Pharmacological action, pharmacodynamics and pharmacokinetics
Hydroxychloroquine has the following pharmacological effects:
- Antiprotozoal.
- Antimalarial.
- Immunosuppressive.
- Anti-inflammatory.
The drug disrupts the replication of Plasmodium genetic material, and therefore is very effective in treating all forms of malaria.
After administration, the maximum concentration of the drug in the blood is determined after 1-2 hours. Hydroxychloroquine has high bioavailability, as well as the ability to accumulate in the respiratory, hepatolienal and central nervous systems.
The drug is able to overcome the placental barrier and penetrate to the fetus. It is excreted mainly in urine and partly in feces.
Indications and contraindications
Hydroxychloroquine is indicated for use in the following diseases:
- Rheumatic pathology (SLE, rheumatoid arthritis).
- Various forms of malaria.
Absolute contraindications to taking the drug are:
- Individual intolerance.
- Pregnancy period.
- Childhood.
- Retinopathy.
Relative contraindications:
- Decreased visual acuity, the presence of scotomas, color blindness and acquired color vision disorders.
- Porphyria.
- Severe mental and neurological pathology.
- Psoriasis.
- Hepatitis, cirrhosis, liver failure.
- Decompensated diseases of the gastrointestinal tract.
- Acute and chronic renal failure.
Hydroxychloroquine Tablets, bottle, 30 pcs., 200 mg, for oral administration, film-coated
Side effect
From the hematopoietic system: frequency unknown - suppression of bone marrow hematopoiesis, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
From the immune system: frequency unknown - urticaria, angioedema, bronchospasm.
Metabolic disorders: often - anorexia; frequency unknown - hypoglycemia, possible exacerbation of porphyria.
From the mental side: often - affective lability; infrequently - nervousness; frequency unknown - psychosis, suicidal behavior.
From the nervous system: often - headache; infrequently - dizziness; frequency unknown - seizures, extrapyramidal disorders such as muscular dystonia, dyskinesia and tremor.
From the organ of vision: often - blurred vision associated with impaired accommodation, which is dose-dependent and reversible; uncommon - retinopathy with pigmentation changes and visual field defects. If hydrochloroquine is discontinued in a timely manner, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, then there is a risk of their progression even after hydrochloroquine is discontinued. Retinal changes may initially be asymptomatic or manifest as paracentral or pericentral scotomas, transient scotomas, and color vision disturbances. Corneal changes may occur, including swelling and clouding. They may be asymptomatic or cause visual disturbances such as halos, blurred vision, or photophobia. These changes may be temporary or reversible. Not known: maculopathy and macular degeneration, which may be irreversible.
From the organ of hearing and labyrinthine disorders: infrequently - vertigo, tinnitus; frequency unknown - hearing loss.
From the cardiovascular system: frequency unknown - prolongation of the QT interval in patients with risk factors, which can lead to the development of cardiac arrhythmias (ventricular arrhythmias, ventricular tachycardia), cardiomyopathy, which can lead to heart failure and, in some cases, lethal outcome. Detection of cardiac conduction abnormalities (such as bundle branch blocks/AV conduction defects) and biventricular hypertrophy may indicate chronic cardiac toxicity. When hydrochloroquine is discontinued, these changes may reverse.
From the digestive system: very often - abdominal pain, nausea; often - diarrhea, vomiting. These symptoms usually resolve immediately after reducing the dose or stopping hydrochloroquine.
From the liver and biliary tract: infrequently - deviations from the norm in liver function tests; frequency unknown - fulminant liver failure.
From the skin of subcutaneous tissues: often - skin rash, itching; uncommon - changes in pigmentation of the skin and mucous membranes, hair bleaching and alopecia (these changes usually disappear quickly after stopping treatment); frequency unknown - bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitivity; exfoliative dermatitis; drug skin reaction accompanied by eosinophilia and systemic manifestations (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP). OHEP must be distinguished from psoriasis, although hydroxychloroquine may exacerbate psoriasis. OHEP may be accompanied by fever and hyperleukocytosis. After discontinuation of hydroxychloroquine, the outcome is usually favorable.
From the musculoskeletal system: infrequently - sensory-motor disorders; frequency unknown - skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (myopathy may be reversible after discontinuation of hydroxychloroquine, but full recovery may take several months), suppression of tendon reflexes and decreased nerve conduction.
Side effects and overdose
The drug is quite toxic and causes many adverse reactions from most organs and systems:
- Organ of vision: metamorphopsia, retinopathy, corneal edema, accommodation disorders.
- Skin and mucous membranes: hypo- or hyperpigmentation, itching, rash, hair loss, psoriasis.
- Digestive tract: dyspeptic disorders, lack of appetite, stool disorders, abdominal pain, liver failure.
- Central nervous system: dizziness, emotional instability, irritability, convulsions, disturbances of consciousness.
- CVS: myocardial hypertrophy, various blockades and conduction disorders.
- Hematopoietic organs: decrease in the number of blood cells.
- Allergic reactions: urticaria, angioedema, anaphylactic shock.
Overdose of Hydrosichloroquine can be acute or chronic. In the first case, the patient suffers from headaches, severe weakness, hypotension, and visual disturbances. In severe cases, convulsions, disturbances of consciousness, respiratory arrest and cardiac arrest may develop. Chronic intoxication is characterized by myocardial hypertrophy.
The patient urgently needs to rinse the stomach with clean water, give adsorbents and an antidote (ammonium chloride). Forced diuresis is also performed.
Hydroxychloroquine
Side effect
From the hematopoietic system:
frequency unknown - suppression of bone marrow hematopoiesis, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
From the immune system:
frequency unknown - urticaria, angioedema, bronchospasm.
From the side of metabolism:
often - anorexia; frequency unknown - hypoglycemia, possible exacerbation of porphyria.
From the mental side:
often - affective lability; infrequently - nervousness; frequency unknown - psychosis, suicidal behavior.
From the nervous system:
often - headache; infrequently - dizziness; frequency unknown - seizures, extrapyramidal disorders such as muscular dystonia, dyskinesia and tremor.
From the side of the organ of vision:
often - blurred vision associated with impaired accommodation, which is dose-dependent and reversible; uncommon - retinopathy with pigmentation changes and visual field defects. If hydrochloroquine is discontinued in a timely manner, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, then there is a risk of their progression even after hydrochloroquine is discontinued. Retinal changes may initially be asymptomatic or manifest as paracentral or pericentral scotomas, transient scotomas, and color vision disturbances. Corneal changes may occur, including swelling and clouding. They may be asymptomatic or cause visual disturbances such as halos, blurred vision, or photophobia. These changes may be temporary or reversible. Not known: maculopathy and macular degeneration, which may be irreversible.
Hearing and labyrinth disorders:
infrequently - vertigo, tinnitus; frequency unknown - hearing loss.
From the cardiovascular system:
frequency unknown - prolongation of the QT interval in patients with risk factors, which can lead to the development of cardiac arrhythmias (ventricular arrhythmias, ventricular tachycardia), cardiomyopathy, which can lead to heart failure and, in some cases, death. Detection of cardiac conduction abnormalities (such as bundle branch blocks/AV conduction defects) and biventricular hypertrophy may indicate chronic cardiac toxicity. When hydrochloroquine is discontinued, these changes may reverse.
From the digestive system:
very often - abdominal pain, nausea; often - diarrhea, vomiting. These symptoms usually resolve immediately after reducing the dose or stopping hydrochloroquine.
From the liver and biliary tract:
uncommon - abnormal liver function tests; frequency unknown - fulminant liver failure.
From the skin and subcutaneous tissues:
often - skin rash, itching; uncommon - changes in pigmentation of the skin and mucous membranes, hair bleaching and alopecia (these changes usually disappear quickly after stopping treatment); frequency unknown - bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitivity; exfoliative dermatitis; drug skin reaction accompanied by eosinophilia and systemic manifestations (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP). OHEP must be distinguished from psoriasis, although hydroxychloroquine may exacerbate psoriasis. OHEP may be accompanied by fever and hyperleukocytosis. After discontinuation of hydrochloroquine, the outcome is usually favorable.
From the musculoskeletal system:
infrequently - sensory-motor disorders; frequency unknown - skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (myopathy may be reversible after discontinuation of hydrochloroquine, but full recovery may take several months), suppression of tendon reflexes and decreased nerve conduction.
Hydroxychloroquine: instructions for use
The drug is taken orally with or after meals. The tablets should be taken with milk.
The treatment regimen depends on the disease and the severity of its manifestations.
For rheumatoid arthritis, drug therapy is carried out for several months. The dosage for adult patients is 6.5 milligrams per kilogram of body weight per day.
Treatment for systemic lupus erythematosus is also long-term. The daily dose is from 0.2 to 0.4 grams.
Treatment for malaria lasts 3 days. The course dose is 2 grams of Hydroxychloroquine.
Hydroxychloroquine, 30 pcs., 200 mg, film-coated tablets
Hydroxychloroquine tablets should be taken orally with meals or with a glass of milk. Treatment of RA. Hydroxychloroquine has cumulative activity. It takes several weeks of taking the drug for its therapeutic effect to manifest itself, while side effects may appear relatively early. The necessary therapeutic effect develops after several months of taking the drug. If there is no objective improvement in the patient's condition within 6 months of taking hydroxychloroquine, the drug should be discontinued. Adults (including older adults) should take the minimum effective dose. They should not exceed 6.5 mg/kg/day (calculated based on “ideal” body weight, not actual body weight) and can be either 200 or 400 mg/day. In patients able to take 400 mg daily Initially, 400 mg daily in divided doses. When obvious improvement is achieved, the dose can be reduced to 200 mg. If the effect decreases, the maintenance dose can be increased to 400 mg. For children. The minimum effective dose should be used. The dose should not exceed 6.5 mg/kg (based on “ideal” body weight). Therefore, the 200 mg tablets are not suitable for children with an “ideal” body weight of less than 31 kg. Use of the drug Hydroxychloroquine for combination therapy of RA. Can be safely used in combination with GCS, salicylates, NSAIDs, methotrexate and other second-line therapeutic agents. After several weeks of using the drug, the doses of corticosteroids and salicylates may be reduced or these drugs may be discontinued. Doses of GCS should be reduced gradually every 4-5 days: the dose of cortisone - by no more than 5-15 mg, the dose of hydrocortisone - by no more than 5-10 mg, the dose of prednisolone and prednisone - by no more than 1-2.5 mg , the dose of methylprednisolone and triamcinolone - no more than 1-2 mg and dexamethasone - no more than 0.25-0.5 mg. Treatment of SLE. The initial average dose in adults is 400 mg 1 or 2 times a day. It should be given over several weeks or months depending on the patient's response. For long-term maintenance therapy, it is sufficient to use the drug in a lower dose - from 200 to 400 mg. Treatment of malaria Prevention of acute attacks of malaria caused by P. malariae and susceptible strains of Plasmodium falciparum Adults - 400 mg weekly on the same day of the week. For children, the weekly dose is 6.5 mg/kg (for calculation, the “ideal” body weight is taken), however, regardless of body weight, it should not exceed the dose for adults. If conditions allow, preventive therapy should begin 2 weeks before entering an endemic area. If this is not possible, then an initial double (loading) dose can be prescribed: adults - 800 mg, children - 12.9 mg/kg of “ideal” body weight (but not more than 800 mg), divided into two doses with a 6-hour interval. Preventive treatment should be continued for 8 weeks after leaving the endemic area. Treatment of acute attacks of malaria For adults, an initial dose of 800 mg is followed by a dose of 400 mg after 6 or 8 hours, and then 400 mg on 2 subsequent days (for a total of 2 g of hydroxychloroquine sulfate). Alternative treatment: A single dose of 800 mg has also been shown to be effective. Doses for adults can also be calculated based on “ideal” body weight, similar to the calculation of doses for children (see.
below). For children, a total dose of 32 mg/kg of “ideal” body weight (but not higher than 2 g) is prescribed for 3 days as follows: first dose - 12.9 mg/kg (single dose not more than 800 mg); second dose - 6.5 mg/kg (not more than 400 mg) 6 hours after the first; third dose - 6.5 mg/kg (not more than 400 mg) 18 hours after the second dose; fourth dose - 6.5 mg/kg (not more than 400 mg) 24 hours after the third dose. Radical treatment of malaria caused by Plasmodium malariae and Plasmodium vivax For radical treatment of malaria caused by Plasmodium malariae and Plasmodium vivax, simultaneous administration of 8-aminoquinolone derivatives is necessary.
Interaction with other medications
The drug slows down the excretion of cardiac glycosides, especially Digoxin, which leads to overdose and intoxication.
Hydroxychloroquine increases the effectiveness of insulin and a number of other hypoglycemic medications, increases the toxicity of antibacterial drugs from the aminoglycoside group and reduces the intensity of antibody formation when administered rabies vaccine.
Antacids impair the absorption of the drug, so the interval between taking them should be at least 4 hours.
Reviews of Hydroxychloroquine
There are a lot of reviews about the drug on the Internet. They are left by patients with rheumatic diseases and people who have had malaria.
Most consumers note the high effectiveness of the drug. It helps cope with infection and manifestations of rheumatic pathology. However, some patients are dissatisfied with the long-term development of the effect and the appearance of various adverse reactions. Moreover, undesirable manifestations may occur after taking the first tablet, but the therapeutic effect will take at least a few days.
Hydroxychloroquine (Plaquenil) is a long-established drug developed decades ago to treat malaria. Now it is used, among other things, in rheumatology.
Professor Didier Raoult from the IHU Méditerranée Infection Hospital in Marseille suggested that this drug could be effective in treating infection caused by SARS-CoV-2. These assumptions were made some time ago, but were not taken seriously by the scientific community. However, a few days ago, a presentation by this author was presented on YouTube, which highlighted the results of a non-randomized open study that included 25 patients. The study demonstrated the effectiveness of hydroxychloroquine - a significant reduction in viral load: on day 6, 25% of patients receiving hydroxychloroquine remained virus-positive, versus 90% in the group of people who did not receive such therapy. The greatest effect was achieved with the combined use of hydroxychloroquine and azithromycin - in these patients, only 5% of cases remained virus carriers after 6 days. The results of the Marseille study have been accepted for publication (https://www.mediterranee-infection.com/).
Chinese colleagues published an article in which the effectiveness of hydroxychloroquine was confirmed in vitro on a culture of infected cells. Pharmacokinetic studies made it possible to select a dose of the drug that should have a virucidal effect in lung tissue (loading dose of 400 mg 2 times a day for 1 day, then 200 mg 2 times a day for 4 days).
The mechanism of the possible positive effect of hydroxychloroquine on the course of COVID-19 is not yet clear. Presumably, it can disrupt the processes of endocytosis, through which viral particles enter the target cell. The drug may also affect any of the components of the immune response involved in antiviral defense.
However, the data obtained to date cannot yet be considered sufficient for the use of hydroxychloroquine in the treatment of patients with COVID-19 in routine practice. This drug is characterized by a large number of potential interactions with drugs prescribed to patients due to concomitant pathology. On the other hand, the drug has been well studied over decades of use, it is used even in pregnant women, the side effects are not so severe (the most common serious one - retinal damage - requires long-term use of the drug). In addition, it is cheap and can be synthesized in large quantities relatively easily.
Hydroxychloroquine is currently being tested as part of a number of protocols for the treatment of patients with COVID-19 (https://laegemiddelstyrelsen.dk/da/nyheder/temaer/ny-coronavirus-covid-19/~/media/5B83D25935DF43A38FF823E24604AC36.ashx).
Based on materials:
COVID-19: Could Hydroxychloroquine Really Be the Answer? - Medscape - Mar 18, 2021. https://www.medscape.com/
Xueting Yao, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, ciaa237, https://doi.org/10.1093/cid/ciaa237 https://academic.oup.com/
Text: Shakhmatova O.O.
