• Pharmcrine

    Call

    +254790173296
  • Pharmcrine

    Work Time

    Mon - Fri 8 AM - 5 PM
  • Pharmcrine

    Address

    Kisii, Kenya

Hydroxychloroquine (Plaquenil)| MOA, Uses,Side effects, and Dosage

Reading time: 7 minutes, 42 seconds

Hydroxychloroquine is a drug that is used in the treatment of chloroquine-sensitive malaria. It is also used in treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda

It is not effective in treating malaria that is chloroquine-resistant.

This drug is sold as a sulfate salt known as hydroxychloroquine sulfate with a brand name Praquenil.

Indications

Hydroxychloroquine in combination with other drugs is used to treat certain auto-immune diseases such as systemic lupus whereby it reduced skin problems and rheumatoid arthritis to prevent swelling and pain. It is also known to prevent damage and reduce risk of long term disability.

In treatment of rheumatic arthritis, hydroxychloroquine belongs to a class of medications known as disease-modifying antirheumatic drugs (DMARDs).

Currently the drug is used to treat

Research on its use in COVID-19

Food and Drug Administration issued a statement to clarify tha no drugs are not approved as treatments for COVID-19, the disease caused by the coronavirus SARS-CoV-2.

It stated that the drug must still be assessed in clinical trials before it is declared safe and effective in treatment of COVID-19. Some medical doctors in the U.S. have wide latitude to prescribe drugs "off-label," . This means that the drugs are sometimes used beyond what they were approved to treat by the FDA.

Check on the FDA update on COVID-19 in facilitating development of treatments

It is said that a number of clinical studies are currently in progress all over the world. Studies in China and France have examined the effectiveness of anti-malarial drugs, including chloroquine and hydroxychloroquine. This study includes the one small-scale study that suggests the positive effects on the same.

What to keep in mind when considering these or any potential treatments for COVID-19, is that a lot of what we know about them so far is effectively anecdotal, and based not on the kind of scientifically rigorous controlled clinical studies that are normally applied.

In vitro and in vivo studies showed a beneficial effect of hydroxychloroquine on thrombosis.

Hydroxychloroquine is the cornerstone of the medical management of SLE and has antithrombotic properties in addition to numerous other benefits.

Hydroxychloroquine has also been shown to modulate blood sugars and improve lipids and overall SLE disease activity, which likely also contribute to its antithrombotic properties.

A 2005 report published in the journal Virology first raised the possibility that chloroquine and its derivative hydroxychloroquine might be effective at treating COVID-19.

The study revealed that chloroquine could prevent the spread of the SARS-CoV virus, which caused severe acute respiratory syndrome nearly 20 years ago, in primate cells grown in culture.

Chloroquine is thought to work by interfering with the ability of the virus to replicate in two ways.

First, the drug enters compartments called endosomes within the cell membrane. Endosomes tend to be slightly acidic, but the chemical structure of the drug boosts their pH, making the compartments more basic. Many viruses, including SARS-CoV, acidify endosomes in order to breach the cell membrane, release their genetic material and begin replication; chloroquine blocks this critical step.

Secondly, it prevents SARS-CoV from plugging into a receptor called angiotensin-converting enzyme 2 on primate cells. When the virus inserts its spike protein into the ACE2 receptor, it sets off a chemical process that alters the structure of the receptor and allows the virus to infect. An adequate dose of chloroquine appears to undermine this process, and in turn, viral replication in general.

It was thought that whatever pertained to SAR-CoV-1 might apply to SARS-CoV-2.

Have a look at the virology journal article here.

Dicontinuation of hydroxychloroquine use in treatment of COVID-19 patients

The Recovery trial also studied the anti-malaria drug hydroxychloroquine, but discontinued its use "due to lack of efficacy."

The drug had been touted as a possible treatment against the deadly virus from as early as February by French epidemiologist Didier Raoult, but several studies have since cast doubt on its potential.

The United States' Food and Drug Administration (FDA) announced on Monday that it had revoked its Emergency Use Authorisation of chloroquine and hydroxychloroquine after clinical trial results led "BARDA [Biomedical Advanced Research and Development Authoity] to conclude that this drug may not be effective to treat COVID-19 and that the drug's potential benefits for such use do not outweigh its known and potential risks".

Pharmacology of hydroxychloroquine

Mechanism of Action

The mechanism of action of hydroxychloroquine is not clearly known but it is thought to impair complement-dependent antigen-antibody reactions; inhibiting locomotion of neutrophils and chemotaxis of eosinophils

It increases lysosomal pH in the antigen presenting cells and interferes with lysosomal degradation of hemoglobin, which in turn interferes with digestive vacuole function

In inflammatory conditions, it works by blocking toll-like receptors on plasmacytoid dendritic cells (PDCs). Hydroxychloroquine reduces activationof dendritic cells and inflammation by decreasing TLR signaling.

The Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-inflammatory process.

In the treatment ofmalaria, hydrochloroquinine works by inhibiting hemozoin biocrystallization, thus facilitating the aggregation of cytotoxic heme. Free cytotoxic heme then accumulates in the parasites, causing their deaths

Pharmacokinetics

Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes specifically CYP2D6, 2C8, 3A4 and 3A5 metabolize hydroxychloroquine to N-desethylhydroxychloroquine.

Pharmacodynamics

Pharmacologically antimalarials are lipophilic weak bases giving them the ability to pass through the plasma membranes easily. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated, raising its concentrations within lysosomes up to 1000 times higher than in culture media.

This increased concentration increases the pH of the lysosome in return from 4 to 6 causing an inhibition of lysosomal acidic proteases diminishing proteolysis effect.

Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.

HCQ is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II major histocompatibility complex molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane

Absorption

Hydroxychloroquine has a good bioavailability because if its rapid and complete absorption

Onset if action may take 4-6 months to show response which then takes several months in rheumatic disease

Duration of action is unknown

It has a peak plasma time between 1-3 hours.

It is protein bound 55%

Upon metabolism it is broken down to Desethylhydroxychloroquine and desethylchloroquine

Hydroxychloroquine has a half-life of 32-50 days then about 60% is excreted in urine.

Dosage and administration

In management of Plasmodium malariae, P ovale, P vivax, or susceptible strains of P falciparum the loading dosage is 800 mg orally, then 400 mg PO 6-8 hours later, then 400 mg (310 mg base) PO at 24 and 48 hours

When used for prophylaxis a dose of 400 mg weekly, starting 2 weeks before exposure and continued for 4 weeks after departure from area. Whenever a prolonged therapy is used complete blood count needs to be obtained periodically

Rheumatoid Arthritis 400-600 mg PO daily for 4-12 weeks; maintenance: 200-400 mg daily.

Systemic Lupus Erythematosus 400 mg PO once or twice daily; maintenance: 200-400 mg PO daily

Porphyria Cutanea Tarda (Off-label) 100-200 mg (77.5-155 mg base) PO 2-3 times/wk

Hydroxychloroquine is usually taken with food or milk to prevent stomach upset

Adverse Effects

Nausea, vomiting, Headache, Dizziness, Irritability, Muscle weakness, Aplastic anemia, Leukopenia, Thrombocytopenia

Corneal changes or deposits (visual disturbances, blurred vision, photophobia; reversible on discontinuance)

Retinal damage with long-term use, Bleaching of hair, Alopecia, Pruritus, Skin and musculoskeletal pigmentation changes, Weight loss, anorexia, Cardiomyopathy.

Hemolysis in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Prolongs QT interval, Ventricular arrhythmias and torsade de pointes

Vertigo, Tinnitus, Nystagmus, Nerve deafness, Deafness

Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance)

Visual field defects (paracentral scotomas)

Visual disturbances (visual acuity), Maculopathies (macular degeneration)

Abdominal pain, Fatigue

Liver function tests abnormal

Hepatic failure acute, Urticaria, Angioedema

Bronchospasm, lossof appetite, Hypoglycemia, Porphyria

Weight loss, Skeletal muscle myopathy or neuromyopathy

Headache, Dizziness, Seizure, Ataxia

Extrapyramidal disorders such as dystonia

Dyskinesia, Tremor, Rash, Pruritus

Pigmentation disorders in skin and mucous membranes

Hair color changes, Alopecia

Dermatitis bullous eruptions including erythema multiforme

Stevens-Johnson syndrome,Toxic epidermal necrolysis

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Photosensitivity

Dermatitis exfoliative, Acute generalized exanthematous pustulosis (AGEP)

Fever, Hyperleukocytosis

Overdose

Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion.

Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.

Contraindications

Hydroxychloroquine is contraindicated in a patients with;

  • Hypersensitivity to 4-aminoquinoline derivatives,
  • Retinal or visual field changes due to 4-aminoquinoline compounds
  • Long-term therapy in children

Caution

Not effective against chloroquine-resistant strains of P. falciparum

The drug should be discontinued in 6 months if there is no improvement.

Use in patients with psoriasis may precipitate a severe attack of psoriasis; use with caution

Use in pregnancy

Hydroxychloroquine is categorized in pregnancy category C: This means that it is used with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies do

Could Hydroxychloroquine Really Be the Answer?

Remember this is a prescription only drug. Don’t take the drug without a doctors prescription.


Post References

  • Pubmed, NCBI, color atlas of pharmacology

  • Revised on: 2021-07-10 02:22:57