How Hydroxychloroquine Works

A variety of antimalarial medications have been shown to be effective for connective tissue diseases sincewas first used to treat systemic lupus erythematosus (SLE) more than 100 years ago. Three of these drugs are now primarily used due to their saf
MECHANISM OF ACTION — Antimalarials have a wide variety of actions, a number of which may be responsible for their immunomodulatory effects [16,17]. The most important mechanisms of action that affect the inflammatory diseases include their effects on the innate immune system and their lysosomotropic actions. Potential mechanisms of action include the following:
One of the most important actions deals with its actions related to toll-like receptors (TLRs). Cytosine phosphate diester-guanine (CpG) DNA stimulates cells through TLR-9, which is found in lysosomes. Chloroquines may block costimulation of the B cell antigen receptor and TLR-9 pathways and, thus, may act as an antiinflammatory agent [18,19]. Furthermore, antimalarials can inhibit activation of intracellular TLR-3 and TLR-7 [20]. Finally, hydroxychloroquine (HCQ) appears to exert an inhibitor effect on toll-like receptor signaling [21]. Nucleic acid-sensing TLRs are located intracellularly and are activated by foreign nucleic acids that are presented to them by intermediate molecules, such as Fc-gamma receptors. TLRs are processed by endosomes before becoming active; thus, antimalarial inhibition of endosomal activation inhibits TLR activation. In addition, the binding of nucleic acids to TLR through nucleic acid-binding epitopes is also mechanically inhibited by antimalarial binding that masks these epitopes [22].
Another important mechanism appears to be interference with normal physiologic function of subcellular compartments that depend upon an acidic milieu. This effect is termed a “lysosomotropic action,” because it was first demonstrated in lysosomes. Antimalarials are weak bases that enter not just lysosomes but all acidic compartments in which they are protonated, that raise the pH, and that interfere with functions dependent upon an acidic pH [23]. Antimalarials antagonize immune stimulation by CpG-DNA (a ligand for TLR-9), and chloroquine inhibits immune stimulation by small nuclear RNA (a ligand for TLR-7) and subsequent production of interferon alpha. TLRs require an acidic pH; thus, an increase in lysosomal pH caused by antimalarials may prevent functional transformation of intracellular TLRs and may inhibit their activation.This mode of action has many secondary effects. It interferes with receptor recycling, intracellular processing, and the secretion of proteins, which leads to a decreased production of cytokines and other inflammatory mediators [11,24-26]. Immune effects include decreased lymphocyte proliferation [11], interference with natural killer cell activity [11], and, possibly, alteration of autoantibody production [27]. In addition, antimalarials may influence the binding of autoantigenic peptides to major histocompatibility complex (MHC) class II molecules, thereby interfering with antigen processing and ultimately with the immune response to autoantigens [28].
It has also been suggested that decreased secretion of monocyte-derived proinflammatory cytokines may be due to non-lysosomotropic effects of antimalarials. These include a decrease in secretion of tumor necrosis factor (TNF)-alpha by stimulated human peripheral blood derived mononuclear cells in response to chloroquine, which was associated with decreased amounts of TNF-messenger RNA [29].
Other actions may play a role in the antirheumatic activity of antimalarials. Antiinflammatory effects may include inhibiting phospholipases, antagonizing prostaglandin, stabilizing lysosomal membranes, decreasing fibronectin release by macrophages, blocking superoxide release, and decreasing metalloproteinase production by synoviocytes [28,30,31]. These drugs also block ultraviolet light absorption, an effect that may protect against lupus skin lesions [32].
Antimalarial agents favorably affect serum lipid concentrations, probably due to effects upon receptor recycling. As an example, when fasting lipid profiles were assessed in 123 patients with systemic lupus erythematosus (SLE) (nearly one-half of whom were taking antimalarials), the mean serum concentrations of total, low density, and very low density cholesterol were significantly lower in those taking antimalarials (12, 16, and 22 percent less than patients not taking these agents, respectively) [33]. High density cholesterol levels are unaffected by antimalarial use [33,34].
HCQ is also a mild anticoagulant. It inhibits platelet aggregation and adhesion without altering the bleeding time, and its use is not associated with increased bleeding [23]. It may decrease the risk of thrombotic events in patients with SLE [35-37], which may be mediated through protecting the annexin A5 anticoagulant shield [38]. It also has a weak inhibitory effect on acetylcholinesterase; a resulting increase in synaptic transmission at neuroglandular sites may contribute to stimulation of salivary flow in Sjögren’s syndrome [39].
Some evidence also suggests that HCQ has a favorable effect on bone mineral density [40-42].

Pharmacology of Chloroquine and Hydroxychloroquine

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Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

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IUniversidade Federal de Pernambuco (UFPE), Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Recife/PE, Brasil.

Mechanism of Action of Hydroxychloroquine in the Antiphospholipid Syndrome

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Objective. The antiphospholipid syndrome (APS) is characterized by thromboembolic events and/or recurrent abortions in the presence of pathogenic antiphospholipid…

Antimalarials in Dermatology: Mechanism of Action, Indications, and Side Effects

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Review Antimalarials in Dermatology: Mechanism of Action, Indications, and Side Effects Antipalúdicos en dermatología: mecanismo de acción, indicaciones y efectos secundarios C. Rodriguez-Caruncho��, , I. Bielsa MarsolServicio de Dermatología, Hospital Universitari Germans Trias i Pujol, Universitat…