key: cord-257344-d13at1y5 authors: Ghasemiyeh, Parisa; Mohammadi-Samani, Soliman title: COVID-19 Outbreak: Challenges in Pharmacotherapy Based on Pharmacokinetic and Pharmacodynamic Aspects of Drug Therapy in Patients with Moderate to Severe Infection date: 2020-09-18 journal: Heart Lung DOI: 10.1016/j.hrtlng.2020.08.025 sha: doc_id: 257344 cord_uid: d13at1y5 The new coronavirus (COVID-19) was first detected in Wuhan city of China in December 2019. Most patients infected with COVID-19 had clinical presentations of dry cough, fever, dyspnea, chest pain, fatigue and malaise, pneumonia, and bilateral infiltration in chest CT. Soon COVID-19 was spread around the world and became a pandemic. Now many patients around the world are suffering from this disease. Patients with predisposing diseases are highly prone to COVID-19 and manifesting severe infection especially with organ function damage such as acute respiratory distress syndrome, acute kidney injury, septic shock, ventilator-associated pneumonia, and death. Till now many drugs have been considered in the treatment of COVID-19 pneumonia, but pharmacotherapy in elderly patients and patients with pre-existing comorbidities is highly challenging. In this review, different potential drugs which have been considered in COVID-19 treatment have been discussed in detail. Also, challenges in the pharmacotherapy of COVID-19 pneumonia in patients with the underlying disease have been considered based on pharmacokinetic and pharmacodynamic aspects of these drugs. Wuhan city of China. The most common clinical signs and symptoms of these patients were dry coughs, fever, dyspnea, and bilateral infiltration in chest CT. All these patients were associated with Wuhan's Huanan Seafood Wholesale Market which sells fish and other live animals such as bats, poultry, snakes, etc. The causative agent, new coronavirus, was first detected through a swab sample which was drawn from the throat of these patients 4 . This new coronavirus was subsequently named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Soon this disease, which called coronavirus disease 2019 (COVID- 19) by World Health Organization (WHO), promptly spreads around the world 5 , and to date over 16.5 million cases have been diagnosed with COVID-19 and this disease became a pandemic. On the late January 2020 COVID-19 Chinese outbreak, were introduced as a public health emergency of international concern 6 . So although previously coronaviruses were considered as a potential cause of the common cold now we know that they are more than just the common cold! 1 Most of the COVID-19 infected patients have an average age of 50s, it is slightly more predominant in the male sex, approximately 25% of infected patients involved with severe disease were required to intensive care unit services and 10% of them were required to mechanical ventilation 3 . A published report from Italian patients revealed that COVID-19 was predominant in men (59.8% in male and 40.2% in female), most of the patients (about 75%) were over 50 years old, approximately 46% of all confirmed patients had mild disease, 25% had severe disease, 5% were in a critical situation, and rest of the patients showed few symptoms, unspecified symptoms or were completely asymptomatic 7 . According to recently published researches, the most common clinical presentations in COVID-19 patients were fever in 83% to 98% of patients, dry cough in 76 to 82%, and fatigue or myalgia in 11 to 44% of them. Other signs and symptoms which have been reported include sore throat, headache, confusion, rhinorrhea, sneezing, ageusia, anosmia, chest pain, hypoxemia, pneumonia, hemoptysis, acute cardiac injury, neurologic complications 8, 9 , and gastrointestinal presentations such as nausea, vomiting, diarrhea and abdominal pain 3, 10-12 . Patients with underlying diseases are highly prone to present with severe infection especially with organ function damage such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), septic shock, and ventilator-associated pneumonia (VAP) 10, 13 . Severe COVID-19 could cause death due to huge alveolar damage and highly progressive respiratory failure 14 . COVID-19 particles could spread through the respiratory mucosa 10 and fecal-oral route 11 . The nucleic acid of the virus was detected in stool, saliva, and respiratory specimens 11 . This virus could be transmitted between humans during the epidemic and then pandemic of COVID-19. Human-to-human transmission could highly accelerate the spread of this virus around the world. This type of transmission among humans is restricted to close contact and through sneezing or coughing of the infected patients who are capable to spread the respiratory droplets. Then these respiratory droplets could settle in oral mucosa and lung of the people who inhaled the contaminated air near (about 6 feet) to the infected patients 15, 16 . Although some researches have been focused on the airborne transmission of this virus but this route of transmission has not been approved yet and further studies are required. Researches revealed that COVID-19 could also be transmitted through asymptomatic carriers with an incubation period of 1 to 19 days 17 . In order to prevent spreading of this new virus: hands should be washed frequently, the face should not be touched with unwashed hands, regular surface disinfecting is required, social distancing from people with respiratory symptoms is essential, sneezing or coughing should be done into the elbow or soft tissue if available 16 . Based on the published reports, in most of the patients with COVID-19, the absolute value of lymphocytes was reduced, which indicated that this novel coronavirus (COVID-19) acts more on lymphocytes especially T lymphocytes, just similar to SARS coronavirus 10 . It seems that COVID-19 could induce a cytokine storm and activate immune responses which could be appeared as changes in the number of white blood cells and immune cells especially lymphocytes, the clinical outcome of such events would be respiratory distress syndrome, septic shock and finally end-organ damage 10 . COVID-19 could also affect the liver which could be presented as hypoproteinemia, elevated aminotransferases, and prolonged prothrombin time. Hepatotoxicity could be attributed to the higher expression of angiotensin converting enzyme II (ACE2) in cholangiocytes, ACE2 could act as an entry receptor for COVID-19. So it seems that this new virus can directly damage the intrahepatic bile ducts 11 . Pathological findings of a liver biopsy from a patient with COVID-19 showed moderate micro-vesicular steatosis and also a mild portal and lobular activity which could be a result of direct SARS-CoV-2 liver damage or antiviral drug-induced hepatotoxicity 14 . Almost all COVID-19 patients had abnormal lung CT when diagnosed. According to the recently published article, an average of 10.5±6.4 segments were involved in patients and the number of involved lung segments was significantly higher in symptomatic patients group in comparison to asymptomatic ones. CT findings revealed that affected COVID-19 patients could present as bilateral lung involvement, peripheral distribution, or diffuse distribution. The most common presentation in chest CT was ground-glass opacity pattern, consolidation, and ill-defined margins 18, 19 . Laboratory confirmation of steatosis could be performed by real-time reverse-transcription polymerase chain reaction (rRT-PCR) 20, 21 . According to WHO approved laboratory testing for COVID-19 diagnosis is based on nucleic acid amplification test (NAAT) such as rRT-PCR which could detect the sequence of the RNA of COVID-19 22 . Governments need to appreciate people to obey social distancing and isolation. In some situations, quarantine of major cities is also suggestive. Global health governance should apply the least restrictive measures for people according to the International Health Regulations (IHR) 23, 24 . Scientists around the world are looking for drugs that could be beneficial in COVID-19 treatment. Many drugs have been studied that are listed in Table 1 with the usual dosage ranges in adults and pediatrics. The latest Guidelines for the Prevention, Diagnosis, and Treatment of Novel Coronavirus-induced Pneumonia, have been suggested antiviral agents containing: Interferon alpha (IFN-α), lopinavir/ritonavir, chloroquine phosphate, ribavirin, and arbidol as potential options in COVID-19 treatment 25 . Drugs that have been considered in COVID-19 management have been classified as investigational drugs, drugs under clinical trials, and drugs that have received U.S. Food and Drug Administration (FDA) as shown in Table 2 . 42 . Although many previous studies emphasized the potential therapeutic effects of these drugs in COVID-19 management, unfortunately some recent publications reported that the efficacy of chloroquine/hydroxychloroquine in COVID-19 management is not consistent. Also, their safety is still remaining a major concern for physicians and pharmacists, since chloroquine/hydroxychloroquine could cause QT prolongation and arrhythmia. Since the possible risks of these drugs could overweigh their potential benefits and efficacy, United States Food and Drug Administration (FDA) no longer recommended these two drugs as potential options for COVID-19 management 43 . Results of a systematic review on the efficacy of hydroxychloroquine or chloroquine on the prevention or treatment of COVID-19 revealed that the available evidences on their benefits and risks are weak and controversial 44 . Results of another systematic review and meta-analysis on 53 randomized clinical trials on administration of hydroxychloroquine in COVID-19 management revealed that hydroxychloroquine administration (case group) was significantly associated with higher incidence of total adverse effects in comparison to placebo or no treatment (control group) in overall population of patients with COVID-19 45 . So, the recruitment of chloroquine/hydroxychloroquine in COVID-19 management is still controversial and further larger multi-center randomized clinical trials are required to evaluate their efficacy, safety, risk-benefit ratio, dose and duration of individualized pharmacotherapy. Also, close patient monitoring, especially cardiac, ocular, and neurotoxicity assessments, are required and strongly recommended during drug administration 46 . Recently published studies revealed that chloroquine could highly reduce COVID-19 replication 40 . Chloroquine is a weak base that could be entrapped in organelles that are membrane-enclosed and have low-pH, so interfering with their acidification process. Therefore chloroquine could inhibit pH-dependent viral fusion and replication. Also, it might inhibit viral assembly in endoplasmic reticulum-Golgi intermediate like structures 47 . Another possible antiviral mechanism of chloroquine is its immunomodulatory effect through cell signaling pathways and regulating the action of proinflammatory cytokines that can enhance its antiviral effect synergistically 40, 48, 49 . Chloroquine/hydroxychloroquine could prevent from COVID-19-induced ARDS by attenuating the pro-inflammatory cytokines and receptors 47 . Hydroxychloroquine can enhance intracellular pH and avoid lysosomal activity in antigen presenting cells containing B cells, also they can avoid antigen processing and MHC-II presentation to T cells. So, T cell activation could be reduced by the action of hydroxychloroquine. It can suppress the cytokine release syndrome (CRS), which is a result of immune system over-activation, caused by COVID-19. According to this mechanism, hydroxychloroquine could alleviate symptoms of mild to severe COVID-19 pneumonia 38 . Chloroquine has different adverse reactions such as cardiovascular adverse reactions 50 . Also the results of a systematic review on dermatologic adverse effects of hydroxychloroquine emphasized that the most common dermatologic reactions due to hydroxychloroquine administration were rash, SJS, toxic epidermal necrolysis (TEN), pruritus, hyperpigmentation, and hair loss. These dermatologic reactions were mostly occurred after cumulative dosages of hydroxychloroquine 51 . In overall, since hydroxychloroquine has lower tissue accumulation potential in comparison with chloroquine, it has fewer adverse drug reactions and would be better choice 38 . Contraindications in chloroquine use contains hypersensitivity to chloroquine (4-aminoquinolone compounds) and the presence of retinal or visual field changes 52 . Chloroquine and hydroxychloroquine have a narrow therapeutic index and poisoning could be occurred with cardiovascular features so it should be used with caution in patients with predisposing cardiovascular disease 37 . Long-term exposure to these drugs could induce cardiomyopathy 38 . Chloroquine in patients consuming heparin, prone the patients to risk of bleeding. Also, chloroquine in patients with digitalization (using digoxin) could cause cardiac block 27 . There is no dosage adjustment available for chloroquine or hydroxychloroquine in patients with hepatic failure but it should be used with caution 52 . There is no dosage adjustments available for chloroquine in patients with renal failure from the manufacture's labeling but according to UpToDate some clinicians use the following guideline 52 : A) Patients with GFR ≥ 10 ml/min: No dosage adjustment is required. B) Patients with GFR < 10 ml/min: Dosage should be reduced to 50%. C) Patients with peritoneal-or hemodialysis: Dosage should be reduced to 50%. required. There is no dosage adjustments available for hydroxychloroquine in renal failure but it should be used with caution 52 . Although some studies showed a low risk of congenital abnormalities in patients receiving chloroquine during pregnancy because of the lack of a pattern in these congenital defects, the possible association is unlikely and it seems that the benefits of its use are higher than risks 53 . Hydroxychloroquine use during pregnancy could not be accompanied by risks for fetuses, especially in low doses. But patient monitoring during pregnancy is required 53 . In general, since chloroquine may induce severe side effects during fetal development, so hydroxychloroquine would be a better option in pregnant women with COVID-19 infection because of its safety profile during pregnancy 38 . According to the American Academy of Pediatrics, chloroquine is compatible with breastfeeding. Although it could be excreted into the milk, this amount was not considered harmful for nursing infants 53 . According to the American Academy of Pediatrics, hydroxychloroquine is compatible with breastfeeding. Small amounts of hydroxychloroquine could be excreted to the milk, but because of the slow elimination rate and the possibility of drug accumulation and toxicity, breastfeeding during hydroxychloroquine therapy should be done with caution 53 . Umifenovir is a broad-spectrum antiviral agent which is effective against enveloped and nonenveloped RNA or DNA viruses especially against influenza virus type A and B, respiratory syncytial virus, SARS-CoV, adenovirus, hepatitis C virus (HCV), etc. Umifenovir was first developed in Russia and now its usage is more common in Russia and China and is less common in western countries. Its possible antiviral mechanism is the inhibition of viral fusion with targeted membrane and preventing from the viral entrance to targeted cells 54 . Umifenovir has a dual pharmacologic action: First is its beneficial effect on respiratory viruses such as the COVID-19 virus and the second is its immune-stimulating function which can activate serum interferon and phagocytes. Since 2004, umifenovir was patented for its beneficial effect in the treatment of severe acute respiratory distress (SARS) coronavirus-induced atypical pneumonia 55 . Results revealed that umifenovir can induce direct viricidal effect so it would be a promising direct-acting antiviral (DAA) agent. Umifenovir could affect critical stages of viral life cycles such as cell attachment, cell internalization, viral replication, assembly, and budding so it also would be a promising host targeting agent (HTA). Its dual pharmacologic function is related to its potential interaction with both cell membranes and with cellular and viral lipids and proteins 55 . The most important adverse reactions associated with umifenovir are diarrhea, nausea, vomiting, dizziness, confusion, and elevated liver enzymes (serum aminotransferases) 27 . Umifenovir is an indole derivative with poor water solubility which could affect its bioavailability and pharmacokinetics. After oral administration of umifenovir, it could rapidly distribute to organs and tissues, maximum plasma concentration (C max ) was achieved after 1 to 1.5 hours. In the Russian population, it had elimination half-life (t ½) of 17 to 21 hours, but t ½ was shorter in the Chinese population. After multiple-dose administration of umifenovir, little drug accumulation could be predictable. The main site of drug metabolization is the liver. Umifenovir could undergo several metabolism pathways such as oxidation at the S site, Ndemethylation, glucuronidation, and conjugation at 5-hydroxy moiety. The potential antiviral effects of umifenovir metabolites are unknown until now 55 . Since the major site of umifenovir metabolization is in the liver, so it should be used with caution in patients with predisposing liver diseases. Animal data revealed that umifenovir therapy couldn't induce embryo-toxic effects during pregnancy. According to these results umifenovir would be a promising safe and well-tolerated antiviral agent in pregnancy with a wide therapeutic index in administration for a few days up to one month 55 . Ribavirin is a nucleoside antihepaciviral agent (anti-HCV) which has been suggested for COVID-19 treatment. Ribavirin is a direct-acting antiviral (DAA) agent 56 . Ribavirin is a nucleoside analog that has antiviral action against a variety of RNA and DNA viruses. The potential antiviral activity of ribavirin is inhibition of inosine monophosphate dehydrogenase (IMPDH) cellular protein and therefore intracellular GTP would be diminished which inhibits RNA replication of viral genomes, so viral growth might be stopped. Another possible antiviral activity of ribavirin is its immunomodulatory effects by suppression of IL-10 57 . Ribavirin also could inhibit RNA polymerase activity and therefore inhibition of RNA fragments' initiation and elongation, so viral protein synthesis could be inhibited. The Ribavirin is contraindicated in patients with hypersensitivity to ribavirin, pregnant women and their partner, patients with severe renal failure, patients with severe hepatic failure, and patients with major hemoglobinopathies such as sickle cell anemia and major thalassemia 52 . Ribavirin distribution could significantly prolonged in erythrocytes for about 16 to 40 days, which is responsible for ribavirin-induced anemia 58 . Ribavirin has hepatic metabolism. Its oral bioavailability (F) is about 64%. Ribavirin elimination half-life (t ½) in the normal population is 24 hours but in patients with pre-existing chronic hepatitis C infection, half-life could be increased to 44 hours. So because of its prolonged half-life and potential overdose toxicity, ribavirin is contraindicated in patients with hepatic failure (Child-Pugh class B and C). Time to peak level (T max ) after oral administration is between 2 to 3 hours. Ribavirin excretion could take place through both urine and feces routes. Because of its renal elimination, dose adjustment in patients with underlying kidney disease is highly essential. According to the previous pharmacokinetic/pharmacodynamic study, Bayesian therapeutic drug monitoring would be a suitable approach to control ribavirin-induced anemia [41] . One of the most important side effects of ribavirin is hemolytic anemia which could worsen cardiac disease in patients with underlying cardiac diseases and it could induce fatal or non-fatal myocardial infarction in them. So ribavirin should be avoided in patients with a history of unstable or severe cardiac diseases. Ribavirin is contraindicated in patients with hepatic decompensation (Child-Pugh class B and C). Ribavirin dosage adjustment in patients with renal failure highly depends on different formulations which are available. These data are shown in Table 3 52 . In children, if serum creatinine level rises over 2 mg/dl during administration, ribavirin should be discontinued promptly 27 . Ribavirin has teratogenic and mutagenic effects. So it is a high-risk drug in pregnancy according to animal data. Also because of its half-life of 12 hours in multiple-dose drug therapy and the possibility of drug accumulation in tissue compartments for up to 6 months, ribavirin administration is contraindicated in pregnant women and also in men who are pregnant women's partner. It was suggested that pregnancy should be avoided during ribavirin therapy and at least 6 months after completion of therapy in women or men 53 . Ribavirin because of the prolonged plasma elimination half-life and molecular weight of 244 Da, potentially would have toxicity in nursing infants but there are no human data available 53 . Ribavirin may precipitate hematologic adverse effects of organ transplantation regimen such as immunosuppressive agents (mycophenolate mofetil, azathioprine, mTOR inhibitors), Trimethoprim/sulfamethoxazole, and valganciclovir. These hematologic adverse reactions would also worsen hematologic reactions related to COVID-19. So close patient monitoring is essential. 62 . Also, lopinavir would be a promising drug of choice in children with COVID-19 27 . Lopinavir/ritonavir are protease inhibitor, anti-retroviral agents. The potential antiviral mechanism of lopinavir/ritonavir is inhibition of viral protease, which is a critical enzyme in viral maturation and infectivity. Low dose ritonavir in combination with lopinavir act as a pharmacokinetic enhancer by inhibition of lopinavir inactivation metabolism 63 . The Since lopinavir undergoes hepatic metabolism through CYP3A4 enzyme, potential drug-drug interactions could occur with all drugs that are strong inhibitors or inducers of CYP3A4 enzyme and P-glycoprotein inhibitors. Also, ritonavir has hepatic metabolism via CYP3A4 and CYP2D6. Ritonavir has serious and life-threatening drug interactions with sedative-hypnotic agents, antiarrhythmic drugs, and ergot alkaloid agents because of the effect of ritonavir on their hepatic metabolism through CYP3A4 AND CYP2D6. Concurrent use of these agents with ritonavir is absolutely contraindicated and should be avoided 52 . Lopinavir/ritonavir is contraindicated in patients with a history of hypersensitivity reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, angioedema, etc. to lopinavir/ritonavir or its components 52 . absorption and oral bioavailability are highly affected by fasting or fed state, its absorption, bioavailability, and peak level (C max ) could be significantly increased with food. But food can delay T max from 2 hours in fasting state to 4 hours in the fed state. Ritonavir also has small renal elimination so dosage adjustment is not required in patients with underlying kidney disease 52 . Lopinavir/ritonavir have major interactions with drugs used in cardiovascular diseases such as anti-coagulating agents (anti-factor Xa inhibitors), none dihydropyridine calcium channel blockers, digoxin, antiarrhythmic agents such as amiodarone, etc. So close patient monitoring is required in COVID-19 patients with pre-existing cardiovascular disease who are planned to treat with lopinavir/ritonavir and sometimes alternative drugs might be considered 52 . In patients with mild to severe hepatic failure, there is no dosage adjustments available but lopinavir has primary liver metabolism and its AUC will be increase by about 30 %, so it should be used with caution 52 . There is no dosage adjustments based on renal function according to the manufacture's labeling 52 . Results revealed that embryo-fetal risk of lopinavir/ritonavir is low, so it is compatible with pregnancy and should not be stopped during pregnancy 53 . Lopinavir and ritonavir with a molecular weight of 629 and 721 Da respectively and their lipid solubility nature, are good candidates for excretion to milk during lactation period but their high plasma protein binding could limit this excretion. A comprehensive data is not available yet. It has been recommended that breastfeeding during lopinavir/ritonavir therapy is better to be avoided especially in developed countries 53 . Immunosuppressive agents are critical drugs in patients undergone solid organ transplantation. Lopinavir/ritonavir cannot be administered in combination with immunosuppressive agents because of the occurrence of strong drug interactions. Lopinavir/ritonavir can enhance the plasma level of immunosuppressive agents such as calcineurin inhibitors and mTOR inhibitors. So if co-administration is essential, immunosuppressive agents dose reduction and therapeutic drug monitoring, to maintain optimum immunosuppressive plasma level, is highly recommended. It has been suggested that during COVID-19 treatment, calcineurin inhibitors (ex. cyclosporine and tacrolimus) and mTOR inhibitors (ex. sirolimus and everolimus) could be discontinued and replaced with lopinavir/ritonavir but it seems that the benefit of this drug discontinuation could not overlay the risk of allograft transplant rejection 66 . Tocilizumab is an interleukin-6 (IL-6) inhibitor which is a disease modifying anti-rheumatic agent 67 . A small retrospective observational study on COVID-19 pneumonia patients receiving tocilizumab revealed that this drug would have potential benefits in these patients such as Since an active immune response against respiratory viruses such as COVID-19 is highly dependent on cytotoxic T cells' action, so in patients with total T cell count of fewer than 800 cells/µL, aggressive intervention is essential. One of the possible approaches in enhancing T cell count in these patients is the administration of tocilizomab, because there is a reverse relationship between T cell count and the number of cytokines such as IL-6 70 . IFN-α is a broad-spectrum antiviral agent that is commonly used in hepatitis management. After Corticosteroids are a double-edged sword, they can inhibit our immune response and so the clearance of COVID-19 could be delayed, but on the other hand, they can suppress our inflammatory response which is highly responsive to the lung damage and ARDS during viral Convalescent plasma or immunoglobulins would be a promising therapy in COVID-19 patients. Previous results revealed that convalescent plasma therapy during viral infection outbreaks, It has been recommended that patients with COVID-19 who are suffering from refractory hypoxemia should be managed with extracorporeal membrane oxygenation (ECMO In some countries such as Switzerland, tocilizumab has been considered in patients with multiorgan failure and inotropic support 82 . ACE2 has a critical role in cardiac and immune systems. ACE2 is related to heart function and it could be a potential cause of hypertension and diabetes mellitus development 83 . Since ACE2 is a functional receptor for COVID-19, in patients with underlying cardiovascular diseases, clinical symptoms of COVID-19 are more severe and fatal than the general population because, in cardiovascular diseases, ACE2 secretion might be enhanced. Administration of reninangiotensin-aldosterone system inhibitors, such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could enhance ACE2 level. Thiazolidinediones and Ibuprofen might also enhance the ACE2 level 83 pneumonia but ARBs, through blockade of angiotensin receptors, may have beneficial effects in these patients. Most of the hepatic metabolites of drugs considered in COVID-19 treatment such as chloroquine, hydroxychloroquine, and lopinavir/ritonavir would be found in urine due to renal elimination. So in patients with chronic kidney disease (CKD), the accumulation of drug metabolites would be expected if administered in routinely recommended doses for the normal population. Therefore, individualized dose adjustment based on kidney function is required for each drug as mentioned above 87 . A small study on COVID-19 patients with end-stage renal disease (ESRD) who undergone hemodialysis, revealed that the number of total T cells (cytotoxic and helper T cells), natural killer (NK) cells, and inflammatory cytokines were significantly lower than these levels in non-hemodialysis patients with COVID-19. This study revealed that ESRD patients with hemodialysis who infected with COVID-19 had a good prognosis and they had mild symptoms of pneumonia, it might be related to the fewer number of inflammatory cytokines and reduced immune function which can avoid CRS but further studies are required to confirm this hypothesis 66 . According to the recent studies, liver abnormalities (such as elevated AST and ALT serum levels) have been occurred after and during infection with COVID-19. These abnormalities would be related to viral infection pathogenesis and direct liver injury or it may be drug-induced 88 . Almost all of the potential drugs in COVID-19 treatment containing chloroquine, hydroxychloroquine, ribavirin, and lopinavir/ritonavir have hepatic metabolism. So injury to the liver because of pre-existing liver disease or acute hepatic failure would impair drug metabolism and therefore drug accumulation and enhancement in plasma level, which can lead to drug toxicity. In these patients, frequent liver function monitoring is essential to achieve an optimal serum drug level 87 . Also, dosage adjustment for each drug should be done individually according to the patients' liver function as mentioned above. The impact of chronic liver diseases such as chronic viral hepatitis, alcoholic and non-alcoholic liver diseases on occurrence of liver injury related to COVID-19 infection, still is not clear. It seems that in patients with underlying liver disease, with the immunocompromised condition, who infected with COVID-19, more intensive and individualized pharmacotherapy is required. Further studies would be also helpful to explain the exact role of pre-existing liver diseases in COVID-19 prognosis 88 . The new coronavirus (COVID-19) was first detected in Wuhan city of China in December 2019. Soon this coronavirus disease 2019 (COVID-19) spreads around the world and became a pandemic. Now many patients around the world are suffering from this disease. Patients with underlying diseases are highly prone to severe COVID-19 pneumonia. Till now many drugs have been considered in the treatment of COVID-19 pneumonia, but pharmacotherapy in patients with pre-existing comorbidities is highly challenging. In this review, different potential drugs which have been considered in COVID-19 treatment have been discussed in detail. Also, challenges in the pharmacotherapy of COVID-19 pneumonia in patients with underlying disease especially heart diseases have been considered based on pharmacokinetic and pharmacodynamic aspects of drugs. 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The Lancet Gastroenterology & Hepatology Ethical Approval: Not required. P.G. and S.M. were contributed equally in data gathering, writing-original draft, reviewing, and revising the final version of this manuscript.