Continuing Education Activity

Chloroquine is a medication used in the management and treatment of malaria and inflammatory diseases. It is in the sulfonamides class of drugs. This activity describes the indications, action, and contraindications for chloroquine as a valuable agent in the therapy of malaria, rheumatoid arthritis, and lupus erythematosus. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment, prevention, and management of patients with malaria and related conditions.

Objectives:

• Summarize the mechanism of action of chloroquine.
• Identify the most common adverse effects of chloroquine.
• Review the appropriate monitoring of patients treated with chloroquine.
• Outline the importance of collaboration and coordination among the interprofessional team that can enhance patient care when prescribing and monitoring chloroquine to improve patient outcomes for patients receiving prophylaxis and treatment with chloroquine.

Indications

Chloroquine is FDA-approved for the treatment and prophylaxis of uncomplicated malaria in countries where chloroquine-sensitive malaria (certain strains of P. falciparum, P. ovale, P. vivax, and P. malariae) is present. These countries include Mexico, areas of Central America to the west of the Panama Canal, the Caribbean, East Asia, as well as some Middle Eastern countries.[1] The FDA also recommends chloroquine for the treatment of extraintestinal amebiasis.[2] Non-FDA-approved indications of chloroquine include the treatment of certain autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus.[3] Also, current research suggests that chloroquine may be helpful as an antitumor medication for the treatment of cancer in association with chemotherapy and radiation.[4]

Mechanism of Action

Chloroquine exerts its antimalarial effects by preventing the polymerization of heme into hemozoin (a food source for the malarial parasite). Chloroquine forms a drug-hemozoin complex, and this complex caps the polymerizing chain, thereby preventing additional polymerization. Along with the prevention of polymerization, the free heme accumulates in the food vacuole, exerting its toxic effects on the parasite.[5] 

Chloroquine also functions as an anti-autoimmune therapy. It exerts its effects by binding to transcriptional factors on T helper 17 cells and preventing differentiation. At the same time, chloroquine also activates the transcription factor Foxp3, driving the formation of regulatory T cells. Regulatory T cells have been shown to treat and prevent autoimmune diseases.[3] Specifically, for the treatment of rheumatoid arthritis, chloroquine prevents the presentation of autoantigens from MHC class II, therefore, preventing activation of CD4+ T cells.[6]

Administration

Chloroquine is currently administered orally when used as a prophylaxis for malaria and the treatment of chronic autoimmune diseases.[7]  For malaria prophylaxis, 500 mg is typically administered orally two weeks before, during, and up to 8 weeks after exposure to an endemic area, taken as a weekly dose. When used as a treatment for extraintestinal amoebas, chloroquine dosing 21 mg/kg for three weeks.[8] Under severe or emergent cases of malaria, chloroquine can be administered parenterally.[9] Some research has shown that parenteral administration is potentially toxic; therefore, subcutaneous administration has been shown to be a more effective method in circumstances of severe malaria.[10] For extraintestinal amebiasis, 1g is administered once daily for 2 days, and then 500mg is administered once daily for 14 to 21 days.

Adverse Effects

Although chloroquine has relatively few side effects when taken as prescribed, higher doses of chloroquine have been shown to have severe adverse effects. The most severe adverse effects associated with high doses of chloroquine include retinal toxicity, long and subtle symptoms of reduced visual acuity, diplopia, and bilateral loss of vision.[11] High doses have also been shown to cause severe psychiatric issues, such as paranoia, hallucinations, and suicidal ideations.[12] 

• Dermatological reactions include pruritus and photosensitivity.
• Retinopathy will typically present with the inability to focus between near and far objects.
• Neuropathy can include seizures, paranoia, and hallucinations.

When administered intramuscularly, chloroquine has been shown to cause potentially lethal hypotension.[13] Patients with glucose-6 phosphate dehydrogenase (G-6-PD) deficiency may cause hemolysis resulting in hemolytic anemia.

Contraindications

Chloroquine has been proven safe to use during pregnancy and in children. Chloroquine has few but serious contraindications. There are reports of cases with death relating to chloroquine administered to patients with porphyria cutaneous tarda.[14] Chloroquine should not be used in patients with retinal or vision changes unless treating acute malaria. Chloroquine is also contraindicated in patients who suffer from a known hydroxychloroquine sensitivity.

Monitoring

Ideally, chloroquine should be dosed depending on body weight and height. For use as malarial prophylaxis, the appropriate chloroquine dose is 5 mg/kg of body weight with a maximum of around 500 mg given on a once per week dosing regimen.[15] In patients with (G-6-PD) deficiency, blood monitoring is recommended to detect any possible hemolytic anemia.

Toxicity

Chloroquine toxicity is rare but has been known to occur when unusually high doses of chloroquine are ingested or after chronic IV administration. Accidental ingestion has also occurred in children.[16] When toxicity is present, the most common symptom is retinal toxicity. Treatment of chloroquine toxicity includes mechanical ventilation and administration of diazepam and epinephrine, although these methods have not been a proven method of treatment in all cases.[17]

Enhancing Healthcare Team Outcomes

Safely and effectively treating and preventing malaria requires an interprofessional team of healthcare providers, including a clinician, infectious disease specialist, nurse, physician assistant, and pharmacist. Similarly, the treatment of autoimmune and inflammatory conditions requires an interprofessional team consisting of primary care providers, healthcare specialists, and pharmacists. Without proper consultation, patients are at risk of exposure to a very preventable disease. Therefore, the recommended order of steps that the team should take for the prevention and prophylaxis of malaria are as follows:

1. The patient informs their primary care provider about plans to travel to a country with malaria prevalence. Similarly, a primary care provider may also ask the patient during a normal history and physical whether the patient intends to travel outside of the country they reside.
2. Once informed of out-of-country travel, the primary care provider will refer the patient to an infectious disease specialist.
3. The infectious disease specialist can assess the risks of transmission and infection of the patient, depending on the country to which they will be traveling.
4. Following the risk assessment, the infectious disease specialist can recommend chloroquine as prophylaxis to malaria if the patient will be in a country where chloroquine-sensitive malaria is present.
5. The pharmacist will provide weight-dependent dosing of chloroquine and provide instructions that maximize the effectiveness of the prophylaxis, such as taking the medication before, during, and after the expected travel.
6. Nursing staff can also counsel the patient regarding proper dosing and administration and answer any questions that the patient may have regarding the use and adverse events associated with chloroquine.

The treatment and prevention of malaria do not stop here. First, the patient must abide by the recommended regimen. If the patient fails to follow the regimen, they put themselves at a higher risk of infection.

Similarly, prescribing chloroquine in the context of inflammatory diseases have a similar recommended course of action:

1. The patient will come to the primary care provider complaining of symptoms related to autoimmune and/or inflammatory disorders.
2. The clinician will perform a history and physical and provide proper referrals for the patient's treatment.
3. Referrals may be necessary for specialists, such as orthopedics and/or genetic counselors. 
4. The specialists can provide the right course of treatment or management of the inflammatory condition, most likely a chronic regimen of medications, including chloroquine. 
5. The pharmacist will adjust the dose depending on the weight and condition of the patient.
6. As above, nursing staff can offer patient counseling and directions on dosing and administration and adverse events for which the patient may need to be aware.

The above exemplified the interprofessional healthcare team approach that makes chloroquine therapy more effective and with fewer adverse events, enhancing patient care. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Freedman DO. Clinical practice. Malaria prevention in short-term travelers. N Engl J Med. 2008 Aug 07;359(6):603-12. [PubMed: 18687641]

2.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Dec 5, 2017. Sulfonamides. [PMC free article: PMC547852] [PubMed: 31643703]

3.

Park TY, Jang Y, Kim W, Shin J, Toh HT, Kim CH, Yoon HS, Leblanc P, Kim KS. Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases. Sci Rep. 2019 Oct 29;9(1):15559. [PMC free article: PMC6820774] [PubMed: 31664129]

4.

Plantone D, Koudriavtseva T. Current and Future Use of Chloroquine and Hydroxychloroquine in Infectious, Immune, Neoplastic, and Neurological Diseases: A Mini-Review. Clin Drug Investig. 2018 Aug;38(8):653-671. [PubMed: 29737455]

5.

Sullivan DJ, Gluzman IY, Russell DG, Goldberg DE. On the molecular mechanism of chloroquine's antimalarial action. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11865-70. [PMC free article: PMC38150] [PubMed: 8876229]

6.

Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. 1993 Oct;23(2 Suppl 1):82-91. [PubMed: 8278823]

7.

Lewis MD, Pfeil J, Mueller AK. Continuous oral chloroquine as a novel route for Plasmodium prophylaxis and cure in experimental murine models. BMC Res Notes. 2011 Jul 28;4:262. [PMC free article: PMC3156757] [PubMed: 21798062]

8.

Ursing J, Eksborg S, Rombo L, Bergqvist Y, Blessborn D, Rodrigues A, Kofoed PE. Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance. PLoS One. 2014;9(1):e86801. [PMC free article: PMC3900653] [PubMed: 24466245]

9.

White NJ, Watt G, Bergqvist Y, Njelesani EK. Parenteral chloroquine for treating falciparum malaria. J Infect Dis. 1987 Feb;155(2):192-201. [PubMed: 3543146]

10.

White NJ, Miller KD, Churchill FC, Berry C, Brown J, Williams SB, Greenwood BM. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations. N Engl J Med. 1988 Dec 08;319(23):1493-500. [PubMed: 3054558]

11.

Braga CB, Martins AC, Cayotopa AD, Klein WW, Schlosser AR, da Silva AF, de Souza MN, Andrade BW, Filgueira-Júnior JA, Pinto Wde J, da Silva-Nunes M. Side Effects of Chloroquine and Primaquine and Symptom Reduction in Malaria Endemic Area (Mâncio Lima, Acre, Brazil). Interdiscip Perspect Infect Dis. 2015;2015:346853. [PMC free article: PMC4556080] [PubMed: 26357512]

12.

Lysack JT, Lysack CL, Kvern BL. A severe adverse reaction to mefloquine and chloroquine prophylaxis. Aust Fam Physician. 1998 Dec;27(12):1119-20. [PubMed: 9919736]

13.

Prakongpan S, Sirimai S, Edwards G, McGrath CS, White NJ. An improved formulation of chloroquine for intramuscular administration: absorption kinetics in rabbits. J Pharm Pharmacol. 1989 Oct;41(10):726-8. [PubMed: 2575156]

14.

Drasch G, Eisenmenger W. [Death following administration of 1,250 mg chloroquine in porphyria cutanea tarda]. Z Rechtsmed. 1986;97(4):285-93. [PubMed: 3577436]

15.

Dresser CK. Chloroquine dose for malaria prevention. Can Fam Physician. 1986 Feb;32:231. [PMC free article: PMC2328098] [PubMed: 21267237]

16.

Wittes R. Adverse reactions to chloroquine and amodiaquine as used for malaria prophylaxis: a review of the literature. Can Fam Physician. 1987 Nov;33:2644-9. [PMC free article: PMC2218695] [PubMed: 21264010]

17.

Clemessy JL, Taboulet P, Hoffman JR, Hantson P, Barriot P, Bismuth C, Baud FJ. Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med. 1996 Jul;24(7):1189-95. [PubMed: 8674334]

Disclosure: Pranshul Goel declares no relevant financial relationships with ineligible companies.

Disclosure: Valerie Gerriets declares no relevant financial relationships with ineligible companies.