| THE USE OF ANTIMALARIAL DRUGS |
| PART II: 1.6 QUININE, QUINIDINE AND RELATED ALKALOIDS |
A. QUININE
Formulations
Efficacy
Quinine is normally effective against falciparum infections that are resistant to chloroquine and sulfa drug-pyrimethamine combinations. Decreasing sensitivity to quinine has been detected in areas of South-East Asia where it has been extensively used for malaria therapy. This has occurred particularly when therapy was given in an unsupervised and ambulatory setting with regimens longer than 3 days. In these settings, patient adherence to therapy is low, leading to incomplete treatment; this may have led to the selection of resistant parasites. There is some cross-resistance between quinine and mefloquine, suggesting that the wide use of quinine in Thailand might have influenced the development of resistance to mefloquine in that country (31). Strains of P. falciparum from Africa are generally highly sensitive to quinine.
Use
Quinine is still the drug of choice for severe falciparum malaria in most countries. It should only be used for uncomplicated malaria when alternatives are unavailable, for example, in the following situations.
Quinine may be a useful first-line treatment in areas with multidrug-resistant malaria where P. falciparum does not respond to chloroquine, sulfa drug- pyrimethamine combinations, and mefloquine. It is usually combined with another drug especially where some degree of quinine resistance may be present, such as in South-East Asia. National drug policy-makers will need to determine whether quinine is a suitable option.
Quinine is a reasonable option for treatment in travellers returning to non-endemic areas who develop malaria, since the drug-resistance pattern of the parasite may not be known and a fully efficacious drug is needed in nonimmunes to prevent progression of uncomplicated malaria to severe disease.
Injectable quinine given by the intramuscular route can be a valuable initial treatment for a patient with uncomplicated malaria who is repeatedly vomiting and therefore unable to take oral drugs. Once vomiting has stopped, oral treatment with an appropriate drug should be resumed.
Quinine can be used as a second-line treatment for patients who fail to respond to the standard first-line therapy and/or are hypersensitive to sulfa drugs. When used in this way, quinine should always be accompanied by another drug.
In the first two of the above situations, a prolonged regimen, which is associated with adverse reactions, contributes to poor treatment adherence and low effectiveness. To improve compliance and maintain its efficacy, quinine is usually combined with tetracycline or doxycycline, although these drugs are contraindicated drugs in children and pregnant women (see below). Clindamycin can be used for these groups.
Quinine (generic form) is included on the essential drug list and is widely available and relatively cheap in many countries. Because of its adverse effects (see below), people rarely take toxic dosages. The drug is appropriate for use under the supervision of a qualified person in patients admitted to health care facilities.
Recommended treatment
Quinine can be given by the oral, intravenous or intramuscular routes. Quinine or quinine-containing compounds such as Quinimax ® should not be given alone for the treatment of malaria as short courses, e.g. 3 days, owing to the possibility of recrudescence (200).
When administered to patients with uncomplicated malaria, quinine should be given orally if possible, by one of the following regimens:
Quinine, 8 mg of base per kg three times daily for 7 days.
Quinine, 8 mg of base per kg three times daily for 3 days
plus
Sulfadoxine 1 500 mg or sulfalene 1500 mg plus pyrimethamine 75 mg given on the first day of quinine treatment.
Quinine 8 mg of base per kg three times daily for 7 days
plus
Doxycycline 100 mg of salt daily for 7 days (not in children under 8 years of age and not during pregnancy); a pharmacologically superior regimen would include a loading dose of 200 mg of doxycycline followed by 100 mg daily for 6 days.
or
Tetracycline 250 mg four times daily for 7 days (not in children under 8 years of age and not in pregnancy).
or
Clindamycin 300 mg four times daily for 5 days (not contraindicated in children and pregnancy).
If oral treatment is not possible, the first dose(s) of quinine should be given intravenously by slow infusion in isotonic fluid or 5% dextrose saline over 4 h. If intravenous infusion is not possible, quinine may be given by intramuscular injection, in which case the drug should be diluted to a concentration of 60 mg/ml and divided into two halves, one half being delivered into each anterior thigh. Whenever parenteral quinine is used, oral treatment should be resumed as soon as the patient is able to take it, and continued for the completion of the course.
Loading doses of quinine are recommended in the management of severe malaria as they establish the optimal blood level of the drug within a few hours. These arguments do not apply in the management of uncomplicated malaria when it is usual to give a standard treatment regimen of quinine without the loading dose. Loading doses of quinine should be avoided when mefloquine has been used within the previous 12 h.
Quinine should be used with caution in the elderly in whom it is metabolized less rapidly (201).
Use in pregnancy
Quinine is safe in pregnancy. Studies have shown that therapeutic doses of quinine do not induce labour and that the stimulation of contractions and evidence of fetal distress associated with the use of quinine may be attributable to fever and other effects of malarial disease (110). The risk of quinine-induced hypoglycaemia is, however, greater than in non-pregnant women, particularly in severe disease. Special vigilance is therefore required.
Drug disposition
Quinine is rapidly absorbed when taken orally, and peak plasma concentrations are reached within 1-3 h. The drug is distributed throughout body fluids being highly protein bound. It readily crosses the placental barrier and is found in cerebrospinal fluid. Quinine is extensively metabolized in the liver, has an elimination half-life of 10-12 h in healthy individuals and is subsequently excreted in the urine, mainly as hydroxylated metabolites (202).
Several pharmacokinetic characteristics differ according to the age of the subject, and are also affected by malaria. The volume of distribution is less in young children than in adults, and the rate of elimination is slower in the elderly than in young adults (201). In patients with acute malaria, the volume of distribution is reduced and systemic clearance is slower than in healthy subjects, these changes being proportional to the severity of the disease. Protein binding of quinine is, however, increased in patients with malaria, as a result of the increased circulating concentration of the binding-protein (alpha-1 acid glycoprotein) (203).
Adverse effects
Cinchonism, a symptom complex characterized by tinnitus, hearing impairment,
and sometimes vertigo or dizziness, occurs in a high proportion of treated
patients. Symptoms appear when the total plasma concentration of quinine is
about 5 mg/l,
i.e. at the lower limit of the therapeutic range of the drug,
which is 5-15 mg/l. The symptoms that are usually reversible generally develop
on the second or third day of treatment and alone rarely constitute a reason for
withdrawing the drug.
Dose-related cardiovascular, gastrointestinal and central nervous system effects may arise following excessive infusion or from accumulation following oral administration. Severe hypotension may develop if the drug is injected too rapidly (204). Quinine may enhance the effects of cardiosuppressant drugs and should be prescribed with caution in individuals taking drugs such as beta-adrenergic blocking agents, digoxin and calcium channel blocking agents, especially in those with cardiac disease. Enhanced cardiac toxicity may occur if quinine therapy is administered to individuals who have taken mefloquine for malaria chemoprophylaxis.
Hypoglycaemia may be caused by quinine since the drug stimulates secretion of insulin from pancreatic beta-cells. Hypoglycaemia is particularly likely to develop after intravenous infusion of quinine in pregnancy, since beta-cells are more susceptible to a variety of stimuli at that time (202).
Overdosage
A single dose of quinine of > 3 g is capable of causing serious and potentially fatal intoxication in adults, preceded by depression of the central nervous system and seizures. Much smaller doses can be lethal in children. Dysrhythmias, hypotension and cardiac arrest can result from the cardiotoxic action and visual disorders may be severe, leading to blindness in rare cases. Emesis should be induced and gastric lavage undertaken as rapidly as possible.
B. QUINIMAX ®
Quinimax ®is an association of four cinchona alkaloids: quinine, quinidine, cinchonine and cinchonidine. It was formerly available as tablets of 100 mg, ampoules of 500 mg, 200 mg and 400 mg and suppositories. Each 100 mg tablet contained 96.10 mg of quinine-resorcine bichlorohydrate (59.3 mg of quinine base), 2.55 mg of quinidine-resorcine bichlorohydrate (1.6 mg of quinidine base), 0.68 mg of cinchonine-resorcine bichlorohydrate (0.4 mg of cinchonine base) and 0.67 mg of cinchonidine-resorcine bichlorohydrate (0.4 mg of cinchonidine base). These have been re-formulated and the preparations now available include tablets of 100 mg and 125 mg of base of all the four components, and ampoules of 125 mg, 250 mg and 500 mg of base of all the four components. Suppositories are no longer available.
Quinimax ®has been shown to be somewhat more effective than quinine in vitro and in animal models, as well as producing somewhat higher plasma levels in humans. A synergistic effect of the association has been claimed but is doubtful. Limited studies show no significant difference between the therapeutic efficacy of Quinimax ®and that of quinine (205). Intramuscular injection of Quinimax ®is better tolerated than intramuscular injection of quinine dihydrochloride. Quinimax ®is used more widely than generic quinine salts in many countries, especially in francophone Africa.
C. QUINIDINE
Quinidine is a distereoisomer of quinine, with similar antimalarial properties. It is available as tablets of 200 mg of quinidine base as the sulfate and as a slow-release formulation (Quinidine SR ®). It is slightly more effective than quinine but has a greater cardiosuppressant effect (110). In other respects the toxicity and drug interactions of quinidine are similar to those of quinine.
Recommended treatment
Quinidine is not recommended for routine treatment of uncomplicated malaria. It is a useful drug for parenteral treatment of severe malaria, and may be used instead of quinine in patients with uncomplicated malaria who require an initial dose of parenteral therapy. Dose regimens are similar to those for quinine.
| The Use of Antimalarial Drugs: Table of Contents |