Chloroquine

The trophozoite in the red blood cell breaks down haemoglobin using lysosomal enzymes. In this digestive process ferriprotoporphyrin IX (haemin) is released from the haemoglobin protein chains. This porphyrin is toxic to the parasite and is usually polymerised to non-toxic malaria pigment. The weak base chloroquine accumulates in the acid lysosome and binds to ferriprotoporphyrin IX. In this way detoxicification of the latter is prevented and the parasite is killed. Since the liver parasite does not feed on haemoglobin and the effect of chloroquine is to prevent detoxification of the haem ring, this drug is not active at the pre-erythrocytic stages of Plasmodium sp. Outside the cell, chloroquine as well as hydroxychloroquine are present mainly in a protonated form, that, due to their positive charge, cannot cross the plasma membrane. However, the non-protonated form can enter the cell. Inside the cell, the molecule gains a proton (H⁺) in a manner inverserly proportional to the pH, i.e. the lower the pH, the more chloroquine will bind an extra proton. Chloroquine will be concentrated in acidic cell organelles, such as Golgi vesicles and lysosomes, where due to the low pH, most chloroquine molecules will be positively charged. Since chloroquine is a weak base, the pH will rise. By increasing this pH, several enzymes such as acid hydrolases can be inhibited. Post-translational modification of newly synthesised proteins can be disturbed.

Chloroquine is available in tablet form as chloroquine sulphate (Nivaquine®) and as chloroquine diphosphate (Resochine®). Other brand names are Daramal®, Anochlor®, Promal®, Avlochlor®. Hydroxychloroquine sulphate (Plaquenil®) is different and is used in rheumatoid arthritis. It is used in psoriasis patients (at the same dosage). The injectable form is chloroquine dihydrochloride. There is a combination tablet of chloroquine 100mg + proguanil 200 mg (Savarine®), which makes compliance easier for prophylactic use (1 tablet daily). The dose is always expressed as base (not as salt). This allows easier comparison between the different products. Nowadays most Nivaquine® tablets contain 100 mg. It is also highly advisable to check the current dose per tablet in the region where you are working, so as not to cause accidental overdosage or underdosage.

• Chloroquine diphosphate 250 mg tablet = 150 mg chloroquine base

• Chloroquine sulphate 200 mg tablet = 150 mg chloroquine base

• Chloroquine dihydrochloride 50 mg/ml = 40 mg base/ml

Chloroquine is a powerful schizonticide. It has strong affinity for various tissues and organs. It is fast-acting and remains in the blood for many days. A brief treatment is therefore possible. The excretion of chloroquine and its metabolites occurs mainly via the kidneys and is slightly improved by acidification of the urine (500 mg vitamin C every 4 hours). Chloroquine may be given orally, SC, IM or SLOWLY IV (infusion). Never inject an ampoule of chloroquine IV rapidly as a bolus. It is essential that rapid infusion is avoided. Chloroquine bihydrochloride IM is well absorbed (>80% even in severe malaria). The injections are not painful.

There are several different treatment regimens. Orally 25 mg/kg is given spread over three days. The following is practical for an adult weighing 60 kg: first, 6 tablets of 100 mg base, followed after 6 hours by another 3 tablets, after 24 hours by another 3 tablets and after 48 hours by another 3 tablets: 6-3-3-3. If parenteral therapy is required due to coma caused by chloroquine-sensitive P. falciparum, chloroquine bihydrochloride may be given IM or IV. The total dose should be 25 mg base/kg. There are several regimens, e.g. 10 mg base/kg over 8 hours, followed by 15 mg base/kg over 24 hours. Another frequently used regimen is 3.5 mg base/kg SC or IM every 6 hours. Parenteral administration should be discontinued as soon as oral administration is possible. In moderate renal impairment (creatinine clearance > 10 ml/min) no adjustment of the dose is necessary.

Chloroquine is cheap and not very toxic in normal use. Some people are allergic (pruritus, rash) or suffer nausea. People with psoriasis are more at risk of side effects. A reversible precipitation of chloroquine in the cornea may occur, resulting in small opacities. This may result in seeing haloes around objects, blurred vision or photophobia. This form of keratopathy may become manifest quite rapidly (a few weeks after beginning treatment). After discontinuing the medication it is completely reversible. Chloroquine accumulates in melanin-containing tissues. Chronic use may lead to abnormalities of the choroid and retina (chorioretinitis). This toxic retinopathy is not reversible. The abnormalities are always bilateral and symmetrical. Often there is maculopathy (bull’s eye) with central and paracentral scotomata, but constriction of the peripheral field of vision may also occur. The total cumulative dose before such problems occur is generally 100 gram chloroquine or more. Hydroxychloroquine has rather lower retinal toxicity. Tinnitus, hearing loss and neural deafness have been reported as possible rare side effects. Sometimes a proximal "chloroquine myopathy" occurs. The muscular weakness in myasthenia gravis is exacerbated by chloroquine and this disorder is a formal contra-indication for the use of this product. Breast feeding may be continued without change while taking chloroquine.

Chloroquine has a narrow safety margin (just 30 mg/kg may be fatal). In case of overdosage myocardial depression, hypotension, severe arrhythmias and tissue hypoxia may occur. ST-segment abnormalities and T-wave inversion occur. Broadening of the QRS complex (>0.12") and ventricular arrhythmias have a poor prognosis. The patient may become comatose, vomit and aspire the stomach contents. In acute intoxication diazepam is given (Valium® 1 mg/kg) and adrenalin (= epinephrine) or dopamine if these are available. First protect the airways and correct any existing cardiovascular disorders and then consider gastric lavage if the overdose was recent. Introducing activated carbon into the stomach is also beneficial. Acidification of the urine, osmotic diuresis, haemoperfusion and haemodialysis are of little use. After oral ingestion of an overdose the effect is evident approximately 1 hour later. Death follows after a further 2 to 3 hours.

The individuals within a population of parasites are not identical. Drugs do not have an equal effect on each variant. The larger the population and the shorter the life cycle of an organism, the faster mutations will become manifest. Of course Anopheles and Plasmodium have changed more in recent decades than have humans (evolutionary pressure due to insecticides and drugs). The first signs of chloroquine-resistant P. falciparum infections occurred in the ’60s, more or less simultaneously in Colombia and Thailand. This resistance spread progressively and is now a significant problem in many countries (see map with zones A, B and C). There are three grades of cloroquine resistance (RI, RII, RIII). In RI the parasitaemia after therapy is so low that it falls below the detection threshold, to rise above it again within 28 days. In RII the parasitaemia is reduced by at least 75 %, but the parasites remain detectabable in the peripheral blood. In RIII chloroquine has no effect on the parasitaemia. In spite of the presence of this resistance, chloroquine still has a place in treatment. It is still active against other plasmodium species. Only some falciparum parasites are resistant and only some have type RIII resistance. In non-urgent situations, therefore, this product may still be used. Recently chloroquine-resistant P. vivax strains have been discovered (Papua New Guinea, Indonesia, India, Brazil, Guyana). To date P. ovale is still 100% susceptible to nivaquine. The first chloroquine-resistant P. malariae has been reported (Malaysia, 2002).

Category: Medicine Notes