Chloroquine

CHLOROQUINE

It is a rapidly acting erythrocytic schizontocide against all species of plasmodia; controls most clinical attacks in 1–2 days with disappearance of parasites from peripheral blood in 1–3 days. Therapeutic plasma concentrations are in the range of 15–30 ng/ml. However, it has no effect on pre and exoerythrocytic phases of the parasite—does not prevent relapses in vivax and ovale malaria.

The mechanism of action of chloroquine is not completely known. It is actively concentrated by sensitive intraerythrocytic plasmodia: higher concentration is found in infected RBCs. By accumulating in the acidic vesicles of the parasite and because of its weakly basic nature, it raises the vesicular pH and thereby interferes with degradation of haemoglobin by parasitic lysosomes. Polymerization of toxic haeme to nontoxic parasite pigment hemozoin is inhibited by formation of chloroquine-heme complex. Heme itself or its complex with chloroquine then damages the plasmodial membranes. Clumping of pigment and changes in parasite membranes follow. Other related antimalarials like quinine, mefloquine, lumefantrine appear to act in an analogous manner.

Chloroquine-resistance among P.vivax has been slow in developing. However, P. falciparum has acquired significant resistance and resistant strains have become prevalent especially in eastern part of India, South East Asia, Africa and South America. Some of these have also acquired resistance to proguanil and S/P (multidrug resistant strains). Because P. falciparum produces the more severe forms of malaria with considerable mortality, emergence of such strains is the biggest threat to the antimalaria programmes, and is the focus of attention for current research efforts.

Chloroquine-resistance among P. falciparum is now widespread in India, but is mostly low grade (RI or late clinical failure). Higher grade resistance (RII, RIII or early treatment failure) averaged 8.7% over the period 1978–2002. The largest number of chloroquine-failures are reported from the North eastern part of India where 24–83% P. falciparum cases are resistant to chloroquine, and some of these (particularly in areas bordering Myanmar) are multidrug resistant. In 73 districts (mostly North eastern states, Orissa, Karnataka, Gujarat) the NVBDCP has switched over to the 2nd line treatment (sulfa-pyrimethamine ACT), due to high rates of chloroquine resistance.

Resistance in P. falciparum is associated with a decreased ability of the parasite to accumulate chloroquine. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentrating ability as well as sensitivity to this drug.

A chloroquine transporter glycoprotein encoded by the Pf mdr1 gene appears to play a role in chloroquine-resistance of P. falciparum but not that of P. vivax. However, other mechanisms of resistance also appear to be involved.

Chloroquine-resistance among P. vivax was first reported from Papua New Guinea in 1989. It has now been confirmed from Columbia, Indonesia, Myanmar and detected in India, but is focal and sporadic, reported from Chennai, Mathura, tribal areas of Madhya Pradesh, Mumbai and Bihar. It manifests as recrudescence within 1–3 weeks of treating vivax malaria with standard dose of chloroquine. Such cases can be treated by quinine given along with doxycycline, followed by primaquine to effect radical cure. Mefloquine is the 2nd alternative.

Other Actions: Chloroquine is active against Entamoeba histolytica and Giardia lamblia also.

It has anti-inflammatory, local irritant and local anaesthetic (on injection), weak smooth muscle relaxant, antihistaminic and antiarrhythmic properties.

Pharmacokinetics

Oral absorption of chloroquine is excellent. About 50% gets bound in the plasma. It has high affinity for melanin and nuclear chromatin: gets tightly bound to these tissue constituents and is concentrated in liver, spleen, kidney, lungs (several hundredfold), skin, leucocytes and some other tissues. Its selective accumulation in retina is responsible for the ocular toxicity seen with prolonged use. Absorption after i.m. injection is also good.

Chloroquine is partly metabolized by liver and slowly excreted in urine. The early plasma t½ varies from 3–10 days. Because of tight tissue binding, small amounts persist in the body with a terminal t½ of 1–2 months.

Adverse Effects

Toxicity of chloroquine is low, but side effects are frequent and unpleasant: nausea, vomiting, anorexia, uncontrollable itching, epigastric pain, uneasiness, difficulty in accommodation and headache. Suppressive doses have been safely given for 3 years.

·       Parenteral administration can cause hypotension, cardiac depression, arrhythmias and CNS toxicity including convulsions (more likely in children).

·       Prolonged use of high doses (as needed for rheumatoid arthritis, DLE, etc.) may cause loss of vision due to retinal damage. Corneal deposits may also occur and affect vision, but are reversible on discontinuation.

·           Loss of hearing, rashes, photoallergy, mental disturbances, myopathy and graying of hair can occur on long-term use.

Chloroquine can be used for treatment of malaria during pregnancy: no abortifacient or teratogenic effects have been reported.

Caution is to be exercised in the presence of liver damage, severe g.i., neurological and haematological diseases. Attacks of seizures, porphyria and psoriasis may be precipitated.

Chloroquine should not be co-administered with mefloquine, amiodarone and other antiarrhythmics.

Preparations and Administration

Chloroquine phosphate: (250 mg = 150 mg base) bitter, tablet should not be chewed. RESOCHIN, CLOQUIN, LARIAGO, NIVAQUINP 250 mg tab, 500 mg forte tab, 100 mg (base) per 10 ml oral susp., 40 mg (base)/ml inj in 2 and 5 ml amp, 30 ml vial.

Parenteral chloroquine (as HCl salt 250 mg = 200 mg base) is used only for severe cases of falciparum malaria and in cerebral malaria with comatose patient as third choice to i.v. quinine/artesunate when the parasite is known or expected to be chloroquine sensitive. Its cardiovascular adverse effects can be prevented by slow i.v. infusion: 10 mg/kg diluted in 5% dextrose and infused over 8 hr, followed by 15 mg/kg infused over 24 hr. Switch over to oral therapy as soon as possible. It can also be given by deep i.m. injection (3 mg/kg 6 hourly). Parenteral chloroquine is contraindicated in children — convulsions and deaths have occurred.

Uses

·  Chloroquine is the drug of choice for clinical cure and suppressive prophylaxis of all types of malaria, except that caused by resistant P. falciparum. Uncomplicated cases are treated orally, while i.v. chloroquine is rarely employed for complicated/cerebral malaria in adults. It completely cures sensitive falciparum disease, but relapses in vivax and ovale malaria are not prevented. In short time visitors to chloroquine-sensitive endemic areas, suppressive doses should be started 1 week before and continued for 4 weeks after returning.

·          Extraintestinal amoebiasis (Ch. No. 60).

·          Rheumatoid arthritis (Ch. No. 15).

·          Discoid lupus erythematosus—very effective; less valuable in systemic LE.

·          Lepra reactions (Ch. No. 56).

·          Photogenic reactions.

·          Infectious mononucleosis: affords symptomatic relief.

Amodiaquine

It is almost identical to chloroquine in properties and is less bitter.

Studies over the past 20 years in Africa have found it to be somewhat faster acting than chloroquine.

In the mid 1980s some fatal cases of toxic hepatitis and agranulocytosis were reported among travellers using amodiaquine for prophylaxis, and WHO in 1990 recommended that it should not be used for prophylaxis of malaria as well as for treatment of chloroquine failures. The 19th WHO expert committee on malaria (1992) did not accept this recommendation totally, and permitted use of amodiaquine for treatment of clinical attacks. Countries which had continued to use amodiaquine did not report any severe reaction.

Experience in Africa over the past 2 decades supports continued use of amodiaquine in uncomplicated falciparum malaria, but it is still not recommended for prophylaxis. There is evidence now that amodiaquine may be effective even in areas with chloroquine-resistant P. falciparum. In combination with artesunate, it is being tried as ACT for chloroquine-resistant falciparum malaria. Side effects of amodiaquine are similar to chloroquine; itching may be less common, but neutropenia has been associated with it in children.

Dose: for treatment of acute attack of malaria: 25–35 mg/ kg over 3 days; CAMOQUIN 200 mg (as HCl = 150 mg base) tab; BASOQUIN 150 mg (base) per 5 ml susp.

Piperaquine