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    HCQ Cardiotoxicity

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    paidisuri
    HCQ can cause cardiotoxicity through several mechanisms including QT interval prolongation and conduction disorders. Risk factors include higher cumulative doses over many years, older age, renal or liver dysfunction, and concomitant medications affecting cardiac conduction. Diagnosis involves cardiac MRI, biopsy, and electrocardiogram monitoring. Recommendations include avoiding HCQ in those with pre-existing cardiac conditions or electrolyte abnormalities, and using the lowest effective dose for the shortest duration possible. Early research suggests HCQ may inhibit SARS-CoV-2 virus in vitro but large clinical trials are still needed to determine safety and efficacy for COVID-19.

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    HCQ Cardiotoxicity

    Uploaded by

    paidisuri
    23 views28 pages
    HCQ can cause cardiotoxicity through several mechanisms including QT interval prolongation and conduction disorders. Risk factors include higher cumulative doses over many years, older age, renal or liver dysfunction, and concomitant medications affecting cardiac conduction. Diagnosis involves cardiac MRI, biopsy, and electrocardiogram monitoring. Recommendations include avoiding HCQ in those with pre-existing cardiac conditions or electrolyte abnormalities, and using the lowest effective dose for the shortest duration possible. Early research suggests HCQ may inhibit SARS-CoV-2 virus in vitro but large clinical trials are still needed to determine safety and efficacy for COVID-19.

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    HCQ

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    HCQ can cause cardiotoxicity through several mechanisms including QT interval prolongation and conduction disorders. Risk factors include higher cumulative doses over many years, older age, renal or liver dysfunction, and concomitant medications affecting cardiac conduction. Diagnosis involves cardiac MRI, biopsy, and electrocardiogram monitoring. Recommendations include avoiding HCQ in those with pre-existing cardiac conditions or electrolyte abnormalities, and using the lowest effective dose for the shortest duration possible. Early research suggests HCQ may inhibit SARS-CoV-2 virus in vitro but large clinical trials are still needed to determine safety and efficacy for COVID-19.

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    Download as pptx, pdf, or txt
    23 views28 pages

    HCQ Cardiotoxicity

    Uploaded by

    paidisuri
    HCQ can cause cardiotoxicity through several mechanisms including QT interval prolongation and conduction disorders. Risk factors include higher cumulative doses over many years, older age, renal or liver dysfunction, and concomitant medications affecting cardiac conduction. Diagnosis involves cardiac MRI, biopsy, and electrocardiogram monitoring. Recommendations include avoiding HCQ in those with pre-existing cardiac conditions or electrolyte abnormalities, and using the lowest effective dose for the shortest duration possible. Early research suggests HCQ may inhibit SARS-CoV-2 virus in vitro but large clinical trials are still needed to determine safety and efficacy for COVID-19.

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    HCQ CARDIOTOXICITY

    Pharmacokinetics
    • HCQ differs from CQ by the presence of
    a hydroxyl group on one of the ethyl groups
    attached to nitrogen in the side chain.
    • Well absorbed
    • Reach steady-state after five half-lives, i.e., 1–
    3 months (half- lives are in the range of 10–30
    days for CQ and 3–20 days for HCQ).
    • After withdrawal, the decrease in tissue
    concentration is about 90–95% in 15 days

    • Similar profile between both drugs in their


    direct comparison of effectiveness and toxicity

    • McChesney EW, Banks WFJ, Sullivan DJ. Metabolism of chloroquine and


    hydroxychloroquine in albino and pigmented rats. Toxicol Appl Pharmacol.
    1965;7:627–36.
    • Scherbel AL, Harrison JW, Atdjian M. Further observations on the use of 4-
    aminoquinoline compounds in patients with rheumatoid arthritis or related
    diseases. Cleve Clin Q. 1958;25:95–111.
    Toxicity
    • Gastro and Neuromyopathy- most common
    • Retinopathy
    • Cardiotoxicity rare

    • Risk for toxicity is less with <5.0 mg/kg real weight/day


    for hydroxychloroquine and <2.3 mg/kg real weight/day
    for chloroquine.
    • Patients are at low risk during the first 5 years of
    treatment

    • Marmor MF et al, for the AAO. Recommendations on Screening for Chloroquine and
    Hydroxychloroquine Retinopathy. Ophthalmology. 2016;123:1386-94
    • Factors associated with hydroxychloroquine
    toxicity include the following:
    • Maintenance dose greater than 5 mg/kg/d based on real
    weight (most critical risk)
    • Cumulative dose greater than 1000 g
    • Age older than 60 years
    • Factors associated with chloroquine toxicity
    include the following:
    • Maintenance dose greater than 2.3 mg/kg/d
    • Obesity
    • Factors associated with toxicity in both drugs
    include the following:
    • Duration of treatment greater than 5 years (critical
    factor)
    • Tamoxifen use (5-fold risk)
    • Evidence of renal insufficiency
    • Evidence of liver disease
    • P450 polymorphisms leading to higher drug
    concentration in blood

    • Mason CG. toxicity of certain systemically administered drugs. J Toxicol Environ


    Health. 1977 May. 2 (5):977-95.
    • The lethal dose of the drug is not well established, although severe
    symptoms occur with ingestion of 4 gm, and fatalities have been
    associated with ingestion of 12 gm.

    • Acute Hydroxychloroquine Overdose: Case Report, Literature Review, And Management Recommendations Am J
    Respir Crit Care Med 181;2010:A6080
    • Chloroquine exhibits a fast open hERG (human ether-a-go-
    go-related-gene) channel block(voltage gated potassium
    channel IKr ), delay cardiac repolarization, can prolong the
    QT interval and increase the risk of torsades de pointes.
    • Inhibitory effects of HCQ on the
    hyperpolarization activated current ion
    channels (also known as “funny current”
    channels,  If), along with delayed rectifier
    potassium currents ( IKr), and L-type calcium
    ion currents ( ICaL)

    • R. Capel, N. Herring, M. Kalla et al., “Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current
    if: novel electrophysiological insights and therapeutic potential,” Heart Rhythm, vol. 12, no. 10, pp. 2186–2194, 2015.
    • HCQ presents a risk, not just in an acute overdose,
    but also with chronic use, especially in patients with
    underlying hepatic or renal diseases.
    • Haran et al., Hydroxychloroquine-Induced Cardiomyopathy: Case Report, Pathophysiology, Diagnosis, and
    Treatment Canadian Journal of Cardiology 2014.08.016.
    • Two main clinical • Out of 127 patients
    manifestations • Conduction disorders 85%
    reported are • Ventricular hypertrophy
    conduction disorders (22%)
    (bundle or • Hypokinesia (9.4%)
    atrioventricular block) • Heart failure (26.8%)
    and myocardial • Pulmonary arterial
    hypertension (3.9%)
    hypertrophy.
    • Valvular dysfunction (7.1%).
    • Outcomes after drug withdrawal reported in
    78 patients
    • Complete recpvery in 44.9% of cases, but with
    unfavorable progression in others, with
    irreversible damage (10.3% with pacemakers),
    deaths (30.8%), or heart transplant (2.6%).
    Extra cardiac toxicity
    • Risk factors for the development of HCQ-induced
    cardiotoxicity are
    • Older age
    • Female sex
    • Longer duration of therapy (>10 years)
    • Elevated perkilogram daily dose
    (>6.5mg/kg/day)
    • Pre-existing cardiac disease
    • Renal insufficiency.
    • Treatment duration prior to the diagnosis
    of cardiomyopathy ranged from 3 months
    to 27 years (mean 10 years).
    Diagnosis
    • Cardiac MRI
    – Non specific
    – Left ventricular or biventricular hypertrophy with
    increased wall thickness, hypokinesia and systolic
    dysfunction.
    – Patchy delayed contrast enhancement
    • Endomyocardial Biopsy
    • Light microscopic study found vacuolization in 100% of
    myocytes.
    • Positive periodic acid–Schiff staining of enlarged granule
    containing myocytes suggested an accumulation of
    polysaccharides.
    • Frustaci et al. explored the clinico-pathologic pathway of
    lysosomal hydrolase activity in heart biopsies collected
    before and after recovery, from a patient experiencing
    cardiomyopathy induced by CQ/HCQ therapy, They found
    that activity of alpha-galactosidase A, beta-galactosidase,
    and arylsulfatase was inhibited in affected cardiomyocytes.
    Recommendations
    • HCQ is not recommended for use in patients
    with
    – Baseline QTc prolongation (e.g., congenital or
    acquired Long QT Syndrome)
    – Second-or third-degree atrioventricular block.
    – Electrolyte imbalances (e.g. hypokalemia/
    hypomagnesemia/ hypocalcemia) must be
    corrected prior to use.

    * Product monograph
    (https://www.canada.ca/en/health-canada.html)
    • Use of HCQ should be undertaken with
    extreme caution in patients with risk factors
    for torsade de pointes.
    • Risk factors for torsade de pointes in the general population include, but are
    not limited to, the following:

    • Heist EK and Ruskin JN (2005). Drug-induced proarrythmia and use of QTc prolonging agents: Clues for clinicians. Heart
    Rhythm 2(11):S1-S8.
    • Concomitant use with other QTc, PR or QRS
    interval prolonging drugs should be avoided or

    undertaken with particular caution.


    Class IA, IC and III antiarrhythmics
    Antidepressants, antipsychotics
    Domperidone
    5-hydroxytryptamine (5-HT)3 receptor Antagonists
    Histone deacetylase inhibitors
    Beta-2 adrenoceptor agonists
    • The magnitude of QT, PR or QRS prolongation
    with HCQ may increase with increasing
    concentrations of the drug.
    • Therefore, the recommended dose should not
    be exceeded (daily doses should not exceed 5
    mg (salt form)/kg ideal (lean) body weight).
    HCQ COVID 19
    • HCQ appears to be safer and more potent in inhibiting
    the causative virus, severe acute respiratory
    syndrome coronavirus 2 (SARS-CoV-2), in vitro.
    • The numerous molecular mechanisms by which they
    can achieve such results remain to be further
    explored.
    • Impair early stage of virus replication by interfering with the pH-
    dependent endosome-mediated viral entry
    • Immunomodulatory effect of HCQ inhibiting the cytokine storm
    by suppressing T cell activation.
    • Early reports of in vivo use have been
    promising.
    • However, no randomized clinical trials have
    been conducted to inform clinical guidance on
    the use, dosing, and duration of
    chloroquine/hydroxychloroquine for
    prophylaxis or treatment of COVID-19.

    • Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J
    Antimicrob Chemother. 2020 Mar 20.
    • Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, 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). Clin Infect Dis. 2020 Mar 9.
    • Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int
    J Antimicrob Agents. 2020 Mar 11. 105938.

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