philipn authored on Jan. 19, 2021, 7:31 p.m. | | Additions are marked like this |
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. 
Dose & medication used in animal studiesACE2-knockout animal studies:
Other animal studies of AT1R blockade:
Dose & medication used in clinical trials
Dosing for AT1R blockadeLarger 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 normotensivesIn 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." In this trial in healthy, normotensive subjects, 100mg losartan od as well as 80mg bid telmisartan were found to be safe. The authors state: "One may also be concerned by safety considerations when administering higher doses of AT1 receptor blockers. This is hardly an issue, since AT1 receptor antagonists do not exhibit any dose-dependent adverse effects. Indeed, AT1 receptor blockers have been used safely at higher doses...inhibition of the renin-angiotensin system hardly causes a decrease in blood pressure in normotensive subjects." In this preliminary report on a trial of telmisartan 80mg bid for COVID-19 treatment, "no differences were observed in blood pressure between telmisartan and control group at day 5 or 8." 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.
Dose & medication used in animal studiesACE2-knockout animal studies:
Other animal studies of AT1R blockade:
Dose & medication used in clinical trials
Dosing for AT1R blockadeLarger 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 normotensivesIn 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." In this trial in healthy, normotensive subjects, 100mg losartan od as well as 80mg bid telmisartan were found to be safe. The authors state: "One may also be concerned by safety considerations when administering higher doses of AT1 receptor blockers. This is hardly an issue, since AT1 receptor antagonists do not exhibit any dose-dependent adverse effects. Indeed, AT1 receptor blockers have been used safely at higher doses...inhibition of the renin-angiotensin system hardly causes a decrease in blood pressure in normotensive subjects." In this preliminary report on a trial of telmisartan 80mg bid for COVID-19 treatment, "no differences were observed in blood pressure between telmisartan and control group at day 5 or 8." Could some ARBs work better than others?Is it possible that some ARBs would work better than others in the context of COVID-19? Half-life & lipophilicity Some ARBs, such as telmisartan, have a terminal elimination half-life of around 24 hours, while other such as losartan have a half-life of around 6-9 hours (via active metabolite EXP3179). Lipophilicity is discussed in "Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID‐19": Liposolubility is relevant for absorption after oral administration and for tissue penetration. Telmisartan stands out among all the representatives of the ARBs for being markedly more lipophilic, expressed both in partition coefficients (octanol/neutral pH buffer), distribution coefficients and distribution volumes (Vd). Telmisartan has a Vd of approximately 500 L, irbesartan 93 L, and both valsartan and olmesartan, candesartan and losartan, approximately 17 L. Further discussion is available in "Pharmacology and clinical efficacy of angiotensin receptor blockers." Non-AT1R mediated effects 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. |
