Quinine

Pharmacokinetics

Quinine given orally is well absorbed. The half-life is 11 hours. Clearance is predominantly by hepatic metabolism; urinary clearance accounts for only 20%. Information on pharmacokinetics in healthy volunteers can be misleading, since plasma quinine concentrations are higher in the presence of malaria infection than in healthy subjects given the same dose [ ]. The dosage regimen therefore needs to be adapted to the severity of the illness and amended as improvement occurs.

A population pharmacokinetic study of intramuscular quinine (loading dose 20 mg/kg salt diluted 1:1 in water) in 120 Ghanaian children with severe malaria showed predictable profiles, which were within the target range for quinine (15–20 μg/ml) and independent of clinical and laboratory variables [ ]. Adverse events included skin induration or abscesses at the injection site (12%), all of which resolved without surgical intervention, and hypoglycemia (10%), a special risk in children who were hypoglycemic at presentation.

Adverse reactions to quinine are common at plasma concentrations over 10 μg/ml. The dose often recommended, 10 mg/kg intravenously over 10–20 minutes, may be too high in patients with cerebral malaria [ ]. In the USA, intravenous quinine has been discontinued in favor of quinidine [ ]. In some areas, a high rate of recrudescence is seen after short-term treatment with quinine. The addition of specific antibiotics may improve the cure rate.

General adverse effects and adverse reactions

Quinine is not pleasant to take, and adverse reactions, including nausea, tinnitus, dizziness, and hypoglycemia, are well recognized and common compared with other antimalarial drugs [ ] in the doses used to treat malaria, although not in the smaller doses used to prevent leg cramps, when classical allergic reactions can still occur [ ]. Most serious adverse reactions are due to the prodysrhythmic properties of quinine, and its effects as a hypoglycemic agent, especially in pregnant women with severe malaria. The prolonged use of normal or low doses of quinine can lead to “cinchonism” in sensitive individuals; this in mild form consists of tinnitus, headache, nausea, and visual disturbances [ ]. Overdosage can cause marked gastrointestinal intolerance, central nervous system disturbances (especially vertigo), visual disorders (very occasionally involving sudden blindness), and cardiovascular problems related to impaired intracardiac conduction. A major risk with quinine is that of direct intravenous injection given too fast. Allergic reactions are not uncommon. They are usually limited to fever and rashes, but angioedema and asthma have been seen. Thrombocytopenic purpura and thrombocytopenia are, at least in some cases, caused by an allergic reaction, and the amounts of quinine present in some “tonics” are sufficient to trigger thrombocytopenia in such patients. Anaphylactic shock has been reported in rare cases [ ].

Placebo-controlled studies

A double-blind, placebo-controlled trial of a 3-day combination regimen of quinine (8 mg/kg tds) and clindamycin (5 mg/kg tds) (n = 53) versus 7-day quinine (8 mg/kg tds intravenously for 3 days, then orally; n = 55) to treat uncomplicated imported falciparum malaria showed no significant differences in the parasite and fever clearance times or the 28-day cure rate (100 versus 96%) [ ]. The frequencies of mild adverse events (tinnitus and nausea) were similar in the two groups. There were two serious adverse events that necessitated treatment withdrawal: one patient taking quinine alone had a hemolytic episode and another had a “severe toxic rash.”

Cardiovascular

Quinine can cause atrioventricular conduction disturbances. In sensitive patients, such changes can occur with normal dosages given over a prolonged period; however, in most cases cardiac effects are due to overdosage.

Electrocardiographic changes, such as prolongation of the QT interval, widening of the QRS complex, and T wave flattening, can be seen with plasma concentrations above 15 μg/ml [ ].

Quinine, and more profoundly quinidine, its diastereomer, can cause ventricular tachycardia, torsade de pointes, and ventricular fibrillation by prolonging the QT interval [ ].

• An 8-year-old child given an incorrect dose of quinine had ventricular tachycardia and status epilepticus after 48 hours; the plasma quinine concentration was 20 μg/ml [ ], compared with the target range of 1.9–4.9 μg/ml.

Respiratory

Quinine can cause allergic asthmatic reactions.

• A 45-year-old woman with long-standing rheumatoid arthritis developed wheeze, severe anxiety, breathlessness, cough, orthopnea, mild fever, chills, and pleuritic chest discomfort after taking a single dose of quinine for nocturnal leg cramps [ ]. A chest X-ray showed diffuse, bilateral pulmonary infiltrates suggestive of pulmonary edema. No cause other than acute quinine ingestion was identified despite thorough cardiac and infectious disease evaluation.

Pulmonary edema is uncommon after treatment with quinine, but a case has been reported [ ].

• A 57-year-old man with leg cramps developed transient acute pulmonary edema and hypotension 30–40 minutes after taking quinine sulfate 300 mg orally on two occasions. He was not taking any other drugs and there was no explanation for either event. Serial troponin T tests, an electrocardiogram, echocardiogram, and coronary angiogram were all normal.

Quinine poisoning can cause respiratory depression.

Nervous system

Tinnitus and vertigo are not uncommon with quinine, especially at higher dosages [ , ].

Headache and tinnitus occur in chronic toxicity (cinchonism) [ ].

Acute intoxication can be followed by convulsions and coma [ ].

• A general organic brain syndrome was observed in a 24-year-old woman with tropical malaria after the third day of treatment with quinine sulfate 500 mg tds; her symptoms were headache, blurred vision, vertigo, tinnitus, impaired hearing, increasing apathy, disorientation, speech changes, incoherent thinking, and disorientation with respect to time and place; recovery followed withdrawal [ ].

A quinine-induced myopathy has been reported [ ].

Sensory systems

Psychiatric

Probable suicide after quinine treatment for chloroquine-resistant malaria has been reported [ ].

• A 27-year-old man with falciparum malaria was given an infusion of quinine 600 mg in 5% dextrose tds until his vomiting stopped. Five hours later he was found dead by hanging using his turban. There was no adverse social history and the patient was in general good health.

The cause of this man’s suicide was not known and it was probably not related to quinine.

Metabolism

Clinical signs and symptoms of hypoglycemia are reported occasionally; most cases are subclinical, but severe cases have been described [ , ]. A study of the effect of quinine on glucose homeostasis in Thai patients with malaria showed a near doubling of plasma insulin concentrations and a corresponding fall in serum glucose concentrations. An additional factor may have been impaired nutritional status and the effects of parenteral quinine in severely ill patients not taking food [ ].

Hematologic

Thrombocytopenia is often reported with quinine. It is probably due to hypersusceptibility rather than a toxic effect, since even the ingestion of minimal amounts of quinine, such as those present in commercial tonic waters, can cause it. A drug–antibody complex has been demonstrated [ ]. In some cases of quinine-induced thrombocytopenia, there was autoantibody-binding to glycoprotein Ib-IX, IIb, and IIIa complexes. In three published cases, quinine-dependent autoantibodies to glycoproteins Ib-IX and IIb/IIIa were associated with both thrombocytopenia and a hemolytic–uremic syndrome [ , ]. Two other patients had recurrent febrile illnesses characterized by hypotension, pancytopenia, coagulopathy, and renal insufficiency, and both had high titers of quinine-dependent antibodies, which showed cross-sensitivity with quinidine. In one case there was a link with tonic water, while the other had taken quinine sulfate for leg cramps before each episode [ ]. A list of nine earlier published cases with antibody findings was added to these two case histories.

Isolated thrombocytopenia after the use of quinine for malaria or leg cramps has been described in isolated cases. The FDA’s Center for Drug Evaluation and Research received 141 reports of isolated thrombocytopenia in association with quinine from 1974 to December 2000 [ ]. After elimination of cases that were confounded by acute or chronic disease or concomitant drug therapy, 64 reports of quinine-associated thrombocytopenia were analysed. Thrombocytopenia occurred soon after the start of therapy (median 7 days) and was often severe (hospitalization reported in 55 of the 64 cases).

Since 1972, the Australian Adverse Drug Reactions Advisory Committee has received 198 reports of thrombocytopenia associated with quinine, four of which had a fatal outcome [ ]. In 17 of the 20 reports received since the beginning of 2000, patients had platelet counts of 0–14 × 10 ⁹ /l; most of them required hospitalization and treatment with platelet transfusions, glucocorticoids, or immunoglobulin. In most cases the platelet count normalized within 1 week of quinine withdrawal. As quinine-induced thrombocytopenia has an immune-based mechanism, the Committee suggested that patients who develop this reaction should subsequently avoid all products that contain quinine, including drinks such as tonic water. They also reminded prescribers that quinine is no longer recommended for the treatment of nocturnal cramps; the FDA withdrew nocturnal cramps as an indication for all quinine products in 1995 because of lack of evidence of efficacy, and the Australian Medicines Handbook advises against its use for this indication.

Glycoprotein epitopes involved in quinine-induced thrombocytopenia have been characterized [ ].

A well-documented report has shown that re-exposure to a single dose of quinine for leg cramps about 40 years after a previous exposure can be sufficient to cause a severe episode of hemolytic–uremic syndrome + thrombotic thrombocytopenic purpura.

• A 67-year-old woman with hypertension, chronic kidney disease (serum creatinine 177 μmol/l (2 mg/dl) and a history of a short period of hemodialysis for acute renal insufficiency 10 years before developed nausea, vomiting, diffuse abdominal cramp, and blurred vision 1 hour after taking one tablet of quinine for leg cramps [ ]. She had a fever of 39.7 °C, a raised blood pressure, and confusion, an anemia of 10.4 g/dl with schistocytes and burr cells, thrombocytopenia of 14 × 10 ⁹ /l, acute renal insufficiency with a serum creatinine of 504 μmol/l (5.7 mg/dl), raised total and direct bilirubin, raised liver enzymes, and raised lactate dehydrogenase activity. She was given antibiotics for presumed sepsis, and her symptoms resolved within 24 hours. However, her urine output continued to fall and hemolytic–uremic syndrome + thrombotic thrombocytopenic purpura was diagnosed. After seven sessions of plasmapheresis, the hematological parameters normalized. After 3 weeks of hemodialysis, kidney function returned to baseline. At a follow-up visit 9 months later, quinine-associated antiplatelet antibodies were detected. She then recalled that about 40 years before she had taken quinine for malaria prophylaxis.

Acute intravascular hemolysis with renal involvement and even renal insufficiency can occur with quinine and can follow relatively small doses. Quinine-induced hemolysis has probably played a role in the clinical syndrome of blackwater fever in the past.

• The combination of renal insufficiency with cortical necrosis, thrombocytopenia, intravascular coagulation, and deposition of fibrin was seen in a 63-year-old woman who had drunk tonic water. She had had two previous episodes of acute renal insufficiency also associated with quinine-containing drinks; this most certainly reflected a hypersensitivity reaction [ ].

• A 65-year-old man, who had taken a single dose of quinine 300 mg for leg cramps, developed both acral necrosis and hemolytic–uremic syndrome, which resolved promptly after treatment with glucocorticoids [ ].

Lupus anticoagulant has been reported with the use of quinine and quinidine, and an associated antiphospholipid syndrome has been described [ ].

Disseminated intravascular coagulation has been attributed to quinine [ ].

• A 79-year-old woman developed disseminated intravascular coagulation. She had taken a dose of quinine for leg cramps 3 months before and on the day before admission. Her only other medication was bendroflumethiazide. Investigations showed a platelet-associated immunoglobulin with positive immunofluorescence on exposure to quinine sulfate.

• Quinine-induced disseminated intravascular coagulation and hemolytic–uremic syndrome occurred in a 78-year-old woman who took quinine 150 mg for leg cramps; this is the first report of the two diseases occurring simultaneously after quinine [ ].

Of 16 patients with quinine-induced disseminated intravascular coagulation, most were women [ ]. The symptoms usually started within hours of taking quinine. Single small doses of quinine may be sufficient to provoke disseminated intravascular coagulation. Most (80%) of the cases presented with gastrointestinal complaints, such as abdominal pain, nausea, vomiting, diarrhea, and hematemesis and/or melena. Other common symptoms were petechial or ecchymotic rashes, back pain, myalgia, headache, fever, chills, and malaise. Typical laboratory results included thrombocytopenia, raised fibrin degradation products, raised D dimers, and coagulopathy. In addition, there can be uremia, raised plasma creatinine, lactate dehydrogenase, and bilirubin, lactic acidosis, reduced haptoglobin, and a urinary sediment. Quinine induces antiplatelet antibodies of the IgG or IgM classes and possibly also antibodies against erythrocytes, neutrophils, T lymphocytes, B lymphocytes, and endothelial cells. In some cases, antibodies were not detected during the initial days of the disease, but were detected after the patient had recovered. Patients with quinine-induced disseminated intravascular coagulation are treated with supportive care and plasmapheresis. Renal function recovered in most cases, but 31% developed chronic renal insufficiency and 19% required permanent hemodialysis. Patients with a history of quinine-induced disseminated intravascular coagulation must avoid quinine and all quinine-containing products.

In a retrospective survey of thrombotic thrombocytopenic purpura with hemolytic–uremic syndrome reported to the Oklahoma TTP/HUS Registry, 17 of 225 cases were associated with quinine (doses not stated) taken long-term for leg cramps [ ]. Patients typically presented with an acute onset of fever, chills, nausea, vomiting, diarrhea, and abdominal pain within hours of quinine ingestion. Laboratory findings included thrombocytopenia, microangiopathic hemolytic anemia, and liver and renal dysfunction. This is an immune-mediated reaction associated with quinine-dependent antiplatelet antibodies and a high mortality (three of the 17 patients). It can be triggered by small amounts of quinine, such as those present in tonic water.