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.