The possible physiologic processes involved in chloroquine metabolism and mediation of pruritus are basis for suggesting possible mechanisms. It has been suggested that chloroquine or its metabolite (monodesethylchloroquine) act as haptens; binding to break down products of parasitized erythrocytes[3
] or possibly interacting with acetyl-glyceryl-ether-phosphoryl-choline (AGEPC), a new class of phospholipids implicated in many aspects of allergy and inflammation[4
] (). This resulting complex act as an antigen, triggering reagenic antibodies (IgE) that bind to the surface of mast cells (that are in large numbers) and basophils.
Cascade of events showing possible mechanism of chloroquine-induced pruritus
These IgE molecules function as receptors and interact with signal transduction system in the membrane of sensitized cell. Upon subsequent exposure, the antigen bridges the IgE molecules and causes activation of phospholipase C, leading to the generation of inositol-1,4,5- triphosphate and diacylglycerol and elevation of intercellular calcium (Ca2+
). These final events trigger the extrusion of the content of the mast cell granules (degranulation) by exocytosis (). The mechanism by which the rise in Ca2+
leads to fusion of secretory granules with plasma membrane is not fully elucidated but it likely to involve activation of Ca2+
/calmodulin-dependent protein kinase and protein kinase C[5
]. Several mediators such as histamine, kallikrein, bradykinin, substance P, prostaglandins and various proteolytic enzymes have been implicated in itching[6
]. These mediators induce or aggravate itch by direct or indirect actions on the sensory nerves and receptors in the skin[8
]. A wide variety of mediators released during allergic response may explain the ineffectiveness of a single drug therapy to inhibit multiple mediators.
Another possible mechanism that has been proposed describes a binding of chloroquine or its metabolite to the region of the dermo-epidermal junction which transmit the itching sensation via slow conducting ‘C’ fibres and which are probably modulated centrally. Scratching is transmitted via fast conducting ‘A’ fibers which temporally suppress the sensation peripheral input (wall’s gate mechanism)[8
It is however possible that these different mechanisms can be at play alone or together in a susceptible individual. One important reason why the mechanism of pruritus is rather complex than what has been illustrated above is the role played by some factors that could be responsible for the induction as well as exacerbation of pruritus, hence influencing the varied response to drug management.