Angiotensin II

Identification

Summary

Angiotensin II is a peptide hormone of the RAAS system used to raise blood pressure in septic or other forms of shock.

Brand Names

Giapreza

Generic Name

Angiotensin II

DrugBank Accession Number

DB11842

Background

Angiotensin II is under investigation for the treatment of Sepsis, Septic Shock, Diabetes Mellitus, and Acute Renal Failure. Angiotensin II has been investigated for the treatment, basic science, and diagnostic of Hypertension, Renin Angiotensin System, and Idiopathic Membranous Nephropathy.

As of December 21, 2017 the FDA approved La Jolla Pharmaceutical's Giapreza (angiotensin II) Injection for Intravenouse Infusion for the indication of acting as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. The novelty of the medication lies in the fact that it is the first and only use of synthetic human angiotensin II to help maintain body blood pressure.

Shock is the inability to maintain blood flow to vital tissues and the potential resultant organ failure and death within hours, no matter young or o ld. As distributive shock is the most common type of shock in the inpatient setting and affects up to one third of patients in the intensive care unit, the FDA determined that there is a need for treatment options for critically ill hypotensive patients who do not adequately respond to currently available therapies.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 1046.1786
Monoisotopic: 1045.534514801
Chemical Formula: C₅₀H₇₁N₁₃O₁₂

Synonyms

5-isoleucine-angiotensin II
5-L-isoleucineangiotensin II
Angiotensin
Angiotensin II
Angiotensin II (human)
Angiotonin
Human angiotensin II
Hypertensin
Ile5-angiotensin II
isoleucine5-angiotensin II

Pharmacology

Indication

Angiotensin II is a vasoconstrictor indicated for increasing blood pressure in adults with septic or other distributive shock ^Label.

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Associated Conditions

Hypotension

Contraindications & Blackbox Warnings

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Pharmacodynamics

Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone-system (RAAS) that has the capacity to cause vasoconstriction and an increase in blood pressure in the human body. ^Label

In the RAAS, juxtaglomerular cells of the renal afferent arteriole synthesize the proteolytic enzyme renin. Although stored in an inactive form called pro-renin, decreases in arterial blood pressure or extracellular fluid volume depletion can cause various enzymatic reactions to release active renin into the systemic circulation and surrounding tissues. Such renin release allows for the production of the alpha-2-globulin angiotensinogen predominantly in the liver and to some extent, the kidneys and other organs. ¹

Angiotensin I, itself a decapeptide with weak biological activity, is produced from angiotensinogen and then quickly converted to angiotensin II by angiotensin converting enzymes (ACE). Consequently, angiotensin II demonstrates its strong vasopressor activity when it is rapidly degraded by aminopeptidases A and M into further entities like angiotensin III and angiotensin IV, respectively. Such species like angiotensin III can then bind and interact with specific G protein coupled receptors like angiotensin receptor 1, or AT-1 ¹ where strong vasoconstricson can occur. ¹

Furthermore, in the ATHOS-3 clinical trial, for the 114 (70%) patient subjects in the angiotensin II arm who reached the target mean arterial pressure (MAP) at Hour 3, the median time to reach the target MAP endpoint was approximately 5 minutes. The angiotensin II was titrated to effect for each individual patient. ^Label.

Mechanism of action

As part of the renin-angiotensin-aldosterone-system (RAAS), angiotensin II raises blood pressure by vasoconstriction, increased aldosterone release by the adrenal zona glomerulosa, sodium and water reabsorption in the proximal tubular cells, and vasopressin secretion ^Label,1

The direct action of angiotensin II on surrounding vessel walls is facilitated by binding to the G-protein-coupled angiotensin II receptor type 1 (AT-1) on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction that results in vasoconstriction ^Label,1.

The RAAS is ultimately regulated by a negative feedback effect of angiotensin II on renin production by the juxtaglomerular cells of the renal afferent arteriole. Unresuscitated septic shock associated with marked hypovolemia, extracellular fluid volume depletion, decreased cardiac output, low arterial blood pressure and decreased systemic vascular resistance causes an increase in renin secretion by the juxtaglomerular cells, resulting in elevated angiotensin II plasma levels and an increased secretion of aldosterone from the adrenal cortex. Angiotensin II binding to AT-1 receptors causes dose-dependent vasoconstriction of both afferent and efferent glomerular arterioles. The most pronounced effect of angiotensin II results on efferent arterioles, resulting in reduced renal blood flow and increased glomerular filtration pressure. ¹

Target	Actions	Organism
UType-1 angiotensin II receptor	agonist	Humans

Absorption

Following the intravenous infusion of angiotensin II in adult patients with septic or other distributive shock, the serum levels of angiotensin II observed were similar at baseline and hour 3 after the intravenous infusion. After 3 hours of treatment, the serum level of angiotensin I (the angiotensin II precursos peptide) is however, reduced by about 40% ^Label.

Volume of distribution

The official prescribing information for angiotensin II notes that no specific studies have yet been conducted that examine the distribution of angiotensin II ^Label.

Protein binding

Not Available

Metabolism

It is metabolized by aminopeptidase A and angiotensin converting enzyme 2 to angiotensin-(2-8) [angiotensin III] and angiotensin-(1-7), respectively in plasma, erythrocytes and many of the major organs (i.e. intestine, kidney, liver and lung). Angiotensin II type 1 receptor (AT1) mediated activity of angiotensin III is approximately 40% of angiotensin II; however, aldosterone synthesis activity is similar to angiotensin II. Angiotensin-(1-7) exerts the opposite effects of angiotensin II on AT1 receptors and causes vasodilation ^Label.

Nevertheless, the official prescribing information also notes that no formal studies have been conducted that examine the metabolism of angiotensin II ^Label.

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Angiotensin II
- Angiotensin 1-7
- Angiotensin III

Route of elimination

The official prescribing information notes that no specific studies have been conducted that examine the elimination of angiotensin II.

Half-life

The plasma half-life of intravenously administered angiotensin II is less than one minute ^Label.

Clearance

The official prescribing information notes that the clearnace of angiotensin II is not dependent on hepatic function or renal function ^Label.

Adverse Effects

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Toxicity

Overdose with angiotensin II would be expected to result in hypertension, necessitating close monitoring and supportive care ^Label. Effects are also expected to be brief as the half-life of angiotensin II is less than one minute ^Label.

In the ATHOS-3 clinical study there was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received angiotensin II compared to placebo treated patients. The major imbalance was in deep venous thromboses - which prompts the potential need to use concurrent venous thromboembolism (VTE) prohphylaxis ^Label.

Adverse effects of noticeable potential (>= 10%) include thromboembolic events (ie. like deep vein thrombosis) including arterial and venous thrombotic events, thrombocytopenia, tachycardia, and fungal infection. Effects whose potential are < 10% include delirium, acidosis, hyperglycemia, peripheral ischemia ^Label.

Concomitant use of angiotensin converting enzymes (ACE) inhibitors may increase the response of angiotensin II ^Label.

Concomitant use of angiotensin II blockers (ARBs) may decrease the response to angiotensin II ^Label.

There are no formal data regarding the safe use of angiotensin II in pregnant women. However, septic or other distributive shock is a medical emergency that can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic or otherdistributive shock is likely to increase the risk of maternal and fetal morbidity and mortality ^Label.

There is no formal data regarding whether or not angiotensin II may become present in human milk and there is no data available on the effects of angiotensin II on the breastfed child or the effects on milk production ^Label.

The safety and efficacy of angiotensin II in pediatric patients has not yet been established ^Label.

There is no difference in the safety or efficacy between patients less than 65 years old and those 65 years or older when treated with angiotensin II ^Label.

There is no difference in pharmacokinetics between male and female patients ^Label.

The pharmacokinetics of angiotensin II are not expected to be influenced by renal impairment or hepatic impairment ^Label.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Levothyroxine	Levothyroxine may increase the vasoconstricting activities of Angiotensin II.
Lidocaine	The risk or severity of hypertension can be increased when Angiotensin II is combined with Lidocaine.
Liothyronine	Liothyronine may increase the vasoconstricting activities of Angiotensin II.
Liotrix	Liotrix may increase the vasoconstricting activities of Angiotensin II.
Oxytocin	The risk or severity of hypertension can be increased when Angiotensin II is combined with Oxytocin.
Patent Blue	The risk or severity of hypotension can be increased when Patent Blue is combined with Angiotensin II.
Thyroid, porcine	Thyroid, porcine may increase the vasoconstricting activities of Angiotensin II.
Thyrotropin alfa	Thyrotropin alfa may increase the vasoconstricting activities of Angiotensin II.

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Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Angiotensin II acetate	31L3HS630A	32044-01-2	VBTZKFAHKJXHBA-PIONDTTLSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Giapreza	Injection, solution, concentrate	2.5 mg/ml	Intravenous	Paion Deutschland Gmb H	2021-01-12	Not applicable
Giapreza	Injection, solution, concentrate	2.5 mg/ml	Intravenous	Paion Deutschland Gmb H	2021-04-01	Not applicable
Giapreza	Injection	2.5 mg/1mL	Intravenous	La Jolla Pharmaceutical Company	2018-02-05	Not applicable
Giapreza	Injection, solution, concentrate	2.5 mg/ml	Intravenous	Paion Deutschland Gmb H	2021-01-12	Not applicable

Chemical Identifiers

UNII: M089EFU921
CAS number: 4474-91-3
InChI Key: CZGUSIXMZVURDU-JZXHSEFVSA-N
InChI: InChI=1S/C50H71N13O12/c1-5-28(4)41(47(72)59-36(23-31-25-54-26-56-31)48(73)63-20-10-14-38(63)45(70)60-37(49(74)75)22-29-11-7-6-8-12-29)62-44(69)35(21-30-15-17-32(64)18-16-30)58-46(71)40(27(2)3)61-43(68)34(13-9-19-55-50(52)53)57-42(67)33(51)24-39(65)66/h6-8,11-12,15-18,25-28,33-38,40-41,64H,5,9-10,13-14,19-24,51H2,1-4H3,(H,54,56)(H,57,67)(H,58,71)(H,59,72)(H,60,70)(H,61,68)(H,62,69)(H,65,66)(H,74,75)(H4,52,53,55)/t28-,33-,34-,35-,36-,37-,38-,40-,41-/m0/s1
IUPAC Name: (3S)-3-amino-3-{[(1S)-1-{[(1S)-1-{[(1S)-1-{[(1S,2S)-1-{[(2S)-1-[(2S)-2-{[(1S)-1-carboxy-2-phenylethyl]carbamoyl}pyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamoyl}-2-methylbutyl]carbamoyl}-2-(4-hydroxyphenyl)ethyl]carbamoyl}-2-methylpropyl]carbamoyl}-4-[(diaminomethylidene)amino]butyl]carbamoyl}propanoic acid
SMILES: CC[C@H](C)[C@H](NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O

References

General References

Correa TD, Takala J, Jakob SM: Angiotensin II in septic shock. Crit Care. 2015 Mar 16;19:98. doi: 10.1186/s13054-015-0802-3. [Article]

External Links

Human Metabolome Database: HMDB0001035
KEGG Compound: C02135
PubChem Compound: 172198
PubChem Substance: 347828186
ChemSpider: 150504
BindingDB: 50236697
RxNav: 1999003
ChEBI: 58506
ChEMBL: CHEMBL408403
ZINC: ZINC000169676920
Wikipedia: Angiotensin

FDA label

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Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Diagnostic	High Blood Pressure (Hypertension)	1
4	Completed	Other	Dyslipidemia / High Blood Pressure (Hypertension)	1
4	Completed	Prevention	Cardiovascular Disease (CVD)	1
4	Completed	Prevention	Cerebrovascular Accident / High Blood Pressure (Hypertension) / Transient Ischemic Attack	1
4	Completed	Prevention	High Blood Pressure (Hypertension) / Infarction, Brain	1
4	Completed	Prevention	Kidney Stones	1
4	Completed	Treatment	Bodycomposition / Exercise Tolerance / Heart Failure / Strength, Muscle / Vasodilation	1
4	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	2
4	Completed	Treatment	Diabetic Nephropathy / Persistent Proteinuria With Type II Diabetes	1
4	Completed	Treatment	Glomerulonephritis , IGA	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	2.5 mg/1mL
Injection, solution, concentrate	Intravenous	2.5 MG/ML
Injection, solution, concentrate	Intravenous	5 MG/ML

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9572856	No	2017-02-21	2030-09-20
US9220745	No	2015-12-29	2034-12-18
US9867863	No	2018-01-16	2029-12-16
US10028995	No	2018-07-24	2034-12-18
US10335451	No	2019-07-02	2029-12-16
US10493124	No	2019-12-03	2034-12-18
US10500247	No	2019-12-10	2029-12-16
US10548943	No	2020-02-04	2029-12-16
US11096983	No	2014-12-18	2034-12-18
US11219662	No	2017-01-06	2037-01-06

Properties

State

Liquid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0156 mg/mL	ALOGPS
logP	-0.87	ALOGPS
logP	-5.3	ChemAxon
logS	-4.8	ALOGPS
pKa (Strongest Acidic)	3.15	ChemAxon
pKa (Strongest Basic)	10.83	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	17	ChemAxon
Hydrogen Donor Count	13	ChemAxon
Polar Surface Area	408.84 Å²	ChemAxon
Rotatable Bond Count	29	ChemAxon
Refractivity	269.81 m³·mol^-1	ChemAxon
Polarizability	107 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Type-1 angiotensin II receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Protein heterodimerization activity
Specific Function: Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name: AGTR1
Uniprot ID: P30556
Uniprot Name: Type-1 angiotensin II receptor
Molecular Weight: 41060.53 Da

Drug created at October 20, 2016 20:53 / Updated at February 21, 2021 18:53

Angiotensin II

Identification

Structure for Angiotensin II (DB11842)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets