Identification

Name
Angiotensin II
Accession Number
DB11842
Type
Small Molecule
Groups
Approved, Investigational
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.

Structure
Thumb
Synonyms
  • 5-isoleucine-angiotensin II
  • 5-L-isoleucineangiotensin II
  • Angiotensin
  • Angiotensin II (human)
  • Angiotonin
  • Human angiotensin II
  • Hypertensin
  • Ile5-angiotensin II
  • isoleucine5-angiotensin II
Product Ingredients
IngredientUNIICASInChI Key
Angiotensin II acetate31L3HS630A32044-01-2VBTZKFAHKJXHBA-PIONDTTLSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GiaprezaInjection2.5 mg/1mLIntravenousLa Jolla Pharmaceutical Company2018-02-05Not applicableUs
Categories
UNII
M089EFU921
CAS number
4474-91-3
Weight
Average: 1046.1786
Monoisotopic: 1045.534514801
Chemical Formula
C50H71N13O12
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

Pharmacology

Indication

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

Associated Conditions
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]

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].

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
Human
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].

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].

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
DrugInteraction
Patent BlueThe therapeutic efficacy of Angiotensin II can be decreased when used in combination with Patent Blue.
Food Interactions
Not Available

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]
External Links
Human Metabolome Database
HMDB0001035
KEGG Compound
C02135
PubChem Compound
172198
PubChem Substance
347828186
ChemSpider
150504
BindingDB
50236697
ChEBI
58506
ChEMBL
CHEMBL408403
Wikipedia
Angiotensin
FDA label
Download (2.45 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherHigh Blood Pressure (Hypertension) / Insulin Resistance1
1CompletedBasic SciencePostural Orthostatic Tachycardia Syndrome (POTS) / Postural Tachycardia Syndrome1
1CompletedTreatmentShock, Septic1
1RecruitingOtherHigh Blood Pressure (Hypertension) / Hypertension,Essential1
2CompletedTreatmentCatecholamine-resistant Hypotension (CRH) / Distributive shock / High Output Shock / Sepsis1
2RecruitingTreatmentCatecholamine-resistant Hypotension (CRH) / Distributive shock / High Output Shock / Shock, Septic1
2Unknown StatusTreatmentAcute Renal Failure (ARF) / Sepsis / Shock, Septic1
3Active Not RecruitingTreatmentIdiopathic Membranous Nephropathy1
3CompletedTreatmentCatecholamine-resistant Hypotension (CRH) / Distributive shock / High Output Shock / Sepsis1
3Not Yet RecruitingTreatmentShock, Septic1
4CompletedDiagnosticHigh Blood Pressure (Hypertension)1
Not AvailableActive Not RecruitingNot AvailableDiabetes Mellitus (DM)1
Not AvailableActive Not RecruitingNot AvailableHigh Blood Pressure (Hypertension)1
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedBasic ScienceHeart Diseases / Vasodilation1
Not AvailableCompletedBasic ScienceInsulin Sensitivity / Microcirculation1
Not AvailableCompletedBasic ScienceRenin Angiotensin System1
Not AvailableRecruitingNot AvailableAdrenal Gland Diseases / Aldosterone Disorder / Blood Pressures1
Not AvailableWithdrawnOtherHigh Blood Pressure (Hypertension)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous2.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9572856No2010-09-202030-09-20Us
US9220745No2014-12-182034-12-18Us
US9867863No2009-12-162029-12-16Us
US10028995No2014-12-182034-12-18Us

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

Taxonomy

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
Alpha-oligopeptide / Tyrosine or derivatives / Phenylalanine or derivatives / Histidine or derivatives / Aspartic acid or derivatives / Isoleucine or derivatives / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Valine or derivatives
show 46 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
angiotensin II (CHEBI:2719) / Angiotensin [KO:K09821] (C02135)

Targets

Kind
Protein
Organism
Human
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 October 01, 2018 16:47