone–proguanil for treatment of chloroquine-resistant malaria. The price of this combination as well as the variable bioavailability of atovaquone limits its use in less affluent countries.
++
Atovaquone alone, primarily used to treat Pneumocystis jiroveci in patients with AIDS, is relatively well tolerated.84 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 are reported.25 No symptoms occurred in one case (at 3 times therapeutic serum concentration). Rash occurred in another, and in the third case, methemoglobinemia was attributed to a simultaneous overdose of dapsone.
++
When used to treat malaria, atovaquone-proguanil side effects include abdominal pain, nausea, vomiting headache, diarrhea, anorexia, and dizziness.9 This combination is also associated with elevated aminotransferases89 and hepatosplenomegaly.9 Reported overdose has caused little serious toxicity.107
++
Atovaquone is reported to have extensive enterohepatic cycling, with 94% of the drug eliminated in the feces.9,66 Although there is no evidence, multiple-dose activated charcoal is a reasonable intervention in selected overdose patients.
+++
ANTIFOLATES AND ANTIBIOTICS
++
+++
Antimalarial Mechanism
++
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.114 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 medications in synergistic combinations leading to inhibition of folate metabolism at 2 different sites.
+++
Pharmacokinetics and Toxicodynamics
++
See Table 59–3 for the pharmacokinetic properties of pyrimethamine, proguanil, and dapsone.
++
Proguanil’s active metabolite, cycloguanil, is primarily responsible for its antimalarial activity. Both the parent drug and active metabolite share substantial renal excretion, making renal insufficiency a risk factor for toxicity.51 Dapsone is chiefly metabolized by CYP2C19 to dapsone hydroxylamine.108 These hydroxylamine metabolites have a long half-life, partially because of enterohepatic recirculation, and concentrate in erythrocytes leading to oxidant stress resulting in methemoglobinemia and hemolysis. Cimetidine competes for the same CYP enzymes, decreasing methemoglobin levels during therapeutic dapsone dosing92 presumably by shunting dapsone metabolism to alternate nontoxic pathways.
+++
Clinical Manifestations
++
The side effects of proguanil during prophylaxis include nausea, diarrhea, and mouth ulcers.63 Because of the interference with folate metabolism, megaloblastic anemia is a rare but potential complication. Megaloblastic bone marrow toxicity is reported in patients with chronic kidney disease.107 Folate supplementation is recommended in pregnancy and CKD to avoid this complication.31 Rarely, neutropenia, thrombocytopenia, rash, and alopecia are also noted. In a single case report, hypersensitivity hepatitis was described.31
++
Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomiting, a rapid onset of seizures, fever, and tachycardia.3,49 Blindness, deafness, and developmental delay have followed. 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. Chronic high dose use is associated with a megaloblastic anemia and bone marrow suppression, requiring folate replacement.3
++
The sulfonamides, including the sulfone dapsone, have a long history of causing idiosyncratic reactions, including neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neuropathy, and hepatitis.63,107 Rare occurrence of life-threatening erythema multiforme major and toxic epidermal necrolysis, associated with pyrimethamine–sulfadoxine prophylaxis, has limited the use of this combination.
++
Acute ingestion of dapsone results in nausea, vomiting, and abdominal pain.49 After overdose, dapsone produces RBC oxidant stress, leading to methemoglobinemia and, to a much lesser extent, sulfhemoglobinemia through formation of an active metabolite (Chap. 124).23,64 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. Additional effects described in overdose include hepatitis and peripheral neuropathy.49
++
Neural tube defects are associated with the use of folic acid antagonists, thus folate supplementation is reasonable in reproductive age women exposed to these agents. Folinic acid (leucovorin) would be a reasonable intervention after an overdose of proguanil or pyrimethamine (Antidotes in Depth: A12). Other efforts should include supportive care.
++
After dapsone ingestion, clinically significant methemoglobinemia should be treated with methylene blue (Chap. 124 and Antidotes in Depth: A43). The long half-life of dapsone and its metabolites often make repetitive doses of methylene blue necessary. The patient’s clinical status is more important than a single methemoglobin level for determining treatment interventions. There is no antidote for sulfhemoglobinemia, but it constitutes an insignificant portion of total hemoglobin.
++
Multiple-dose activated charcoal is recommended for patients with a dapsone overdose and no contraindicators.64 Exchange transfusion is a reasonable intervention for patients who fail to respond to methylene blue. Hemodialysis decreased methemoglobinemia concentrations in case reports but subsequent rebound dapsone concentrations were observed.79 Continuous veno-venous hemofiltration increased dapsone clearance 3-fold in a single case report. These extracorporeal methods of removal are not routinely recommended. Hyperbaric oxygen has been used in case reports as an adjunct to methylene blue in the treatment of methemoglobinemia but is not routinely recommended (Antidotes in Depth: A43).
++
Cimetidine supplementation is a reasonable intervention after dapsone overdose. Other antioxidants, ascorbic acid and vitamin E, have been used to treat methemoglobinemia12 but are not routinely recommended because their slow onset of action makes a benefit unlikely.
++
Shared cytochrome P450 metabolic pathways and genetic polymorphisms are increasingly recognized as contributing factors in drug–drug interactions and toxicity. The clarification of various antimalarial metabolic pathways has led to concern for potential toxicity due to these interactions. The clinical relevance of these interactions is unclear, however. Genetic polymorphism is described in the metabolism of proguanil and dapsone and may be a contributing factor to the hypersensitivity reactions noted with dapsone.53,91 Table 55–3 highlights the known potentially significant metabolic interactions of antimalarials.
++
The development of drug resistance and search for treatments with improved efficacy, compliance and side-effect profiles fuels an ongoing pursuit for better antimalarials. Tafenoquinone (WR-238605 or etauine) is an 8-aminoquinoline with greater activity against liver-stage parasites than primaquine. It appears to have fewer side effects than primaquine, less hemolytic toxicity and a longer half-life enabling less frequent dosing that could increase compliance.29 At the time of this writing, phase III trials of tafenoquine are ongoing. A number of new ACTs are being studied in different countries, but are not yet recommended by the WHO because of insufficient evidence. These new ACTs include combinations of artesunate and pyronaridine, arterolane and piperaquine, artemisinin and piperaquine base, artemisinin and napthoquine.118
++
Although there is no supporting evidence, one case series discussed eculizumab, a monoclonal antibody targeting the terminal portion of the complement cascade, as a potential therapy for AKI associated with quinine-induced thrombotic microangiopathy.40 Because the role of complement in quinine-induced thrombotic microangiopathy remains unclear and it deviates from the FDA-approved indication, the use of eculizumab for quinine hypersensitivity is not presently recommended.
++
The complicated structure and life cycle of malaria protozoa has made the development of an effective malaria vaccine an elusive undertaking. Despite these difficulties, the Malaria Vaccine Technology Roadmap has focused strategic efforts since 2006. The most advanced vaccine in development, RTS,S/AS01, provides modest protection (26%–50%)42 against P. falciparum.83 Funding for a large-scale implementation pilot using this vaccine is established. Vaccinations in several sub-Saharan African countries began in 2018.
++
Malaria is a parasitic infection of human erythrocytes caused by protozoan parasites in the Plasmodium genus with a unique life cycle 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. Early intubation along with high-dose epinephrine and diazepam 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.
Understanding antimalarial metabolism and toxicity, creating improved antimalarial medications, and vaccine development are among the many future research efforts under way today.
++
G. Randall Bond, MD, contributed to this chapter in previous editions.
1. +
Brown
D. Atremisinin and a new generation of antimalarial drugs. Educ Chem. 2006;43:97–99.
2. +
Adjei
GO, et al. Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose.
Ghana Med J. 2009;43:135–138.
[PubMed: 20126327]
4. +
AlKadi
HO. Antimalarial drug toxicity: a review.
Chemotherapy. 2007;53:385–391.
[PubMed: 17934257]
5. +
Antinori
S, et al. Biology of human malaria plasmodia including
Plasmodium knowlesi.
Mediterr J Hematol Infect Dis. 2012;4:e2012013.
[PubMed: 22550559]
8. +
Aweeka
FT, German
PI. Clinical pharmacology of artemisinin-based combination therapies.
Clin Pharmacokinet. 2008;47:91–102.
[PubMed: 18193915]
12. +
Barclay
JA, et al. Dapsone-induced methemoglobinemia: a primer for clinicians.
Ann Pharmacother. 2011;45:1103–1115.
[PubMed: 21852596]
13. +
Bateman
DN, et al. Pharmacokinetics and clinical toxicity of
quinine overdosage: lack of efficacy of techniques intended to enhance elimination.
Q J Med. 1985;54:125–131.
[PubMed: 3983356]
14. +
Beutler
E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective.
Blood. 2008;111:16–24.
[PubMed: 18156501]
15. +
Birkett
AJ. Status of vaccine research and development of vaccines for malaria.
Vaccine. 2016;34:2915–2920.
[PubMed: 26993333]
16. +
Bodenhamer
JE, Smilkstein
MJ. Delayed cardiotoxicity following
quinine overdose: a case report.
J Emerg Med. 1993;11:279–285.
[PubMed: 8340583]
19. +
Bougie
DW, et al. Patients with quinine-induced immune thrombocytopenia have both “drug-dependent” and “drug-specific” antibodies.
Blood. 2006;108:922–927.
[PubMed: 16861345]
20. +
Brandfonbrener
M, et al. The effect of serum potassium concentration on
quinidine toxicity.
J Pharmacol Exp Ther. 1966;154:250–254.
[PubMed: 5922987]
21. +
Breckenridge
AM, Winstanley
PA. Clinical pharmacology and malaria.
Ann Trop Med Parasitol. 1997;91:727–733.
[PubMed: 9625927]
23. +
Carrazza
MZ, et al. Clinical and laboratory parameters in
dapsone acute intoxication.
Rev Saude Publica. 2000;34:396–401.
[PubMed: 10973160]
24. +
Chattopadhyay
R, et al. Assessment of safety of the major antimalarial drugs.
Expert Opin Drug Saf. 2007;6:505–521.
[PubMed: 17877439]
26. +
Clemessy
JL, et al. Therapeutic trial of
diazepam versus placebo in acute
chloroquine intoxications of moderate gravity.
Intensive Care Med. 1996;22:1400–1405.
[PubMed: 8986493]
28. +
Crevoisier
CA, et al. 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. 1995;39:1892–1895.
[PubMed: 7486943]
30. +
Crouzette
J, et al. Experimental assessment of the protective activity of
diazepam on the acute toxicity of
chloroquine.
J Toxicol. 1983;20:271–279.
31. +
Davis
TM. Adverse effects of antimalarial prophylactic drugs: an important consideration in the risk-benefit equation.
Ann Pharmacother. 1998;32:1104–1106.
[PubMed: 9793605]
32. +
Davis
TM. Antimalarial drugs and glucose metabolism.
Br J Clin Pharmacol. 1997;44:1–7.
[PubMed: 9241090]
33. +
Davis
TM, et al. Neurological, cardiovascular and metabolic effects of
mefloquine in healthy volunteers: a double-blind, placebo-controlled trial.
Br J Clin Pharmacol. 1996;42:415–421.
[PubMed: 8904612]
34. +
de Souza
NB, et al. 4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents.
Biomed Pharmacother. 2011;65:313–316.
[PubMed: 21704476]
35. +
Efferth
T, Kaina
B. Toxicity of the antimalarial artemisinin and its dervatives.
Crit Rev Toxicol. 2010;40:405–421.
[PubMed: 20158370]
36. +
Ezzet
F, et al. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria.
Antimicrob Agents Chemother. 2000;44:697–704.
[PubMed: 10681341]
37. +
Flanagan
KL, et al.
Quinine levels revisited: the value of routine drug level monitoring for those on parenteral therapy.
Acta Trop. 2006;97:233–237.
[PubMed: 16387280]
38. +
Fraunfelder
F, et al. Drug induced ocular side effects. In: Clinical Ocular Toxicity: Drugs, Chemicals and Herbs. Philadelphia, PA: Elseviers Saunders; 2008:45–287.
39. +
Gangitano
JL, Keltner
JL. Abnormalities of the pupil and visual-evoked potential in
quinine amblyopia.
Am J Ophthalmol. 1980;89:425–430.
[PubMed: 7369302]
40. +
George
JN, et al. After the party’s over.
N Engl J Med. 2017;376:74–80.
[PubMed: 28052232]
41. +
Goldenberg
AM, Wexler
LF.
Quinine overdose: review of toxicity and treatment.
Clin Cardiol. 1988;11:716–718.
[PubMed: 3066541]
42. +
Goncalves
BP, et al. Preparing for future efficacy trials of severe malaria vaccines.
Vaccine. 2016;34:1865–1867.
[PubMed: 26923455]
44. +
Grant
WM, Schuman
JS.
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.
45. +
Greenwood
BM, et al. Malaria: progress, perils, and prospects for eradication.
J Clin Invest. 2008;118:1266–1276.
[PubMed: 18382739]
46. +
Guly
U, Driscoll
P. The management of quinine-induced blindness.
Arch Emerg Med. 1992;9:317–322.
[PubMed: 1449580]
47. +
Gunawan
CA, et al. Quinine-induced arrhythmia in a patient with severe malaria.
Acta Med Indones. 2007;39:27–32.
[PubMed: 17297207]
48. +
Gustafsson
LL, et al. Disposition of
chloroquine in man after single intravenous and oral doses.
Br J Clin Pharmacol. 1983;15:471–479.
[PubMed: 6849784]
49. +
Jaeger
A, et al. Clinical features and management of poisoning due to antimalarial drugs.
Med Toxicol Adverse Drug Exp. 1987;2:242–273.
[PubMed: 3306266]
50. +
John
CC.
Primaquine plus artemisinin combination therapy for reduction of malaria transmission: promise and risk.
BMC Med. 2016;14:65.
[PubMed: 27039396]
51. +
Jolink
H, et al. Pancytopenia due to proguanil toxicity in a returning traveller with fever.
Eur J Clin Pharmacol. 2010;66:811–812.
[PubMed: 20407763]
52. +
Jordan
P, et al.
Hydroxychloroquine overdose: toxicokinetics and management.
J Toxicol. 1999;37:861–864.
53. +
Kaneko
A, et al. Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations.
Pharmacogenetics. 1999;9:317–326.
[PubMed: 10471063]
54. +
Kantele
A, Jokiranta
TS. Review of cases with the emerging fifth human malaria parasite,
Plasmodium knowlesi.
Clin Infect Dis. 2011;52:1356–1362.
[PubMed: 21596677]
55. +
Karbwang
J, et al. Cardiac effect of halofantrine.
Lancet. 1993;342:501.
[PubMed: 8102461]
58. +
Kissinger
E, 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. 2000;63:48–55.
[PubMed: 11357994]
60. +
Liles
NW, et al. Diversity and severity of adverse reactions to
quinine: a systematic review.
Am J Hematol. 2016;91:461–466.
[PubMed: 26822544]
62. +
Lockey
D, Bateman
DN. Effect of oral activated charcoal on
quinine elimination.
Br J Clin Pharmacol. 1989;27:92–94.
[PubMed: 2706191]
63. +
Luzzi
GA, Peto
TE. Adverse effects of antimalarials. An update.
Drug Saf. 1993;8:295–311.
[PubMed: 8481216]
64. +
MacDonald
RD, McGuigan
MA. Acute
dapsone intoxication: a pediatric case report.
Pediatr Emerg Care. 1997;13:127–129.
[PubMed: 9127424]
66. +
Marra
F, et al. Atovaquone-proguanil for prophylaxis and treatment of malaria.
Ann Pharmacother. 2003;37:1266–1275.
[PubMed: 12921511]
67. +
McCarthy
S. Malaria prevention,
mefloquine neurotoxicity, neuropsychiatric illness, and risk-benefit analysis in the Australian Defence Force.
J Parasitol Res. 2015;2015:287651.
[PubMed: 26793391]
68. +
Medhi
B, et al. Pharmacokinetic and toxicological profile of artemisinin compounds: an update.
Pharmacology. 2009;84:323–332.
[PubMed: 19851082]
70. +
Megarbane
B, et al. Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships.
Clin Toxicol (Phila). 2010;48:904–915.
[PubMed: 21080867]
71. +
Megarbane
B, et al.
Epinephrine requirement based on the reported ingested dose in
chloroquine poisoning: usefulness and limitations of dose-effect modelling.
Clin Toxicol (Phila). 2011;49:193–194.
[PubMed: 21495891]
72. +
Miller
LG, Panosian
CB. Ataxia and slurred speech after
artesunate treatment for falciparum malaria.
N Engl J Med. 1997;336:1328.
[PubMed: 9132599]
73. +
Monlun
E, et al. Cardiac complications of halofantrine: a prospective study of 20 patients.
Trans R Soc Trop Med Hyg. 1995;89:430–433.
[PubMed: 7570888]
74. +
Morady
F, et al. Antagonism of
quinidine’s electrophysiologic effects by
epinephrine in patients with ventricular tachycardia.
J Am Coll Cardiol. 1988;12:388–394.
[PubMed: 3392332]
76. +
Nadjm
B, Behrens
RH. Malaria: an update for physicians.
Infect Dis Clin North Am. 2012;26:243–259.
[PubMed: 22632637]
77. +
Netland
KE, Martinez
J. Abortifacients: toxidromes, ancient to modern—a case series and review of the literature.
Acad Emerg Med. 2000;7:824–829.
[PubMed: 10917335]
78. +
Neubauer
AS, et al. The multifocal pattern electroretinogram in
chloroquine retinopathy.
Ophthalmic Res. 2004;36:106–113.
[PubMed: 15017107]
79. +
Neuvonen
PJ, et al. Acute
dapsone intoxication: clinical findings and effect of oral charcoal and haemodialysis on
dapsone elimination.
Acta Med Scand. 1983;214:215–220.
[PubMed: 6660028]
80. +
Nosten
F, Price
RN. New antimalarials. A risk-benefit analysis.
Drug Saf. 1995;12:264–273.
[PubMed: 7646825]
81. +
Nosten
F, et al. Cardiac effects of antimalarial treatment with halofantrine.
Lancet. 1993;341:1054–1056.
[PubMed: 8096959]
84. +
Peters
BS, et al. Adverse effects of drugs used in the management of opportunistic infections associated with HIV infection.
Drug Saf. 1994;10:439–454.
[PubMed: 7917073]
85. +
Phillips
RE, et al. Hypoglycaemia and counterregulatory hormone responses in severe falciparum malaria: treatment with Sandostatin.
Q J Med. 1993;86:233–240.
[PubMed: 8327638]
86. +
Phillips
RE, et al. Effectiveness of SMS 201-995, a synthetic, long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinaemia.
Lancet. 1986;1:713–716.
[PubMed: 2870226]
87. +
Prescott
LF, et al. Treatment of
quinine overdosage with repeated oral charcoal.
Br J Clin Pharmacol. 1989;27:95–97.
[PubMed: 2706192]
88. +
Price
R, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.
Am J Trop Med Hyg. 1999;60:547–555.
[PubMed: 10348227]
89. +
Pussard
E, Verdier
F. Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics.
Fundam Clin Pharmacol. 1994;8:1–17.
[PubMed: 8181791]
91. +
Reilly
TP, et al. Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and
dapsone: implications for differences in adverse drug reactions.
J Pharmacol Exp Ther. 1999;288:951–959.
[PubMed: 10027831]
95. +
Roche
RJ, et al.
Quinine induces reversible high-tone hearing loss.
Br J Clin Pharmacol. 1990;29:780–782.
[PubMed: 2198912]
96. +
Ryan
ET, Kain
KC. Health advice and immunizations for travelers.
N Engl J Med. 2000;342:1716–1725.
[PubMed: 10841875]
97. +
Sabto
JK, et al. Hemodialysis, peritoneal dialysis, plasmapheresis and forced diuresis for the treatment of
quinine overdose.
Clin Nephrol. 1981;16:264–268.
[PubMed: 7307355]
99. +
Selzer
A, Wray
HW.
Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias.
Circulation. 1964;30:17–26.
[PubMed: 14197832]
101. +
Silamut
K, et al. Alpha 1-acid glycoprotein (orosomucoid) and plasma protein binding of
quinine in falciparum malaria.
Br J Clin Pharmacol. 1991;32:311–315.
[PubMed: 1777366]
103. +
Smith
HR, et al. Dermatological adverse effects with the antimalarial drug
mefloquine: a review of 74 published case reports.
Clin Exp Dermatol. 1999;24:249–254.
[PubMed: 10457122]
105. +
Splawski
I, et al. Molecular basis of the long-QT syndrome associated with deafness.
N Engl J Med. 1997;336:1562–1567.
[PubMed: 9164812]
106. +
Tange
RA. Ototoxicity.
Adverse Drug React Toxicol Rev. 1998;17:75–89.
[PubMed: 9838967]
107. +
Taylor
WR, White
NJ. Antimalarial drug toxicity: a review.
Drug Saf. 2004;27:25–61.
[PubMed: 14720085]
108. +
Toker
I, et al. Methemoglobinemia caused by
dapsone overdose: which treatment is best?
Turk J Emerg Med. 2015;15:182–184.
[PubMed: 27239625]
109. +
Touze
JE, et al. Electrocardiographic changes and halofantrine plasma level during acute falciparum malaria.
Am J Trop Med Hyg. 1996;54:225–228.
[PubMed: 8600754]
110. +
Tran
TH, et al. A controlled trial of artemether or
quinine in Vietnamese adults with severe falciparum malaria.
N Engl J Med. 1996;335:76–83.
[PubMed: 8649493]
111. +
Lilly, USA, LLC.
Quinidine gluconate injection. USP [package insert]. Indianapolis, IN: Lilly, USA, LLC; 2012.
112. +
van Hensbroek
MB, et al. A trial of artemether or
quinine in children with cerebral malaria.
N Engl J Med. 1996;335:69–75.
[PubMed: 8649492]
113. +
van Riemsdijk
MM, et al.
Atovaquone plus chloroguanide versus
mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events.
Clin Pharmacol Ther. 2002;72:294–301.
[PubMed: 12235450]
114. +
Vinetz
J, et al. Chemotherapy of malaria. In: Brunton
L, et al., eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill Companies; 2011.
115. +
Warhurst
DC. Antimalarial drugs. An update.
Drugs. 1987;33:50–65.
[PubMed: 3545765]
116. +
White
NJ. Cardiotoxicity of antimalarial drugs.
Lancet Infect Dis. 2007;7:549–558.
[PubMed: 17646028]
117. +
White
NJ. The treatment of malaria.
N Engl J Med. 1996;335:800–806.
[PubMed: 8703186]
120. +
Wolf
LR, et al. Cinchonism: two case reports and review of acute
quinine toxicity and treatment.
J Emerg Med. 1992;10:295–301.
[PubMed: 1624742]