Home Books Fitzpatrick's Dermatology in General Medicine, 8e

Chapter 226. Aminoquinolines

Susannah E. McClain; Jeffrey R. LaDuca; Anthony A. Gaspari

Aminoquinolines at a Glance

Aminoquinolines have been used in clinical medicine for more than a century, initially as antimalarial compounds.
Multiple mechanisms of action, particularly impaired lysosomal acidification by antigen presenting cells, inhibition of natural killer and T-cell activation, and inhibition of lipid mediators of inflammation.
Propensity for melanin pigment, absorb ultraviolet light, and exhibit photoprotective properties against ultraviolet-mediated injury of the skin.
Aminoquinolines used to treat dermatologic conditions include hydroxychloroquine, chloroquine, and quinacrine.
Hydroxychloroquine is the most commonly used aminoquinoline for skin conditions and is well studied for chronic cutaneous lupus erythematosus.
Other aminoquinoline-responsive conditions: porphyria cutanea tarda, polymorphous light eruption, cutaneous sarcoidosis, dermatomyositis, and other conditions.
Laboratory monitoring is mandatory during aminoquinoline therapy to detect hematologic abnormalities (hemolysis and drug-induced cytopenias), liver injury, and ophthalmologic toxicity (retinopathy).
Children are especially susceptible to aminoquinoline toxicities, and lower doses must be used than in adults.
Drug interactions are possible, and cigarette smoking decreases efficacy of aminoquinolines by inducing cytochrome P450 enzymes.

Antimalarial compounds have been used to treat skin diseases for more than a century. Three compounds, chloroquine (CQ), hydroxychloroquine (HCQ), and quinacrine (QE), have been most studied. The 4-aminoquinolines are a family of compounds derived from quinine, a naturally occurring alkaloid originally procured from the South American cinchona bark tree.1 CQ and HCQ, the principal members of this class of compounds, are the most often used for therapeutic use in dermatology. QE, classified as an acridine, has also been used in dermatologic therapy. Interestingly, the use of these medications for treatment and prophylaxis of malaria is waning due to increased resistance.

The precise mechanisms by which antimalarial compounds exert their actions are still unknown. However, several discrete mechanisms for each compound have been determined. In the treatment of malaria, aminoquinolines concentrate in the Plasmodium digestive vacuole and prevent polymerization of toxic heme released during proteolysis of hemoglobin.2 Mechanisms by which these compounds influence skin diseases are varied and include, among others, their effects on antigen presentation, cytokines, toll-like receptors, and prostaglandins.

CQ and HCQ are lipophilic weak bases that pass through plasma membranes in their protonated state, become trapped, and accumulate inside acidic vesicles such as lysosomes,1,3,4 accounting for their effects in Plasmodium. HCQ induces signs of lysosomal and mitochondrial membrane permeabilization.5 By raising intralysosomal pH from 4–6, acidic proteases become inactivated and subsequent proteolysis is inhibited. Subsequently, antigen processing and presentation by dendritic cells may be impaired because of an inability to digest these foreign antigens within the lysosomal compartment.6 Additionally, CQ has been shown to disrupt antigenic peptide loading on class II MHC molecules and subsequent presentation to the opposing T cell.1,7 Inhibition of calcium signaling within the T cell may be an additional mechanism.8 Conversely, CQ has been more recently shown to enhance human CD8+ T cell responses.9 QE inhibits Na-K adenosine triphosphatase activity ...