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Identification
- Summary
Protamine sulfate is a blood factor used when the reversal of the anticoagulant effect of heparin is necessary and for the treatment of heparin overdose.
- Generic Name
- Protamine sulfate
- DrugBank Accession Number
- DB09141
- Background
Since it's earliest discovery in salmon rine sperm heads in the late 1800's to its formal introduction via US FDA approval in 1939, protamine sulfate has occupied an important therapeutic niche as perhaps the only viable option for reversing the anticoagulant effect of heparin use for over 77 years 1,2. Subsequently, because most invasive surgical procedures involve the routine use of heparin to prevent potentially surgery-complicating blood clotting, most cases of major bleeding in these frequent procedures are managed with the use of protamine sulfate 1. The agent elicits this heparin reversal predominantly via the formation of an inactive complex between the anionic nature of heparin and its own cationic state 1,2,7.
Despite the relative importance of protamine sulfate's medical indication, the medication can notoriously cause a variety of potentially rare but genuinely severe adverse effects that include systemic hypotension, pulmonary hypertension, liver and kidney tissue damage, and anaphylactic reaction, amongst others 1,7. As a consequence, whenever protamine sulfate use is clinically considered, careful consideration must be given as to whether the use of the agent could decrease the safety of the procedure or worsen the recovery of a patient after the procedure 1,2,7.
Regardless, protamine sulfate continues to see contemporary use given its genuine effectiveness in reversing heparin effects. Although current up to date reviews and studies continue to search for new therapeutic alternatives to protamine sulfate, most substitutes possess similar and unacceptable adverse effects 1,2. Of the few agents that may be considered potentially successful alternatives - including idarucizumab for dabigatran reversal - their cost of procurement and potential range in reversing all parenteral anticoagulants are sometimes considered high and limited, respectively 1,2.
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Protein Based Therapies
Blood factors - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Protamine sulfate
Pharmacology
- Indication
Protamine sulfate is indicated for counteracting or reversing the anticoagulant effect of heparin as necessary 9,10,7,8. Such reversal may, for example, be required often before surgery; after renal hemodialysis; post open heart surgery; whenever excessive bleeding results from heparin use; and/or for the treatment of heparin overdosage, among other similar or related circumstances 9,10,7,8.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Heparin overdose •••••••••••• - Contraindications & Blackbox Warnings
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When not complexed with heparin, protamine sulfate by itself demonstrates a weak anticoagulant effect and also evidently prolongs the euglycaemic phase of the human body when used as an excipient in certain injectable insulin formulations 10. Furthermore, some animal studies have suggested that the long-term oral administration of protamine sulfate may favourably decrease serum lipid concentrations, presumably by enhancing the actions of the carnitine palmitoyltransferase-2 and acyl-CoA oxidase enzymes 10. Related studies have also shown that protamine sulfate may be able to decrease intestinal fat absorption and might possess certain antibacterial effects 10.
Additionally, studies have also determined that protamine sulfate elicits effects on the clotting factors human factor Xa and human antithrombin (AT) 10. In particular, it has been shown that protamine sulfate is capable of transforming and degrading factor Xa to inactive moieties, transforming Xa-AT complexes, promoting the digestive degradation of primary Xa-AT complexes to tertiary complexes, and ultimately promotes a reduction in total complex formulation via the hydrolysis of factor Xa moieties 10.
- Mechanism of action
It is generally understood that, when administered as an antidote to heparin, protamine sulfate is a fairly strong basic protein that subsequently binds with strongly acidic heparin to produce a stable and inactive complex (salt) 9,10,7,8. This inactive complex between protamine sulfate and heparin neutralizes the anticoagulant effect of both solitary protamine and heparin 9,10,7,8. In this way, protamine sulfate is used as an effective antidote to reverse the activity of heparin, and is useful for treating hemorrhage as a result of severe heparin or low-molecular weight heparin overdosage 9,10,7,8. Moreover, protamine sulfate is also frequently used in the same manner to neutralize the effect of heparin given before surgery and during extracorporeal circulation procedures like those performed in hemodialysis or cardiac surgery 9,10,7,8.
Target Actions Organism UCoagulation factor X Not Available Humans UAntithrombin-III Not Available Humans - Absorption
In general, based on data obtained from protamine sulfate administered in healthy humans the AUC demonstrated during the initial infusion is concave 10. Protamine concentrations were less than the limit of detection after twenty minutes or less, although the onset of action had been reported to appear within thirty to sixty seconds after intravenous administration 9,10,7,8 It is, however, generally documented that the neutralization of heparin occurs within five minutes after the intravenous administration of protamine sulfate 9,7,8.
Moreover, protamine concentration-versus-time data appears to be substantially different between men and women, where weight-adjusted protamine sulfate dosing ended up in significantly decreased AUC and substantially greater plasma clearance and volume of distribution at steady state in women as compared to men 10.
- Volume of distribution
In a study group of twenty-six patients aged between 26 to 80 years and undergoing a cardiac operation with cardiopulmonary bypass, the volume of distribution of protamine sulfate administered was recorded as being 5.4L (with a range of 0.82 to 34L) 3.
- Protein binding
Data regarding the protein binding of protamine sulfate is not readily available or accessible.
- Metabolism
The metabolic fate of the inactive heparin-protamine complex has not yet been formally elucidated 9,10,7,8. Nevertheless, considering protamine sulfate is itself objectively a mixture of basic protein peptide sulfates prepared from sperm or roe of appropriate species of fish (typically of the families Clupeidae or Salmonidae), the involvement of basic protein catalysis via the participation of endogenous peptidases may presumably play a part in the metabolism of protamine sulfate 10. Moreover, as protamine sulfate specifically reverses the anticoagulant activities of heparin by complexing with it, it has also been proposed that the heparin-protamine complex may be plausibly metabolized in part by the lytic enzyme fibrinolysin - a process which would also free heparin 9,7,8.
- Route of elimination
Data from limited studies regarding the elimination of protamine sulfate from the human body have determined that protamine excretion is predominantly renal 4.
- Half-life
The half-life of protamine sulfate in healthy individual volunteers without heparin in the body was determined to be about a median 7.4 minutes (from a range of 5.9-9.3 minutes) 3. For surgical patients undergoing a cardiac operation with cardiopulmonary bypass with the use/presence of heparin in the body, the half-life recorded was a median 4.5 minutes (from a range of 1.9-18 minutes) 3.
- Clearance
In a study group of twenty-six patients aged between 26 to 80 years and undergoing a cardiac operation with cardiopulmonary bypass, the clearance of protamine sulfate administered was recorded as being 1.4 L/min (with a range of 0.61 to 3.8 L/min) 3.
- Adverse Effects
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Administration of protamine sulfate intravenously could result in severe drop in blood pressure, dyspnea, bradycardia, pulmonary hypertension and anaphylaxis 9,10,7,8. Systemic hypertension, nausea, vomiting and lassitude were also reported 9,10,7,8. Overdosage of this drug may theoretically result in hemorrhage 9,10,7,8.
Nevertheless, any possible carcinogenicity, mutagenicity, effects upon pregnancy, effects on the newborn, on children, elderly individuals and a few other groups at risk have revealed there to be no animal toxicology cited in the literature to indicate that any of these risk factors might be present for protamine sulfate 10.
- 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.Not Available
- Food Interactions
- No interactions found.
Products
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Name Kind UNII CAS InChI Key Protamine unknown 72G3UY6T4N 9012-00-4 Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Protamine Sulfate Inj 10mg/ml USP Liquid 10 mg / mL Intravenous Lyphomed, Division Of Fujisawa Canada Inc. 1989-12-31 1996-09-10 Canada 
Protamine Sulfate Injection USP Liquid 10 mg / mL Intravenous Omega Laboratories Ltd 2000-01-26 Not applicable Canada Protamine Sulfate Injection USP Solution 10 mg / mL Intravenous Sandoz Canada Incorporated 1998-03-03 Not applicable Canada Protamine Sulfate Injection, USP Solution 10 mg / mL Intravenous Fresenius Kabi 1989-12-31 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Protamine Sulfate Injection, solution 10 mg/1mL Intravenous Fresenius Kabi USA, LLC 2000-10-18 Not applicable US 
Protamine Sulfate Injection, solution 10 mg/1mL Intravenous Cardinal Health 2000-10-18 2016-03-31 US Protamine Sulfate Injection, solution 10 mg/1mL Intravenous HF Acquisition Co LLC, DBA HealthFirst 2019-10-13 Not applicable US
Categories
- Drug Categories
- 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
- 0DE9724IHC
- CAS number
- 9009-65-8
References
- General References
- Sokolowska E, Kalaska B, Miklosz J, Mogielnicki A: The toxicology of heparin reversal with protamine: past, present and future. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):897-909. doi: 10.1080/17425255.2016.1194395. Epub 2016 Jun 6. [Article]
- Bromfield SM, Wilde E, Smith DK: Heparin sensing and binding - taking supramolecular chemistry towards clinical applications. Chem Soc Rev. 2013 Dec 7;42(23):9184-95. doi: 10.1039/c3cs60278h. Epub 2013 Sep 10. [Article]
- Butterworth J, Lin YA, Prielipp RC, Bennett J, Hammon JW, James RL: Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg. 2002 Nov;74(5):1589-95. [Article]
- DeLucia A 3rd, Wakefield TW, Kadell AM, Wrobleski SK, VanDort M, Stanley JC: Tissue distribution, circulating half-life, and excretion of intravenously administered protamine sulfate. ASAIO J. 1993 Jul-Sep;39(3):M715-8. [Article]
- Product info [Link]
- product info [Link]
- Dailymed: Protamine sulfate Monograph [Link]
- Prosulf (protamine sulfate) 10 mg/ml Solution for Injection [Link]
- Protamine Sulfate Injection, USP Product Information [File]
- UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]
- External Links
- KEGG Drug
- D02224
- PubChem Substance
- 347910415
- 8825
- Wikipedia
- Protamine_sulfate
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data4 Completed Prevention Valve Stenoses, Aortic 1 somestatus stop reason just information to hide 4 Completed Treatment Atrial Fibrillation / Catheter Ablation 1 somestatus stop reason just information to hide 4 Recruiting Prevention Valve Stenoses, Aortic 1 somestatus stop reason just information to hide 3 Not Yet Recruiting Treatment Valve Stenoses, Aortic / Valvular Heart Diseases 1 somestatus stop reason just information to hide Not Available Unknown Status Treatment Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous Injection, solution Intravenous 10 mg/ml Solution Parenteral 71.500 mg Injection, solution Intravenous 50 mg/5ml Injection, solution Intravenous 5000 iu/5ml Solution Intravenous 10 mg/ml Injection Intravenous 1 % Injection, solution Intravenous 10 mg/1mL Liquid Intravenous 10 mg / mL Solution Intravenous 10 mg / mL Injection Intravenous 10 mg/ml Injection Intravenous 1 % w/v Solution 10 mg/1ml Injection, solution Parenteral 10 mg/ml Solution Parenteral 1400 I.E. - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. Factor Xa activates pro-inflammatory signaling pathways in a protease-activated receptor (PAR)-dependent manner (PubMed:24041930, PubMed:30568593, PubMed:34831181). Up-regulates expression of protease-activated receptors (PARs) F2R, F2RL1 and F2RL2 in dermal microvascular endothelial cells (PubMed:35738824). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL6, in cardiac fibroblasts and umbilical vein endothelial cells in PAR-1 (F2R)-dependent manner (PubMed:30568593, PubMed:34831181). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2, IL6, TNF-alpha/TNF, IL-1beta/IL1B, IL8/CXCL8 and IL18, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Induces expression of adhesion molecules, such as ICAM1, VCAM1 and SELE, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Increases expression of phosphorylated ERK1/2 in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Triggers activation of the transcription factor NF-kappa-B in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Up-regulates expression of plasminogen activator inhibitor 1 (SERPINE1) in atrial tissues (PubMed:24041930)
- Specific Function
- Calcium ion binding
- Gene Name
- F10
- Uniprot ID
- P00742
- Uniprot Name
- Coagulation factor X
- Molecular Weight
- 54731.255 Da
References
- UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade (PubMed:15140129, PubMed:15853774). AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa (PubMed:15140129). Its inhibitory activity is greatly enhanced in the presence of heparin
- Specific Function
- Heparin binding
- Gene Name
- SERPINC1
- Uniprot ID
- P01008
- Uniprot Name
- Antithrombin-III
- Molecular Weight
- 52601.935 Da
References
- UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]
Drug created at September 30, 2015 18:50 / Updated at September 15, 2024 01:12