Chloroquine and Hydroxychloroquine: Drug Administration
Drug formulations
Chloroquine has a bitter taste, which can deter children from taking it, so a sweet effervescent formulation of chloroquine phosphate has been compared with chloroquine tablets in a pharmacodynamic study. However, sweet-tasting medications carry a risk of accidental overdose in children.
Drug administration route
If given intravenously, chloroquine should be diluted and infused slowly, since rapid injection causes toxic concentrations. Toxicity and even death have been reported after intramuscular administration of larger doses; this is probably connected with rapid absorption in such cases.
Drug overdose
Acute intoxication, either accidental or in attempted suicide, can cause headache, drowsiness, vision disturbance, vomiting and diarrhea, cardiovascular collapse, and respiratory failure. Deaths have been recorded at blood concentrations of 1 ug/ml. Compared with adults, mortality in children after acute chloroquine poisoning is extremely high. Although the clinical presentation is mostly similar to that in adults (apnea, seizures, cardiac dysrhythmias), a single 300 mg chloroquine tablet was enough to kill a 12-month-old female infant.
Deaths from chloroquine overdose have been reported with doses as low as 2-3 g in adults, and the death rate is as high as 25%. The effects of chloroquine overdose include cardiac effects (such as dysrhythmias, reduced myocardial contractility, and hypotension) and central nervous system complications (such as confusion, coma, and seizures).
There have been three reports of chloroquine overdose, two from Oman and one from the Netherlands. The two reports from Oman were similar to previously published reports of chloroquine overdose associated with cardiac dysfunction, confusion, and coma; both patients had standard treatment with activated charcoal, diazepam infusions, and positive inotropic drugs, and both survived. The single case report from the Netherlands gave pharmacokinetic measurements performed before, during, and after hemoperfusion. This showed that hemoperfusion extracted very little chloroquine and was unlikely to be of any use in chloroquine overdose, as would be expected from the high protein binding and large volume of distribution of chloroquine.
In Zimbabwe, 544 cases of poisoning by a single agent were identified in a retrospective hospital record review. Antimalarial drugs accounted for the largest proportion of admissions (53%), and chloroquine accounted for 96% of these (279 cases). The median length of hospital stay in those who took chloroquine was significantly shorter (1 versus 2 days) and more patients took chloroquine deliberately (80% versus 69%). The mortality rate from chloroquine poisoning was significantly higher than from poisoning with other drugs (5.7% versus 0.7%).
Overdose with hydroxychloroquine is far less common than with chloroquine. Three of eight patients died. Life-threatening symptoms, such as hypotension, conduction disturbances, and hypokalemia can occur within 30 minutes of ingestion and are similar to those seen in chloroquine overdose. The lethal plasma concentration of hydroxychloroquine is not well established. Therapeutic drug concentrations are usually less than 1 µmol/l. Serious toxicity has been reported at plasma concentrations of 2.1-29 µmol/l.
Management of hydroxychloroquine overdose is similar to that of chloroquine overdose, including the use of charcoal for drug adsorption, diazepam for seizures and sedation, early intubation and mechanical ventilation, and potassium replacement for severe hypokalemia.
Chloroquine/Hydroxychloroquine (US: Aralen): Organs and Systems
Cardiovascular
Electrocardiographic changes, comprising altered T waves and prolongation of the QT interval, are not uncommon during high-dose treatment with chloroquine. The clinical significance of this is uncertain. With chronic intoxication, a varying degree of atrioventricular block can be seen; first-degree right bundle branch block and total atrioventricular block have been described. Symptoms depend on the severity of the effects: syncope, Stokes-Adams attacks, and signs of cardiac failure can occur. Acute intoxication can cause cardiovascular collapse and/or respiratory failure. Cardiac complications can prove fatal in both chronic and acute intoxication.
Third-degree atrioventricular conduction defects have been reported in two patients with rheumatoid arthritis after prolonged administration of chloroquine.
Intravenous administration can result in dysrhythmias and cardiac arrest; the speed of administration is relevant, but also the concentration reached: deaths have been recorded with blood concentrations of 1 µg/ml; concentrations after a 300 mg dose are usually 50-100 µg/ml.
Long-term chloroquine can cause cardiac complications, such as conduction disorders and cardiomyopathy (restrictive or hypertrophic), by structural alteration of the interventricular septum. Thirteen cases of cardiac toxicity associated with long-term chloroquine and hydroxychloroquine have been reported in patients with systemic autoimmune diseases. The cumulative doses were 600-2281 g for chloroquine and 292-4380 g for hydroxychloroquine.
A 64-year-old woman with systemic lupus erythematosus took chloroquine for 7 years (cumulative dose 1000 g). She developed syncope, and the electrocardiogram showed complete heart block; a permanent pacemaker was inserted. The next year she presented with biventricular cardiac failure, skin hyperpigmentation, proximal muscle weakness, and chloroquine retinopathy. Coronary angiography was normal. An echocar-diogram showed a restrictive cardiomyopathy. A skeletal muscle biopsy was characteristic of chloroquine myopathy. Chloroquine was withdrawn and she improved rapidly with diuretic therapy.
Chloroquine cardiomyopathy occurred during long-term (7 years) treatment for rheumatoid polyarthritis in a 42-year-old woman, who had an isolated acute severe conduction defect, confirmed by histological study with electron microscopy.
Regular cardiac evaluation should be considered for those who have taken a cumulative chloroquine dose of 1000 g, particularly elderly patients.
More than one mechanism may underlie the cardiac adverse effects of chloroquine. Severe hypokalemia after a single large dose of chloroquine has been documented, and some studies show a correlation between plasma potassium concentrations and the severity of the cardiac effects.
Light and electron microscopic abnormalities were found on endomyocardial biopsy in two patients with cardiac failure. The first had taken hydroxychloroquine 200 mg/day for 10 years, then 400 mg/day for a further 6 years; the second had taken hydroxychloroquine 400 mg/day for 2 years. A similar case was reported after the use of 250 mg/day for 25 years.
Respiratory
Respiratory collapse can occur with acute overdosage.
Acute pneumonitis probably due to chloroquine has been described.
A 41-year-old man with chronic discoid lupus erythe-matosus was given chloroquine 150 mg bd for 10 days followed by 150 mg/day. After 2 weeks he developed fever, a diffuse papular rash, dyspnea, and sputum. A chest X-ray showed peripheral pulmonary infiltrates. He improved on withdrawal of chloroquine and treatment with cefpiramide and roxithromycin. No organism was isolated. A subsequent oral challenge with chloroquine provoked a similar reaction.
Nervous system
The incidence of serious nervous system events among patients taking chloroquine for less than a year has been estimated as one in 13 600.
Chloroquine, especially in higher doses, can cause a marked neuromyopathy, characterized by slowly progressive weakness of insidious onset. In many cases this weakness first affects the proximal muscles of the legs. Reduction in nerve conduction time and electromyographic abnormalities typical of both neuropathic and myopathic changes can be found. Histologically there is a vacuolar myopathy. Neuromyopathy is a rare adverse effect and is usually limited to patients taking 250-750 mg/day for prolonged periods. The symptoms can be accompanied by other manifestations of chloroquine toxicity. An 80-year-old woman developed symptoms after taking chloroquine 300 mg/day for 6 months, once more demonstrating that a standard dosage can be too much for elderly people.
A spastic pyramidal tract syndrome of the legs has been reported. In young children the features of an extrapyramidal syndrome include abnormal eye movements, tris-mus, torticollis, and torsion dystonia.
Chloroquine can cause seizures in patients with epilepsy. The mechanism is uncertain, but it may include reductions in inhibitory neurotransmitters and pharmacokinetic interactions that alter anticonvulsant concentrations. Tonic-clonic convulsions were reported in four patients in whom chloroquine was part of a prophylactic regimen. Antiepileptic treatment was required to control the seizures. None had further seizures after withdrawal of the antimalarial drugs.
Chloroquine and desethylchloroquine concentrations have been studied in 109 Kenyan children during the first 24 hours of admission to hospital with cerebral malaria. Of the 109 children 100 had received chloroquine before admission. Blood chloroquine and desethylchloroquine concentrations were no higher in children who had seizures than in those who did not, suggesting that chloroquine does not play an important role in the development of seizures in malaria.
A 59-year-old woman had a generalized convulsion 24 hours after returning from a trip to Vietnam. She had a history of partial complex seizures (controlled with carbamazepine) due to a previous ruptured cerebral aneurysm. For the preceding 3 weeks she had been taking chloroquine 100 mg/day and proguanil 200 mg/day. A blood film was negative for malaria. A CT scan of the brain showed changes compatible with the previous hemorrhage. She was successfully treated with clobazam (dose not stated) until withdrawal of chemoprophylaxis.
The interaction between chloroquine and carbamazepine was not examined. Chloroquine should not be given to adults with a history of epilepsy.
Neuromuscular function
Severe neuromyopathy has been reported in patients taking chloroquine.
Chloroquine-induced neuromyopathy is a complication of chloroquine treatment of autoimmune disorders or long-term use of chloroquine as a prophylactic antimalarial drug.
Chloroquine and Hydroxychloroquine: Organs and Systems: Sensory Systems
Psychological, psychiatric
Many mental changes attributed to chloroquine have been described, notably agitation, aggressiveness, confusion, personality changes, psychotic symptoms, and depression. Acute mania has also been recognized. The mental changes can develop slowly and insidiously. Subtle symptoms, such as fluctuating impairment of thought, memory, and perception, can be early signs, but may also be the only signs. The symptoms may be connected with the long half-life of chloroquine and its accumulation, leading to high tissue concentrations. Chloroquine also inhibits glutamate dehydrogenase activity and can reduce concentrations of the inhibitory transmitter GAB A.
In some cases with psychosis after the administration of recommended doses, symptoms developed after the patients had taken a total of 1.0-10.5 g of the drug, the time of onset of behavioral changes varying from 2 hours to 40 days. Most cases occurred during the first week and lasted from 2 days to 8 weeks.
Transient global amnesia occurred in a healthy 62-year-old man, 3 hours after he took 300 mg chloroquine. Recovery was spontaneous after some hours.
In one center, toxic psychosis was reported in four children over a period of 18 months. The children presented with acute delirium, marked restlessness, outbursts of increased motor activity, mental inaccessibility, and insomnia. One child seemed to have visual hallucinations. In each case, chloroquine had been administered intramuscularly because of fever. The dosages were not recorded. The children returned to normal within 2 weeks.
Metabolism
Hypoglycemia was reported in a fatal chloroquine intoxication in a 32-year-old black Zambian male. Hypoglycemia has also been seen in patients, especially children, with cerebral malaria. Further studies have shown that the hypoglycemia in these African children was usually present before the antimalarial drugs had been started; in a study in Gambia hypoglycemia occurred after treatment with the drug had been started, although it was not necessarily connected with the treatment. Convulsions were more common in hypoglycemic children. This commonly unrecognized complication contributes to morbidity and mortality in cerebral Plasmodium falciparum malaria. Hypoglycemia is amenable to treatment with intravenous dextrose or glucose, which may help to prevent brain damage.
Although hydroxychloroquine has been used to treat porphyria cutanea tarda, there are reports that it can also worsen porphyria.
Electrolyte balance
Severe hypokalemia after a single large dose of chloroquine has been documented, and some studies show a correlation between plasma potassium concentrations and the severity of the cardiac effects. In a retrospective study of 191 consecutive patients who had taken an overdose of chloroquine (mean blood chloroquine concentration 20 µmol/l; usual target concentration up to 6 µmol/l), the mean plasma potassium concentration was 3.0 mmol/1 (0 and was significantly lower in those who died than in those who survived. Plasma potassium varied directly with the systolic blood pressure and inversely with the QRS and QT intervals. Plasma potassium varied inversely with the blood chloroquine.
Hematologic
Chloroquine inhibits myelopoiesis in vitro at therapeutic concentrations and higher. In a special test procedure, a short-lasting anti-aggregating effect could be seen with chloroquine concentrations of 3.2-32 µg/ml. These effects have clinical consequences. Chloroquine and related aminoquinolines have reportedly caused blood dyscrasias at antimalarial doses. Leukopenia, agranulocytosis, and the occasional case of thrombocytopenia have been reported. There is some evidence that myelosuppression is dose-dependent. This is in line with the hypothesis that 4-aminoquinoline therapy merely accentuates the cytopenia linked to other forms of bone marrow damage.
Some studies have pointed to inhibitory effects of chloroquine on platelet aggregability. In an investigation, this aspect of chloroquine was studied in vitro in a medium containing ADP, collagen, and ristocetin. There was a highly significant effect at chloroquine concentrations of 3.2-32 µg/ml. However, there were no significant differences in platelet responses to ADP or collagen 2 or 6 hours after adding chloroquine, compared with pre-drug values. The investigators believed that these data provided no cause for concern in using chloroquine for malaria prophylaxis in patients with impaired hemostasis.
Mouth and teeth
Pigmentation of the palate can occur as a part of a more generalized pigmentation in patients taking chloroquine. Several patients seen with chloroquine retinopathy in Accra have been observed to present with depigmented patches in the skin of the face. This may be associated with a greyish pigmentation of the mucosa of the hard palate. Two such cases are reported here to illustrate the condition. Stomatitis with buccal ulceration has occasionally been mentioned.
Gastrointestinal
Gastrointestinal discomfort is not unusual in patients receiving chloroquine, and diarrhea can occur. Changes in intestinal motility may be to blame; intramuscular injection of chloroquine caused a shortened orofecal time in the five cases in which this was measured. Overdosage can cause vomiting.
Chloroquine and Hydroxychloroquine: Organs and Systems: Skin
Nails
Chloroquine can turn the nail bed blue-brown and the nail itself can develop longitudinal stripes and show a blue-grey fluorescence.
Immunologic
Allergic contact dermatitis, which progressed to generalized dermatitis and conjunctivitis, followed later by severe asthma, occurred in a 60-year-old worker in the pharmaceutical industry after exposure to hydroxychloroquine. Patch-testing showed delayed sensitivity to hydroxychloroquine. Equivalent tests in five healthy volunteers were negative. The patch test reactions were pustular, and a biopsy was interpreted as multiform contact dermatitis. Bronchial exposure to hydroxychloroquine dust produced delayed bronchial obstruction over the next 20 hours, progressing to fever and generalized erythema (hematogenous contact dermatitis).
Chloroquine and Hydroxychloroquine: Organs and Systems. Skin
Skin lesions and eruptions of different types have been attributed to chloroquine, including occasional cases of epidermal necrolysis.
The most common dermatological adverse event associated with chloroquine is skin discomfort (often called pruritus). It is much more common in people with darker skins and has been ascribed to chloroquine binding to increased melanin concentrations in the skin. In a pharmacokinetic study, the ratio of AUCo-48 for chloroquine and its major metabolite desethylchloroquine was significantly higher in the plasma and urine of 18 patients with chloroquine-induced pruritus than in that of 18 patients without. These results imply that differences in metabolism and higher chloroquine concentrations may be partly responsible for chloroquine-induced pruritus.
Pruritus begins about 10 hours after the start of treatment, with a maximum intensity at about 24 hours. These times correspond to maximum serum concentrations of chloroquine and its metabolites after oral ingestion. In many cases, the itch is confined to the palms of the hands and the soles of the feet. In a study in Nigeria, the incidence of pruritus was 60-75%; the itch was considered unbearable in 40%, and 30% refused further chloroquine. In a second study, there was an even higher incidence. In a study elsewhere, the incidence of pruritus was 27%.
Not surprisingly, pruritus is a major cause of non-adherence to treatment, and it may contribute largely to the emergence and spread of resistant P. falciparum. Pruritus is more often seen in black-skinned than in white-skinned people in Africa, a difference that has been ascribed to the binding of chloroquine to melanin, and hence a racial predisposition. No such reports have come from America. Antihistamine treatment can have a preventive effect on pruritus. Other treatments that have been mentioned include prednisone and niacin, but the results were not impressive.
A few cases of psoriasis, or severe exacerbation of psoriasis shortly after the start of treatment, have been reported.
Photosensitivity and photo-allergic dermatitis have been seen, particularly during prolonged therapy with high doses.
Blue-black pigmentation involving the palate and facial, pretibial, and subungual areas occurs rarely, but it has been associated with retinopathy. The nail bed can turn blue-brown and the nail itself may develop longitudinal stripes and show a blue-grey fluorescence.
Chloroquine can cause vitiligo.
Fatal toxic epidermal necrolysis has been associated with hydroxychloroquine.
A 39-year-old woman with rheumatoid arthritis took hydroxychloroquine 200 mg bd for painful synovitis, in addition to meloxicam, co-dydramol, and Gaviscon. She inadvertently took twice the prescribed dose of hydroxychloroquine, but stopped it after 2 weeks because of nausea. The next day she developed a widespread blotchy erythema and 2 weeks later was admitted to hospital with clinical and histological toxic epidermal necrolysis and deteriorated rapidly with multiorgan failure; she died 1 week later.
There have been only a few isolated reports of Stevens-Johnson syndrome associated with hydroxychloroquine. Recently, a clear temporal relation to the start of treatment with hydroxychloroquine has been documented in a patient with rheumatoid arthritis.
An increased frequency of skin reactions to hydroxychloroquine was noted in 11 patients (seven of whom had systemic lupus erythematosus, two discoid lupus, and two a lupus-like syndrome) when a coloring agent (sunshine yellow E was removed from the formulation; the authors were unable to explain this unexpected finding.
There have been four case reports of photosensitivity associated with hydroxychloroquine which has an estimated incidence of about 10 per 1000 patient-years.
Hydroxychloroquine causes skin reactions such as urticaria. There is some support for the contention that hydroxychloroquine causes skin reactions more often than chloroquine.
Chloroquine/Hydroxychloroquine (US: Aralen): Organs and Systems: Sensory Systems
Eyes
Chloroquine and its congeners can cause two typical effects in the eye, a keratopathy and a specific retinopathy. Both of these effects are associated with the administration of the drug over longer periods of time.
Keratopathy
Chloroquine-induced keratopathy is limited to the corneal epithelium, where high concentrations of the drug are readily demonstrable. Slit lamp examination shows a series of punctate opacities scattered diffusely over the cornea; these are sometimes seen as lines just below the center of the cornea, while thicker yellow lines may be seen in the stroma. The keratopathy is often asymptomatic, fewer than 50% of patients having complaints. The commonest symptoms are the appearance of halos around lights and photophobia. Keratopathy can appear after 1-2 months of treatment, but dosages of under 250 mg/day usually do not cause it. Dust exposure can lead to similar changes. The incidence of keratopathy is high, occurring in 30-70% of patients treated with higher dosages of chloroquine. The condition is usually reversible on withdrawal and does not seem to involve a threat to vision. There are differences in incidence between chloroquine and hydroxychloroquine. In a survey of 1500 patients, 95% of the patients taking chloroquine had corneal deposition of the drug, while less than 10% of patients taking hydroxychloroquine showed any corneal changes.
Retinopathy
The retinopathy encountered with the prolonged use of chloroquine or related drugs is a much more serious adverse effect and can lead to irreversible damage to the retina and loss of vision. However, it is not possible to predict in which patients and in what proportion of patients an early retinopathy will progress to blindness. The typical picture is that of the “bull’s eye,” an intact foveal area surrounded by a depigmented ring, the whole lesion being enclosed in a scattered hyperpigmented area. At this stage the retinal vessels are contracted, there are changes in the peripheral retinal pigment epithelium, and the optic disk is atrophic. In the early stages there are changes in the macular retinal pigment epithelium.
However, the picture is not always clear, and peripheral retinal changes may appear as the first sign. Another sign may be unilateral paramacular retinal edema. The macular changes and the “bull’s eye” are occasionally seen in patients who have never been treated with chloroquine or related drugs. Retinopathy can occur after chloroquine antimalarial chemoprophylaxis for less than 10 years: the lowest reported total dose was 110 g. A case of hydroxychloroquine-induced retinopathy in a 45-year-old woman with systemic lupus erythematosus has illustrated that maculopathy can be associated with other 4-aminoquinolines.
The resulting functional defects are varied: difficulty in reading, scotomas, defective color vision, photophobia, light flashes, and a reduction in visual acuity. Symptoms do not parallel the retinal changes. By the time that visual acuity has become impaired, irreversible changes will have taken place.
Testing of visual acuity, central fields (with or without the use of red targets), contrast sensitivity, dark adaptation, and color vision provides no early indication of chloroquine retinopathy. Careful ophthalmoscopic examination of the macula can be a sensitive index when visual acuity remains intact. More sophisticated tests, such as the measurement of the critical flicker fusion frequency and the Amsler grid test (detection of small peripheral scotoma), can be useful. It is important to trace, if at all possible, the results of a pretreat-ment ophthalmological examination after dilatation of the pupils, thus reducing the possibility of confusing senile degenerative changes with chloroquine-induced abnormalities.
Despite the fact that the retinopathy has been known for many years, it is still not clear why certain patients develop these changes while others do not. There is a clear relation to daily dosage: the retinopathy is rarely seen with daily doses below 250 mg of chloroquine or 400 mg of hydroxychloroquine; the daily dose seems to be more important than the total dose.
Nevertheless, cases of retinopathy have been described after the use of small doses for relatively short periods of time, while prolonged treatment and total doses of a kilogram or more have been used in many other patients without any evidence of macular changes. In the published cases there is usually no information about other treatments given previously or concomitantly.
More cases are seen in older people. Patients with lupus erythematosus are more susceptible than patients with rheumatoid arthritis. The presence of nephropathy increases the likelihood of retinopathy, as does the concomitant use of probenecid. Exposure to sunlight may be of importance, since light amplifies the risk of retinopathy. The retinopathic changes are probably connected with the concentrating capacity of the melanin-containing epithelium. Chloroquine inhibits the incorporation of amino acids into the retinal pigment epithelium.
Little is yet known about the development of the retinopathy after withdrawal of treatment. Retinal changes in the early stages are probably reversible if the drug is withdrawn, and progression of a severe maculopathy to blindness seems to be less frequent than feared. In 1650 patients with 6/6 vision and relative scotomas there was no further decline in visual acuity after drug withdrawal, but 63% of patients who presented with absolute scotomas lost further vision over a median period of 6 years.
This suggests that withdrawal of chloroquine at an early stage halts progression of the disease.
Three patients with chloroquine retinopathy have been studied with multifocal electroretinography. All three had been taking chloroquine for rheumatological diseases and all had electroretinographic changes that were more sensitive than full field electroretinography. It may be that multifocal electroretinography will be a useful technique in the assessment of suspected cases of subtle chloroquine retinopathy.
The need for routine ophthalmological testing of all patients who take chloroquine is under discussion, an obvious element being the cost/benefit ratio. The best current opinion seems to be that at doses not exceeding 6.5 mg/kg/day of hydroxychloroquine, given for not longer than 10 years and with periodic checking of renal and hepatic function, the likelihood of retinal damage is negligible and ophthalmological follow-up is not required. However, patients taking chloroquine or higher doses of hydroxychloroquine should be checked.
Other adverse effects on the eyes
Rhegmatogenous retinal detachment and bitemporal hemianopsia have both been seen in association with chloroquine retinopathy. Bilateral edema of the optic nerve occurred in a woman who took chloroquine 200 mg/day for 2.5 months. Diplopia and impaired accommodation (characterized by difficulty in changing focus quickly from near to far vision and vice versa) also affect a minority of patients.
Ears
Ototoxicity has been mentioned occasionally over the years; tinnitus and deafness can occur in relation to high doses; symptoms described after injection of chloroquine phosphate include a case of cochlear vestibular dysfunction in a child. However, there is insufficient evidence to attribute ototoxicity to chloroquine in humans, except as a rare individualized phenomenon. In guinea pigs given chloroquine 25 mg/kg/day intraperitoneally, one of the first signs of intoxication was ototoxicity.
Unilateral sensorineural hearing loss occurred in a 7-year-old girl with idiopathic pulmonary hemosiderosis after she had taken hydroxychloroquine 100 mg bd for 2 years.
Taste
Disturbances of taste and smell have been attributed to chloroquine.
Chloroquine/Hydroxychloroquine (US: Aralen): Side Effects
Chloroquine is rapidly and almost completely absorbed from the intestinal tract, peak serum concentrations being reached in 1-6 hours (average 3 hours). It is extensively distributed and redistribution follows. It is slowly metabolized by side-chain de-ethylation. The half-life is 30-60 days. Elimination is mainly via the kidney. Malnutrition can slow down the rate of metabolism.
Comparative studies
Amodiaquine and chloroquine have been compared in an open, randomized trial in uncomplicated falciparum malaria in Nigerian children. The doses were amodiaquine 10 mg/kg/day for 3 days and chloroquine 10 mg/kg/day for 3 days. After 28 days, the cure rate was significantly higher with amodiaquine than chloroquine (95% versus 58%). The rates of adverse events, most commonly pruritus (10%) and gastrointestinal disturbances (3%), were similar in the two groups. Cross-resistance between the two aminoquinolines is common, and there are concerns regarding toxicity of amodiaquine with repeated use.
General adverse effects
There are relatively few adverse effects at the doses of chloroquine that are used for malaria prophylaxis and standard treatment doses. However, the use of higher doses than those recommended, for example because of problems with resistance, can cause problems. Infants are very easily overdosed. In the treatment of rheumatoid arthritis and lupus erythematosus, larger doses are used, often for long periods of time, and with this use the incidence of adverse effects is high. Neuromyopathy, neuritis, myopathy, and cardiac myopa-thy can cause serious problems. Retinopathy can lead to blindness. Chloroquine has a long half-life and accumulates in the tissues, including the brain. Concentrations in the brain can have a bearing on mental status and psychotic syndromes. Chloroquine interferes with the action of several enzymes, including alcohol dehydrogenase, and blocks the sulfhydryl-disulfide interchange reaction. Allergic reactions are generally limited to rashes and pruritus.
Chloroquine and Hydroxychloroquine: Organs and Systems
Long-Term Effects
Drug tolerance
Chloroquine-resistant falciparum malaria was first reported in 1960. As of 1996, chloroquine resistance became widespread throughout the world and in many areas there is multidrug resistance. Preventive administration of drugs such as chloroquine, primaquine, and pyrimethamine, as well as the use of various sulfonamide mixtures and combinations of sulfonamides with trimethoprim, has progressively lost its usefulness. Currently, hardly half a century after the therapeutic breakthroughs occurred, quinine is once more one of the most valuable drugs in the treatment of malaria and there is a desperate need for other effective drugs.
Alongside the well-known development of resistance by P. falciparum to chloroquine, the emergence of chloroquine-resistant Plasmodium vivax is now clear. An increased frequency of cerebral malaria appears to coincide with the growing emergence of the chloroquine-resistant strains in Francophone Africa.
Second-Generation Effects
Pregnancy
Chloroquine inactivates DNA, and crosses the placenta in animals. Caution has generally been advised with respect to the use of chloroquine and related compounds during pregnancy, but except for one (perhaps coincidental) case, there have been no reports of complications to mother or child from treatment with chloroquine during pregnancy.
An observational comparison in a rural Ghanaian hospital of 2083 pregnant women and 3084 historical controls showed no serious adverse events with chloroquine che-moprophylaxis (300 mg/week), but a high rate of pruritus. There was a decrease in anemia in pregnancy but no increase in perinatal mortality or birth weight in the chloroquine-treated mothers, although this was only in comparison with historical controls.
Susceptibility Factors
Genetic factors
Mutations in the ABCR gene (a photoreceptor-specific Adenosine and adenosine triphosphate-binding cassette transporter gene) have been associated with Stargardt disease, which has some features similar to chloroquine-induced retinopathy. In a case-control study of eight cases of chloroquine-induced retinopathy, five of the eight cases had mis-sense mutations in the ABCR gene, two of which have been associated with Stargardt disease. It may be that polymorphisms in the ABCR gene predispose to chloroquine-induced retinopathy.
Age
Small children have usually been considered as being relatively more sensitive to the effects of overdosage, but it has been calculated that on a mg/kg body weight basis, adults are in fact equally sensitive. Young children seem to be truly more susceptible to gastric irritation. Patients with a history of mania or epilepsy should be careful in taking chloroquine. The hypoxemic effects of chloroquine, reflecting cardiac and respiratory toxicity, pose a particular problem in the newborn, in whom existing malarial infection may not become clinically manifest until some months after birth.
Compared with adults, mortality in children after acute chloroquine poisoning is extremely high. Although the clinical presentation is mostly similar to that in adults (apnea, seizures, cardiac dysrhythmias), a single 300 mg chloroquine tablet was enough to kill a 12-month-old female infant.
Other features of the patient
Skin reactions to hydroxychloroquine occur more often in patients with dermatomyositis than in patients with systemic lupus erythematosus, as has been shown in a retrospective, age-, sex-, and race-matched case-control study in 78 patients. Twelve of 39 patients with dermatomyositis developed a skin reaction to hydroxychloroquine, compared with only one of 39 patients with lupus erythematosus.
Chloroquine/Hydroxychloroquine (US: Aralen): Drug-Drug Interactions
Amlodipine
Syncope occurred in a hypertensive 48-year-old man who took oral chloroquine sulfate (total 600 mg base) while also taking amlodipine 5 mg/day. Chloroquine and amlodipine both cause vasodilatation, perhaps by release of nitric oxide, and the syncope in this case was probably due to a synergistic mechanism. Malaria itself can also provoke orthostatic reactions, which may be why syncope is not a reported adverse effect of chloroquine. However, in this patient malaria had been excluded.
Antibiotics
Studies of chloroquine used in combination with antibiotics showed an antagonistic effect with penicillin but a synergistic effect with chlortetracycline. Urinary tests after single doses of ampicillin 1 g and chloroquine 1 g showed a significant reduction in the systemic availability of the ampicillin.
Chlorphenamine
Chlorphenamine enhances the efficacy of chloroquine in acute uncomplicated falciparum malaria, but the disposition of chloroquine in these circumstances is unpredictable. Chloroquine (25 mg/kg) was given orally over 3 days in combination with chlorphenamine to Nigerian children with parasitemia. The peak whole blood chloroquine concentration was increased and the time to peak concentration shortened. In small trials there seemed to be an increase in QT interval with this combination, but less than with halofantrine. However, in other studies, the addition of chlorphenamine to chloroquine did not amplify the cardiac effects of chloroquine.
Ciclosporin
Chloroquine can increase ciclosporin blood concentrations.
Cimetidine
Cimetidine enhanced the susceptibility of P. falciparum to chloroquine in vitro in 60% of isolates.
Digoxin
The pharmacokinetic interaction of quinidine with digoxin also occurs with quinine and hydroxychloroquine.
Fansidar (sulfadoxine + pyrimethamine)
The combined use of Fansidar (sulfadoxine + pyrimethamine) with chloroquine has been reported to result in more severe adverse reactions. However, an increased risk has not been reported in recent studies.
Halofantrine
There is an increased risk of dysrhythmias, including tor-sade de pointes, when halofantrine is combined with quinine/quinidine or chloroquine and any other drug that prolongs the QT interval.
Insulin
There may be an interaction of chloroquine with insulin. An oral glucose load given to healthy subjects and to patients with non-insulin-dependent diabetes mellitus, before and during a short course of chloroquine, showed a small but significant reduction in fasting blood glucose concentration in the control group and improvement in glucose tolerance in the patients. The response seems to reflect reduced degradation of insulin rather than increased pancreatic output.
Quinine
Chloroquine antagonizes the action of quinine against P. falciparum in vivo. However, no such evidence of antagonism was found in a study in which Malawian children with cerebral malaria were treated with quinine. There was no difference in survival and rate of recovery in patients who had also been given chloroquine compared with those who had not.
Thyroxine
A marked increase in serum TSH occurred in the same patient on two occasions after several weeks of antimalarial prophylaxis with chloroquine and proguanil, the likely mechanism being enzyme induction and increased thyroxine catabolism.
Vaccines
Chloroquine 300 mg/week adversely affected the antibody response to human diploid-cell rabies vaccine administered concurrently. The mean rabies-neutralizing antibody titer was significantly reduced on each day of testing. In contrast, retrospective studies of the response to pneumococcal polysaccharide in patients with systemic lupus erythematosus taking chloroquine or hydroxychloroquine, and of the response to tetanus-measles-meningococcal vaccine in a region of Nigeria where malaria is endemic, did not show an effect on antibody production. However, it was pointed out that the altered immune status of patients with systemic lupus erythematosus makes it difficult to compare their response to that of young healthy adults receiving rabies vaccine. Illness and nutritional state could have influenced the findings in the Nigerian study.
Verapamil
Verapamil completely reversed pre-existing in vitro resistance to chloroquine to below the cut-off point of 70 nmol/l.
Smoking
Antimalarial drugs (chloroquine, hydroxychloroquine, or quinacrine) were given to 36 patients with cutaneous lupus, of whom 17 were smokers and 19 non-smokers. The median number of cigarettes smoked was one pack/day, with a median duration of 12.5 years. There was a reduction in the efficacy of antimalarial therapy in the smokers. Patients with cutaneous lupus should therefore be encouraged to stop smoking and consideration may be given to increasing the doses of antimalarial drugs in smokers with refractory cutaneous lupus before starting a cytotoxic agent.
| Dosage forms of Chloroquine: | |||
|---|---|---|---|
| Chloroquine ph 250 mg tablet | Chloroquine Phosphate 250 mg tablet | Novo-Chloroquine 250 mg Tablet | Chloroquine phosphate powdr |
| Chloroquine Phosphate 500 mg tablet | Chloroquine ph 500 mg tablet | Aralen phosphate 500 mg tablet | Aralen 500 mg tablet |
Synonyms of Chloroquine:
Chloraquine, Chlorochine, Chloroquina, Chloroquine Phosphate, Chloroquinium, Chlorquin, Clorochina, Hydroxychloroquine Sulfate
How can i get Chloroquine online over the counter?
You can buy Chloroquine OTC in online drugstore with low cost.
Therapeutic classes of Chloroquine:
Amebicides, Antimalarials, Antirheumatic Agents
Delivery
Australia, Canada, Mexico, New Zealand, USA, Europe [Belgium, France, Norway, Holland, Ireland, Spain, Switzerland, Great Britain (UK), Italy] and etc.