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{{Short description|Medication for slow heart rate}}
{{Short description|Medication for slow heart rate}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
{{Drugbox
| Watchedfields = changed
| Watchedfields = verified
| verifiedrevid = 477495291
| verifiedrevid = 477495291
| INN = Isoprenaline
| image = Isoprenaline.svg
| width = 225px
| USAN = Isoproterenol
| IUPAC_name = (''RS'')-4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol
| image = Isoprenaline.svg
| width = 225


<!--Clinical data-->| tradename = Many<ref name=brands/>
<!-- Clinical data -->
| tradename = Isuprel, many others<ref name="IndexNominum2004" /><ref name="Drugs.com" />
| Drugs.com =
| Drugs.com = {{drugs.com|monograph|isoproterenol}}
| MedlinePlus = a601236
| MedlinePlus = a601236
| pregnancy_AU = A
| pregnancy_AU = A
| legal_AU = S4
| legal_AU = S4
| pregnancy_US = C
| pregnancy_US = C
| legal_status = Rx-only
| legal_status = Rx-only
| routes_of_administration = Inhalation (80–120 μg), intravenous injection (IV)
| routes_of_administration = [[Intravenous infusion|Intravenous]], [[intramuscular injection]], [[subcutaneous injection]], [[intracardiac injection]], [[inhalational administration|inhalation]], [[sublingual administration]], [[rectal administration]]<ref name="DrugBank" /><ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | access-date=31 July 2024}}</ref>


<!--Pharmacokinetic data-->| bioavailability =
<!-- Pharmacokinetic data -->
| bioavailability = [[Oral administration|Oral]]: Very low<ref name="Waldeck2002" /><ref name="ConollyDaviesDollery1972" />
| protein_bound =
| protein_bound = 69% (mostly to [[human serum albumin|albumin]])<ref name="DrugBank" />
| metabolism =
| metabolism = [[Methylation]] ({{Abbrlink|COMT|Catechol O-methyltransferase}}), [[conjugation (biochemistry)|conjugation]] ([[sulfation]])<ref name="Morgan1990" /><ref name="DrugBank" />
| elimination_half-life = ~2 minutes
| metabolites = • 3-''O''-Methylisoprenaline<ref name="DrugBank" /><br />• [[Sulfate]] [[conjugation (biochemistry)|conjugate]]s<ref name="Morgan1990" />
| onset = [[Inhalational administration|Inhalation]]: 2–5{{nbsp}}min<ref name="Sterling1995" />
| elimination_half-life = {{Abbrlink|IV|Intravenous infusion}}: 2.5–5{{nbsp}}min<ref name="DrugBank">{{cite web | title=Isoprenaline: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=19 February 1948 | url=https://go.drugbank.com/drugs/DB01064 | access-date=31 July 2024}}</ref><br />[[Oral administration|Oral]]: 40{{nbsp}}min<ref name="DrugBank" />
| duration_of_action = [[Inhalational administration|Inhalation]]: 0.5–2{{nbsp}}hours<ref name="Sterling1995" />
| excretion = [[Urine]]: 59–107%<ref name="DrugBank" /><br />[[Feces]]: 12–27%<ref name="DrugBank" />


<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}
<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 7683-59-2
| CAS_number = 7683-59-2
| ATC_prefix = C01
| ATC_prefix = C01
| ATC_suffix = CA02
| ATC_suffix = CA02
| ATC_supplemental = {{ATC|R03|AB02}}<br />{{ATC|R03|CB01}}
| ATC_supplemental = {{ATC|R03|AB02}}<br />{{ATC|R03|CB01}}
| PubChem = 3779
| PubChem = 3779
| IUPHAR_ligand = 536
| IUPHAR_ligand = 536
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01064
| DrugBank = DB01064
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3647
| ChemSpiderID = 3647
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = L628TT009W
| UNII = L628TT009W
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08090
| KEGG = D08090
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 434
| ChEMBL = 434
| synonyms = Isoproterenol; Isopropylnorepinephrine; Isopropylnoradrenaline; Isopropydine; WIN-5162


<!--Chemical data-->| C = 11
<!-- Chemical data -->
| IUPAC_name = 4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol
| H = 17
| N = 1
| C=11 | H=17 | N=1 | O=3
| SMILES = CC(C)NCC(O)c1cc(O)c(O)cc1
| O = 3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| smiles = CC(C)NCC(O)c1cc(O)c(O)cc1
| StdInChI = 1S/C11H17NO3/c1-7(2)12-6-11(15)8-3-4-9(13)10(14)5-8/h3-5,7,11-15H,6H2,1-2H3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C11H17NO3/c1-7(2)12-6-11(15)8-3-4-9(13)10(14)5-8/h3-5,7,11-15H,6H2,1-2H3
| StdInChIKey = JWZZKOKVBUJMES-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JWZZKOKVBUJMES-UHFFFAOYSA-N
}}
}}
<!-- Definition and medical uses -->
'''Isoprenaline''', also known as '''isoproterenol''' and sold under the brand name '''Isuprel''' among others, is a [[sympathomimetic]] [[medication]] which is used in the treatment of acute [[bradycardia]] (slow heart rate), [[heart block]], and rarely for [[asthma]], among other indications.<ref name="Isuprel-Label">{{cite web|title=Label: Isoproterenol hydrochloride injection, solution|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a58f95fa-18f9-4938-8e3f-f33244f68298|publisher=NIH DailyMed|access-date=June 21, 2017|date=September 10, 2013}}</ref> It is used by [[intravenous administration|injection into a vein]], [[intramuscular injection|muscle]], [[subcutaneous injection|fat]], or the [[intracardiac injection|heart]], by [[inhalational administration|inhalation]], and in the past [[sublingual administration|under the tongue]] or [[rectal administration|into the rectum]].<ref name="DrugBank" /><ref name="Drugs@FDA" />


<!-- Side effects, mechanism, and chemistry -->
'''Isoprenaline''', or '''isoproterenol''' (brand name: Isoprenaline Macure), is a [[medication]] used for the treatment of [[bradycardia]] (slow heart rate), [[heart block]], and rarely for [[asthma]]. It is a non-selective [[Beta-adrenergic agonist|β adrenoceptor agonist]] that is the isopropylamine analog of [[epinephrine]] (adrenaline).<ref name=USlabel2013>{{cite web|title=Label: Isoproterenol hydrochloride injection, solution|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a58f95fa-18f9-4938-8e3f-f33244f68298|publisher=NIH DailyMed|access-date=June 21, 2017|date=September 10, 2013}}</ref>
[[Side effect]]s of isoprenaline include [[tachycardia|rapid heart beat]], [[palpitation|heart palpitation]]s, and [[arrhythmia]]s, among others.<ref name="Isuprel-Label" /> Isoprenaline is a [[binding selectivity|selective]] [[agonist]] of the [[β-adrenergic receptor]]s, including both the [[β1-adrenergic receptor|β<sub>1</sub>-]] and [[β2-adrenergic receptor|β<sub>2</sub>-adrenergic receptor]]s.<ref name="Isuprel-Label" /> By activating these [[receptor (biochemistry)|receptor]]s, it increases [[heart rate]] and the [[myocardial contractility|force of heart contraction]]s.<ref name="MotwaniSaunders2024">{{cite journal | vauthors = Motwani SK, Saunders H | title=Inotropes | journal=Anaesthesia & Intensive Care Medicine | volume=25 | issue=3 | date=2024 | doi=10.1016/j.mpaic.2023.11.019 | pages=185–191}}</ref> Chemically, isoprenaline is a [[synthetic compound|synthetic]] [[catecholamine]] and is the ''N''-[[isopropyl]] [[structural analogue|analogue]] of [[norepinephrine]] (noradrenaline) and [[epinephrine]] (adrenaline).<ref name="PubChem" /><ref name="DrugBank" /><ref name="ChemSpider" /><ref name="Konzett1981" />

<!-- History, society, and culture -->
Isoprenaline was one of the first [[synthetic compound|synthetic]] [[sympathomimetic]] [[amine]]s and was the first [[binding selectivity|selective]] β-adrenergic receptor agonist.<ref name="Morgan1990" /><ref name="RuženaJindraRenáta2020" /> The medication was discovered in 1940<ref name="Waldeck2002" /> and was introduced for medical use in 1947.<ref name="MozayaniRaymon2003" />


==Medical uses==
==Medical uses==
It is used to treat [[heart block]] and episodes of [[Adams–Stokes syndrome]] that are not caused by [[ventricular tachycardia]] or fibrillation, in emergencies for [[cardiac arrest]] until electric shock can be administered, for bronchospasm occurring during anesthesia, and as an adjunct in the treatment of [[hypovolemic shock]], [[septic shock]], low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock.<ref name=USlabel2013/>
Isoprenaline is used to treat [[heart block]] and episodes of [[Adams–Stokes syndrome]] that are not caused by [[ventricular tachycardia]] or [[fibrillation]], in emergencies for [[cardiac arrest]] until [[defibrillation|electric shock]] can be administered, for [[bronchospasm]] occurring during [[anesthesia]], and as an [[adjunct therapy|adjunct]] in the treatment of [[hypovolemic shock]], [[septic shock]], low [[cardiac output]] ([[hypoperfusion]]) states, [[congestive heart failure]], and [[cardiogenic shock]].<ref name="Isuprel-Label" /> It is also used to prevent [[Torsades de Pointes]] in patients with [[long QT]] refractory to [[magnesium]] and to treat patients with intermittent Torsades de Pointes refractory to treatment with magnesium.<ref name="Cohagan2022">{{cite book | vauthors = Cohagan B, Brandis D | chapter = Torsade de Pointes | date = August 2022 | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing |id={{NCBIBook2|NBK459388}} |pmid=29083738 }}</ref> Isoprenaline is used in the acute management of bradycardia, though not in the chronic treatment of bradycardia.<ref name="KusumotoSchoenfeldBarrett2019">{{cite journal | vauthors = Kusumoto FM, Schoenfeld MH, Barrett C, Edgerton JR, Ellenbogen KA, Gold MR, Goldschlager NF, Hamilton RM, Joglar JA, Kim RJ, Lee R, Marine JE, McLeod CJ, Oken KR, Patton KK, Pellegrini CN, Selzman KA, Thompson A, Varosy PD | title = 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society | journal = Circulation | volume = 140 | issue = 8 | pages = e382–e482 | date = August 2019 | pmid = 30586772 | doi = 10.1161/CIR.0000000000000628 | url = }}</ref>


Historically, it was used to treat asthma via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations.<ref name=Mozayan2003book/> The U.S. National Asthma Education and Prevention Program Expert Panel recommends against its use as a nebulizer for acute bronchoconstriction.<ref>{{cite web|last1=National Asthma Education and Prevention Program Expert Panel|title=Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma|url=https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf|publisher=NIH National Heart, Lung, and Blood Institute|date=August 28, 2007}}</ref>
Historically, it was used to treat [[asthma]] via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations.<ref name="MozayaniRaymon2003" /> The U.S. National Asthma Education and Prevention Program Expert Panel recommends against its use as a nebulizer for acute bronchoconstriction.<ref name="NAEPP2007">{{cite web|last1=National Asthma Education and Prevention Program Expert Panel |title= Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma |url= https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf |publisher=NIH National Heart, Lung, and Blood Institute|date=August 28, 2007}}</ref>


===Available forms===
Isoprenaline can also ameliorate the impairment of intestinal stem cells mediated by β<sub>2</sub>-adrenoreceptors after chemotherapy.<ref>{{cite journal|vauthors=Zeng H, Li H, Yue M |displayauthors=etal |title=Isoprenaline protects intestinal stem cells from chemotherapy-induced damage |journal=British Journal of Pharmacology |date=February 2020 |volume=177 |issue=3 |pages=687–700 |doi=10.1111/bph.14883}}</ref>
Many formulations of isoprenaline appear to have been discontinued in the [[United States]] and many other countries.<ref name="Drugs@FDA" /><ref name="IndexNominum2004" /><ref name="Drugs.com" /><ref name="DrugBank" /> In the United States, it remains available only as an [[injection (medicine)|injectable]] [[Solution (chemistry)|solution]].<ref name="Drugs@FDA" /> It was previously also available in the United States as a solution, metered [[aerosol]], powder, or disc for [[inhalational administration|inhalation]] and as a [[tablet (pharmacy)|tablet]] for [[sublingual administration|sublingual]] and [[rectal administration]], but these formulations were discontinued.<ref name="Drugs@FDA" />


==Contraindications==
==Contraindications==
It should not be used in people with tachyarrhythmias, tachycardia or heart block caused by digitalis poisoning, ventricular arrhythmias which require inotropic therapy, or with [[angina]].<ref name=USlabel2013/>
It should not be used in people with [[tachyarrhythmia]]s (except in special circumstances),<ref name="JongmanJepkes-BruinRamdat2007">{{cite journal | vauthors = Jongman JK, Jepkes-Bruin N, Ramdat Misier AR, Beukema WP, Delnoy PP, Oude Lutttikhuis H, Dambrink JH, Hoorntje JC, Elvan A | title = Electrical storms in Brugada syndrome successfully treated with isoproterenol infusion and quinidine orally | journal = Netherlands Heart Journal | volume = 15 | issue = 4 | pages = 151–155 | date = April 2007 | pmid = 17612676 | pmc = 1847769 | doi = 10.1007/BF03085972 }}</ref> [[tachycardia]] or [[heart block]] caused by [[digitalis]] poisoning, [[ventricular arrhythmia]]s which require [[Inotrope#Positive inotropic agents|inotropic]] therapy, or with [[angina]].<ref name="Isuprel-Label" />


==Adverse effects==
==Side effects==
Adverse effects of isoprenaline include nervousness, headache, dizziness, nausea, visual blurring, tachycardia, [[palpitations]], angina, Adams-Stokes attacks, [[pulmonary edema]], [[hypertension]], [[hypotension]], ventricular arrhythmias, tachyarrhythmias, difficulty breathing, sweating, mild tremors, weakness, flushing, and [[pallor]].<ref name=USlabel2013/> Isoproterenol has been reported to cause insulin resistance leading to diabetic ketoacidosis.<ref>{{cite journal |vauthors=Hoff R, Koh CK |title=Isoproterenol Induced Insulin Resistance Leading to Diabetic Ketoacidosis in Type 1 Diabetes Mellitus. |journal=Case Reports in Endocrinology |date=2018 |volume=2018 |pages=4328954 |doi=10.1155/2018/4328954 |pmid=30647979|pmc=6311779 |doi-access=free }}</ref>
[[Side effect]]s of isoprenaline may include [[nervousness]], [[headache]], [[dizziness]], [[nausea]], [[blurred vision]], [[tachycardia]], [[palpitations]], [[angina]], [[Adams–Stokes syndrome|Adams-Stokes attack]]s, [[pulmonary edema]], [[hypertension]], [[hypotension]], [[ventricular arrhythmia]]s, [[tachyarrhythmia]]s, [[difficulty breathing]], [[sweating]], mild [[tremor]]s, [[weakness]], [[flushing (physiology)|flushing]], and [[pallor]].<ref name="Isuprel-Label" /> Isoprenaline has been reported to cause [[insulin resistance]] leading to [[diabetic ketoacidosis]].<ref name="HoffKoh2018">{{cite journal | vauthors = Hoff R, Koh CK | title = Isoproterenol Induced Insulin Resistance Leading to Diabetic Ketoacidosis in Type 1 Diabetes Mellitus | journal = Case Reports in Endocrinology | volume = 2018 | pages = 4328954 | date = 2018 | pmid = 30647979 | pmc = 6311779 | doi = 10.1155/2018/4328954 | doi-access = free }}</ref>


==Pharmacology==
==Overdose==
The adverse effects of isoprenaline are also related to the drug's cardiovascular effects. Isoprenaline can produce [[tachycardia]] (an elevated [[heart rate]]), which predisposes people who take it to [[cardiac arrhythmia]]s.<ref name=Mozayan2003book/>
[[Overdose]] of isoprenaline may produce effects including [[tachycardia]], [[arrhythmia]]s, [[palpitation]]s, [[angina]], [[hypotension]], [[hypertension]], and [[cardiovascular disease|myocardial necrosis]].<ref name="DrugBank" /><ref name="Isuprel-Label" />


==Pharmacology==
===Pharmacodynamics===
===Pharmacodynamics===
Isoprenaline is a [[Beta-1 adrenergic receptor|β<sub>1</sub>]] and [[Beta-2 adrenergic receptor|β<sub>2</sub>]] adrenoreceptor agonist and has almost no activity on [[alpha adrenergic receptor]]s.<ref name=Mozayan2003book/> Its agonist effects at [[TAAR1]] provide it with pharmacodynamic effects that resemble those of the endogenous [[trace amine]]s, like [[tyramine]].<ref name="TAAR1 ligands and TA adrenergic receptor binding">{{cite journal | vauthors = Kleinau G, Pratzka J, Nürnberg D, Grüters A, Führer-Sakel D, Krude H, Köhrle J, Schöneberg T, Biebermann H | title = Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e27073 | date = October 2011 | pmid = 22073124 | pmc = 3205048 | doi = 10.1371/journal.pone.0027073 | bibcode = 2011PLoSO...627073K | doi-access = free }}<br />"[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205048/table/pone-0027073-t001/ Table 1: EC<sub>50</sub> values of different agonists at hTAAR1, hADRB1 and hADRB2.]"</ref>
Isoprenaline is a [[beta-1 adrenergic receptor|β<sub>1</sub>-]] and [[beta-2 adrenergic receptor|β<sub>2</sub>-adrenergic receptor]] [[full agonist]] and has almost no [[biological activity|activity]] at the [[alpha adrenergic receptor|α-adrenergic receptor]]s at lower concentrations.<ref name="MozayaniRaymon2003" /><ref name="EmilienMaloteaux1998">{{cite journal | vauthors = Emilien G, Maloteaux JM | title = Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists | journal = Eur J Clin Pharmacol | volume = 53 | issue = 6 | pages = 389–404 | date = February 1998 | pmid = 9551698 | doi = 10.1007/s002280050399 | url = }}</ref> It has similar [[affinity (pharmacology)|affinity]] for the β<sub>1</sub>- and β<sub>2</sub>-adrenergic receptors.<ref name="EmilienMaloteaux1998" /><ref name="Sterling1995">{{cite journal | vauthors = Sterling LP | title = Beta adrenergic agonists | journal = AACN Clin Issues | volume = 6 | issue = 2 | pages = 271–278 | date = May 1995 | pmid = 7743429 | doi = 10.1097/00044067-199505000-00010 | url = }}</ref> At higher concentrations, isoprenaline can also evoke responses mediated by α-adrenergic receptors.<ref name="Sterling1995" /><ref name="FurchgottBhadrakom1953">{{cite journal | vauthors = Furchgott RF, Bhadrakom S | title = Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 108 | issue = 2 | pages = 129–143 | date = June 1953 | pmid = 13062084 | url = https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=13062084 }}</ref><ref name="CopikBaldysNguyen2015">{{cite journal | vauthors = Copik AJ, Baldys A, Nguyen K, Sahdeo S, Ho H, Kosaka A, Dietrich PJ, Fitch B, Raymond JR, Ford AP, Button D, Milla ME | title = Isoproterenol acts as a biased agonist of the alpha-1A-adrenoceptor that selectively activates the MAPK/ERK pathway | journal = PLOS ONE | volume = 10 | issue = 1 | pages = e0115701 | date = 21 January 2015 | pmid = 25606852 | pmc = 4301629 | doi = 10.1371/journal.pone.0115701 | bibcode = 2015PLoSO..1015701C | doi-access = free }}</ref> Its agonist effects at the [[trace amine-associated receptor 1]] (TAAR1) additionally provide it with [[pharmacodynamic]] effects that resemble those of the endogenous [[trace amine]]s, like [[tyramine]].<ref name="KleinauPratzkaNürnberg2011">{{cite journal | vauthors = Kleinau G, Pratzka J, Nürnberg D, Grüters A, Führer-Sakel D, Krude H, Köhrle J, Schöneberg T, Biebermann H | title = Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e27073 | date = October 2011 | pmid = 22073124 | pmc = 3205048 | doi = 10.1371/journal.pone.0027073 | doi-access = free | bibcode = 2011PLoSO...627073K | quote = Table 1. EC50 values of different agonists at hTAAR1, hADRB1 and hADRB2 }}</ref>


Isoprenaline's effects on the [[cardiovascular system]] (non-selective) relate to its actions on cardiac β<sub>1</sub> receptors and β<sub>2</sub> receptors on smooth muscle within the [[tunica media]] of [[arteriole]]s. Isoprenaline has positive inotropic and [[chronotropic]] effects on the heart. β<sub>2</sub> adrenoceptor stimulation in arteriolar smooth muscle induces vasodilation. Its inotropic and chronotropic effects elevate [[Systole|systolic]] [[blood pressure]], while its vasodilatory effects tend to lower [[Diastole|diastolic]] blood pressure. The overall effect is to decrease [[mean arterial pressure]] due to the β<sub>2</sub> receptors' vasodilation.<ref>{{cite book|last1=Korbut|first1=Ryszard|title=Farmakologia|date=2017|publisher=Wydawnictwo Lekarskie PZWL|isbn=9788320053685|pages=36|language=pl}}</ref>
Isoprenaline's effects on the [[cardiovascular system]] (non-selective) relate to its actions on [[heart|cardiac]] β<sub>1</sub>-adrenergic receptors and β<sub>2</sub>-adrenergic receptors on [[smooth muscle]] within the [[tunica media]] of [[arteriole]]s. Isoprenaline has [[Inotrope#Positive inotropic agents|positive inotropic]] and [[chronotropic]] effects on the heart. β<sub>2</sub>-Adrenergic receptor stimulation in [[arteriole|arteriolar]] smooth muscle induces [[vasodilation]]. Its inotropic and chronotropic effects elevate [[systole|systolic]] [[blood pressure]], while its vasodilatory effects tend to lower [[diastole|diastolic]] blood pressure. The overall effect is to decrease [[mean arterial pressure]] due to the vasodilation caused by β<sub>2</sub>-adrenergic receptor activation.<ref name="Korbut2017">{{cite book| vauthors = Korbut R |title=Farmakologia|date=2017|publisher=Wydawnictwo Lekarskie PZWL|isbn=978-83-200-5368-5|page=36|language=pl}}</ref>


The [[isopropylamine]] group in isoprenaline makes it selective for β-adrenergic receptors.<ref name="Mehta2011" />
The [[isopropylamine]] group in isoprenaline makes it selective for β receptors. The free [[catechol]] [[hydroxyl]] groups keep it susceptible to enzymatic metabolism.<ref>{{cite web|last1=Mehta|first1=Akul|title=Notes - Medicinal Chemistry of the Peripheral Nervous System - Adrenergics and Cholinergic|url=http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html|publisher=Pharmaxchange|access-date=June 21, 2017|date=January 27, 2011|archive-url=https://web.archive.org/web/20101104022742/http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html|archive-date=4 November 2010|url-status=dead}}</ref>

The adverse effects of isoprenaline are also related to the drug's [[cardiovascular]] effects. Isoprenaline can produce [[tachycardia]] (an elevated [[heart rate]]), which predisposes people who take it to [[cardiac arrhythmia]]s.<ref name="MozayaniRaymon2003" />


===Pharmacokinetics===
===Pharmacokinetics===
====Absorption====
The plasma half-life for isoprenaline is approximately two minutes.{{citation needed|date=June 2017}}
Data on the [[absorption (pharmacokinetics)|absorption]] of isoprenaline are limited.<ref name="DrugBank" /> [[Oral administration|Oral]] isoprenaline is [[absorption (pharmacokinetics)|well-absorbed]] but is subject to strong [[first-pass metabolism]]<ref name="George1981" /> and is approximately 1,000{{nbsp}}times less [[potency (pharmacology)|potent]] than [[intravenous administration]].<ref name="ConollyDaviesDollery1972" /> Hence, its oral [[bioavailability]] is very low.<ref name="Waldeck2002" /><ref name="ConollyDaviesDollery1972" /> Another study suggested that its oral bioavailability, based on [[pharmacodynamic]] activity via different routes, was slightly less than 4%.<ref name="George1981">{{cite journal | vauthors = George CF | title = Drug metabolism by the gastrointestinal mucosa | journal = Clin Pharmacokinet | volume = 6 | issue = 4 | pages = 259–274 | date = 1981 | pmid = 6113909 | doi = 10.2165/00003088-198106040-00002 | url = }}</ref><ref name="Redwood1969">{{cite journal | vauthors = Redwood D | title = Conservative treatment of chronic heart block | journal = Br Med J | volume = 1 | issue = 5635 | pages = 26–29 | date = January 1969 | pmid = 5761891 | pmc = 1981820 | doi = 10.1136/bmj.1.5635.26 | url = }}</ref>

====Distribution====
Isoprenaline is minimally able to cross the [[blood–brain barrier]] and hence is a [[peripherally selective drug]].<ref name="OlesenHougårdHertz1978">{{cite journal | vauthors = Olesen J, Hougård K, Hertz M | title = Isoproterenol and propranolol: ability to cross the blood-brain barrier and effects on cerebral circulation in man | journal = Stroke | volume = 9 | issue = 4 | pages = 344–349 | date = 1978 | pmid = 209581 | doi = 10.1161/01.str.9.4.344 | url = | quote = Mean extraction of isoproterenol in a single passage of the brain circulation was 3.8% and the calculated PS product was 2.0 ml/100g/min. The mean extraction of propranolol was 63.0% and the mean PS product 46.7 ml/100 g/min. [...] Passage of Isoproterenol and Propranolol Across Blood–Brain Barrier: No data are available in the literature concerning the ability of isoproterenol to cross the blood-brain barrier. From the hydrophilic nature of the molecule one might expect diffusion to be very slow, but the possibility of active uptake mechanisms still existed. The extraction of 3.8% found in the present study corresponds to that of sodium or other hydrophilic molecules.12 It is likely that a significant part of this extraction stems from areas known to be devoid of a blood-brain barrier. The extraction is clearly much smaller than that seen for amino acids and other substances that pass the barrier by facilitated diffusion.14}}</ref><ref name="CrystalSalem2002">{{cite journal | vauthors = Crystal GJ, Salem MR | title = Beta-adrenergic stimulation restores oxygen extraction reserve during acute normovolemic hemodilution | journal = Anesth Analg | volume = 95 | issue = 4 | pages = 851–857, table of contents | date = October 2002 | pmid = 12351256 | doi = 10.1097/00000539-200210000-00011 | url = | quote = The lack of effect of blood-borne catecholamines, including isoproterenol, on cerebral blood flow has been attributed to their inability to cross the blood-brain barrier (26).}}</ref> This is attributed to its high [[hydrophilicity]].<ref name="OlesenHougårdHertz1978" /> Whereas the extraction of isoprenaline in a single passage of the brain circulation following [[intravenous injection]] in humans was 3.8%, the extraction of propranolol, which is a more [[lipophilic]] compound and is readily able to cross into the brain, was 63.0%.<ref name="OlesenHougårdHertz1978" />

The [[plasma protein binding]] of isoprenaline is 68.8 ± 1.2%.<ref name="DrugBank" /> It is bound mainly to [[human serum albumin|albumin]].<ref name="DrugBank" />

====Metabolism====
Isoprenaline is [[metabolism|metabolized]] by [[catechol O-methyltransferase|catechol ''O''-methyltransferase]] (COMT) and [[conjugation (biochemistry)|conjugation]] by [[sulfation]].<ref name="Morgan1990" /><ref name="ProcacciniSawyerWatt2019">{{cite book |doi=10.1016/B978-1-4557-0760-7.00019-X |chapter=Pharmacology of Cardiovascular Drugs |title=Critical Heart Disease in Infants and Children |year=2019 | vauthors = Procaccini DE, Sawyer JE, Watt KM |pages=192–212.e6 |isbn=978-1-4557-0760-7 |s2cid=81053428 }}</ref><ref name="Szymanski2022">{{cite book | vauthors = Szymanski MW, Singh DP |chapter=Isoproterenol |title=StatPearls |date=2023 |publisher=StatPearls Publishing |id={{NCBIBook2|NBK526042}} |pmid=30252298 }}</ref><ref name="DrugBank" /> It does not appear to be [[glucuronidation|glucuronidated]].<ref name="Morgan1990" /> There is very large [[interindividual variability]] in the sulfation of isoprenaline.<ref name="Morgan1990" /> The free [[catechol]] [[hydroxyl]] groups keep it susceptible to enzymatic metabolism.<ref name="Mehta2011">{{cite web| vauthors = Mehta A |title=Notes - Medicinal Chemistry of the Peripheral Nervous System - Adrenergics and Cholinergic |url= http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html |publisher=Pharmaxchange |access-date=June 21, 2017 |date=January 27, 2011|archive-url= https://web.archive.org/web/20101104022742/http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html|archive-date=4 November 2010|url-status=dead}}</ref> The drug is a poor [[substrate (biochemistry)|substrate]] for [[monoamine oxidase]] (MAO) and is not metabolized by this enzyme.<ref name="Morgan1990" /><ref name="Isuprel-Label" /> This is in contrast to [[epinephrine]] and [[norepinephrine]].<ref name="Morgan1990" /> Isoprenaline is much more strongly metabolized and conjugated with oral administration than with intravenous administration.<ref name="ConollyDaviesDollery1972" /> Its [[metabolite]] 3-''O''-methylisoprenaline, formed by COMT, is [[biological activity|active]] as a weak [[beta blocker|β-adrenergic receptor antagonist]].<ref name="Morgan1990" />

====Elimination====
Isoprenaline is [[excretion|excreted]] primarily in the [[urine]], as [[sulfate]] [[conjugation (biochemistry)|conjugate]]s.<ref name="Morgan1990" /><ref name="ProcacciniSawyerWatt2019" /><ref name="Szymanski2022" /><ref name="DrugBank" /> It is excreted 59 to 107% in urine and 12 to 27% in [[feces]].<ref name="DrugBank" /> A majority of isoprenaline is excreted in urine in conjugated form, whereas 6.5 to 16.2% is excreted as unchanged isoprenaline and 2.6 to 11.4% is excreted as 3-O-methylisoprenaline and conjugates.<ref name="DrugBank" /><ref name="ConollyDaviesDollery1972" />

The [[elimination half-life]] of isoprenaline by [[intravenous administration]] is approximately 2.5 to 5{{nbsp}}minutes.<ref name="DrugBank" /> Its half-life with [[oral administration]] is approximately 40{{nbsp}}minutes.<ref name="DrugBank" /><ref name="ConollyDaviesDollery1972">{{cite journal | vauthors = Conolly ME, Davies DS, Dollery CT, Morgan CD, Paterson JW, Sandler M | title = Metabolism of isoprenaline in dog and man | journal = Br J Pharmacol | volume = 46 | issue = 3 | pages = 458–472 | date = November 1972 | pmid = 4656607 | pmc = 1666503 | doi = 10.1111/j.1476-5381.1972.tb08143.x | url = }}</ref>


==Chemistry==
==Chemistry==
Isoprenaline, also known as ''N''-isopropyl-3,4,β-trihydroxyphenethylamine or as ''N''-isopropylnorepinephrine, is a [[substituted phenethylamine]] and [[synthetic compound|synthetic]] [[catecholamine]] [[chemical derivative|derivative]].<ref name="PubChem">{{cite web | title=Isoproterenol | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3779 | access-date=31 July 2024}}</ref><ref name="DrugBank" /><ref name="ChemSpider">{{cite web | title=Isoprenaline | website=ChemSpider | date=21 July 2022 | url=https://www.chemspider.com/Chemical-Structure.3647.html | access-date=31 July 2024}}</ref><ref name="Isuprel-Label" /> It is the ''N''-[[isopropyl]] [[structural analogue|analogue]] of [[norepinephrine]] (3,4,β-trihydroxyphenethylamine) and [[epinephrine]] (3,4,β-trihydroxy-''N''-methylphenethylamine).<ref name="PubChem" /><ref name="Konzett1981">{{cite journal | vauthors = Konzett H | title=On the discovery of isoprenaline | journal=Trends in Pharmacological Sciences | volume=2 | date=1981 | doi=10.1016/0165-6147(81)90259-5 | pages=47–49}}</ref>
It is structurally related to [[epinephrine]].<ref name=USlabel2013/>

Isoprenaline is a [[small-molecule]] [[chemical compound|compound]] with the [[molecular formula]] C<sub>11</sub>H<sub>17</sub>NO<sub>3</sub> and a [[molecular weight]] of 211.26{{nbsp}}g/mol.<ref name="PubChem" /><ref name="DrugBank" /><ref name="ChemSpider" /><ref name="Isuprel-Label" /> It is a [[hydrophilic]] compound<ref name="OlesenHougårdHertz1978" /> with a predicted [[partition coefficient|log P]] of -0.6 to 0.25.<ref name="PubChem" /><ref name="DrugBank" /><ref name="ChemSpider" /> For comparison, the experimental log P values of epinephrine and norepinephrine are -1.37 and -1.24, respectively.<ref name="PubChem-Epinephrine">{{cite web | title=Epinephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/5816 | access-date=1 August 2024}}</ref><ref name="PubChem-Norepinephrine">{{cite web | title=Norepinephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/439260 | access-date=1 August 2024}}</ref>

Isoprenaline is used pharmaceutically as the [[hydrochloride]] and [[sulfate]] [[salt (chemistry)|salt]]s.<ref name="IndexNominum2004" /> It is also used to a much lesser extent as the [[free base]].<ref name="IndexNominum2004" />

Isoprenaline is a [[racemic mixture]] of [[levorotatory]] and [[dextrorotatory]] [[enantiomer]]s.<ref name="PubChem" /><ref name="DrugBank" /><ref name="ChemSpider" /> The levorotatory or (''R'')-enantiomer of isoprenaline is known as levisoprenaline ({{Abbrlink|INN|International Nonproprietary Name}}) but was never marketed.<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="MortonHall2012-Levisoprenaline">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA164 | access-date=2024-08-01 | page=164}}</ref>

Synthetic analogues closely related to isoprenaline include [[arbutamine]], [[dichloroisoprenaline]] (dichloroisoproterenol), [[hexoprenaline]], [[isoetharine]] (α-ethylisoprenaline), [[orciprenaline]] (metaproterenol; a [[positional isomer]] of isoprenaline), [[prenalterol]], and [[soterenol]] (3-methanesulfonamidylisoprenaline), among others.<ref name="Waldeck2002" />


==History==
==History==
Isoprenaline was discovered in 1940<ref name="Waldeck2002">{{cite journal | vauthors = Waldeck B | title = Beta-adrenoceptor agonists and asthma--100 years of development | journal = Eur J Pharmacol | volume = 445 | issue = 1-2 | pages = 1–12 | date = June 2002 | pmid = 12065188 | doi = 10.1016/s0014-2999(02)01728-4 | url = }}</ref> and was developed in the 1940s.<ref name="Morgan1990" /> It was first approved for medical use in 1947 in the [[United States]].<ref name="MozayaniRaymon2003">{{cite book| vauthors = Mozayani A, Raymon L |title=Handbook of Drug Interactions: A Clinical and Forensic Guide|date=2003|publisher=Springer Science & Business Media|isbn=978-1-59259-654-6|pages=541–542|url=https://books.google.com/books?id=dwMyBwAAQBAJ&pg=PA541|language=en}}</ref> Isoprenaline was one of the first [[synthetic compound|synthetic]] [[sympathomimetic]] [[amine]]s, was the first [[binding selectivity|selective]] [[beta-adrenergic agonist|β-adrenergic receptor agonist]], and was the first major sympathomimetic agent devoid of [[vasopressor|pressor]] effects.<ref name="Morgan1990">{{cite journal | vauthors = Morgan DJ | title = Clinical pharmacokinetics of beta-agonists | journal = Clin Pharmacokinet | volume = 18 | issue = 4 | pages = 270–294 | date = April 1990 | pmid = 1969785 | doi = 10.2165/00003088-199018040-00002 | url = }}</ref><ref name="RuženaJindraRenáta2020">{{cite journal | vauthors = Ružena Č, Jindra V, Renáta H | title=Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis | journal=Open Chemistry | volume=18 | issue=1 | date=18 June 2020 | issn=2391-5420 | doi=10.1515/chem-2020-0056 | pages=628–647| doi-access=free }}</ref>
It was first approved in the US in 1947.<ref name=Mozayan2003book>{{cite book|last1=Mozayani|first1=Ashraf|last2=Raymon|first2=Lionel|title=Handbook of Drug Interactions: A Clinical and Forensic Guide|date=2003|publisher=Springer Science & Business Media|isbn=9781592596546|pages=541–542|url=https://books.google.com/books?id=dwMyBwAAQBAJ&pg=PA541|language=en}}</ref>

Between 1963 and 1968 in England, Wales, Scotland, Ireland, Australia, and New Zealand there was an increase in deaths among people using isoprenaline to treat asthma. This was attributed to overdose: the inhalers produced in that area were dispensing five times the dosage dispensed by inhalers produced in the US and Canada, where the deaths were not observed.<ref>{{cite journal |author1=Pierce, Neil |author2=Hensley, Michael J. | year = 1998 | title = Epidemiologic Studies of Beta Agonists and Asthma Deaths | journal = Epidemiologic Studies | volume = 20 | issue = 2|pages=173–186 |pmid=9919437|doi=10.1093/oxfordjournals.epirev.a017979 | doi-access = free }}</ref><ref>{{cite journal|last1=Jalba|first1=MS|title=Three generations of ongoing controversies concerning the use of short acting beta-agonist therapy in asthma: a review.|journal=The Journal of Asthma|date=2008|volume=45|issue=1|pages=9–18|doi=10.1080/02770900701495512|pmid=18259990|s2cid=31732029}}</ref>
Between 1963 and 1968 in England, Wales, Scotland, Ireland, Australia, and New Zealand there was an increase in deaths among people using isoprenaline to treat asthma. This was attributed to unintentional [[overdose]]: the inhalers produced in that area were dispensing five times the dosage dispensed by inhalers produced in the United States and Canada, where the deaths were not observed.<ref name="PearceHensley1998">{{cite journal | vauthors = Pearce N, Hensley MJ | title = Epidemiologic studies of beta agonists and asthma deaths | journal = Epidemiologic Reviews | volume = 20 | issue = 2 | pages = 173–186 | year = 1998 | pmid = 9919437 | doi = 10.1093/oxfordjournals.epirev.a017979 | doi-access = free }}</ref><ref name="Jalba2008">{{cite journal | vauthors = Jalba MS | title = Three generations of ongoing controversies concerning the use of short acting beta-agonist therapy in asthma: a review | journal = The Journal of Asthma | volume = 45 | issue = 1 | pages = 9–18 | date = 2008 | pmid = 18259990 | doi = 10.1080/02770900701495512 | s2cid = 31732029 }}</ref>

The short [[duration of action]] and poor [[oral administration|oral]] activity of isoprenaline led to the development of the much longer-acting and orally active [[orciprenaline]] (metaproterenol).<ref name="Derendorf1995">{{cite book | vauthors = Dserendorf H | title=Drug Actions: Basic Principles and Theraputic Aspects | publisher=CRC-Press | year=1995 | isbn=978-0-8493-7774-7 | url=https://books.google.com/books?id=IvN4mZxraMkC&pg=PA227 | access-date=1 August 2024 | page=227}}</ref><ref name="Morgan1990" />


==Society and culture==
==Society and culture==

===Brands===
===Names===
As of June 2017, isoprenaline was marketed under many brand names worldwide and as two different salts: Aleudrina, Asthpul, Iludrin, Isomenyl, Isoprenalin, Isoprenalina, Isoprenalina, Isoprenalina, Isoprenaline, Isoprenaline Macure, Isoprénaline, Isoprénaline, Isoprenaline hydrochloride, Isoprenaline sulfate, Isoprenalinesulfaat, Isoprenalinsulfat, Isoprenalinum, Isopropydine, Isopropylnoradrenaline, Isoproterenol, Isoproterenol, Isoproterenol, Isoproterenol hydrochloride, Isoproterenol sulfate, Isuprel, Isuprel, Neo-Epinine, Neodrenal, Proternol, Saventrine, and Win 5162.<ref name=brands>{{cite web|title=Isoprenaline international brands|url=https://www.drugs.com/international/isoprenaline.html|publisher=Drugs.com|access-date=June 21, 2017}}</ref> It is also marketed as a [[combination drug]] with [[cromoglicic acid]] as Frenal Compositum, in combination with [[pronase]] as Isopal P, and in combination with [[atropine]] as Stmerin D.<ref name=brands/>
''Isoprenaline'' is the major [[generic term|generic name]] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA710 | access-date=1 August 2024 | page=710}}</ref><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | series=Index Nominum: International Drug Directory | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA662 | access-date=1 August 2024 | page=662}}</ref><ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA157 | access-date=1 August 2024 | page=157}}</ref><ref name="Drugs.com">{{cite web | title=Isoprenaline | website=drugs.com | date=6 August 2017 | url=https://www.drugs.com/international/isoprenaline.html | archive-url=https://web.archive.org/web/20190626083242/https://www.drugs.com/international/isoprenaline.html | archive-date=26 June 2019 | url-status=dead | access-date=1 August 2024}}</ref> ''Isoprenalina'' is its [[Italian language|Italian]] generic name and its {{Abbrlink|DCIT|Denominazione Comune Italiana}}.<ref name="IndexNominum2004" /><ref name="Drugs.com" /> ''Isoprenaline hydrochloride'' and ''isoprenaline sulfate'' are its {{Abbrlink|BANM|British Approved Name}} in the case of the [[hydrochloride]] and [[sulfate]] [[salt (chemistry)|salt]]s, respectively.<ref name="IndexNominum2004" /> ''Isoproterenol'' is another important synonym of the drug.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="Drugs.com" /> ''Isoproterenol hydrochloride'' is its {{Abbrlink|USAN|United States Adopted Name}} and {{Abbrlink|JAN|Japanese Accepted Name}} in the case of the hydrochloride salt and ''isoproterenol sulfate'' is its {{Abbr|USAN|United States Adopted Name}} and {{Abbr|JAN|Japanese Accepted Name}} in the case of the sulfate salt.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="MortonHall2012" /><ref name="Drugs.com" /> Other synonyms of the drug include ''isopropylnorepinephrine'', ''isopropylnoradrenaline'', and ''isopropydine''.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="MortonHall2012" /><ref name="Drugs.com" /> It is additionally known by the former developmental code name ''WIN-5162''.<ref name="IndexNominum2004" /><ref name="Drugs.com" />

Isoprenaline has been marketed under many brand names worldwide.<ref name="IndexNominum2004" /><ref name="Drugs.com" /> These include Aleudrina, Asthpul, Iludrin, Iprenol, Isomenyl, Isuprel, Isoprenaline, Isoprenalina, Isoproterenol, Neo-Epinine, Neodrenal, Proternol, and Saventrine, among others.<ref name="IndexNominum2004" /><ref name="Drugs.com" /> It is also marketed as a [[combination drug]] with [[cromoglicic acid]] as Frenal Compositum, in combination with [[pronase]] as Isopal P, and in combination with [[atropine]] as Stmerin D.<ref name="Drugs.com" />


==References==
==References==
{{reflist|30em}}
{{Reflist}}



{{Cardiac stimulants excluding cardiac glycosides}}
{{Drugs for obstructive airway diseases}}
{{Drugs for obstructive airway diseases}}
{{Adrenergic receptor modulators}}
{{Adrenergics}}
{{Adrenergic and dopaminergic agents}}
{{Stimulants}}
{{TAAR ligands}}
{{TAAR ligands}}
{{Phenethylamines}}


[[Category:Antiasthmatic drugs]]
[[Category:Antiasthmatic drugs]]
[[Category:Alpha-adrenergic agonists]]<!-- At higher concentrations -->
[[Category:Beta1-adrenergic agonists]]
[[Category:Beta1-adrenergic agonists]]
[[Category:Beta2-adrenergic agonists]]
[[Category:Beta2-adrenergic agonists]]
[[Category:Bronchodilators]]
[[Category:Cardiac stimulants]]
[[Category:Catecholamines]]
[[Category:Catecholamines]]
[[Category:Chemical substances for emergency medicine]]
[[Category:Drugs acting on the cardiovascular system]]
[[Category:Inotropic agents]]
[[Category:Inotropic agents]]
[[Category:TAAR1 agonists]]
[[Category:Isopropylamino compounds]]
[[Category:Peripherally selective drugs]]
[[Category:Phenylethanolamines]]
[[Category:Phenylethanolamines]]
[[Category:Isopropyl compounds]]
[[Category:Sympathomimetic amines]]
[[Category:TAAR1 agonists]]
[[Category:Vasodilators]]

Latest revision as of 22:22, 24 September 2024

Isoprenaline
Clinical data
Trade namesIsuprel, many others[1][2]
Other namesIsoproterenol; Isopropylnorepinephrine; Isopropylnoradrenaline; Isopropydine; WIN-5162
AHFS/Drugs.comMonograph
MedlinePlusa601236
Pregnancy
category
  • AU: A
Routes of
administration		Intravenous, intramuscular injection, subcutaneous injection, intracardiac injection, inhalation, sublingual administration, rectal administration[3][4]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: Very low[5][6]
Protein binding69% (mostly to albumin)[3]
MetabolismMethylation (COMTTooltip Catechol O-methyltransferase), conjugation (sulfation)[7][3]
Metabolites• 3-O-Methylisoprenaline[3]
• Sulfate conjugates[7]
Onset of actionInhalation: 2–5 min[8]
Elimination half-lifeIVTooltip Intravenous infusion: 2.5–5 min[3]
Oral: 40 min[3]
Duration of actionInhalation: 0.5–2 hours[8]
ExcretionUrine: 59–107%[3]
Feces: 12–27%[3]
Identifiers
  • 4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.028.807 Edit this at Wikidata
Chemical and physical data
FormulaC11H17NO3
Molar mass211.261 g·mol−1
3D model (JSmol)
  • CC(C)NCC(O)c1cc(O)c(O)cc1
  • InChI=1S/C11H17NO3/c1-7(2)12-6-11(15)8-3-4-9(13)10(14)5-8/h3-5,7,11-15H,6H2,1-2H3 checkY
  • Key:JWZZKOKVBUJMES-UHFFFAOYSA-N checkY
  (verify)

Isoprenaline, also known as isoproterenol and sold under the brand name Isuprel among others, is a sympathomimetic medication which is used in the treatment of acute bradycardia (slow heart rate), heart block, and rarely for asthma, among other indications.[9] It is used by injection into a vein, muscle, fat, or the heart, by inhalation, and in the past under the tongue or into the rectum.[3][4]

Side effects of isoprenaline include rapid heart beat, heart palpitations, and arrhythmias, among others.[9] Isoprenaline is a selective agonist of the β-adrenergic receptors, including both the β1- and β2-adrenergic receptors.[9] By activating these receptors, it increases heart rate and the force of heart contractions.[10] Chemically, isoprenaline is a synthetic catecholamine and is the N-isopropyl analogue of norepinephrine (noradrenaline) and epinephrine (adrenaline).[11][3][12][13]

Isoprenaline was one of the first synthetic sympathomimetic amines and was the first selective β-adrenergic receptor agonist.[7][14] The medication was discovered in 1940[5] and was introduced for medical use in 1947.[15]

Medical uses

[edit]

Isoprenaline is used to treat heart block and episodes of Adams–Stokes syndrome that are not caused by ventricular tachycardia or fibrillation, in emergencies for cardiac arrest until electric shock can be administered, for bronchospasm occurring during anesthesia, and as an adjunct in the treatment of hypovolemic shock, septic shock, low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock.[9] It is also used to prevent Torsades de Pointes in patients with long QT refractory to magnesium and to treat patients with intermittent Torsades de Pointes refractory to treatment with magnesium.[16] Isoprenaline is used in the acute management of bradycardia, though not in the chronic treatment of bradycardia.[17]

Historically, it was used to treat asthma via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations.[15] The U.S. National Asthma Education and Prevention Program Expert Panel recommends against its use as a nebulizer for acute bronchoconstriction.[18]

Available forms

[edit]

Many formulations of isoprenaline appear to have been discontinued in the United States and many other countries.[4][1][2][3] In the United States, it remains available only as an injectable solution.[4] It was previously also available in the United States as a solution, metered aerosol, powder, or disc for inhalation and as a tablet for sublingual and rectal administration, but these formulations were discontinued.[4]

Contraindications

[edit]

It should not be used in people with tachyarrhythmias (except in special circumstances),[19] tachycardia or heart block caused by digitalis poisoning, ventricular arrhythmias which require inotropic therapy, or with angina.[9]

Side effects

[edit]

Side effects of isoprenaline may include nervousness, headache, dizziness, nausea, blurred vision, tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias, difficulty breathing, sweating, mild tremors, weakness, flushing, and pallor.[9] Isoprenaline has been reported to cause insulin resistance leading to diabetic ketoacidosis.[20]

Overdose

[edit]

Overdose of isoprenaline may produce effects including tachycardia, arrhythmias, palpitations, angina, hypotension, hypertension, and myocardial necrosis.[3][9]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Isoprenaline is a β1- and β2-adrenergic receptor full agonist and has almost no activity at the α-adrenergic receptors at lower concentrations.[15][21] It has similar affinity for the β1- and β2-adrenergic receptors.[21][8] At higher concentrations, isoprenaline can also evoke responses mediated by α-adrenergic receptors.[8][22][23] Its agonist effects at the trace amine-associated receptor 1 (TAAR1) additionally provide it with pharmacodynamic effects that resemble those of the endogenous trace amines, like tyramine.[24]

Isoprenaline's effects on the cardiovascular system (non-selective) relate to its actions on cardiac β1-adrenergic receptors and β2-adrenergic receptors on smooth muscle within the tunica media of arterioles. Isoprenaline has positive inotropic and chronotropic effects on the heart. β2-Adrenergic receptor stimulation in arteriolar smooth muscle induces vasodilation. Its inotropic and chronotropic effects elevate systolic blood pressure, while its vasodilatory effects tend to lower diastolic blood pressure. The overall effect is to decrease mean arterial pressure due to the vasodilation caused by β2-adrenergic receptor activation.[25]

The isopropylamine group in isoprenaline makes it selective for β-adrenergic receptors.[26]

The adverse effects of isoprenaline are also related to the drug's cardiovascular effects. Isoprenaline can produce tachycardia (an elevated heart rate), which predisposes people who take it to cardiac arrhythmias.[15]

Pharmacokinetics

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Absorption

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Data on the absorption of isoprenaline are limited.[3] Oral isoprenaline is well-absorbed but is subject to strong first-pass metabolism[27] and is approximately 1,000 times less potent than intravenous administration.[6] Hence, its oral bioavailability is very low.[5][6] Another study suggested that its oral bioavailability, based on pharmacodynamic activity via different routes, was slightly less than 4%.[27][28]

Distribution

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Isoprenaline is minimally able to cross the blood–brain barrier and hence is a peripherally selective drug.[29][30] This is attributed to its high hydrophilicity.[29] Whereas the extraction of isoprenaline in a single passage of the brain circulation following intravenous injection in humans was 3.8%, the extraction of propranolol, which is a more lipophilic compound and is readily able to cross into the brain, was 63.0%.[29]

The plasma protein binding of isoprenaline is 68.8 ± 1.2%.[3] It is bound mainly to albumin.[3]

Metabolism

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Isoprenaline is metabolized by catechol O-methyltransferase (COMT) and conjugation by sulfation.[7][31][32][3] It does not appear to be glucuronidated.[7] There is very large interindividual variability in the sulfation of isoprenaline.[7] The free catechol hydroxyl groups keep it susceptible to enzymatic metabolism.[26] The drug is a poor substrate for monoamine oxidase (MAO) and is not metabolized by this enzyme.[7][9] This is in contrast to epinephrine and norepinephrine.[7] Isoprenaline is much more strongly metabolized and conjugated with oral administration than with intravenous administration.[6] Its metabolite 3-O-methylisoprenaline, formed by COMT, is active as a weak β-adrenergic receptor antagonist.[7]

Elimination

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Isoprenaline is excreted primarily in the urine, as sulfate conjugates.[7][31][32][3] It is excreted 59 to 107% in urine and 12 to 27% in feces.[3] A majority of isoprenaline is excreted in urine in conjugated form, whereas 6.5 to 16.2% is excreted as unchanged isoprenaline and 2.6 to 11.4% is excreted as 3-O-methylisoprenaline and conjugates.[3][6]

The elimination half-life of isoprenaline by intravenous administration is approximately 2.5 to 5 minutes.[3] Its half-life with oral administration is approximately 40 minutes.[3][6]

Chemistry

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Isoprenaline, also known as N-isopropyl-3,4,β-trihydroxyphenethylamine or as N-isopropylnorepinephrine, is a substituted phenethylamine and synthetic catecholamine derivative.[11][3][12][9] It is the N-isopropyl analogue of norepinephrine (3,4,β-trihydroxyphenethylamine) and epinephrine (3,4,β-trihydroxy-N-methylphenethylamine).[11][13]

Isoprenaline is a small-molecule compound with the molecular formula C11H17NO3 and a molecular weight of 211.26 g/mol.[11][3][12][9] It is a hydrophilic compound[29] with a predicted log P of -0.6 to 0.25.[11][3][12] For comparison, the experimental log P values of epinephrine and norepinephrine are -1.37 and -1.24, respectively.[33][34]

Isoprenaline is used pharmaceutically as the hydrochloride and sulfate salts.[1] It is also used to a much lesser extent as the free base.[1]

Isoprenaline is a racemic mixture of levorotatory and dextrorotatory enantiomers.[11][3][12] The levorotatory or (R)-enantiomer of isoprenaline is known as levisoprenaline (INNTooltip International Nonproprietary Name) but was never marketed.[35][36][37]

Synthetic analogues closely related to isoprenaline include arbutamine, dichloroisoprenaline (dichloroisoproterenol), hexoprenaline, isoetharine (α-ethylisoprenaline), orciprenaline (metaproterenol; a positional isomer of isoprenaline), prenalterol, and soterenol (3-methanesulfonamidylisoprenaline), among others.[5]

History

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Isoprenaline was discovered in 1940[5] and was developed in the 1940s.[7] It was first approved for medical use in 1947 in the United States.[15] Isoprenaline was one of the first synthetic sympathomimetic amines, was the first selective β-adrenergic receptor agonist, and was the first major sympathomimetic agent devoid of pressor effects.[7][14]

Between 1963 and 1968 in England, Wales, Scotland, Ireland, Australia, and New Zealand there was an increase in deaths among people using isoprenaline to treat asthma. This was attributed to unintentional overdose: the inhalers produced in that area were dispensing five times the dosage dispensed by inhalers produced in the United States and Canada, where the deaths were not observed.[38][39]

The short duration of action and poor oral activity of isoprenaline led to the development of the much longer-acting and orally active orciprenaline (metaproterenol).[40][7]

Society and culture

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Names

[edit]

Isoprenaline is the major generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[35][1][36][2] Isoprenalina is its Italian generic name and its DCITTooltip Denominazione Comune Italiana.[1][2] Isoprenaline hydrochloride and isoprenaline sulfate are its BANMTooltip British Approved Name in the case of the hydrochloride and sulfate salts, respectively.[1] Isoproterenol is another important synonym of the drug.[35][1][2] Isoproterenol hydrochloride is its USANTooltip United States Adopted Name and JANTooltip Japanese Accepted Name in the case of the hydrochloride salt and isoproterenol sulfate is its USAN and JAN in the case of the sulfate salt.[35][1][36][2] Other synonyms of the drug include isopropylnorepinephrine, isopropylnoradrenaline, and isopropydine.[35][1][36][2] It is additionally known by the former developmental code name WIN-5162.[1][2]

Isoprenaline has been marketed under many brand names worldwide.[1][2] These include Aleudrina, Asthpul, Iludrin, Iprenol, Isomenyl, Isuprel, Isoprenaline, Isoprenalina, Isoproterenol, Neo-Epinine, Neodrenal, Proternol, and Saventrine, among others.[1][2] It is also marketed as a combination drug with cromoglicic acid as Frenal Compositum, in combination with pronase as Isopal P, and in combination with atropine as Stmerin D.[2]

References

[edit]
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  30. ^ Crystal GJ, Salem MR (October 2002). "Beta-adrenergic stimulation restores oxygen extraction reserve during acute normovolemic hemodilution". Anesth Analg. 95 (4): 851–857, table of contents. doi:10.1097/00000539-200210000-00011. PMID 12351256. The lack of effect of blood-borne catecholamines, including isoproterenol, on cerebral blood flow has been attributed to their inability to cross the blood-brain barrier (26).
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  39. ^ Jalba MS (2008). "Three generations of ongoing controversies concerning the use of short acting beta-agonist therapy in asthma: a review". The Journal of Asthma. 45 (1): 9–18. doi:10.1080/02770900701495512. PMID 18259990. S2CID 31732029.
  40. ^ Dserendorf H (1995). Drug Actions: Basic Principles and Theraputic Aspects. CRC-Press. p. 227. ISBN 978-0-8493-7774-7. Retrieved 1 August 2024.


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