Angiotensin II

Identification

Name
Angiotensin II
Accession Number
DB11842
Description

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
Thumb
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.

Associated Conditions
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

TargetActionsOrganism
AType-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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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.

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
LevothyroxineLevothyroxine may increase the vasoconstricting activities of Angiotensin II.
LidocaineThe risk or severity of hypertension can be increased when Angiotensin II is combined with Lidocaine.
LiothyronineLiothyronine may increase the vasoconstricting activities of Angiotensin II.
LiotrixLiotrix may increase the vasoconstricting activities of Angiotensin II.
Patent BlueThe risk or severity of hypotension can be increased when Patent Blue is combined with Angiotensin II.
Thyroid, porcineThyroid, porcine may increase the vasoconstricting activities of Angiotensin II.
Thyrotropin alfaThyrotropin alfa may increase the vasoconstricting activities of Angiotensin II.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Angiotensin II acetate31L3HS630A32044-01-2VBTZKFAHKJXHBA-PIONDTTLSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GiaprezaInjection2.5 mg/1mLIntravenousLa Jolla Pharmaceutical Company2018-02-05Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
C01CX09 — Angiotensin ii
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Oligopeptides
Alternative Parents
Tyrosine and derivatives / Phenylalanine and derivatives / Histidine and derivatives / Aspartic acid and derivatives / Isoleucine and derivatives / Valine and derivatives / Proline and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Phenylpropanoic acids
show 21 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / 3-phenylpropanoic-acid / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Amine / Amino acid / Amino acid or derivatives / Amphetamine or derivatives / Aromatic heteromonocyclic compound
show 46 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
angiotensin II (CHEBI:2719) / Angiotensin [KO:K09821] (C02135)

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[[email protected]](C)[[email protected]](NC(=O)[[email protected]](CC1=CC=C(O)C=C1)NC(=O)[[email protected]@H](NC(=O)[[email protected]](CCCN=C(N)N)NC(=O)[[email protected]@H](N)CC(O)=O)C(C)C)C(=O)N[[email protected]@H](CC1=CN=CN1)C(=O)N1CCC[[email protected]]1C(=O)N[[email protected]@H](CC1=CC=CC=C1)C(O)=O

References

General References
  1. 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. [PubMed:25886853]
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
Download (2.45 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentBody Composition / Exercise Tolerance / Heart Failure / Strength, Muscle / Vasodilation1
4CompletedDiagnosticHigh Blood Pressure (Hypertension)1
4CompletedOtherDyslipidemia / High Blood Pressure (Hypertension)1
4CompletedPreventionCardiovascular Heart Disease1
4CompletedPreventionHigh Blood Pressure (Hypertension) / Infarction, Brain1
4CompletedPreventionKidney Stones1
4CompletedTreatmentHigh Blood Pressure (Hypertension)1
4CompletedTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1
4CompletedTreatmentIgA Glomerulonephritis1
4CompletedTreatmentIgA Nephropathy2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous2.5 mg/1mL
Injection, solution, concentrateIntravenous2.5 MG/ML
Injection, solution, concentrateIntravenous5 MG/ML
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9572856No2017-02-212030-09-20US flag
US9220745No2015-12-292034-12-18US flag
US9867863No2018-01-162029-12-16US flag
US10028995No2018-07-242034-12-18US flag
US10335451No2019-07-022029-12-16US flag
US10493124No2019-12-032034-12-18US flag
US10500247No2019-12-102029-12-16US flag
US10548943No2009-12-162029-12-16US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0156 mg/mLALOGPS
logP-0.87ALOGPS
logP-5.3ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)3.15ChemAxon
pKa (Strongest Basic)10.83ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count13ChemAxon
Polar Surface Area408.84 Å2ChemAxon
Rotatable Bond Count29ChemAxon
Refractivity269.81 m3·mol-1ChemAxon
Polarizability107.02 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
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 on October 20, 2016 14:53 / Updated on June 12, 2020 10:53

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