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 ||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.