2.1. Angiotensin receptor blockers (ARB)
Losartan is an angiotensin receptor blocker (ARB) hypothesised to block the attachment of SARS-CoV-2 to cells expressing ACE2, thereby preventing viral entry into host cells (Gurwitz, 2020). Losartan is a well-tolerated compound used in the treatment of hypertension, heart failure and diabetes (Goa & Wagstaff, 1996; Ripley & Hirsch, 2010). For these indications, losartan treatment is lifelong and is typically administered at a dose of 25 - 50 mg once a day, which can be increased to 100 mg if tolerated and deemed necessary (Dohme, 2003). Clinical trials for losartan use in COVID-19 are currently recruiting patients. Whilst exact dosing regimens vary between the trials, they are based upon the standard dose and will see patients given 25 – 50 mg daily losartan treatment for 7 – 14 days (clinical trials identifiers: NCT04335123, NCT04312009 and NCT04311177).
When used for its intended therapeutic conditions, losartan is considered to be a relatively safe compound. The most common adverse events (AEs) reported during clinical trials were headache, dizziness, fatigue and hypotension (Goa & Wagstaff, 1996; Usai et al.; Weber, 1997). Laboratory findings during clinical trials reported mild elevations in alanine aminotransferase (ALT) but these were self-limiting and did not result in acute liver failure (Goa & Wagstaff, 1996). More recently, cases of losartan-induced hepatotoxicity have been reported, albeit rarely (LiverTox, 2017a). Losartan is associated with serious cases of foetal toxicity and so cannot be administered to women in the second and third trimesters of pregnancies (Nayar, Singhal, Aggarwal, & Malhotra, 2003).
There is controversy regarding the use of losartan in COVID-19 trials as the expression of ACE2 can be significantly increased following ARB treatment. However, contradictory results for the potential of ARB-induced ACE2 upregulation have also been reported (Ferrario et al., 2005; Klimas et al., 2015; Tignanelli et al., 2020). Given that ACE2 is already highly expressed within the lungs, a further increase in ACE2 expression may have the potential to increase viral entry into the lungs, thus exacerbating the potential for pulmonary involvement (Fang, Karakiulakis, & Roth, 2020). Evidence of increased myocardial injury and chronic damage to the cardiovascular system have been reported in patients infected with SARS-CoV-2 (Zheng, Ma, Zhang, & Xie, 2020). ACE2 is also expressed within the cardiovascular system and it has been suggested that this may underlie cardiac effects via enhanced viral entry into the myocardium (Zheng et al., 2020). It is important to note that human data thus far does not support the hypothesis that ARBs (and ACE-inhibitors) increase the risk of severe COVID-19 disease since epidemiological studies have largely shown either a protective effect or no adverse effects on mortality in COVID-19 (Tignanelli et al., 2020). Importantly, the latest advice from the Medicines and Healthcare products Regulatory Agency (MHRA) recommends those taking ARBs and ACE inhibitors for high blood pressure should continue doing so (Medicines and healthcare products Regulatory Agency, 2020a). Data from clinical trials for losartan in COVID-19 will provide additional safety data and much needed clarification on the role of ARBs and ACE2 in COVID-19.
Losartan has an overall favourable drug-drug interaction (DDI) profile, however concerns over the use of losartan and non-steroidal anti-inflammatory drugs (NSAIDs) during COVID-19 treatment have been raised (Sica, Gehr, & Ghosh, 2005). Evidence initially suggested that there was a theoretical potential for NSAIDs to worsen COVID-19 symptoms. However, the Commission on Human Medicines deemed that there was insufficient evidence to confirm this association and that NSAIDs were safe to use in individuals with symptoms of COVID-19 (Commission on Human Medicines, 2020; Torjesen, 2020). However, NSAIDs have the potential to attenuate the effects of losartan to reduce hypertension thereby leading to an increase in blood pressure, which would be an undesirable side-effect in COVID-19 patients with hypertension, lung inflammation and cardiac damage (Pavlicević, Kuzmanić, Rumboldt, & Rumboldt, 2008). In such patients, BP should be closely monitored.