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If ARBs (or other drugs modulating the renin-angiotensin system) help in COVID-19, what would be the ideal dosing and medication to use?  This page explores this question.

200mg of losartan, given orally, was used in a swine model of possible COVID-19 pathophysiology. Photo CC-BY Susanne Rysz, Johan Lundberg, et al.

Dose & medication used in animal studies

ACE2-knockout animal studies:

Other animal studies of AT1R blockade:

Dose & medication used in clinical trials

Losartan dosing in animal studies versus human trials. Animal dosing converted to human equivalent, and values obtained from lists on this page. Total dose over 24 hours is used. For acute injury animal models, dose is doubled to account for hypothetical, higher 24-hour protection as would be likely ideal for viral injury. Error bars represent standard deviation.

Dosing for AT1R blockade

ARBs may deliver adequate antihypertensive effects with common doses, but larger doses may be needed for high blockade of AT1R. In "Angiotensin II Receptor Blockade in Normotensive Subjects," 50mg losartan od (Fig. 3) displaced ~42% of Ang II at 4 hours and ~18% at 24 hours, or an average of 30% displacement of Ang II over 24 hours. In comparison, 100mg losartan bid was found to displace 80% of Ang II at 4 hours and 55% at 24 hours (Table 4), or an average of 68% displacement of Ang II over 24 hours.  In this same study of normotensive subjects, 80mg bid telmisartan had similar effects as 100mg bid losartan on displacement of Ang II.

High dose ARBs in normotensives

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Would some ARBs work better than others?

Several of the animal studies use I.V. losartan. When given orally or intraperitoneally, losartan is metabolized by the liver into EXP3174, its longer-lasting, higher-affinity metabolite. When given via I.V., losartan is not metabolized into EXP3174 ("EXP3 174: The Major Active Metabolite of Losartan", Tamaki, et al).

Thrombosis and losartan versus first-pass metabolite EXP3174.

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12916 - mechanical activation of AT1R versus Ang II-activation of AT1R

..however, in this trial losartan was given both intraperitoneally (first dose), and then via i.v. With i.v. administration, the first-pass effect would be skipped and losartan would not be metabolized into EXP3174, its longer-lasting, higher-affinity metabolite.

..but in a follow-up study, olmesartan, but not irbesartan, attenuated ventilator-induced diaphragm dysfunction as well.

If ARBs (or other drugs modulating the renin-angiotensin system) help in COVID-19, what would be the ideal dosing and medication to use?  This page explores this question.

200mg of losartan, given orally, was used in a swine model of possible COVID-19 pathophysiology. Photo CC-BY Susanne Rysz, Johan Lundberg, et al.

Dose & medication used in animal studies

ACE2-knockout animal studies:

Other animal studies of AT1R blockade:

Dose & medication used in clinical trials

Losartan dosing in animal studies versus human trials. Animal dosing converted to human equivalent, and values obtained from lists on this page. Total dose over 24 hours is used. For acute injury animal models, dose is doubled to account for hypothetical, higher 24-hour protection as would be likely ideal for viral injury. Error bars represent standard deviation.

Dosing for AT1R blockade

Larger doses than those used for hypertension may be needed to achieve high blockade of AT1R. In "Angiotensin II Receptor Blockade in Normotensive Subjects," 50mg losartan od (Fig. 3) displaced ~42% of Ang II at 4 hours and ~18% at 24 hours, or an average of 30% displacement of Ang II over 24 hours. In comparison, 100mg losartan bid was found to displace 80% of Ang II at 4 hours and 55% at 24 hours (Table 4), or an average of 68% displacement of Ang II over 24 hours.  In this same study of normotensive subjects, 80mg bid telmisartan had similar effects as 100mg bid losartan on displacement of Ang II.

Conditions in which ARBs are used for high AT1R blockade rather than just antihypertensive effects include heart failure, where the HEAAL study found 150mg od losartan superior to 50mg od losartan; and Marfan syndrome.

High dose ARBs in normotensives

In Marfan syndrome, high doses of losartan are used by normotensives; 100mg of losartan daily has been shown to be beneficial. In the COMPARE trial of 100mg losartan for Marfan syndrome, "mean arterial pressure 3 years after inclusion was 86 mmHg in the losartan group and 87 mmHg in the control group."

Would some ARBs work better than others?

Several of the animal studies use I.V. losartan. When given orally or intraperitoneally, losartan is metabolized by the liver into EXP3174, its longer-lasting, higher-affinity metabolite. When given via I.V., losartan is not metabolized into EXP3174 ("EXP3 174: The Major Active Metabolite of Losartan", Tamaki, et al).

Thrombosis and losartan versus first-pass metabolite EXP3174.

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12916 - mechanical activation of AT1R versus Ang II-activation of AT1R

..however, in this trial losartan was given both intraperitoneally (first dose), and then via i.v. With i.v. administration, the first-pass effect would be skipped and losartan would not be metabolized into EXP3174, its longer-lasting, higher-affinity metabolite.

..but in a follow-up study, olmesartan, but not irbesartan, attenuated ventilator-induced diaphragm dysfunction as well.