A closer look at the pharmacology of Giapreza

Let’s take a closer look at the pharmacology of Giapreza. Angiotensin-II (Ang2) is now an FDA approved vasopressor. With this new addition to the available options, experts are combing over the available literature to determine whether or not to incorporate it into their daily practice. The ATHOS-3 trial has demonstrated that Ang2 is, at minimum, safe and effective when added to norepinephrine (or another similarly dosed vasopressor).1 While this trial should be critically appraised, and has been done so by EMCrit, REBEL EM and others, I want to take a step back and examine the pharmacology of Ang2. By doing so, hopefully, I can add some perspective in how it is exerting its effects and maybe even predict some therapeutic misadventures that are likely to occur once exposed to thousands of patients in real-world settings.

Ang2 is a critical element in the renin-angiotensin-aldosterone system (RAAS). RAAS is analogous to the coagulation cascade, in that, the one we all learned in school tremendously oversimplified. Similarly, by stating Ang2 is a vasopressor via agonist actions on the AT1 receptor is an oversimplification. Acknowledging this is a complex pathway, to understand the effects of Ang2 let’s look at some elements of the RAAS in more depth from our core pharmacology textbooks.2,3

Image credit: https://commons.wikimedia.org/wiki/File:Renin-anigotensin_system_and_potential_steps_of_blockage..png

Ang2 basics

Angiotensinogen is converted to angiotensin-I (Ang1) by renin. From our understanding of the pharmacotherapy for hypertension, we’re familiar with the conversion of Ang1 by angiotensin-converting enzyme (ACE) to Ang2. Ang2, then goes on to exert its effects on angiotensin 1 (AT1), and AT2 receptors.

The AT1 agonist effects lead to increased peripheral resistance via the coupling of Gq to activate the PLCβ–IP3–Ca2+ pathway
The AT2 agonist effects lead to decreased resistance through numerous mechanisms including NO synthesis, bradykinin production, and inhibition of Ca2+ channel antagonism

The net effect is AT1 agonist effects, under normal physiological scenarios.

Lesser-known RAAS elements [Ang3, Ang4, Ang(1-7), & ACE2]

Ang1 is a decapeptide consisting of the following peptide sequence: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu. Thus Ang1 can be referred to as Ang(1-10) and depending on the location of enzymatic cleavage, downstream Ang metabolites follow a logical nomenclature (ie, Ang(1-7), Ang(2-8), Ang(3-8), etc.). This is relevant since there are other metabolites from Ang1 other than Ang2 that have physiologic effects and follow this nomenclature.

Ang2 can be converted by aminopeptidase (AP) to Ang3 and again by AP to Ang4 which have effects on AT2 and AT4 receptors, respectively.

Ang3 has approximately the same effects of aldosterone equal to Ang2, but is 25% as potent (vs Ang2) on BP elevation, and 10% as potent (vs Ang2) adrenal medulla stimulation.
Ang4 has minimal hemodynamic effects but has some fascinating effects on memory and cognition

ACE2, different from ACE, and expressed in the endothelium of kidneys, heart and testes, produces Ang(1-7) either directly from Ang1 to Ang(1-7), or by metabolizing Ang2 to Ang(1-7). The actions of Ang(1-7) on Mas receptors oppose those of Ang2 similar to AT2 activation. However, in most physiological scenarios the ratio of ACE-Ang2/ACE2-Ang(1–7) favors the effects of Ang2.

Ang(1-7) is gaining attention in terms of the therapeutic benefit itself. There is growing research in humans based on animal models supporting its numerous potential benefits including (but not limited to): antiarrhythmic effects, anti-thrombosis, protection of endothelial function, improvement in NO release and increased cardiac output.

There are several other newly identified components of RAAS including alamandine, AngA, Ang(1-9), Ang(1-5), MrgD receptors.

The complex effects of these peptides are outlined in the following table:

Net effects of Ang2

Once formed, the effects of Ang2 can be described in three main phases: fast pressor response, slow pressor response, and vascular/cardiac remodeling and hypertrophy.

Fast pressor response

Naturally, the fast pressor response is the desirable effect of the newly approved Giapreza®, the brand name for Ang2. Breaking down the fast pressor response further, there is three mechanisms by which Ang2 exerts the fast pressor response:

As previously stated, stimulation of the Gq–PLC–IP3–Ca2+ pathway –> rapid increase in peripheral resistance
Ang2 can also increase the blood pressure set point for baroreceptor reflex through actions in the CNS thus cause either no change in HR or a slight decrease

Inhibition of norepinephrine reuptake (increased release from nerve terminals) and by enhancing the vascular response to norepinephrine
Depolarization of adrenal chromaffin cells leading to release of catecholamines

Slow pressor response/Vascular and cardiac remodeling
The slow pressor response, with onset after days of continuous therapy with Ang2, is a result of sodium reabsorption in the proximal tubule, and further sodium retention through the actions of aldosterone. Ultimately this sodium retention leads to increased plasma volumes. However, Ang2 can have complex effects on renal function. Depending on renal hemodynamics Ang2 can either cause GFR to be increased or decreased.

Decreases in GFR can occur as a result of Ang2 through increased resistance renal vascular smooth muscle, by enhancing renal sympathetic tone, and by facilitating intrarenal adrenergic transmission.
Increased GFR can occur during renal artery hypotension (i.e. shock), the effects of Ang2 are on the efferent arteriole, thus an increase in GFR. On the flip side, giving this patient an ACEi/ARB would potentiate acute renal failure.

To a lesser extent, Ang2 stimulates the synthesis of endothelin-1 and superoxide anion. By these mechanisms over time, and from our understanding of the neurohormonal theory of heart failure, Ang2 stimulates remodeling of the cardiovascular system. This inflammatory chemokine and cytokine response to Ang2 involved in vascular and cardiac remodeling also results in increased release of plasminogen activator inhibitor 1 and augmenting the expression of adhesion proteins in vascular cells, which may be of concern in the critically ill.

Ang2 is certainly not a straightforward drug that we are adding to the already complex pharmacotherapy in shock. While the pharmacology of Ang2 is supportive of the theory of addressing multiple pathways of improving vascular resistance and perfusion, there are numerous unanswered questions.

Some risks of complications or blunting of benefits of Ang2 could be observed with concomitant neutral endopeptidase inhibitors (aka NEP, neprilysin) such as sacubitril, or DPP4 inhibitors by limiting the production of Ang(1-7).

Some other critiques of Ang2 I have heard anecdotally include the incidence of thrombosis in ATHOS-3. As outlined above, while this is certainly possibly explained through some of the unwanted effects of Ang2, the available evidence is certainly not sufficiently powered to appropriately describe this risk. A lack of mortality/morbidity benefit is another common critique from pharmacy circles. I think this is another scenario where would we expect a vasopressor to improve mortality in a large, diverse population? Probably not. However, in specific patient cases, there may be a morbidity benefit that may be small but clinically important.

While it is easy to critique Ang2, and its evidence, we mustn’t forget that no available vasopressor has gone through any regulatory approval for use – yet we use them daily. Furthermore, sympathomimetics and vasopressin have similar, complex effects on numerous other physiologic pathways that led to their associated deleterious effects. I believe Ang2 will have a role in the management of shock. However, I do not expect it to replace any available regimen, and won’t be surprised if there are serious adverse events that arise in clinical practice.

1. Khanna A, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. PMID: 28528561
2. Reid IA. Vasoactive Peptides. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2249&sectionid=175218037. Accessed December 29, 2017.
3. Hilal-Dandan R. Renin and Angiotensin. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13eNew York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=170106980. Accessed December 29, 2017.
4. Chawla LS, et al. The use of angiotensin II in distributive shock. Crit Care. 2016; 20: 137. PMCID: PMC4882778
5. https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1896-6
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