Antimalarials

Since the onset of COVID-19 pandemic, antimalarials (hydroxychloroquine and chloroquine) potential beneficial use was hypothesized, Food and Drug Administration (FDA) authorized its emergency use promptly¹⁵. Later, new clinical information studies¹⁶,¹⁷ have found that hydroxychloroquine did not show benefits for patients with COVID-19 and did not prevent viral exposed, so the use was discontinued.

Currently, these drugs are not recommended for this indication

Hydroxychloroquine and chloroquine have immunomodulatory properties, inhibit viral entry, by increase endosomal and lysosomal pH and attenuating virus ability to release its genetic material into the cell¹⁵. Its use can result in retinopathy and ototoxicity¹⁴. Hypoglycemia, neurological alterations, and hepatotoxicity were reported. Patients with renal failure require correction dose¹⁴.

Antimalarials produce CV alterations, it modulates coronary arterial vasodilation by nitric oxide production reductions in coronary artery endothelial cells. On the other hand, antimalarials alter diastolic performance, and produces myocardial fibrosis and arrhythmias¹⁵. Cardiotoxicity and cardiac AE were associated to long-term used and dose dependent¹². Ventricular arrhythmias and torsade de pointes were reported¹³,¹⁴. Bundle branch block, atrioventricular block, and prolonged QT were associated (< 10%)¹⁴. Baseline and follow-up electrocardiography were recommended¹²,¹⁴. Antimalarials increase levels of mammalian target of rapamycin inhibitors, calcineurin inhibitors, and beta-blockers. Aspirin decreases antimalarial levels. Antimalarials with antiarrhythmics are contraindicated for prolongation of the QT interval¹⁴ (Table 1).

Antivirals

Protease inhibitors such as lopinavir/ritonavir and darunavir/ritonavir are antiviral combinations, who demonstrated inhibition activity against coronaviruses¹¹-¹⁴. Some AE are gastrointestinal such as nausea and diarrhea, and hepatotoxicity, increased alanine aminotransferase (ALT) serum levels and pancreatitis. Hematological: hemolytic anemia, neutropenia, and increase bleeding were reported. Hyperglycemia and skin reactions were seen.

Lopinavir/ritonavir regulates of fatty acid oxidation and cholesterol synthesis, increasing serum levels, and elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system, associated with depressed contractility and cardiac hypertrophy. An altered connexin 43 expression may be linked to perturbed gap junction assembly and arrhythmogenesis, it can precede ventricular fibrillation in rat models¹⁸.

CV AE was prolonged QT and PR intervals and 2^nd and 3^rd degree heart block¹¹-¹⁴. Hyperlipidemia was also associated. CV drugs such as antiarrhythmics amiodarone, flecainide, ivabradine, ranolazine, lovastatin, pitavastatin, and simvastatin are contraindicated¹⁴. Antivirals increase level of antiplatelets, beta-blockers, calcium channel blockers, digoxin, mineralocorticoids receptor agents, and direct oral anticoagulant. The use of antivirals with warfarin presented variable effects on the international normalized ratio (INR)¹⁴. Serious effects report and use alternative recommended with bosentan, propafenone, rivaroxaban, edoxaban, and sildenafil (Table 1).

Remdesivir is a nucleotide analog who inhibits viral RNA polymerases, FDA approved a compassionate use¹⁹. Remdesivir is a substrate of several cytochrome P450 enzymes in vitro, however, clinical implications are unclear since the pro-drug is rapidly metabolized by plasma hydrolases²⁰. Any CV action is ignored. General AE is increased hepatic enzymes, diarrhea, hypernatremia, and renal impairment. CV AE was seen in a compassionate study, deep vein thrombosis atrial fibrillation hypotension⁵ (Table 1). Wang et al.²¹ reported no serious CV AE (tachycardia and acute coronary syndrome).

Adjunctive therapies

Anthelmintics

Ivermectin is an FDA-approved anti-parasitic agent which was also proven to exert antiviral activities²⁴. AE was hepatic, neurological, skin reactions, and interference with Vitamin K metabolism²⁵ - CV interactions are not described. Hypotension and nonspecific electrocardiogram (EKG) changes were close monitoring. Interactions reported with antiarrhythmics, calcium channel blockers, statin, and warfarin²⁵ (Table 1).

Antibiotics

Azithromycin is a macrolide who prevents bacterial superinfection and may have immunomodulatory properties¹¹. It inhibits protein synthesis, decreases inflammation and viral replication²⁶. Also, reduces cyotkine reproduction¹, neutrophil chemotaxis and improves apoptosis¹¹,¹³,¹⁴. General AE reported was diarrhea associated to clostridium difficile, abnormal liver function, cholestatic jaundice, and myasthenia gravis symptoms¹⁴. Serious CV side effects are uncommon²⁷, however, they may include prolonged QT interval, risk of developing ventricular tachycardia, and torsades de pointes, especially in the elderly, in uncorrected hypokalemia or hypomagnesemia, in pre-existing QT interval prolongation or those taking anti-arrhythmic drugs²⁶,²⁷ (Table 1). The mechanism of induced QT prolongation is the inhibition of repolarization of cardiac cells through potassium channels²⁸.

Immunotherapy (immunoglobulin)

It is hypothesized that antibodies from recovered patients may help with both free virus and infected cell immune clearance¹¹. Anaphylaxis, myalgia, back pain, and nausea were the principal AE¹⁴. Supraventricular tachycardia and bradycardia were reported in patients who had history of heart disease²⁹, its mechanism is uncertain. Hypotension is a rare symptom related to immunoglobulin. Arterial or venous thrombosis was reported as serious AE²⁹. Related acute lung injury was associated, uses with caution.

Dexamethasone

Severe COVID-19 patients may present cytokine storm that is associated to lung involvement of acute respiratory distress syndrome (ARDS) and multiorgan failure⁸,⁹. A therapeutic that may modulate and antagonize viral mediated hyperinflammation is dexamethasone, a corticosteroid, that can inhibit pro-inflammatory mediators³⁰ such as C-reactive protein, tumor necrosis factor, IL, and also reduce the production of inflammatory autacoids³⁰ (prostaglandins, prostacyclin, leukotrienes, and thromboxane²⁶), observed in severe ARDS patients. Recent preliminary evidence suggests that dexamethasone reduced mortality in invasive mechanical ventilation in COVID-19 patients³¹. Dexamethasone had actions in several organs and systems (endocrine, metabolic, etc.). General AE includes hyperglycemia, alkalosis, potassium loss, sodium retention, increase of ALT/AST serum levels, acne, and urticaria. Myopathies, glaucoma, and depression were related. CV AE such as hypertension, edema, and heart failure deterioration was associated to secondary sodium retention. It increases the risk of developing venous thromboembolism. Bradycardia and arrhythmias were also associated.

Conclusions

The source of our references is based on recent publications as well as online technology applications with pharmacopoeia information.

We believe this article, describes an important clinical perspective that could improve hospital therapeutic considerations, personalized pharmacovigilance, contribute, and help in daily clinical practice, which we add just in one table.

In general, these studies are limited because most of the recent COVID-19 reviews are case reports, with small retrospective or non-randomized studies and regional bias. It is important to emphasize the CV-AE resulting from the interaction of both CV and COVID-19 medications.

Physiopathological, clinical, therapeutic, and pronostic interactions in a new disease are dynamically changing according to advances in scientific research.