Table 1.

The cardiovascular risks of potential anti-COVID-19 drugs

Drugs	Pharmacologic mechanism	Evidences of anti-COVID-19	FDA approved Indications	Clinical trials for COVID-19#	CV drug interactions	Cardiovascular risks	Other organ toxicity	Ref.
Anti-viral drugs
Remdesivir	A nucleotide prodrug, transforming to adenosine analogue, causing RNA pre-mature termination and inhibiting viral replication	• Reducing viral copy numbers in SARS-CoV-2 and binding to the active site on RNA polymerase of SARS-CoV-2	RSV, Junin virus, Nipah virus, Hendra virus, and research on Ebola virus	NCT04302766 NCT04280705 • NCT04292730; NCT04292899*	A substrate of CYP2C8, CYP2D6, CYP3A4, and transporters OATP1B1 and P-gp but due to rapid distribution, metabolism and clearance, drug interaction is minimal.	CV toxicity has yet to be reported	Liver toxicity (rare)	14, 15, 17, 73
Atazanavir	An analog of the peptide chain substrate binding to the active site HIV protease and preventing the pro-form of viral proteins cleaving into the working form.	Binding to SARS-CoV-2 3C-like proteinase (3CLpro); Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine in vitro experiments	HIV	Not yet lunched	An inhibitor of CYP3A4, UGT1A1, CYP2C8, and OATP1B1	Dose-dependent PR and QTc prolongations	Liver toxicity	21–24
Ritonavir/lopinavir	A nucleoside analogue and protease inhibitor of HIV; SARS, MERS?	Binding to SARS-CoV-23C-like proteinase (3CLpro); Though no significant benefits in clinical improvement and mortality in a randomized clinical trial (ChiCTR2000029308)	HPV; HIV	NCT04252885 NCT04275388 NCT04276688 NCT04286503 NCT02845843 NCT04307693 NCT04261907 NCT04295551 NCT00578825	Inhibitors of CYP3A and drug transporters such as P-gp, BCRP, and OATP1B1	PR/QTc prolongation; rare reports of 2nd or 3rd degree AVB; lopinavir/ritonavir; decreased serum concentrations of clopidogrel and prasugrel but increase statins, ticagrelor, rivaroxaban, and apixaban	Liver toxicity, pancreatitis, GI upset, neurotoxicity	22, 26, 28, 29, 33, 42, 73
Favipiravir	A selective inhibition of viral RNA-dependent RNA polymerase	Suppressing viral RNA-dependent RNA polymerase of SARS-CoV-2; in vitro?	Influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus	NCT04303299 (THDMS-COVID-19); NCT04310228; ChiCTR2000029600 (plus IFN-α)	Only a weak inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4	Minimal clinically significant drug interactions	Not reported	34–38
Ribavirin	A nucleoside inhibitor, stopping viral RNA synthesis and mRNA capping	Binding to the active site on RNA polymerase on SARS-CoV-2; in vitro?	HCV, RSV and some viral hemorrhagic fevers	NCT04276688	No report of cytochrome P450 enzyme mediated metabolism of ribavirin.	Ribavirin has no characterized direct CV toxicity; ribavirin has variable effects on warfarin dosing	Liver toxicity, hematologic disorder	40, 43, 44
Ivermectin	An influx of Cl− ions through the cell membrane of invertebrates by activation of specific ivermectin-sensitive ion channels.	Inhibiting the nuclear transport activity of SARS-CoV-2; currently on in vitro study	Head lice, scabies, strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis	Not yet lunched	An inducer of several cytochrome P450 isoenzymes, including CYP1A, 2B, and 3A	Tachycardia, orthostatic hypotension, PR interval prolongation	Dermatitis, GI upset	4, 45–51
Immune-modulating drugs
Chloroquine/hydroxychloroquine (HCQ)	Sequestering protons in lysosomes to increase the intracellular pH; interfering with the glycosylation of its cellular receptor, ACE2; reduce the viral copy number of SARS-CoV-2.	Reducing viral copy numbers in SARS-CoV-2; Under debates between China and France?	Anti-malaria. Treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda	NCT04286503 NCT04303507 NCT04307693 NCT04261517 NCT04303299 NCT04334512 More than 50 ongoing trials combined with Zithromax, vitamin, zinc	Metabolism by CYPs 2C8, 3A4 and 2D6 (increased concentration beta-blockers)	Intermediate-to-delayed cardiotoxicity 1. Direct: restrictive or dilated cardiomyopathy 2. Altered conduction: AV block, bundle branch block, torsade de pointes, ventricular tachycardia/fibrillation	Neutropenia, seizure, blurred vision, GI upset	10, 12, 13, 37, 53, 55–59
Tocilizumab	Anti-IL-6 receptor monoclonal antibody	Anti-cytokine storm? In vitro?	Rheumatoid arthritis, juvenile idiopathic arthritis.	NCT04306705 (TACOS); NCT04320615 (COVACTA)	Reversal of IL-6 inducing suppression of CYP3A4, CYP2C19, CYP2C9, and CYP1A2, resulting in higher drug exposure of substrate drugs	Hypertension, increased serum cholesterol; no known effect on QTc interval	Allergic reaction, susceptible to infection	62–68
Interferon-β1	A cytokine produced by innate immune cells, including macrophages, dendritic cells, and non-immune cells	Recognizing viral components by pattern recognition receptors (PRR) (Liu, 2005)	Multiple sclerosis	NCT04293887	Reduce the activity of hepatic cytochrome P450-dependent enzymes	No clinically significant effects on QTc prolongation have been observed. PVC and AVB case report	Flu-like symptoms	69–72, 74, 86
Fingolimod	An oral immune-modulating agent with high potent of functional antagonist on the lipid sphingosine-1-phosphate (S1P) receptors in the lymph node T cells	As an effective immunology modulator, fingolimod with potentials of anti-SARS-CoV-2	Multiple sclerosis, refractory	NCT04280588	Metabolism by CYP4F2. Us in caution when combined with class Ia and III anti-arrhythmic agents and beta-blockers	Pros: Arthero-protection, anti-hypertrophy Cons: Bradycardia, AVB, hypertension	Liver toxicity, headache, GI upset, flu-like symptoms	80–84

The FDA-approved CV drugs involved with COVID-19

CV cardiovascular, GI gastrointestinal, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, RNA ribonucleic acid, RSV respiratory syncytial virus, HIV human immunodeficiency virus, HPV human papillomavirus, AVB atrioventricular block

^#Clinical trials summarized here till April 13, 2020