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Antimalarials
Antimalarials Frank C. Koranda, M.D. Iowa City, fA The antimalarials, chloroquine, hydroxychloroquine, and quinacrine, are used primarily for malaria; but they can be beneficial for cutaneous lupus erythematosus (LE), polymorphous light eruption, solar urticaria, and porphyria cutanea tarda. Antimalarials bind to deoxyribonucleic acid (DNA) which prevents DNA and ribonucleic acid (RNA) polymerase reactions and DNA heat inactivation; and they inhibit the LE cell phenomenon, antinuclear antibody reactions, and suppress lymphocyte transformation. By competing with calcium ion, they stabilize membranes and have an anesthetic effect. Their anti-inflammatory potential is due to their inhibition of hydrolytic enzymes, stabilization of lysosomes, interference with prostaglandin synthesis, blocking of chemotaxis. and antagonism of histaminic responses. The antimalarials have no sunscreening properties. The most common toxic effects are cutaneous pigmentation, nausea, vomiting, diarrhea, mild ileus, and cycloplegia. There has been a reluctance to use chloroquine and hydroxychloroquine because of the possibility of retinopathy. However, if the "safe" daily dose limit of chloroquine, 2 mg per pound of body weight, and of hydroxychloroquine, 3.5 mg per pound of body weight, is followed, the chance of retinopathy is slight. Quinacrine does not cause retinopathy, but it has more cutaneous side effects than the other two agents. (J AM ACAD DERMATOL 4:650-655, 1981.)
Discoid lupus erythematosus (DLE) was first treated with an antimalarial, quinine, in 1894 by Payne' of Great Britain. In 1928, Martenstein'' used pamaquine (Plasmochin) for DLE. In 1940, Prokoptchouk" noted good results with quinacrine (Atabrine) in thirty-five patients with DLE. However, it was Page's report in 195 I ~ on the effectiveness of quinacrine for OLE that established a nonmalarial use for these drugs. Page also observed that in three of his lupus patients with rheumatoid arthritis there was improvement of both conditions. The antimalarials, quinacrine (Atabrine), chloFrom the University of Iowa College of Medicine. Reprintrequeststo: Dr. Frank C. Koranda. University of Iowa Hospital, Department of Dermatology, Iowa City, IA 52242.
650
roquine (Aralen), and hydroxychloroquine (Plaquenil), are beneficial for a number of cutaneous diseases. However, the potential for irreversible retinopathy from chloroquine and hydroxychloroquine has tempered earlier enthusiasm. CHEMISTRY AND METABOLISM The basic chemical structure of chloroquine and hydroxychloroquine is the 4-aminoquinolone nucleus (Fig. 1). Quinacrine differs in that it has an extra benzene ring, making it an acridine compound. However, the 4-aminoquinolone nucleus is still the underlying structure of all antimalarials. The antimalarials are bitter to taste, watersoluble, and readily and almost completely absorbed from the gastrointestinal tract even in the presence of diarrhea. They reach a maximum 0190-9622/81/060650+06$00.60/0 © 1981 Am Acad Dermatol
Volume 4 Number 6 June, 1981
plasma concentration within 8 to 12 hours. 5 However, the plasma concentration remains low (90 to 170 /Lg/dl), whereas tissue levels are high, 200 to 20,000 times plasma, depending upon the tissue. The antimalarials have an affinity for the liver, spleen, lungs, adrenals, skin, white blood cells, and a particular affinity for the pigment epithelium of the eye. For chloroquine and hydroxychloroquine, it usually takes 3 to 4 weeks to reach a plasma-tissue equilibrium. For quinacrine, it may take up to 3 months. The metabolism of the antimalarials is not well defined. They are excreted mainly through the kidneys. Excretion is very slow and may be accelerated by acidification of the urine. There have been detectable levels of chloroquine in the urine 5 years after taking the drug."
Antimalarials
651
CI'fY~
0v HN -
CH-(CH 2) 3N(C 2 H al2
I
CH 3
Chloroquine (Aralen)
Modes of action The antimalarials have a wide and overlapping range of action. Although they have been used for 30 years for lupus erythematosus, rheumatoid arthritis, and other conditions, the precise reasons for their efficacy have not been determined. Interactions with nucleic acids. Antimalarials readily combine with DNA. The antimalarialDNA complex retards DNA and RNA polymerase reactions and inhibits DNA replication and transcription to RNA. 7 This interference with RNA and DNA biosynthesis, which interrupts protein synthesis, may be the basis for the antibacterial and antimalarial effects of these drugs. ChloroquineDNA binding also protects DNA against heat denaturation. Dubois" demonstrated that the in vitro addition of quinacrine to LE sera and white cells would suppress the LE cell phenomenon. Chloroquine in vitro has also been shown to inhibit the LE cell phenomenon, antinuclear antibody reactions, and rheumatoid factor. 9 These observations suggest that antimalarial-DNA binding may alter the DNA antigenicity and prevent it from complexing with antibody. If this mechanism does occur in vivo, such a disruption of immune complex formation could prevent complement activation. Immunologic. Lymphocyte transformation can be suppressed by chloroquine; the number of circulating T cells in DLE patients is decreased, and
Quinacrine (Atabrine, Mepacrine)
Fig. 1. Structural formulas for chloroquine (Aralen), hydroxychloroquine (Plaquenil), and quinacrine (Atabrine, rneparacrine).
in vitro complement-mediated hemolysis is inhibited. l o - 12 However, the antimalarials have no suppressive effect on primary or secondary antibody stimulation .13 Anesthetic. The antimalarials stabilize membranes, the outer cellular membrane, sarcoplasmic reticulum, and mitochondrial membranes, by competing with calcium ion for binding sites. 14 This competitive blocking prolongs the duration and reduces the amplitude of the membrane action potential and thus produces a local anesthetic effect. This anesthetic effect may be responsible for the depressant effect on cardiac muscle and the muscles in the gut, arteries, trachea, and ciliary body. Anti-inflammatory. Chloroquine has been demonstrated to be a lysosomal stabilizer, but the mechanism is unknown.w'" Independent of lysosomal stabilization, the antimalarials inhibit hydrolytic enzymes and some other enzymes.!? Chloroquine can function as a prostaglandin antagonist by impeding prostaglandin biosynthesis. I!! Another possible anti-inflammatory mechanism is
652
Koranda
chemotaxis inhibition. Chloroquine decreases neutrophil, macrophage, and eosinophil chemotaxis and neutrophil phagocytosis. 19.20 Chloroquine retards histamine-induced guinea pig ileum contraction and decreases the pulmonary histamine content in rats. 21,22 This antihistaminic effect has been applied by treating bronchial asthma with chloroquine, but this is not a standard usage.F' Other properties. Hydroxychloroquine has been shown to decrease sludging of erythrocytes and to inhibit platelet aggregation.Pv'" Although antimalarials are used to treat various photosensitive dermatoses, there is no evidence that they have any sunscreening or sun-absorptive properties.f"
Toxicity The potential toxic effects of the antimalarials are as numerous as the modes of action. The lethal dose for an adult is 3 to 6 gm of chloroquine. For a child, 1 gm may be lethal. The acute symptoms are weakness, dyspnea, difficulty in swallowing, hoarseness, hypotension, tremors, coma, and convulsions, followed by cardiopulmonary arrest. Treatment is with the necessary life support measures and acidification of the urine or the administration of dimercaprol (BAL) to increase elimination of the drug." Cutaneous. Lemon-yellow discoloration of the skin is a unique hallmark for quinacrine. Even at a minimum daily dosage of 100 mg, 36% of patients will be affected.P The sclera as well as the skin may be discolored, and there may be confusion with icterus. Bilirubin levels are normal. Quinacrine, chloroquine, and hydroxychloroquine may produce graying of the scalp hair, beard, eyelashes, and eyebrows. This is a reversible effect. The incidence of this graying has decreased with the lower doses of the drugs which are presently used. All three drugs may cause a bluish-black, ecchymosis-like pigmentation of the pretibia, palate, face, and nail beds. This pigmentation disappears slowly after stopping the drug. The pigmentation of the hard palate occurs in 25% of patients on long-term chloroquine therapy. The pigmentation of the nail beds may be diffuse or may occur as transverse bands. Lichenoid dermatitis, urticaria, exfoliative
Journal of the American Academy of Dermatology
erythroderma, and exacerbation of psoriasis have been reported with all three drugs. Squamous cell carcinomas of the palms have recently been observed in Australian veterans who had a severe lichenoid reaction from prophylactic quinacrine during World War IU 9 Gastrointestinal and neuromuscular. Although nausea and vomiting may occur, this can usually be controlled by decreasing the dosage or switching to another antimalarial. These symptoms are more frequent with chloroquine than with hydroxychloroquine. Other common symptoms are diarrhea, sweating, pruritus, headache, and insomnia. All of these drugs have been reported to cause psychoses and seizures, but these effects were usually associated with higher dosages than are currently prescribed.Pv" The antimalarials may lead to vacuolar myopathy with a myasthenia gravis-type condition.32.33 This is a rare, probably idiosyncratic, and usually reversible reaction. Cardiac conduction blocks, T-wave depression and inversion, and depressed cardiac muscle response have been noted. 34.35 Because of the muscle depressant effect, patients may develop symptoms of mild ileus, cycloplegia, and presbyopia after starting therapy. Accommodation to these symptoms usually takes place after a few weeks of treatment. Hematologic. All of the antimalarials are capable of inducing a severe leukopenia. This leukopenia may be more frequent in the first 3 months of treatment, but it may occur later. Quinacrine has also been observed to produce an aplastic anemia. During World War II when quinacrine 100 mg daily was used for malaria chemoprophylaxis, the incidence of aplastic anemia was 2.84 per 100,000 males per year. Although caution is advised in patients with a glucose-6-phosphate dehydrogenase deficiency (G6PD), G6PD hemolysis seems to be a problem only with primaquine. Teratogenic. Chloroquine does cross the placenta and concentrates in fetal tissues. 35 Congenital defects such as deafness, mental retardation, and convulsions have occurred in the newborn of women who received chloroquine during pregnancy.36.:37 Ocular. In the initial stages of therapy, all three drugs may cause blurring of vision and!or double
Volume 4 Number 6 June, 1981
vision. This is due to the depressant effect on the muscles and usually passes with time or with a decrease in dose. Both chloroquine and hydroxychloroquine may be deposited in the cornea. These deposits are visible with slit lamp examination. Although they are usually asymptomatic, they can produce the sensation of seeing halos about alight. 38 These deposits are dose-related, reversible, and are not a contraindication to continued use. The distressing ocular complication is irreversible retinopathy which may be progressive even after cessation of treatment. Both chloroquine and hydroxychloroquine have been implicated. Because chloroquine was more widely used than hydroxychloroquine and often used at greater equivalent dosages (Table I), retinopathy has been more commonly associated with it than with hydroxychloroquine. There is a common clinical perception that hydroxychloroquine may be less retinotoxic, but there is no absolute evidence that this is so. Due care must be exercised with both drugs. The retinopathy is dose-related. Most of the cases have occurred after a total cumulative dose of 200 gm, and it is written that this total dose should not be exceeded. But based on a series of 928 patients, Mackenzie'" proposed that the occurrence of retinopathy is primarily related to exceeding a maximum daily dose rather than to the total dose or to the duration of therapy. The "safe" daily dose for chloroquine is 2 mg per pound of body weight, and for hydroxychloroquine, 3.5 mg per pound of body weight." If higher daily doses are administered, the antimalarials may not be able to be excreted and may accumulate to a retinotoxic level. Chloroquine and hydroxychloroquine may somehow block the light energy absorbing function of retinal melanin which may contribute to the retinopathy.w" Therefore, discontinuing the drug for 2 months in the summer, if the disease condition permits, and the wearing of sunglasses that decrease light transmission by 50% may be prophylactic. Two other hypotheses for the retinopathy are that the binding of the drug to the retinal pigment epithelium inhibits protein synthesis with a resultant destruction of the rods and the cones and that
Antimalarials
653
Table I. Equivalent and usual doses of antimalarials Antimalarial
Equivalent doses
Usual daily doses
Chloroquine Hydroxychloroquine Quinacrine
250 mg 400 mg 100 mg
250 mg 400 mg 100 mg
prolonged lysosomal stabilization leads to dysfunction of the Iysosomes with ensuing retinal damage.v"" A baseline ophthalmologic examination and follow-up eye examinations every 4 to 6 months are indicated. Funduscopy combined with red testingof central fields have been reported to be the most sensitive means of recognizing chloroquine and hydroxychloroquine toxicity at a reversible premaculopathy stage. 45 However, the red testing of central fields is not easily done, and many ophthalmologists do not agree that it has any particular value over funduscopy and other more standard tests. 46 Electro-oculography, electroretinography, and angiography do not seem to have any special advantage for early detection of retinopathy.v":" With funduscopy, the earliest changes are irregular macular pigmentation and loss of foveal reflex. However, these same changes can occur in senile macular atrophy, which may begin between the ages of 50 and 60 years. 46 Systemic lupus erythematosus may itself produce retinal changes similar to those of chloroquine toxicity. 50 It has also been proposed that lupus erythematosus patients are more susceptible to the retinopathy than are rheumatoid arthritis patients. 51 The funduscopic picture of the bull's-eye macular lesion is the classic form of advanced chloroquine toxicity, but it is not pathognomonic since it, too, may occur in other diseases. 52 Although quinacrine does not cause retinopathy, a baseline ophthalmologic examination is still prudent. CLINICAL APPLICATIONS AND GUIDELINES
Rheumatoid arthritis is the only disease for which there is double-blind evidence of the moderate effectiveness of antimalarials. However,
Journal of the American Academy of Dermatology
654 Koranda
there is other good, reliable documentation for their use in cutaneous lupus erythematosus, polymorphous light eruption, solar urticaria, and porphyria cutanea tarda. As with most drugs, there are anecdotal reports citing their application in a variety of other diseases. Antimalarials are indicated for cutaneous lupus erythematosus when it is unresponsive to topical and intralesional corticosteroids and is an ongoing, progressive, destructive process. Once the disease is under control, gradual decreasing of the dosage should be attempted. It may be possible to discontinue the drug for the winter months or for more prolonged periods. When antimalarials are used for solar urticaria and for polymorphous light eruption, they should be used only during active phases of the disease and tapered off as remission occurs. Various dose schedules have been used. Over recent years lower dosages for all diseases have become prevalent. For an average-weight (150pound) individual, the "safe" daily limit for chloroquine would be about 250 mg and for hydroxychloroquine, 400 mg. While this is a lesser dose than some recommended schedules and while it may not always be the optimal therapeutic dose, it is a "safe" upper limit to prevent retinopathy. If the patient cannot tolerate or does not respond to one of the drugs, the other should be tried. Both chloroquine and hydroxychloroquine should not be used together since their retinal effects are additive. However, quinacrine can be used alone or can be used with either of the other drugs. The usual daily dose of quinacrine is 100 mg, but the starting dose is often 100 mg three times a day. This starting dose is gradually decreased as the disease comes under control. Chloroquine is efficacious for porphyria cutanea tarda since it forms a stable complex with porphyrins, leading to a marked porphyrinuria and a remission. 53 When it was first used for this disease, in doses of 250 mg to 1,000 mg per day for 4 to 7 days, there would be a severe toxic reaction of fever, nausea, vomiting, myalgia, abdominal pain, and toxic hepatitis. 54 These toxic effects may be avoided with low-dose chloroquine treatment of 125 mg 2 to 3 times a week for 6 to 18 months. 55 Another treatment plan to obviate toxic
effects requires one to four plebotomies followed by 250 mg chloroquine daily for a week. 56 Prior to therapy with antimalarials, the following baseline studies should be accomplished: 1. Ophthalmologic examination 2. Complete blood count 3. Glucose-6-phosphate dehydrogenase (although the three antimalarials reviewed do not seem to cause a G6PD deficiency hemolysis, the pharmaceutical warnings with these drugs still caution care in patients with G6PD deficiency) 4. 24-hour urine sample for uroporphyrins and coproporphyrins to rule out an underlying porphyria cutanea tarda, if clinically indicated 5. BUN, creatinine, and liver function tests
At 4- to 6-month intervals, follow-up eye examinations should be performed. For the first 3 months, complete blood counts are done monthly, and thereafter, every 4 to 6 months. The antimalarials are efficacious drugs for the conditions cited and can be used with limited risks if the guidelines and' 'safe" dosage schedules are followed. REFERENCES I. Payne JF: A postgraduate lecture on lupus erythematosus. Clin J 4:223-229, 1894. 2. Martenstein H: Subacute lupus erythematosus and tubercular cervical adenopathy. Treatment with plasmochin. Z Hautkr 27:248-249, 1928. 3. Prokoptchouk AJ: Treatment of lupus erythematosus with acridine. Z Hautkr 66:112, 1940. (Abst.) 4. Page F: Treatment of lupus erythematosus with mepacrine. Lancet 2:755-758,1951. 5. Rubin M, Zvaifier NJ: The metabolism of chloroquine. Clin Res 10:22, 1962. (Abst.) 6. Rubin M, Bernstein NH, Zvaifier NJ: Studies on the pharmacology of chloroquine: Recommendations for the treatment of retinopathy. Arch Ophthalmol 70:474-481, 1963. 7. Yielding LW, Yielding KL: Nucleic acid structural requirement for binding of chloroquine. Ala J Med Sci 10:403-409, 1973. 8. Dubois EL: Effect of quinacrine (Atabrine) upon lupus erythematosus phenomenon. Arch Dermatol 71:570574, 1955. 9. Bencze G, Johnson GD: Inhibition of antinuclear factor reaction by chloroquine. Immunology 9:201-202, 1965. 10. Hurvitz D, Hirschhorn K: Suppression of in vitro lymphocyte response by chloroquine. N Engl J Med 273:23-26, 1965. II. Szegedi G: Studies on T and B lymphocytes in the peripheral blood of discoid lupus erythematosus patients with and without chloroquine treatment. Acta Derm Venereol (Stockh) 56:47, 1976.
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12. Stollar D, Levine L: The reaction between L.E. serum and denatured DNA: Inhibition by haptenes and chloroquine. Arthritis Rheum 5:660, 1962, (Abst.) 13. Kalmanson GM, Guze LB: Studies on the effects of hydroxychloroquine on immune responses. J Lab Clin Med 65:484-489, 1965. 14. Manku MS, Horrobin DF: Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants and methylxanthines as prostaglandin agonists and antagonists. Lancet 2:1115-1117,1976. 15. Lie SO, Schofield B: Inactivation of lysosomal function in normal cultured human fibroblasts by chloroquine, Biochem Pharmacol 22:3109-3114, 1973. 16. Weissmann G: Labilization and stabilization of lysosomes. N Engl J Med 273: 1143-1149, 1965. 17. Sams WM Jr: Chloroquine: Mechanism of action. Mayo Clinic Proc 42:300-309, 1967. 18. Greaves MV, McDonald-Gibson W: Effect of nonsteroid anti-inflammatory and antipyretic drugs on prostaglandin biosynthesis by human skin. J Invest Dermatol 61: 127129, 1973. 19. Ward PA: The chemosuppression of chemotaxis. J Exp Med 124:209-225, 1966. 20. Gauderer CA, Gleich GJ: Inhibition of eosinophilotaxis by chloroquine and corticosteroids. Proc Soc Exp BioI Med 157:129-134,1978. 21. Deshpande VR, Sharma ML, Dashputra PG: Antihistaminic action of antimalarials. Indian J Physiol Pharmacol 7:259-266, 1963. 22. Agarwal SL, Deshmankar BS, Bhargava V: Chloroquine in bronchial asthma. J Pharm Pharmacol 15:693, 1963. (Letter.) 23, Ciszek J, Walczak J: Treatment of bronchial asthma with chloroquine. Polish Med J 10: 1125-1 130, 1970. 24, Cecchi E, Ferraris E: Desludging action of hydroxychloroquine in rheumatoid arthritis. Acta Rheum Scand8:214-22I,1962. 25. Carter AE, Eban R, Perrott RD: Prevention of postoperative deep venous thrombosis and pulmonary embolism. Br Med J 1:312-314,1971. 26. Sams WM Jr, Carroll NY: The "spectral shift" phenomenon of chloroquine. Arch Dermatol 93:123-128, 1966. 27. Zvaifler NJ: Antimalarial treatment of rheumatoid arthritis. Med Clin North Am 52:759-764, 1968, 28. Dubois EL: Antimalarials in the management of discoid and systemic Iupus erythematosus. Semin Arthritis Rheum 8:33-51, 1978. 29. Bauer F: Late sequelae of atabrine dermatitis-a new premalignant entity. Aust J Dermatol 19:9-12, 1978. 30. Torrey EF: Chloroquine seizures: Report of four cases. JAMA 204:867-870, 1968. 31. Sapp OL III: Toxic psychosis due to quinacrine and chloroquine. JAMA 187:373-375, 1964. 32. Eadie MI, Ferrier TM: Chloroquine myopathy. J Neurol Neurosurg Psychiatry 29:331-337, 1966. 33. Whisnant JP, Espinosa RE, Kierland RR: Chloroquine neuromyopathy. Mayo Clin Proc 38:501-513, 1963. 34. Alving AS, Eichelberger L, Craige B Jr: Studies on the chronic toxicity of chloroquine. J Clin Invest 27:60-65, 1948. 35. Ullberg S, Lindquist NG, Sjostrand SE: Accumulation of
Antimalarials 655
36. 37. 38.
39. 40.
41. 42.
43.
44.
45.
46.
47. 48.
49. 50. 51.
52.
53.
54.
55.
56.
chorioretinotoxic drugs in the foetal eye. Nature 227: 1257-1258, 1970. Lewis R, Laversen NH, Birnbaum S: Malaria associated with pregnancy. Obstet Gynecol 42:696-700, 1973. Hart CW, Naunton RF: The ototoxicity of chloroquine phosphate. Arch Otolaryngol 80:407-412, 1964. Calkins LL: Corneal epithelial changes observed during chloroquine therapy. Arch OphthalmoI 60:981-988, 1958. Mackenzie AH: An appraisal of chloroquine. Arthritis Rheum 13:280-291, 1970. Mackenzie AH, Szilagy PJ: Light may provide energy for retinal damage during chloroquine treatment. Arthritis Rheum 11:496, 1968. (Abst.) Rubin M, Slonicki A: A mechanism for the toxicity of chloroquine. Arthritis Rheum 9:537, 1966, (Abst.) Gonasun LM, Potts AM: In vitro inhibition of protein synthesis in the retinal pigment epithelium by chloroquine. Invest Ophthalmol 13: 107- Il5, 1974, Meier-Ruge W: Experimental investigation of the morphogenesis of chloroquine retinopathy. Arch Ophthalmol 73:540-544, 1965. Solze DA, McConnell DG: Ultrastructural changes in rat photoreceptor inner segment during experimental chloroquine retinopathy. Ophthalmol Res 1:140-148, 1970. Percival SPB, Meanock 1: Chloroquine: Ophthalmological safety, and clinical assessment in rheumatoid arthritis. Br Med J 3:579-584, 1968. Elman A, Gullberg R, Nilsson E, et al: Chloroquine retinopathy in patients with rheumatoid arthritis. Scand J Rheumatol 5:161-166, 1976, Bernstein HN: Cloroquine ocular toxicity. Surv Ophthalmol 12:415-447, 1967. Sassaman FW, Cassidy JT, Alpern M: Electroretinography in patients with connective tissue diseases treated with hydroxychloroquine. Am J OphthalmoI70:515-523, 1970. Percival SPB, Behrman J: Ophthalmological safety of chloroquine. Br J Ophthalmol 53: 101-109, 1969. Dubois EL, editor: Lupus erythematosus. Los Angeles, 1976, USC Press, pp. 323-326. Scherbel AL, Mackenzie AH, Nousek JE, et al: Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy: Study of 741 patients treated with and without chloroquine. N Engl J Med 273:360-366, 1965. Weise E, Yannuzzi LA: Ring maculopathies mimicking chloroquine retinopathy. Am I Ophthalmol 78:205-210, 1974. Scholnick PL, Epstein J, Marver HS: The molecular basis of action of chloroquine in porphyria cutanea tarda. J Invest Dermatol 61:226-232, 1973. Kowertz MJ: The therapeutic effect of chloroquine hepatic recovery in porphyria cutanea tarda. JAMA 223:515-519, 1973. Kordac V, Semradova M: Treatment of porphyria cutanea tarda with chloroquine. Br J Dennatol 90:95-100, 1974. Swanbeck G, Wennersten G: Treatment of porphyria cutanea tarda with chloroquine and phlebotomy. Br J Dermatol97:77-81, 1977.
Discoid lupus erythematosus (DLE) was first treated with an antimalarial, quinine, in 1894 by Payne' of Great Britain. In 1928, Martenstein'' used pamaquine (Plasmochin) for DLE. In 1940, Prokoptchouk" noted good results with quinacrine (Atabrine) in thirty-five patients with DLE. However, it was Page's report in 195 I ~ on the effectiveness of quinacrine for OLE that established a nonmalarial use for these drugs. Page also observed that in three of his lupus patients with rheumatoid arthritis there was improvement of both conditions. The antimalarials, quinacrine (Atabrine), chloFrom the University of Iowa College of Medicine. Reprintrequeststo: Dr. Frank C. Koranda. University of Iowa Hospital, Department of Dermatology, Iowa City, IA 52242.
650
roquine (Aralen), and hydroxychloroquine (Plaquenil), are beneficial for a number of cutaneous diseases. However, the potential for irreversible retinopathy from chloroquine and hydroxychloroquine has tempered earlier enthusiasm. CHEMISTRY AND METABOLISM The basic chemical structure of chloroquine and hydroxychloroquine is the 4-aminoquinolone nucleus (Fig. 1). Quinacrine differs in that it has an extra benzene ring, making it an acridine compound. However, the 4-aminoquinolone nucleus is still the underlying structure of all antimalarials. The antimalarials are bitter to taste, watersoluble, and readily and almost completely absorbed from the gastrointestinal tract even in the presence of diarrhea. They reach a maximum 0190-9622/81/060650+06$00.60/0 © 1981 Am Acad Dermatol
Volume 4 Number 6 June, 1981
plasma concentration within 8 to 12 hours. 5 However, the plasma concentration remains low (90 to 170 /Lg/dl), whereas tissue levels are high, 200 to 20,000 times plasma, depending upon the tissue. The antimalarials have an affinity for the liver, spleen, lungs, adrenals, skin, white blood cells, and a particular affinity for the pigment epithelium of the eye. For chloroquine and hydroxychloroquine, it usually takes 3 to 4 weeks to reach a plasma-tissue equilibrium. For quinacrine, it may take up to 3 months. The metabolism of the antimalarials is not well defined. They are excreted mainly through the kidneys. Excretion is very slow and may be accelerated by acidification of the urine. There have been detectable levels of chloroquine in the urine 5 years after taking the drug."
Antimalarials
651
CI'fY~
0v HN -
CH-(CH 2) 3N(C 2 H al2
I
CH 3
Chloroquine (Aralen)
Modes of action The antimalarials have a wide and overlapping range of action. Although they have been used for 30 years for lupus erythematosus, rheumatoid arthritis, and other conditions, the precise reasons for their efficacy have not been determined. Interactions with nucleic acids. Antimalarials readily combine with DNA. The antimalarialDNA complex retards DNA and RNA polymerase reactions and inhibits DNA replication and transcription to RNA. 7 This interference with RNA and DNA biosynthesis, which interrupts protein synthesis, may be the basis for the antibacterial and antimalarial effects of these drugs. ChloroquineDNA binding also protects DNA against heat denaturation. Dubois" demonstrated that the in vitro addition of quinacrine to LE sera and white cells would suppress the LE cell phenomenon. Chloroquine in vitro has also been shown to inhibit the LE cell phenomenon, antinuclear antibody reactions, and rheumatoid factor. 9 These observations suggest that antimalarial-DNA binding may alter the DNA antigenicity and prevent it from complexing with antibody. If this mechanism does occur in vivo, such a disruption of immune complex formation could prevent complement activation. Immunologic. Lymphocyte transformation can be suppressed by chloroquine; the number of circulating T cells in DLE patients is decreased, and
Quinacrine (Atabrine, Mepacrine)
Fig. 1. Structural formulas for chloroquine (Aralen), hydroxychloroquine (Plaquenil), and quinacrine (Atabrine, rneparacrine).
in vitro complement-mediated hemolysis is inhibited. l o - 12 However, the antimalarials have no suppressive effect on primary or secondary antibody stimulation .13 Anesthetic. The antimalarials stabilize membranes, the outer cellular membrane, sarcoplasmic reticulum, and mitochondrial membranes, by competing with calcium ion for binding sites. 14 This competitive blocking prolongs the duration and reduces the amplitude of the membrane action potential and thus produces a local anesthetic effect. This anesthetic effect may be responsible for the depressant effect on cardiac muscle and the muscles in the gut, arteries, trachea, and ciliary body. Anti-inflammatory. Chloroquine has been demonstrated to be a lysosomal stabilizer, but the mechanism is unknown.w'" Independent of lysosomal stabilization, the antimalarials inhibit hydrolytic enzymes and some other enzymes.!? Chloroquine can function as a prostaglandin antagonist by impeding prostaglandin biosynthesis. I!! Another possible anti-inflammatory mechanism is
652
Koranda
chemotaxis inhibition. Chloroquine decreases neutrophil, macrophage, and eosinophil chemotaxis and neutrophil phagocytosis. 19.20 Chloroquine retards histamine-induced guinea pig ileum contraction and decreases the pulmonary histamine content in rats. 21,22 This antihistaminic effect has been applied by treating bronchial asthma with chloroquine, but this is not a standard usage.F' Other properties. Hydroxychloroquine has been shown to decrease sludging of erythrocytes and to inhibit platelet aggregation.Pv'" Although antimalarials are used to treat various photosensitive dermatoses, there is no evidence that they have any sunscreening or sun-absorptive properties.f"
Toxicity The potential toxic effects of the antimalarials are as numerous as the modes of action. The lethal dose for an adult is 3 to 6 gm of chloroquine. For a child, 1 gm may be lethal. The acute symptoms are weakness, dyspnea, difficulty in swallowing, hoarseness, hypotension, tremors, coma, and convulsions, followed by cardiopulmonary arrest. Treatment is with the necessary life support measures and acidification of the urine or the administration of dimercaprol (BAL) to increase elimination of the drug." Cutaneous. Lemon-yellow discoloration of the skin is a unique hallmark for quinacrine. Even at a minimum daily dosage of 100 mg, 36% of patients will be affected.P The sclera as well as the skin may be discolored, and there may be confusion with icterus. Bilirubin levels are normal. Quinacrine, chloroquine, and hydroxychloroquine may produce graying of the scalp hair, beard, eyelashes, and eyebrows. This is a reversible effect. The incidence of this graying has decreased with the lower doses of the drugs which are presently used. All three drugs may cause a bluish-black, ecchymosis-like pigmentation of the pretibia, palate, face, and nail beds. This pigmentation disappears slowly after stopping the drug. The pigmentation of the hard palate occurs in 25% of patients on long-term chloroquine therapy. The pigmentation of the nail beds may be diffuse or may occur as transverse bands. Lichenoid dermatitis, urticaria, exfoliative
Journal of the American Academy of Dermatology
erythroderma, and exacerbation of psoriasis have been reported with all three drugs. Squamous cell carcinomas of the palms have recently been observed in Australian veterans who had a severe lichenoid reaction from prophylactic quinacrine during World War IU 9 Gastrointestinal and neuromuscular. Although nausea and vomiting may occur, this can usually be controlled by decreasing the dosage or switching to another antimalarial. These symptoms are more frequent with chloroquine than with hydroxychloroquine. Other common symptoms are diarrhea, sweating, pruritus, headache, and insomnia. All of these drugs have been reported to cause psychoses and seizures, but these effects were usually associated with higher dosages than are currently prescribed.Pv" The antimalarials may lead to vacuolar myopathy with a myasthenia gravis-type condition.32.33 This is a rare, probably idiosyncratic, and usually reversible reaction. Cardiac conduction blocks, T-wave depression and inversion, and depressed cardiac muscle response have been noted. 34.35 Because of the muscle depressant effect, patients may develop symptoms of mild ileus, cycloplegia, and presbyopia after starting therapy. Accommodation to these symptoms usually takes place after a few weeks of treatment. Hematologic. All of the antimalarials are capable of inducing a severe leukopenia. This leukopenia may be more frequent in the first 3 months of treatment, but it may occur later. Quinacrine has also been observed to produce an aplastic anemia. During World War II when quinacrine 100 mg daily was used for malaria chemoprophylaxis, the incidence of aplastic anemia was 2.84 per 100,000 males per year. Although caution is advised in patients with a glucose-6-phosphate dehydrogenase deficiency (G6PD), G6PD hemolysis seems to be a problem only with primaquine. Teratogenic. Chloroquine does cross the placenta and concentrates in fetal tissues. 35 Congenital defects such as deafness, mental retardation, and convulsions have occurred in the newborn of women who received chloroquine during pregnancy.36.:37 Ocular. In the initial stages of therapy, all three drugs may cause blurring of vision and!or double
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vision. This is due to the depressant effect on the muscles and usually passes with time or with a decrease in dose. Both chloroquine and hydroxychloroquine may be deposited in the cornea. These deposits are visible with slit lamp examination. Although they are usually asymptomatic, they can produce the sensation of seeing halos about alight. 38 These deposits are dose-related, reversible, and are not a contraindication to continued use. The distressing ocular complication is irreversible retinopathy which may be progressive even after cessation of treatment. Both chloroquine and hydroxychloroquine have been implicated. Because chloroquine was more widely used than hydroxychloroquine and often used at greater equivalent dosages (Table I), retinopathy has been more commonly associated with it than with hydroxychloroquine. There is a common clinical perception that hydroxychloroquine may be less retinotoxic, but there is no absolute evidence that this is so. Due care must be exercised with both drugs. The retinopathy is dose-related. Most of the cases have occurred after a total cumulative dose of 200 gm, and it is written that this total dose should not be exceeded. But based on a series of 928 patients, Mackenzie'" proposed that the occurrence of retinopathy is primarily related to exceeding a maximum daily dose rather than to the total dose or to the duration of therapy. The "safe" daily dose for chloroquine is 2 mg per pound of body weight, and for hydroxychloroquine, 3.5 mg per pound of body weight." If higher daily doses are administered, the antimalarials may not be able to be excreted and may accumulate to a retinotoxic level. Chloroquine and hydroxychloroquine may somehow block the light energy absorbing function of retinal melanin which may contribute to the retinopathy.w" Therefore, discontinuing the drug for 2 months in the summer, if the disease condition permits, and the wearing of sunglasses that decrease light transmission by 50% may be prophylactic. Two other hypotheses for the retinopathy are that the binding of the drug to the retinal pigment epithelium inhibits protein synthesis with a resultant destruction of the rods and the cones and that
Antimalarials
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Table I. Equivalent and usual doses of antimalarials Antimalarial
Equivalent doses
Usual daily doses
Chloroquine Hydroxychloroquine Quinacrine
250 mg 400 mg 100 mg
250 mg 400 mg 100 mg
prolonged lysosomal stabilization leads to dysfunction of the Iysosomes with ensuing retinal damage.v"" A baseline ophthalmologic examination and follow-up eye examinations every 4 to 6 months are indicated. Funduscopy combined with red testingof central fields have been reported to be the most sensitive means of recognizing chloroquine and hydroxychloroquine toxicity at a reversible premaculopathy stage. 45 However, the red testing of central fields is not easily done, and many ophthalmologists do not agree that it has any particular value over funduscopy and other more standard tests. 46 Electro-oculography, electroretinography, and angiography do not seem to have any special advantage for early detection of retinopathy.v":" With funduscopy, the earliest changes are irregular macular pigmentation and loss of foveal reflex. However, these same changes can occur in senile macular atrophy, which may begin between the ages of 50 and 60 years. 46 Systemic lupus erythematosus may itself produce retinal changes similar to those of chloroquine toxicity. 50 It has also been proposed that lupus erythematosus patients are more susceptible to the retinopathy than are rheumatoid arthritis patients. 51 The funduscopic picture of the bull's-eye macular lesion is the classic form of advanced chloroquine toxicity, but it is not pathognomonic since it, too, may occur in other diseases. 52 Although quinacrine does not cause retinopathy, a baseline ophthalmologic examination is still prudent. CLINICAL APPLICATIONS AND GUIDELINES
Rheumatoid arthritis is the only disease for which there is double-blind evidence of the moderate effectiveness of antimalarials. However,
Journal of the American Academy of Dermatology
654 Koranda
there is other good, reliable documentation for their use in cutaneous lupus erythematosus, polymorphous light eruption, solar urticaria, and porphyria cutanea tarda. As with most drugs, there are anecdotal reports citing their application in a variety of other diseases. Antimalarials are indicated for cutaneous lupus erythematosus when it is unresponsive to topical and intralesional corticosteroids and is an ongoing, progressive, destructive process. Once the disease is under control, gradual decreasing of the dosage should be attempted. It may be possible to discontinue the drug for the winter months or for more prolonged periods. When antimalarials are used for solar urticaria and for polymorphous light eruption, they should be used only during active phases of the disease and tapered off as remission occurs. Various dose schedules have been used. Over recent years lower dosages for all diseases have become prevalent. For an average-weight (150pound) individual, the "safe" daily limit for chloroquine would be about 250 mg and for hydroxychloroquine, 400 mg. While this is a lesser dose than some recommended schedules and while it may not always be the optimal therapeutic dose, it is a "safe" upper limit to prevent retinopathy. If the patient cannot tolerate or does not respond to one of the drugs, the other should be tried. Both chloroquine and hydroxychloroquine should not be used together since their retinal effects are additive. However, quinacrine can be used alone or can be used with either of the other drugs. The usual daily dose of quinacrine is 100 mg, but the starting dose is often 100 mg three times a day. This starting dose is gradually decreased as the disease comes under control. Chloroquine is efficacious for porphyria cutanea tarda since it forms a stable complex with porphyrins, leading to a marked porphyrinuria and a remission. 53 When it was first used for this disease, in doses of 250 mg to 1,000 mg per day for 4 to 7 days, there would be a severe toxic reaction of fever, nausea, vomiting, myalgia, abdominal pain, and toxic hepatitis. 54 These toxic effects may be avoided with low-dose chloroquine treatment of 125 mg 2 to 3 times a week for 6 to 18 months. 55 Another treatment plan to obviate toxic
effects requires one to four plebotomies followed by 250 mg chloroquine daily for a week. 56 Prior to therapy with antimalarials, the following baseline studies should be accomplished: 1. Ophthalmologic examination 2. Complete blood count 3. Glucose-6-phosphate dehydrogenase (although the three antimalarials reviewed do not seem to cause a G6PD deficiency hemolysis, the pharmaceutical warnings with these drugs still caution care in patients with G6PD deficiency) 4. 24-hour urine sample for uroporphyrins and coproporphyrins to rule out an underlying porphyria cutanea tarda, if clinically indicated 5. BUN, creatinine, and liver function tests
At 4- to 6-month intervals, follow-up eye examinations should be performed. For the first 3 months, complete blood counts are done monthly, and thereafter, every 4 to 6 months. The antimalarials are efficacious drugs for the conditions cited and can be used with limited risks if the guidelines and' 'safe" dosage schedules are followed. REFERENCES I. Payne JF: A postgraduate lecture on lupus erythematosus. Clin J 4:223-229, 1894. 2. Martenstein H: Subacute lupus erythematosus and tubercular cervical adenopathy. Treatment with plasmochin. Z Hautkr 27:248-249, 1928. 3. Prokoptchouk AJ: Treatment of lupus erythematosus with acridine. Z Hautkr 66:112, 1940. (Abst.) 4. Page F: Treatment of lupus erythematosus with mepacrine. Lancet 2:755-758,1951. 5. Rubin M, Zvaifier NJ: The metabolism of chloroquine. Clin Res 10:22, 1962. (Abst.) 6. Rubin M, Bernstein NH, Zvaifier NJ: Studies on the pharmacology of chloroquine: Recommendations for the treatment of retinopathy. Arch Ophthalmol 70:474-481, 1963. 7. Yielding LW, Yielding KL: Nucleic acid structural requirement for binding of chloroquine. Ala J Med Sci 10:403-409, 1973. 8. Dubois EL: Effect of quinacrine (Atabrine) upon lupus erythematosus phenomenon. Arch Dermatol 71:570574, 1955. 9. Bencze G, Johnson GD: Inhibition of antinuclear factor reaction by chloroquine. Immunology 9:201-202, 1965. 10. Hurvitz D, Hirschhorn K: Suppression of in vitro lymphocyte response by chloroquine. N Engl J Med 273:23-26, 1965. II. Szegedi G: Studies on T and B lymphocytes in the peripheral blood of discoid lupus erythematosus patients with and without chloroquine treatment. Acta Derm Venereol (Stockh) 56:47, 1976.
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12. Stollar D, Levine L: The reaction between L.E. serum and denatured DNA: Inhibition by haptenes and chloroquine. Arthritis Rheum 5:660, 1962, (Abst.) 13. Kalmanson GM, Guze LB: Studies on the effects of hydroxychloroquine on immune responses. J Lab Clin Med 65:484-489, 1965. 14. Manku MS, Horrobin DF: Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants and methylxanthines as prostaglandin agonists and antagonists. Lancet 2:1115-1117,1976. 15. Lie SO, Schofield B: Inactivation of lysosomal function in normal cultured human fibroblasts by chloroquine, Biochem Pharmacol 22:3109-3114, 1973. 16. Weissmann G: Labilization and stabilization of lysosomes. N Engl J Med 273: 1143-1149, 1965. 17. Sams WM Jr: Chloroquine: Mechanism of action. Mayo Clinic Proc 42:300-309, 1967. 18. Greaves MV, McDonald-Gibson W: Effect of nonsteroid anti-inflammatory and antipyretic drugs on prostaglandin biosynthesis by human skin. J Invest Dermatol 61: 127129, 1973. 19. Ward PA: The chemosuppression of chemotaxis. J Exp Med 124:209-225, 1966. 20. Gauderer CA, Gleich GJ: Inhibition of eosinophilotaxis by chloroquine and corticosteroids. Proc Soc Exp BioI Med 157:129-134,1978. 21. Deshpande VR, Sharma ML, Dashputra PG: Antihistaminic action of antimalarials. Indian J Physiol Pharmacol 7:259-266, 1963. 22. Agarwal SL, Deshmankar BS, Bhargava V: Chloroquine in bronchial asthma. J Pharm Pharmacol 15:693, 1963. (Letter.) 23, Ciszek J, Walczak J: Treatment of bronchial asthma with chloroquine. Polish Med J 10: 1125-1 130, 1970. 24, Cecchi E, Ferraris E: Desludging action of hydroxychloroquine in rheumatoid arthritis. Acta Rheum Scand8:214-22I,1962. 25. Carter AE, Eban R, Perrott RD: Prevention of postoperative deep venous thrombosis and pulmonary embolism. Br Med J 1:312-314,1971. 26. Sams WM Jr, Carroll NY: The "spectral shift" phenomenon of chloroquine. Arch Dermatol 93:123-128, 1966. 27. Zvaifler NJ: Antimalarial treatment of rheumatoid arthritis. Med Clin North Am 52:759-764, 1968, 28. Dubois EL: Antimalarials in the management of discoid and systemic Iupus erythematosus. Semin Arthritis Rheum 8:33-51, 1978. 29. Bauer F: Late sequelae of atabrine dermatitis-a new premalignant entity. Aust J Dermatol 19:9-12, 1978. 30. Torrey EF: Chloroquine seizures: Report of four cases. JAMA 204:867-870, 1968. 31. Sapp OL III: Toxic psychosis due to quinacrine and chloroquine. JAMA 187:373-375, 1964. 32. Eadie MI, Ferrier TM: Chloroquine myopathy. J Neurol Neurosurg Psychiatry 29:331-337, 1966. 33. Whisnant JP, Espinosa RE, Kierland RR: Chloroquine neuromyopathy. Mayo Clin Proc 38:501-513, 1963. 34. Alving AS, Eichelberger L, Craige B Jr: Studies on the chronic toxicity of chloroquine. J Clin Invest 27:60-65, 1948. 35. Ullberg S, Lindquist NG, Sjostrand SE: Accumulation of
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