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
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Hormones / Peptides - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- 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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- Contraindications & Blackbox Warnings
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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 agonistHumans - 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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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 Integrate drug-drug
interactions in your softwareChloroprocaine The risk or severity of adverse effects can be increased when Angiotensin II is combined with Chloroprocaine. 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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- No interactions found.
Products
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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 Region Image Giapreza Injection, solution, concentrate 2.5 mg/ml Intravenous Paion Deutschland Gmb H 2021-04-01 Not applicable EU 
Giapreza Injection 0.5 mg/1mL Intravenous La Jolla Pharmaceutical Company 2022-09-15 Not applicable US 
Giapreza Injection, solution, concentrate 2.5 mg/ml Intravenous Paion Deutschland Gmb H 2021-01-12 Not applicable EU Giapreza Injection 2.5 mg/1mL Intravenous La Jolla Pharmaceutical Company 2018-02-05 Not applicable US Giapreza Injection, solution, concentrate 2.5 mg/ml Intravenous Paion Deutschland Gmb H 2021-01-12 Not applicable EU
Categories
- ATC Codes
- C01CX09 — Angiotensin ii
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Angiotensin II, antagonists & inhibitors
- Angiotensins
- Autacoids
- Biological Factors
- Cardiac Stimulants Excl. Cardiac Glycosides
- Cardiac Therapy
- Cardiovascular Agents
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Inflammation Mediators
- Nerve Tissue Proteins
- Neuropeptides
- Oligopeptides
- Peptide Hormones
- Peptides
- Proteins
- Vasoconstriction
- Vasoconstrictor Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- M089EFU921
- CAS number
- 4474-91-3
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
- 1999003
- ChEBI
- 131170
- ChEMBL
- CHEMBL408403
- ZINC
- ZINC000169676920
- Wikipedia
- Angiotensin
- FDA label
- Download (2.45 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Heart Failure 1 4 Active Not Recruiting Treatment Myocardial Infarction With Non-obstructive Coronary Arteries 1 4 Completed Diagnostic Hypertension 1 4 Completed Other Dyslipidemia / Hypertension 1 4 Completed Prevention Cardiovascular Disease (CVD) 1 4 Completed Prevention Hypertension / Infarction, Brain 1 4 Completed Prevention Hypertension / Stroke / Transient Ischemic Attack 1 4 Completed Prevention Kidney Stones 1 4 Completed Treatment Acute Kidney Injury (AKI) / Septic Shock 1 4 Completed Treatment Bodycomposition / Exercise Tolerance / Heart Failure / Strength, Muscle / Vasodilation 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravenous 0.5 mg/1mL 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) Region US9572856 No 2017-02-21 2030-09-20 US US9220745 No 2015-12-29 2034-12-18 US US9867863 No 2018-01-16 2029-12-16 US US10028995 No 2018-07-24 2034-12-18 US US10335451 No 2019-07-02 2029-12-16 US US10493124 No 2019-12-03 2034-12-18 US US10500247 No 2019-12-10 2029-12-16 US US10548943 No 2020-02-04 2029-12-16 US US11096983 No 2021-08-24 2034-12-18 US US11219662 No 2017-01-06 2037-01-06 US US11559559 No 2014-12-18 2034-12-18 US
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- 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 December 01, 2022 11:27