Chapter 226. Aminoquinolines

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 and stabilizes cell membranes.10 It also concentrates in lysosomes. The effects are most appreciated in macrophages and phagocytic cells where phagocytosis and chemotaxis are impaired.11,12 Additionally, cellular enzymes and receptors dependent on lysosomes for function or activation are also affected, thus altering cells’ responsiveness to mitogenic stimuli.3

Antimalarials decrease T-cell release of interleukin (IL)-1, IL-6, tumor necrosis factor-α, and interferon-γ.13,14 IL-1, IL-6, and tumor necrosis factor-α play a role in the hepatic production of acute-phase reactants.15 Low concentrations of CQ and QE inhibit the pro-IL-6 stimulatory effect of cytosine-phosphorothiolated guanine-oligodeoxynucleotides on human peripheral blood mononuclear cells.16,17 More recently, it has been found that CQ elevated the expression of B7–2 (CD86, a costimulatory molecule) and intercellular adhesion molecule-1 (CD54, an adhesion molecule) in peripheral mononuclear cells, thus increasing IL-10-producing cells.18 CQ has also been implicated in the inhibition of natural killer cell activity, decreased production of IL-2 from activated lymphocytes, and alteration of antigen-antibody complexes. QE also inhibits natural killer cells and blocks the primary proliferative response of cytotoxic T cells to allogeneic non-T-cell antigens.15 Last, the arachidonic acid pathway is affected by antimalarial compounds. CQ inhibits phospholipase A2 and C.15 QE also inhibits phospholipase A2 production19,20 and increases nitric oxide release.21 Thus prostaglandin, leukotriene, bradykinin, and histamine levels can all be decreased. QE antagonizes the generation of superoxide anions.22

A novel mechanism of action of the antimalarials has recently been elucidated with respect to its inhibition of toll-like receptor (TLR) 9 family receptors.1 TLRs are intracytoplasmic receptors whose activation of the innate immune system in response to microbial peptides induces a significant inflammatory response. Additionally, further research has highlighted the importance of the innate immune response underlying the pathogenesis of systemic lupus erythematosus (SLE).23 Consequently, these TLRs who, as a class, are known as “pattern recognition receptors” (PRRs), have become a subject of intense investigation underlying the pathogenesis of SLE. It has recently been shown that host immune complexes containing DNA or RNA play an important role in activating endogenous TLRs (especially TLR-9 and TLR-7), thus leading to the eventual activation of the innate immune system, of which interferon alpha plays a crucial role.24,25 Additionally, TLR-9 expression is strongly associated with SLE activity.25 These specific nucleic acid binding TLRs bind their ligands in the lysosome, where an acidic environment promotes this binding.26 As the antimalarial agents specifically target microsomes by disrupting endosomal maturation and changing the pH, they block the TLR interaction (TLR-3, -7, and -9) with nucleic acid ligands.27 In vitro studies have identified that nanomolar concentrations of chloroquine specifically were potent inhibitors of IL-6 production by monocytes, an effect now known to be directly mediated by the inhibition of TLR-9.1 Antigen presenting cells are the primary targets of these interactions, thus accounting for a clinically slower response, as they initiate and prime the subsequent immune reactions.1 The 4-aminoquinolines have an affinity for melanin pigment. In the epidermis (as well as retina), they bind in high concentrations. In the skin, CQ absorbs ultraviolet (UV) light in a concentration-dependent manner.28 There is an increase in minimal erythema doses (MEDs) to UVB in lupus patients after taking oral chloroquine for 3 months, theoretically resulting from the anti-inflammatory and/or photoprotective mechanisms of the drugs.1,29 Topical CQ applied before UV irradiation protects against UVB- and UVA-induced erythema.30 QE has also been shown to inhibit photodynamic actions.31 It has been proposed that the beneficial effect of the HCQ and CQ in various photodermatoses may result from the ability of these drugs to enhance the protective early limb of the UV response.32

CQ and QE have been shown to bind cellular DNA by intercalation between base pairs, thus stabilizing the DNA.33–35 RNA transcription and subsequent translation are inhibited. These may be the mechanisms by which these molecules affect lupus.36

Antimalarial compounds also exhibit a myriad of ancillary effects. HCQ has been shown to improve lipid profiles, specifically causing a 15%–20% reduction in serum total cholesterol, triglycerides, and LDL levels.37 Both CQ and HCQ improve glucose profiles by decreasing insulin degradation38,39 and inhibit platelet aggregation.40 High doses of CQ may produce an antioxidant effect.41 Through membrane stabilization, antimalarials can produce a local anesthetic effect.3 In vitro, HCQ has been shown to induce apoptosis in B-chronic lymphocytic leukemia cells.42 CQ, HCQ, and QE have all been shown to interfere with human immunodeficiency virus type 1, SARS coronavirus, and influenza replication and function possibly due to disruption of protein glycosylation.43–46

The molecular structures of CQ, HCQ, and QE are closely related (Fig. 226-1). CQ and HCQ are 4-aminoquinolines, with HCQ differing from CQ by the presence of a hydroxyl group at the end of the side chain.1 The addition of a benzene ring classifies QE as an acridine. The pharmacokinetics and pharmacology of these compounds are similar, but importantly there is no cross reactivity between the aminoquinolines and QE (Table 226-1). All are bitter, water-soluble, and readily absorbed from the gastrointestinal tract with relatively good bioavailability, achieving peak concentrations within 8–12 hours. CQ and HCQ have large volumes of distribution (over 100 L/kg) and prolonged half-lives.47 The volume of distribution for QE may be even larger than that of CQ and HCQ. QE is extensively bound to plasma proteins, whereas CQ and HCQ are only partially bound (60%).48–50 The half-life of QE is substantially less than the other compounds.50 CQ is metabolized (dealkylated) in the liver by P450 enzymes into two active metabolites, desethylchloroquine and bisdesethylchloroquine.51 The metabolic fate of QE is less certain. CQ and its metabolites are stored in relatively high concentrations in the liver, spleen, lungs, adrenals, and kidneys with the highest concentration found in melanin-containing cells of the retina and skin.52 Approximately 50% of CQ is eliminated by the kidneys unchanged.48 HCQ is also metabolized in the liver (N-desethylated) into three chief metabolites: (1) desethylhydroxychloroquine, (2) desethylchloroquine, and (3) bisdesethylchloroquine.47 The parent compound and metabolites are taken up by lysosomes and concentrated in lysosome-rich tissues. Renal clearance accounts for approximately 15%–25% of the total clearance.53 The renal excretion of CQ, HCQ, and QE can be enhanced with acidification of the urine.54 QE is excreted in urine, bile, sweat, and saliva.50 Renal excretion only accounts for approximately 11% of its clearance. The highest tissue concentrations of QE are found in the liver and spleen.52 Equivalent doses of these compounds are 250 mg of CQ, 400 mg of HCQ, and 100 mg of QE. Smoking may alter the pharmacokinetics of antimalarial compounds, as clinical evidence of decreased efficacy of these medications in smokers has been documented.55 Decreased absorption, increased plasma clearance, or induction of the cytochrome P450 system may be mechanisms by which smoking alters the metabolism of these compounds.56

A recent study has highlighted the relationship between whole blood concentrations of HCQ and disease activity in SLE patients.57 Results of whole blood levels in 143 SLE patients who had received 6 months of HCQ at a dose of 400 mg/day demonstrated large variability in blood concentrations (possibly due to compliance). The mean concentration of patients with inactive disease was 1,079 ng/mL compared with the mean level of patients with active disease, which was 694 ng/mL. Additionally, the authors found that a low blood level of HCQ was associated with disease exacerbation in the follow-up period. The conclusion was that whole drug concentrations of HCQ should be maintained above 1,000 ng/mL, indicating a need for regular drug assaying and individualized dosing schedules to maintain this level.

Typical doses used in dermatology are 250–500 mg/day for CQ, 200–400 mg/day for HCQ, and 100–200 mg/day for QE. Evidence of efficacy is generally seen after 1–3 months of use, but it may take up to 3–6 months to achieve maximum clinical efficacy. After this time, the dose may be tapered to a minimum effective dose. Again, there is no cross-reactivity between QE and CQ and HCQ.58 Thus, the use of QE in combination with HCQ and/or CQ has been deemed safe, and an adverse reaction to the 4-aminoquinolone group does not preclude the use of QE. In refractory skin conditions, addition of QE to HCQ or CQ has been deemed beneficial, and response may be seen in 6–8 weeks after the addition of QE.59 If QE is added to CQ, the dose of CQ may need to be decreased to reduce potential for toxicity. Triquin, a combination of CQ (65 mg), HCQ (50 mg), and QE (25 mg) was used in the early 1970s. Nevertheless, the concomitant use of CQ and HCQ increases the risk for retinopathy (see Section “Complications”). Thus, this combination should be restricted to only severe cases. QE is not currently commercially available; production stopped in 1992. QE powder (veterinary grade, Sigma) can be formulated into capsules. Panorama Pharmacy in California, with an additional purification step, will prepare QE capsules.

The US Food and Drug Administration-approved indications for CQ, HCQ, and QE are limited. As is often seen in dermatology, these compounds are frequently used in an off-label manner. Treatment of malaria is the only indication shared by all three drugs. HCQ has the most labeled uses, including rheumatoid arthritis, discoid lupus, and systemic lupus erythematosus. Extraintestinal amebiasis is the only other approved use for CQ. QE had been approved for treatment of giardiasis when it was manufactured. Experience with HCQ in dermatology is more extensive. Its lower incidence of ocular toxicity (see Section “Complications”) makes it a favored choice. In recalcitrant disease, CQ is often substituted with increased efficacy. The current difficulty in obtaining QE may account for the relatively fewer indications (Table 226-2).

Cutaneous Lupus Erythematosus

(See Chapter 155)

Antimalarial drugs have been used for the cutaneous manifestations of lupus (acute cutaneous, subacute cutaneous, and chronic cutaneous LE) since the 1930s.60 CQ and QE were found to be effective in the treatment of cutaneous lupus also during World War II.61 A double-blind trial of HCQ for discoid lupus showed a 70% response rate and that it was more efficacious than placebo at 3 months and 1 year of treatment.62 A review of 20 clinical trials involving the use of QE for cutaneous lupus showed an overall 73% response rate.63 Antimalarials are typically used as steroid-sparing agents in patients whose symptoms cannot be controlled by topical steroids and sun protection. Widespread cutaneous lesions, hypertrophic and verrucous lesions, and longstanding discoid lesions do not respond as well. Systemic symptoms such as fever, renal, or hematologic abnormalities seen in systemic lupus erythematosus typically do not respond to antimalarial therapy, but fatigue, arthralgias, myalgias, serositis, and mucosal ulcerations do respond to therapy.64 In addition, antimalarials have effectively treated nonspecific cutaneous manifestations of LE, such as mucosal ulcerations, calcinosis cutis, lupus panniculitis, and photosensitivity.65 Lupus panniculitis specifically has been reported to respond well to antimalarial therapy, with 23 out of 33 patients in one study demonstrating clinical improvement.66 The onset of action for antimalarial therapy is typically 4–8 weeks; after which time, one may consider adding or changing therapies. More rapid response may be seen with the addition of QE.63 When HCQ is ineffective as a monotherapy, CQ may be more efficacious, but the combination of HCQ and CQ is generally avoided to prevent retinal toxicity. The use of QE alone or in combination with either HCQ or CQ has also been suggested as providing a response in recalcitrant patients. A recent report evaluating 34 patients unresponsive to HCQ therapy alone identified the majority of patients rapidly and significantly responded to the addition of QE to their therapeutic regimen.67 Triquin, a combination of all three drugs, has also been used in cutaneous lupus erythematosus with success.

Polymorphous Light Eruption

(See Chapter 91)

Polymorphous light eruption (PMLE) is an inflammatory reaction seen on sun-exposed skin. IL-1, -6, and -8 may play a role in the inflammatory process.68 Chloroquines decrease IL-1 and -6 and release and absorb UVA light. Although generally not used as first-line treatments, these drugs have been used for PMLE for several years69,70 and placebo-controlled trials have proven efficacy for this indication.71 Two trials demonstrated increased sun tolerance and moderate clinical improvement identified by skin rash reduction, which was statistically significant.1,72,73 Intermittent HCQ at doses of 200–400 mg/day prior to sun exposure can be effectively tried if photoavoidance and/or prophylactic UVB/UVA are not viable options. Topical sunscreens should also be used in conjunction with antimalarial therapy. In northern climates, discontinuation of therapy during winter months may decrease cumulative side effects of antimalarial therapy.

Porphyria Cutanea Tarda

(See Chapter 132)

The first reported case of CQ therapy for porphyria cutanea tarda (PCT) was published in 1957,74 and its use can lead to long-term remission.1,75 Chloroquines inhibit porphyrin synthesis and mobilize lysosomal stores of porphyrins, allowing for the formation of water-soluble complexes, which are then excreted by the kidneys.76 Although phlebotomy remains the primary treatment of choice for PCT, antimalarial therapy may be used in conjunction with phlebotomy or when phlebotomy is contraindicated or has previously been used without success. Hepatotoxicity is a concern, and liver enzymes should be followed closely during therapy. Headache, nausea, fever, elevated transaminases, and urinary excretion of porphyrins occur 3–4 days after initiation of therapy with CQ at 250 mg/day.77 Prolonged remissions have been reported with short courses of high dose HCQ (250 mg three times daily), but high doses routinely lead to marked increases in liver transaminases.78 Low-dose CQ therapy (125 mg twice weekly for 2 weeks followed by 250 mg twice weekly thereafter) gave a 94% response rate in one study of 53 patients.79 Alternatively, HCQ used at 100 mg three times weekly for 1 month, then 200 mg three times weekly for 1 month, then advanced to 200 mg daily has been proposed.80 These lower dosing schedules seem to alleviate the severe acute hepatotoxicity. A combination of phlebotomy before initiation of CQ therapy may also reduce the severity of hepatotoxicity.81

Sarcoidosis

(See Chapter 152)

Antimalarial therapy for cutaneous manifestation of sarcoidosis was first described nearly half a century ago. Original reports on the efficacy of antimalarials in the treatment of sarcoidosis demonstrated initial clinical improvements on treatment during a 6-month course, with little further improvement after 1 year, indicating the treatment was likely suppressive rather than curative.82 Additionally, relapses off of these medications are common, further supporting the notion that these therapies are not curative.82–87 The proposed mechanism of action relies on the antimalarials’ capacity to block antigen processing and presentation to CD-4+ T cells, thus inhibiting granuloma formation.83,88 A 1996 review of the subject concluded that antimalarials were highly effective, with greater than 70% response rate.89 Two to three mg/kg/day of HCQ has been reported as being effective in 12 of 17 patients treated.90 CQ therapy initiated at 500 mg/day for 2 weeks, then a maintenance dose of 250 mg/day has been described as safe and effective.91 Therapy may also be effective for associated hypercalcemia. Another granulomatous disease, generalized granuloma annulare, has also been reported to respond to HCQ.1,92–94

Cutaneous Dermatomyositis

(See Chapter 156)

Although the muscle disease in this condition often responds well to systemic corticosteroids, the cutaneous lesions are generally recalcitrant to this therapy. Cutaneous symptoms unresponsive to traditional therapies have been reported to respond well to antimalarial therapy. It is in these patients that antimalarial therapy be strongly considered, as well as in those patients with cutaneous involvement without any muscle involvement (“amyopathic dermatomyositis”).1 Monotherapy with either HCQ 200 mg bid (less than 6.5 mg/kg/day) or CQ 250 mg qd (less than 3.5 mg/kg/day) is often adequate to control skin manifestations. The addition of QE to either HCQ or CQ has been shown to be beneficial in patients who do not respond to a 4-aminoquinolone alone.59

Oral Lichen Planus

Because the lesions of oral LP are clinically indistinct from those of mucosal LE, an open trial enrolling oral LP patients was undertaken to assess their response to HQC.95 Nine out of the ten enrollees exhibited a rapid, excellent response to therapy with 200–400 mg/day HQC, with a minority flaring after discontinuation of therapy (3 months). Although corticosteroids are the first-line therapy for this disorder, recalcitrant lesions may respond to antimalarial therapy.

Chronic Ulcerative Stomatitis

There are only a handful of cases reported in the literature describing this rare disorder which occurs primarily in older female patients. Clinicopathologically, this disease mimics erosive lichen planus but is traditionally unresponsive to corticosteroid therapy. The cases reported, however, demonstrated a complete response to antimalarial therapy lasting for several months to years. These medications are now considered first-line therapy for this rare condition.96

Miscellaneous

Antimalarials have been reported to be useful in cases of epidermolysis bullosa, eosinophilic fasciitis, atopic dermatitis, solar urticaria, scleroderma, urticarial vasculitis, and reticular erythematous mucinosis, and Sjögren syndrome.1,96–101

Use of antimalarial compounds in dermatology is varied. Each disease state is treated differently with special concerns pertaining to the disease entity. As such, dosing for each condition is dependent on the underlying pathology. Usual starting doses for HCQ are between 200 and 400 mg/day. Equivalent dosing for CQ is 250–500 mg/day, and for QE, 100–200 mg/day. However, initiation of therapy and maintenance dosing may be different for each disease. Combination therapy with these medications also alters the dosing.

Given the degree of variation among dermatoses potentially responsive to antimalarials, many principles govern the initiation of therapy. Of utmost importance is the establishment of the correct diagnosis through clinical, histologic, and serologic evaluations. Next, one must make the determination as to whether antimalarials have been shown efficacious in the diagnosed dermatosis (see Table 226-2). After an established diagnosis has been made, one should determine whether the patient is an appropriate candidate for antimalarial therapy based on comorbid conditions and medication interactions. A rigorous laboratory monitoring protocol must be established, as adverse hematologic and metabolic side effects have been reported with the use of these medications. Patients who are deficient in the glucose-6-phosphate dehydrogenase (G6PD) enzyme are more prone to a hemolytic anemia. Thus, baseline evaluation of G6PD enzyme, complete blood cell count, and serum chemistry panel should be performed before initiation of therapy in all patients. Ocular toxicity is a serious side effect associated with the use of HCQ and CQ, and baseline evaluation by an ophthalmologist is necessary. Slit-lamp assessment, fundoscopic examination, and assessment of visual acuity and fields should be included.

Laboratory monitoring should include a complete blood count performed monthly for 3 months to evaluate for the presence of hemolytic (or, less commonly, aplastic) anemia. Thereafter, quarterly to semiannual complete blood counts should be obtained. A comprehensive metabolic panel should be checked monthly for 3 months, then every 4–6 months thereafter, paying special attention to the liver enzymes, particularly in those patients who are taking hepatotoxic medications and in those patients with porphyria. Quarterly to semiannual chemistries should be followed while on maintenance therapy.

Proposed guidelines for monitoring for the development of ocular toxicity vary widely in the literature. At baseline and on each follow-up visit, patients must be asked about any changes in visual acuity and simple screening tests for acuity may be sufficient. Should patients report changes in vision, an ophthalmologist referral is then appropriate. Current American Academy of Ophthalmology (AAO) screening guidelines recommend that patients be prescribed doses of hydroxychloroquine ≤6.5 mg/kg/day or chloroquine ≤3mg/kg/day.102,103 Additionally, the guidelines divide patients into those who are “low risk” (receive lower dose for <5 years) and “high risk” (receive higher doses, have other risk factors such as high body fat level, concomitant kidney, liver, or retinal disease, or >60 years of age). Patients should have a baseline ophthalmologic examination within 1 year of beginning the medication, which includes a baseline slit-lamp, fundoscopic, visual field, and acuity examinations. The “low-risk” group requires no further testing (if they have a normal baseline evaluation) until the 5-year therapy mark has been reached; the “high-risk” group should have annual ophthalmologic examinations. After 5 years of continuous therapy, annual examinations are recommended because of the risk for ocular toxicity reported in patients on long-term therapy.103

Most side effects of antimalarial therapy are reversible (Box 226-1). Decreased dosing or drug withdrawal may completely alleviate a majority of side effects encountered with these drugs. Without proper monitoring, however, these drugs have the potential for serious and permanent side effects.104

Gastrointestinal complaints of anorexia, nausea, vomiting, diarrhea, and weight loss are the most commonly encountered side effects (10% for HCQ; 20% for CQ; 30% for QE).105 Acute symptoms from high doses of CQ and HCQ include blurred vision, cardiovascular toxicities, hypotension, neurotoxicity, and respiratory or cardiac arrest.48,49 In children, as little as 0.75 g of CQ can be fatal (2.25–3.0 g in adults).106 Lethal doses of HCQ are considered to be in a similar range.48,49 Several cases of overdose have been reported. Management of overdose consists of gastric lavage, ventilation, and inotropic support.107–111 As little as one or two tablets of CQ or HCQ can be dangerous in children. Appropriate monitoring is necessary after accidental ingestion.112 A lethal dose of QE has not been determined.

Patients with G6PD deficiencies are susceptible to CQ- and HCQ-induced hemolytic anemia, although rarely when taken in therapeutic ranges. Aplastic anemia with QE113,114 and agranulocytosis with CQ or QE have also been reported. All of the antimalarials have reportedly caused severe, reversible leukopenia.1

Adverse cutaneous effects can be seen with antimalarial therapy. Exacerbation of preexisting psoriasis in as many as 18% of patients with psoriasis has been documented with the use of these medications.115 CQ is responsible for most psoriatic flare-ups, while QE is more likely to induce exfoliative erythroderma. HCQ is much less likely to exacerbate psoriasis.116

In the general population, incidence of pruritus and rashes secondary to antimalarial use is reported to be 10%–20%.117 Dose-related QE-induced drug eruptions were reported during World War II. One in 2,000 soldiers taking 100 mg daily reported an adverse reaction, whereas 1 in 600 soldiers taking 200 mg daily had an adverse reaction.114 Lichenoid reactions accounted for approximately 20% of the cutaneous reactions in this series.

The antimalarials have a high affinity for melanin, which may account for the blue-black cutaneous discoloration in 10% to 30% of patients treated with these compounds for a prolonged course. The shins, face, hard palate, and nail beds are most commonly affected.118,119 The discoloration may fade slowly over months after the drug is discontinued. QE may cause an even more pronounced hyperpigmentation than that seen with CQ or HQC. Histopathological evaluation of lesional skin sections shows the presence of melanin granules and hemosiderin deposition within the dermis. More commonly, a dose-related yellowish staining occurs with QE and affects the skin, sclera, and bodily secretions. This discoloration also fades after drug withdrawal. Stevens-Johnson syndrome has also been reported in a patient treated with HCQ.120

Ocular toxicity is the most worrisome side effect of antimalarial therapy. Neuromuscular eye toxicity, corneal deposits, and potentially irreversible retinopathy can all occur. Blurred vision and reduction in accommodation power can occur from the depressive effect on ocular muscles during the initial weeks of therapy (transient and self-limited). CQ is deposited in the basal epithelium of the cornea. Deposition of HCQ can also occur but is less likely at therapeutic doses.121 These depositions can be responsible for patient complaints of blurred vision, halos around lights, and photophobia upon initiating therapy.122 The corneal deposits are dose related, reversible with cessation of therapy, and not a contraindication for continued therapy. CQ has an affinity for retinal pigment epithelium and can be stored there for years, even after discontinuation of therapy. Antimalarial-induced retinopathy can be reversible (premaculopathy) or irreversible (true retinopathy). Premaculopathy includes changes in visual fields or fundoscopic examination, not associated with vision loss. These changes may progress to irreversible disease if the offending drug is continued. True retinopathy is associated with bilateral, permanent visual field abnormalities. Risk of true retinopathy from antimalarial therapy has been studied and debated. It appears as though the risk is greater for CQ than HCQ.121,123 Doses less than 3.0 mg/kg/day for CQ and less than 6.5 mg/kg/day for HCQ are believed to decrease the risk of a true retinopathy.124 Higher doses and impaired renal function may increase the risk. The true risk of HCQ-induced retinopathy is felt to be quite rare. As such, the question of screening as a cost-effective measure is debated. A case of bull's eye maculopathy has been associated with QE therapy for malaria.125

Other, less likely side effects of antimalarial therapy include neurotoxicity (most commonly headaches and nightmares),1 myotoxicity (myalgias, fatigue),126 ototoxicity,127,128 acute generalized exanthematous pustulosis,129 cardiotoxicity (conduction disturbances, congestive heart failure),57 and rhabdomyolysis.130

Drug Interactions

There are several important medication interactions to consider when prescribing antimalarials. Most importantly, it is recommended that HCQ and CQ not be coadministered due to the potential for retinal toxicity. CQ or HCQ may increase penicillamine and digoxin levels when used simultaneously with these medications.48,49 Cyclosporine levels may be increased by CQ.48 Metoprolol levels may be increased with use of HCQ.131 CQ may reduce the bioavailability of ampicillin.48 Antacids and Kaolin may decrease the GI absorption of CQ. A minimum of 4 hours should exist between administration of antacids and antimalarials.48 Cimetidine may increase CQ levels,48 increasing potential for other side effects. Concurrent use of CQ and mefloquine may increase the risk of seizures. CQ increases the risk of hepatotoxicity when administered with other hepatotoxic agents. Monitoring liver enzymes is recommended.48 Finally, smoking induces the cytochrome P450 enzyme system and may alter the bioavailability of antimalarial therapy. Decreased efficacy of antimalarial therapy in smokers has been published.132

Pediatric Use

CQ and HCQ have been used in the pediatric population.133,134 However, concern over toxicity exists.135,136 Antimalarials are now considered generally safe in children when treating rheumatic disorders, such as lupus erythematosus, dermatomyositis, juvenile rheumatoid arthritis, and morphea, as well as in panniculitis and PCT.137 When the dose is appropriately adjusted for body weight, the risk for toxicity in children is felt to be no greater than for adults.

Pregnancy

Use of antimalarial drugs in pregnancy is now generally accepted as safe. It is recognized that 4-aminoquinalines cross the placenta and accumulate in fetal tissues.52 Congenital defects have been rarely reported with antimalarial drug use in pregnancy.138 In one study of 27 pregnancies exposed to HCQ or CQ, no congenital anomalies were identified.139 Another review of 33 lupus patients with 36 pregnancies exposed to HCQ reported no evidence of teratogenic effects.140 Larger reviews in Britain and North America support the use of 4-aminoquinalines during pregnancy.141–143 In addition, discontinuation of antimalarial therapy for the treatment of lupus may cause a significant flare-up of disease, which can be associated with prematurity, growth retardation, and increased fetal loss.144–147 The safety of QE is less well documented.

Breastfeeding

Antimalarial use during breastfeeding is relatively contraindicated. CQ and HCQ are both excreted in breast milk, albeit in small amounts.1,148 In the case of HCQ, infants are exposed to 2% of the maternal dose per kilogram per day and 1% of the maternal dose of CQ.58 As the half-life is long and elimination slow, potential exists for accumulation of drug in the infant.149