Describe chloroquine with its mechanism, uses, adverse effects and resistance.

Mechanism and Pharmacokinetics

• Accumulates several thousandfold within the vacuole because it becomes protonated and trapped at low pH — ion trapping put to therapeutic use
• Free haem then damages parasite membranes and enzymes
• Enormous volume of distribution (about 13,000 L), extensive tissue binding (liver, spleen, kidney, and melanin-containing tissue including the retina), and a half-life of days to weeks
• A loading dose is therefore required, and the drug persists long after the course ends

Uses

• P. Vivax malaria — still the treatment of choice in India, followed by primaquine for 14 days for radical cure
• P. Falciparum — NO longer used, because resistance is widespread; an artemisinin combination is required
• Extraintestinal amoebiasis — it concentrates in the liver, so it is an alternative in amoebic liver abscess
• Rheumatoid arthritis, SLE and photosensitive skin disease — as hydroxychloroquine, which is better tolerated for long-term use
• Lepra reactions and infectious mononucleosis occasionally

Adverse Effects

• Common and dose-related — nausea, vomiting, abdominal pain, headache, blurred vision, difficulty in accommodation
• Pruritus — intense and characteristic in dark-skinned people; a frequent and under-recognised cause of non-adherence
• Retinopathy — with prolonged high cumulative doses, as in rheumatological use; a bull’s-eye maculopathy that is irreversible and may progress after stopping. Annual ophthalmic screening is required after 5 years
• Other long-term effects — myopathy, neuropathy, ototoxicity, skin and hair depigmentation
• Cardiac — QT prolongation; and in overdose, profound hypotension, arrhythmia and death — chloroquine is one of the more lethal drugs in deliberate self-poisoning, which matters where it is freely available
• Haemolysis in G6PD deficiency is mild compared with primaquine

Resistance

• Mediated by the PfCRT transporter, which pumps chloroquine out of the food vacuole so it never reaches an effective concentration
• Widespread in P. Falciparum across Asia, Africa and South America; first recorded in the 1950s and now near-universal
• P. Vivax remains largely sensitive in India, though resistant vivax has been reported from parts of South-East Asia and Oceania, and must be considered where treatment fails
• Verapamil reverses resistance in vitro by blocking the transporter, but this has not translated into practical treatment

Applied Aspects

• Never treat falciparum malaria with chloroquine in India; species identification by microscopy or rapid test must precede treatment
• Always follow vivax treatment with primaquine for radical cure, after assessing G6PD status; otherwise relapse is near-certain
• Annual eye examination for anyone on long-term hydroxychloroquine for rheumatological disease, and dose limitation by ideal body weight
• Warn patients about pruritus and treat it, rather than allowing it to cause abandonment of treatment
• Keep chloroquine out of reach in households — ingestion of a few tablets can kill a small child, and it is a common agent in self-poisoning in malaria-endemic areas