What are antimalarial medications?
Antimalarial medications are drugs with immunomodulatory and anti-inflammatory effects. They are used to treat various skin conditions.
Antimalarial medications used in dermatology include:
- Chloroquine
- Hydroxychloroquine
- Quinacrine (mepacrine).
Hydroxychloroquine has largely replaced quinacrine and chloroquine due to its better safety profile [1].
How do antimalarial medications work?
Antimalarials are:
- Anti-inflammatory
- Antiproliferative
- Immunomodulatory
- Photoprotective
- Weakly antithrombotic (they reduce blood clotting).
Anti-inflammatory effects of antimalarials
Antimalarial drugs reduce the production of cytokines that induce an inflammatory response by activating macrophages, dendritic cells, and lymphocytes where they are trapped within cytoplasmic lysosomes (enzyme-filled organelles that dissolve molecules) [2].
- Lysosomal pH is increased
- Lysosomal protease activity is decreased
- The binding of autoantigens to the class II major histocompatibility complex (MHC) is reduced
- There is decreased stimulation of toll-like receptor (TLR) 9
- TLRs 3, 7 and 8 are activated
- There is increased loading of class I MHC antigens.
Antiproliferative and immunomodulatory effects of antimalarials
The anti-proliferative and immunomodulatory effects are mediated by:
- Decreased lymphocyte proliferation
- Interference with natural killer cell activity
- Alteration of autoantibody production [2].
- Antimalarials accumulate in the skin to provide a physical photoprotective barrier by absorbing certain wavelengths of light.
- They dampen the usual inflammatory response of keratinocytes to exposure to ultraviolet radiation [3].
Antimalarial medications prevent platelet aggregation and act as prostaglandin antagonists due to inhibition of phospholipase A2 [3]. It is unclear whether the antithrombotic effect is therapeutically useful. Hydroxychloroquine has been associated with a 15–20% decrease in serum cholesterol, triglyceride, and low-density lipoprotein levels [1]. It reduces glucose by decreasing insulin degradation resulting in lower levels of glycated haemoglobin (HbA1c). It is antiviral, antineoplastic, and may improve bone density.
The pharmacokinetics of antimalarials
Chloroquine and hydroxychloroquine are chemically similar and are part of the amino-quinoline family.
- Amino-quinolines are mostly absorbed in the gastrointestinal tract.
- Peak plasma concentrations are reached within 4–12 hours.
- Stable concentrations are achieved after 4–6 weeks. Patients should be aware that it might take 2–3 months to notice a therapeutic effect.
- About 50% of the drug is excreted through the kidneys. Therefore dose adjustments should be made in patients with severe renal impairment.
- 60–70% of the drug binds to plasma proteins that are deposited in tissues such as the liver, spleen, kidney, and lung.
- There is a high affinity for melanin-containing cells in the skin and the retina. The deposition of amino-quinolines in these cells can lead to toxicity, resulting in pigmentation changes and retinal toxicity [1].
- For an identical dose of hydroxychloroquine and chloroquine, tissue levels of chloroquine are 2.5 times those of hydroxychloroquine. Hence chloroquine is more toxic [1].
There is no cross-reactivity between the 4-aminoquinolines and quinacrine due to differences in the chemical structure; therefore, an adverse reaction to an aminoquinoline does not preclude the use of quinacrine.
What are antimalarials used for?
Antimalarial drugs are first-line medications for:
They are used second-line to treat:
Antimalarials are sometimes used to treat other inflammatory skin conditions.
Disorders treated with antimalarials
Other inflammatory skin conditions treated with antimalarials
Other inflammatory skin conditions treated with antimalarial drugs include:
- Actinic lichen planus
- Actinic prurigo
- Actinic reticuloid
- Annular elastolytic giant cell granuloma
- Anti-phospholipid syndrome
- Atopic dermatitis
- Chronic actinic dermatitis
- Chronic erythema nodosum
- Cutaneous CD8+ pleomorphic T-cell lymphoma
- Eosinophilic fasciitis
- Epidermolysis bullosa
- Erosive lichen planus
- Follicular mucinosis
- Frontal fibrosing alopecia
- Graft versus host disease
- Histiocytic necrotising lymphadenitis (Kikuchi Fujimoto disease)
- Lichen planopilaris
- Lichen sclerosus
- Lipodermatosclerosis
- Morphoea
- Necrobiosis lipoidica
- Reticular erythematous mucinosis
- Schnitzler syndrome
- Solar urticaria
- Systemic sclerosis
- Urticaria
- Urticarial vasculitis
- Nodular panniculitis.
What are the contraindications with antimalarial medications?
Antimalarial drugs should not be used in patients with known hypersensitivity to the drug or pre-existing retinopathy. Care should be taken with children, the elderly, in pregnant and lactating women, and patients with severe renal impairment.
Smoking
Smoking has been reported to inhibit the P450 enzyme system, decreasing the efficacy of antimalarial therapy, especially in patients on chloroquine [4]. Patients on antimalarial medications are advised not to smoke.
What monitoring is required with antimalarial medications?
- The patient's full blood count should be checked monthly for the first three months, then every 4–6 months.
- The patient's renal function should be checked at baseline, after one month, after three months, and then every 4–6 months (more frequent surveillance is needed if laboratory values are abnormal or in high-risk patients).
- A pregnancy test should be undertaken in women of childbearing age.
- There should be a baseline ophthalmic examination within the first year of commencing therapy. In the absence of risk factors listed below, annual screening should be performed after five years [5].
Hydroxychloroquine levels can be measured in the blood.
- No standardised therapeutic level has been validated.
- Levels of > 500 ng/mL indicate adherence to treatment [4].
- In systemic lupus erythematosus, significant improvement and remission have been associated with blood levels of > 750 ng/mL.
What are the side effects and risks of antimalarials?
Except for severe retinopathy, adverse effects from antimalarial drugs usually resolve when they are discontinued.
Ocular side effects
Corneal deposits
- Corneal deposits occur in 90% of patients on chloroquine and do not occur in patients on hydroxychloroquine; quinacrine can also cause deposits.
- Corneal deposits are usually asymptomatic, and treatment can be continued.
- Patients can experience transient halos and heightened light sensitivity.
- The deposition is dose-related, occurring 4–6 weeks after therapy is initiated.
Retinopathy
Chloroquine, and hydroxychloroquine to a lesser extent can cause irreversible retinal toxicity. The cause is thought to be a high affinity for melanin-containing cells in the retinal pigment epithelium [1]. The risk of toxicity is dependent on several factors.
Major risk factors for retinal toxicity include:
- A daily dose of hydroxychloroquine > 5.0 mg/kg actual body weight
- A daily dose of chloroquine > 2.3 mg/kg actual body weight
- Renal impairment
- Concomitant treatment with tamoxifen
- Pre-existing retinopathy
- A duration of use > 5 years.
Routine screening is essential because early antimalarial retinopathy does not cause symptoms.
Damage patterns vary with ethnicity.
- Caucasian patients present with bull’s eye retinopathy or paracentral scotoma (island of vision loss).
- Patients with Asian heritage present with more peripheral defects.
Gastrointestinal adverse effects
Antimalarial drugs can cause transient or persisting nausea, flatulence, vomiting or diarrhoea that resolves with the reduction or cessation of medication. Symptoms can be minimised by taking the medication with food.
Cutaneous adverse effects
The cutaneous adverse effects of antimalarial drugs include:
- Urticaria
- Lichenoid eruptions
- Alopecia
- Photosensitivity
- Exfoliative dermatitis
- Erythema annulare centrifugum
- A brownish discolouration of the nail bed
- Pigmentation.
- Hydroxychloroquine can cause grey-blue skin depigmentation in the sun-exposed areas in ~25% of patients on long-term therapy [2].
- Quinacrine causes yellowing of the sclera and skin that is not related to liver injury; this discolouration is more prominent in fair-skinned patients.
Neuropsychological effects
Neuropsychological side effects due to antimalarial medications are rare and usually occur in patients treated at higher doses than those used in dermatology. Psychosis, irritability, depression, insomnia, and nightmares have been reported. Antimalarial medications have rarely been known to induce a seizure in predisposed individuals.
Neuromuscular effects
- Hydroxychloroquine has been reported to cause proximal myopathy.
- Chloroquine has been reported to cause neuromyopathy, myalgia, and fatigue.
Haematological effects
Haematological side effects are uncommon with antimalarial drugs. Haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anaemia, and leukopenia have been reported but are rare [6]. Screening for G6PD deficiency is not routinely recommended for hydroxychloroquine but is required for chloroquine.
Drug interactions with antimalarial medications
Anti-malarial medicines can cause several interactions with other medications [2].
Antimalarial drugs increase the plasma levels of:
- Digoxin
- Methotrexate
- D-penicillamine
- Ciclosporin
- Beta-blockers.
There are synergistic antiarrhythmic effects with chloroquine and amiodarone.
Antimalarials decrease the bioavailability of penicillin.
There is increased bioavailability of antimalarial agent with:
- Cimetidine
- Ritonavir.
There is decreased bioavailability of the antimalarial agent with:
- Cholestyramine
- Antacids
There is an increased risk of myopathy with antimalarials and:
- Aminoglycosides
- Corticosteroids.
Antimalarial drugs decrease the effect of:
- Neostigmine
- Physostigmine.
Pregnancy and antimalarial medications
Antimalarial medications cross the placenta and are considered Category D in pregnancy. Category D implies that they should only be taken during pregnancy if the benefits outweigh the risks. However:
- Hydroxychloroquine has not been associated with congenital defects, stillbirth, prematurity, low birth weight, fetal death, or infant retinopathy.
- Hydroxychloroquine reduces the risk of cardiac manifestations of neonatal lupus in pregnant women with anti-SSA/Ro-positive systemic lupus erythematosus (SLE) [7].
- Hydroxychloroquine is also safe during lactation.
Chloroquine can cause fetal retinopathy and should not be used in pregnancy [4]. Hence, hydroxychloroquine is a safer option for women planning a pregnancy or breastfeeding.