Antimalarial Agents - Clinical Tree

Questions

Q21.1 What are the proposed mechanisms by which antimalarials work in various dermatoses discussed in this chapter? (Pg. 236)
Q21.2 In general, concerning responses of lupus erythematosus to antimalarials, (1) which cutaneous subsets respond well, (2) which cutaneous subsets respond less well, and (3) which systemic features/organ systems respond well? (Pg. 237)
Q21.3 How strong is the evidence that cigarette smoking impairs the efficacy of the antimalarials for cutaneous lupus erythematosus? (Pgs. 238, 242)
Q21.4 How do the 4-aminoquinolines (such as hydroxychloroquine) and 8-aminoquinolines (such as primaquine) differ in the need for a baseline glucose-6-phosphate dehydrogenase (G6PD) determination? (Pgs. 239, 241)
Q21.5 Concerning retinal toxicity with chloroquine and hydroxychloroquine, (1) what is the difference between ‘premaculopathy’ and ‘true retinopathy’, and (2) which of these findings is irreversible? (Pg. 239)
Q21.6 How often should a screening eye examination be performed for patients on long-term antimalarial therapy? (Pgs. 239, 240x2)
Q21.7 What are some of the most important risk factors for retinal toxicity from antimalarial therapy? (Pg. 240x2)
Q21.8 Concerning adverse cutaneous reactions to antimalarials, (1) what are some of the most common reactions, and (2) how do hydroxychloroquine, chloroquine, and quinacrine compare in the incidence of these adverse cutaneous reactions? (Pg. 241x2)
Q21.9 What is the recommended ‘maintenance’ dosage range, with an acceptably low incidence of retinopathy, for antimalarial therapy with hydroxychloroquine or chloroquine therapy? (Pg. 242)
Q21.10 Concerning relatively common adverse effects from antimalarials, what are the main options when patients experience (1) significant gastrointestinal adverse effects, and (2) develop a morbilliform or lichenoid drug eruption? (Pg. 242)
Q21.11 In which important ways does the dosage scheme differ when antimalarial agents are used in porphyria cutanea tarda? (Pg. 243)

Abbreviations used in this chapter

AAO

American Academy of Ophthalmology

AE

Adverse effects/events

CQ

Chloroquine

CS

Corticosteroid

DNA

Deoxyribonucleic acid

FAF

Fundus autofluorescence

GI

Gastrointestinal

G6PD

Glucose-6-phosphate dehydrogenase

HCQ

Hydroxychloroquine

HIV

Human immunodeficiency virus

LE

Lupus erythematosus

LFT

Liver function test

mfERG

Multifocal electroretinogram

PCT

Porphyria cutanea tarda

PMLE

Polymorphous light eruption

SD-OCT

Spectral domain optical coherence tomography

SLE

Systemic lupus erythematosus

UVB

Ultraviolet B

Introduction

The antimalarial drugs that have been used for the treatment of dermatologic disorders include hydroxychloroquine (HCQ), chloroquine (CQ), and quinacrine. Quinacrine was taken off the market, but compounding pharmacies in the United States are able to provide the drug for individual patients. However, in some instances quinacrine may become inaccessible to patients because their insurance carrier does not recognize it as a pharmacologic entity. In addition, the prescribing physician needs to be aware that there is no approved use for quinacrine in humans at this time. The most commonly used antimalarials (HCQ and CQ) are 4-aminoquinolines ( Table 21.1 ) and derivatives of quinine, a naturally occurring substance. Quinine is an alkaloid derived from the bark of the South American cinchona tree. This bark is believed to have been used initially for its antipyretic effects, and so the cinchona tree has also become known as the ‘fever’ tree. In the 1800s, quinine became popular as an effective antimalarial agent. Interestingly, quinine in unextracted form was first used in 1631 to treat malaria in Rome, which was endemic in the 17th century due extensive swamps and marshes around the city.

Table 21.1

Antimalarial Agents

Generic Name	Trade Name	Manufacturer	Tablet/Capsule Sizes (mg)	Standard Dosage Range	Pricing (dated Jul 2019)
Hydroxychloroquine HCl	Plaquenil	Sanofi-Aventis or generic	200 mg (scored)	200–400 mg/day or 6.5 mg/kg per day	US$35.99 for 60 tablets (generic) US$204.33 brand name
Chloroquine phosphate (oral only) or HCl	Aralen or generic	Sanofi-Aventis or generic	500 mg (scored) or 250 mg (generic)	250–500 mg/day or 3 mg/kg per day	250 mg 30 tablets US$70.99 500 mg 25 tablets US$196.37
Quinacrine HCl	Must be compounded	None	100 mg ^a	100–200 mg/day	Varies

a Historically available size; now requires special order.

World War I provided the impetus for the synthetic production of antimalarials. Quinacrine hydrochloride was synthesized in 1930, chloroquine phosphate in 1934, and hydroxychloroquine sulfate in 1946. The initial dermatologic use of antimalarials is attributed to Payne’s use of quinine in lupus erythematosus (LE) in 1894. In 1951, Page used quinacrine to treat cutaneous LE.

Pharmacology

Table 21.2 lists key pharmacologic concepts for antimalarial agents.

Table 21.2

Pharmacology Key Concepts—Antimalarial Agents

Name	Absorption and bioavailability			Elimination
Name	Peak Effect (hour)	Bioavailable (%)	Protein Binding (%)	Half-Life (days)	Metabolism	Excretion
Hydroxychloroquine	4	74	45	40–50	Desethylchloroquine and desethylhydroxychloroquine metabolites	20% excreted unchanged in urine; also biliary excretion
Chloroquine	5	50	50–65	40–50	Desethylchloroquine is metabolite	42%–47% excreted unchanged in urine
Quinacrine	1–3	100	80	5–14	None	Urine, bile, sweat, saliva

Structure

Most antimalarials are substituted 4-aminoquinolines. Quinacrine has an extra benzene ring and is considered an acridine compound. Drug structures for HCQ and CQ are shown in Figure 21.1 .

Absorption and Bioavailability

Antimalarials are bitter, water-soluble, crystalline powders that are absorbed rapidly and completely from the gastrointestinal (GI) tract. Maximal plasma levels of quinacrine are achieved within 1 to 3 hours after ingestion. These drugs bind avidly to tissue proteins; therefore, the concentrations are highest in liver, spleen, and kidney tissues, especially in nuclei and mitochondria.

Various single- and repeated-dosage regimens for HCQ and CQ yield nearly identical plasma level curves with peaks at 4 and 5 hours, respectively. Distributions of the two drugs in tissue are qualitatively similar; the lowest concentrations are found in bone, skin, fat, and brain tissues and greater concentrations (in ascending order) in muscle, eye, heart, kidney, liver, lung, spleen, and adrenal gland tissues. The absolute amounts are 2.5 times higher for CQ than for HCQ. It is possible for some tissues to accumulate concentrations of these 4-aminoquinolines several hundred times the concentrations in plasma.

Metabolism and Excretion

The major pathway of biotransformation is not known, but alterations must be extensive. About half of a daily dose of CQ is excreted unchanged in the urine, and smaller amounts are detected in feces, sweat, breast milk, saliva, and bile.

The terminal half-lives of CQ and HCQ are similar, at 40 to 50 days. These long half-lives are attributed to extensive tissue uptake and slow release into circulation. The attainment of steady-state concentrations in 3 to 4 months may account for the slow appearance of therapeutic benefit. Because the half-life of HCQ varies between 40 to 50 days, it might be detected in whole blood up to 5 months after a single dose.

Their metabolisms differ in one respect: CQ breaks down into one first-stage metabolite (desethylchloroquine) and HCQ breaks down into two metabolites (desethylhydroxychloroquine and desethylchloroquine). The first-stage desethyl compounds break down in turn to the primary amine metabolite.

There is also a difference in the relative amounts of drug excreted in urine and feces. After a single dose, approximately three times more CQ than HCQ can be accounted for in urine, and three times more HCQ than CQ can be accounted for in feces. The data suggest that HCQ forms an ether glucuronide that is excreted in bile. The low proportion (roughly 20%) of unchanged HCQ eliminated by the kidneys indicates that no dosage adjustment is necessary for patients with mild-to-moderate renal function impairment.

Mechanism of Action

The exact mechanism by which antimalarials act to affect various diseases is not fully understood. Q21.1 Among the postulates for the mechanism of action are effects on (1) light filtration, (2) immunosuppressive actions, (3) anti-inflammatory actions, (4) antiproliferative effects through an inhibition of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) biosynthesis, (5) antiviral effects, (6) inhibition of thrombocyte aggregation, and (7) reductions of lipid and vitamin D levels. Explanations for these possible mechanisms are discussed later.

Effects on Photosensitivity Dermatoses

Antimalarials inhibit ultraviolet-induced cutaneous reactions in LE and polymorphous light eruption (PMLE), perhaps through their effects on prostaglandin metabolism, inhibition of superoxide production, or their ability to bind to DNA. Nguyen and colleagues suggest that 4-aminoquinolone antimalarials enhanced ultraviolet B (UVB)-induced factors involved in protection against UV-induced damage.

Immunosuppressive Effects

Antimalarial compounds raise intracytoplasmic pH levels, stabilize the microsomal membrane and disrupt proper endosomal maturation, thus blocking Toll-like receptor interactions with ligands, including nucleic acids. This can result in a decreased ability of macrophages to express major histocompatibility complex antigens on the cell surface. Fox and Kang demonstrated a dose-dependent inhibition of the release of interleukin (IL)-2 from a CD4+ T-cell clone by both CQ and HCQ. Antimalarials may inhibit the formation of antigen–antibody complexes through their inhibition on Toll-like receptor induction of type I interferons. They have also been shown to reduce lymphocyte responsiveness to mitogens in vitro.

Anti-inflammatory Effects

Anti-inflammatory effects of antimalarials may also be an important factor in their action. Antimalarials have been noted to reduce lysosomal size and might possibly inhibit their function. These drugs also impair chemotaxis of various inflammatory cells.

Other Mechanisms Of Action

An additional effect that may be of importance is the ability of antimalarials to inhibit platelet aggregation and adhesion, thereby inhibiting thrombus formation. Multiple reports have demonstrated fewer thromboembolic events in patients with LE and antiphospholipid antibody syndrome when treated with antimalarial therapy. There are also reports documenting lower lipid levels. The effects on cholesterol might be enhanced in patients with LE who are also on corticosteroid (CS) therapy. Other studies have suggested a decrease in cholesterol and possible protection from coronary artery disease in patients with systemic LE (SLE) on prednisone. Finally, Ornstein and Sperber noted antiviral effects, as demonstrated by a modest decrease in human immunodeficiency virus (HIV) load.

Clinical Use

Box 21.1 lists indications for antimalarials whereas the ‘Risk Profile’ of antimalarials ( Box 21.2 ) lists contraindications.

Box 21.1

Antimalarials Indications

US Food and Drug Administration-Approved Indications

Lupus erythematosus (in selected cases)

Nondermatologic Indications of Interest Include:

Malaria (all three antimalarials)
Rheumatoid arthritis (hydroxychloroquine)

Off-Label Dermatologic Uses

Photosensitivity Dermatoses

Porphyria cutanea tarda
Polymorphous light eruption (PMLE)
Solar urticaria
Dermatomyositis (cutaneous features)

Granulomatous Dermatoses

Sarcoidosis
Granuloma annulare (generalized)
Other granulomatous dermatoses

Lymphocytic Infiltrates – Benign

Lymphocytoma cutis
Lymphocytic infiltrate of Jessner
Panniculitis
Panniculitis (idiopathic)
Chronic erythema nodosum
Lupus panniculitis

Other Dermatoses

Oral lichen planus
Chronic ulcerative stomatitis
Reticular erythematous mucinosis
Pemphigus foliaceus
Atopic dermatitis
Urticarial vasculitis
Vasculitis
Localized scleroderma
Chronic graft-versus-host disease
Follicular mucinosis
Psoriatic arthritis

Box 21.2

Drug Risks Profile—Antimalarials (Hydroxychloroquine)

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. Accessed May 20, 2018 ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).

Contraindications
Known hypersensitivity to HCQ, 4-aminoquinolines, or components of formulation
Boxed Warnings
None listed
Warnings & Precautions ^a
Ocular ^a Retinal toxicity, potentially irreversible, esp. high doses, duration >5 years, renal impairment (concomitant tamoxifen) ^a Current AAO guidelines limit HCQ to 5 mg/kg/da Cutaneous ^a Use with caution in psoriasis patients ^a Use with tremendous caution in patients with porphyrias ^a Morbilliform/exanthematous reactions common Neurologic/Neuromuscular Proximal myopathy, neuromyopathy rarely with long-term treatment Psychiatric Suicides rarely reported	Cardiovascular Cardiomyopathy (AV block, sick sinus syndrome, QT prolongation, etc.) GI ^a Caution with use GI disorders, commonly induces nausea Hematologic Effects ^a Bone marrow suppression reported—agranulocytosis, anemia, aplastic anemia, thrombocytopenia, leukopenia Suggest periodic CBC monitoring with long-term therapy Metabolic Severe hypoglycemia possible (including without DM treatment)
Pregnancy Prescribing Status
Traditional US Food and Drug Administration rating —category C	Newer rating ^b —probably compatible

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 Food and Drug Administration rulings.

AAO, American Academy of Ophthalmology; AV, atrioventricular; CBC, complete blood count; DM, diabetes mellitus; HCQ, hydroxychloroquine.

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