Protamine sulfate

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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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.

TargetActionsOrganism
UCoagulation factor XNot AvailableHumans
UAntithrombin-IIINot AvailableHumans
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
Adverseeffects
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Toxicity

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

Products2
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Active Moieties
NameKindUNIICASInChI Key
Protamineunknown72G3UY6T4N9012-00-4Not applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Protamine Sulfate Inj 10mg/ml USPLiquid10 mg / mLIntravenousLyphomed, Division Of Fujisawa Canada Inc.1989-12-311996-09-10Canada flag
Protamine Sulfate Injection USPLiquid10 mg / mLIntravenousOmega Laboratories Ltd2000-01-26Not applicableCanada flag
Protamine Sulfate Injection USPSolution10 mg / mLIntravenousSandoz Canada Incorporated1998-03-03Not applicableCanada flag
Protamine Sulfate Injection, USPSolution10 mg / mLIntravenousFresenius Kabi1989-12-31Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Protamine SulfateInjection, solution10 mg/1mLIntravenousCardinal Health2000-10-182016-03-31US flag
Protamine SulfateInjection, solution10 mg/1mLIntravenousHF Acquisition Co LLC, DBA HealthFirst2019-10-13Not applicableUS flag
Protamine SulfateInjection, solution10 mg/1mLIntravenousFresenius Kabi USA, LLC2000-10-18Not applicableUS flag

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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. Product info [Link]
  6. product info [Link]
  7. Dailymed: Protamine sulfate Monograph [Link]
  8. Prosulf (protamine sulfate) 10 mg/ml Solution for Injection [Link]
  9. Protamine Sulfate Injection, USP Product Information [File]
  10. UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]
KEGG Drug
D02224
PubChem Substance
347910415
RxNav
8825
Wikipedia
Protamine_sulfate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionValve Stenoses, Aortic1
4CompletedTreatmentAtrial Fibrillation / Catheter Ablation1
Not AvailableRecruitingTreatmentCardiac Surgery With Cardiopulmonary Bypass1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous
InjectionIntravenous1 %
Injection, solutionIntravenous10 mg/1mL
LiquidIntravenous10 mg / mL
SolutionIntravenous10 mg / mL
SolutionIntravenous
InjectionIntravenous10 mg/ml
InjectionIntravenous1 % w/v
Solution10 mg/1ml
SolutionParenteral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific 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.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory a...
Gene Name
SERPINC1
Uniprot ID
P01008
Uniprot Name
Antithrombin-III
Molecular Weight
52601.935 Da
References
  1. UKPAR MHRA Prosulf (protamine sulphate) 10mg/ml Solution for Injection Assessment [File]

Drug created on September 30, 2015 18:50 / Updated on October 20, 2021 19:48