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Isoprenaline

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Isoprenaline
Clinical data
Trade namesIsuprel, many others[1][2]
Other namesIsoproterenol; Isopropylnorepinephrine; Isopropylnoradrenaline; Isopropydine; WIN-5162
AHFS/DrugsMonograph
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)
Pharmacokineticdata
BioavailabilityOral:Very low[5][6]
Protein binding69% (mostly toalbumin)[3]
MetabolismMethylation(COMTTooltip Catechol O-methyltransferase),conjugation(sulfation)[7][3]
Metabolites• 3-O-Methylisoprenaline[3]
•Sulfateconjugates[7]
Onset of actionInhalation:2–5min[8]
Eliminationhalf-lifeIVTooltip Intravenous infusion:2.5–5min[3]
Oral:40min[3]
Duration of actionInhalation:0.5–2hours[8]
ExcretionUrine:59–107%[3]
Feces:12–27%[3]
Identifiers
  • 4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.028.807Edit this at Wikidata
Chemical and physical data
FormulaC11H17NO3
Molar mass211.261g·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,6H2,1-2H3checkY
  • Key:JWZZKOKVBUJMES-UHFFFAOYSA-NcheckY
(verify)

Isoprenaline,also known asisoproterenoland sold under the brand nameIsuprelamong others, is asympathomimeticmedicationwhich is used in the treatment of acutebradycardia(slow heart rate),heart block,and rarely forasthma,among other indications.[9]It is used byinjection into a vein,muscle,fat,or theheart,byinhalation,and in the pastunder the tongueorinto the rectum.[3][4]

Side effectsof isoprenaline includerapid heart beat,heart palpitations,andarrhythmias,among others.[9]Isoprenaline is aselectiveagonistof theβ-adrenergic receptors,including both theβ1-andβ2-adrenergic receptors.[9]By activating thesereceptors,it increasesheart rateand theforce of heart contractions.[10]Chemically, isoprenaline is asyntheticcatecholamineand is theN-isopropylanalogueofnorepinephrine(noradrenaline) andepinephrine(adrenaline).[11][3][12][13]

Isoprenaline was one of the firstsyntheticsympathomimeticaminesand was the firstselectiveβ-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 treatheart blockand episodes ofAdams–Stokes syndromethat are not caused byventricular tachycardiaorfibrillation,in emergencies forcardiac arrestuntilelectric shockcan be administered, forbronchospasmoccurring duringanesthesia,and as anadjunctin the treatment ofhypovolemic shock,septic shock,lowcardiac output(hypoperfusion) states,congestive heart failure,andcardiogenic shock.[9]It is also used to preventTorsades de Pointesin patients withlong QTrefractory tomagnesiumand 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 treatasthmavia 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 theUnited Statesand many other countries.[4][1][2][3]In the United States, it remains available only as aninjectablesolution.[4]It was previously also available in the United States as a solution, meteredaerosol,powder, or disc forinhalationand as atabletforsublingualandrectal administration,but these formulations were discontinued.[4]

Contraindications

[edit]

It should not be used in people withtachyarrhythmias(except in special circumstances),[19]tachycardiaorheart blockcaused bydigitalispoisoning,ventricular arrhythmiaswhich requireinotropictherapy, or withangina.[9]

Side effects

[edit]

Side effectsof isoprenaline may includenervousness,headache,dizziness,nausea,blurred vision,tachycardia,palpitations,angina,Adams-Stokes attacks,pulmonary edema,hypertension,hypotension,ventricular arrhythmias,tachyarrhythmias,difficulty breathing,sweating,mildtremors,weakness,flushing,andpallor.[9]Isoprenaline has been reported to causeinsulin resistanceleading todiabetic ketoacidosis.[20]

Overdose

[edit]

Overdoseof isoprenaline may produce effects includingtachycardia,arrhythmias,palpitations,angina,hypotension,hypertension,andmyocardial necrosis.[3][9]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Isoprenaline is aβ1-andβ2-adrenergic receptorfull agonistand has almost noactivityat theα-adrenergic receptorsat lower concentrations.[15][21]It has similaraffinityfor 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 thetrace amine-associated receptor 1(TAAR1) additionally provide it withpharmacodynamiceffects that resemble those of the endogenoustrace amines,liketyramine.[24]

Isoprenaline's effects on thecardiovascular system(non-selective) relate to its actions oncardiacβ1-adrenergic receptors and β2-adrenergic receptors onsmooth musclewithin thetunica mediaofarterioles.Isoprenaline haspositive inotropicandchronotropiceffects on the heart. β2-Adrenergic receptor stimulation inarteriolarsmooth muscle inducesvasodilation.Its inotropic and chronotropic effects elevatesystolicblood pressure,while its vasodilatory effects tend to lowerdiastolicblood pressure. The overall effect is to decreasemean arterial pressuredue to the vasodilation caused by β2-adrenergic receptor activation.[25]

Theisopropylaminegroup in isoprenaline makes it selective for β-adrenergic receptors.[26]

The adverse effects of isoprenaline are also related to the drug'scardiovasculareffects. Isoprenaline can producetachycardia(an elevatedheart rate), which predisposes people who take it tocardiac arrhythmias.[15]

Pharmacokinetics

[edit]

Absorption

[edit]

Data on theabsorptionof isoprenaline are limited.[3]Oralisoprenaline iswell-absorbedbut is subject to strongfirst-pass metabolism[27]and is approximately 1,000times lesspotentthanintravenous administration.[6]Hence, its oralbioavailabilityis very low.[5][6]Another study suggested that its oral bioavailability, based onpharmacodynamicactivity via different routes, was slightly less than 4%.[27][28]

Distribution

[edit]

Isoprenaline is minimally able to cross theblood–brain barrierand hence is aperipherally selective drug.[29][30]This is attributed to its highhydrophilicity.[29]Whereas the extraction of isoprenaline in a single passage of the brain circulation followingintravenous injectionin humans was 3.8%, the extraction of propranolol, which is a morelipophiliccompound and is readily able to cross into the brain, was 63.0%.[29]

Theplasma protein bindingof isoprenaline is 68.8 ± 1.2%.[3]It is bound mainly toalbumin.[3]

Metabolism

[edit]

Isoprenaline ismetabolizedbycatecholO-methyltransferase(COMT) andconjugationbysulfation.[7][31][32][3]It does not appear to beglucuronidated.[7]There is very largeinterindividual variabilityin the sulfation of isoprenaline.[7]The freecatecholhydroxylgroups keep it susceptible to enzymatic metabolism.[26]The drug is a poorsubstrateformonoamine oxidase(MAO) and is not metabolized by this enzyme.[7][9]This is in contrast toepinephrineandnorepinephrine.[7]Isoprenaline is much more strongly metabolized and conjugated with oral administration than with intravenous administration.[6]Itsmetabolite3-O-methylisoprenaline, formed by COMT, isactiveas a weakβ-adrenergic receptor antagonist.[7]

Elimination

[edit]

Isoprenaline isexcretedprimarily in theurine,assulfateconjugates.[7][31][32][3]It is excreted 59 to 107% in urine and 12 to 27% infeces.[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]

Theelimination half-lifeof isoprenaline byintravenous administrationis approximately 2.5 to 5minutes.[3]Its half-life withoral administrationis approximately 40minutes.[3][6]

Chemistry

[edit]

Isoprenaline, also known asN-isopropyl-3,4,β-trihydroxyphenethylamine or asN-isopropylnorepinephrine, is asubstituted phenethylamineandsyntheticcatecholaminederivative.[11][3][12][9]It is theN-isopropylanalogueofnorepinephrine(3,4,β-trihydroxyphenethylamine) andepinephrine(3,4,β-trihydroxy-N-methylphenethylamine).[11][13]

Isoprenaline is asmall-moleculecompoundwith themolecular formulaC11H17NO3and amolecular weightof 211.26g/mol.[11][3][12][9]It is ahydrophiliccompound[29]with a predictedlog Pof -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 thehydrochlorideandsulfatesalts.[1]It is also used to a much lesser extent as thefree base.[1]

Isoprenaline is aracemic mixtureoflevorotatoryanddextrorotatoryenantiomers.[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 includearbutamine,dichloroisoprenaline(dichloroisoproterenol),hexoprenaline,isoetharine(α-ethylisoprenaline),orciprenaline(metaproterenol; apositional isomerof isoprenaline),prenalterol,andsoterenol(3-methanesulfonamidylisoprenaline), among others.[5]

History

[edit]

Isoprenaline was discovered in 1940[5]and was developed in the 1940s.[7]It was first approved for medical use in 1947 in theUnited States.[15]Isoprenaline was one of the firstsyntheticsympathomimeticamines,was the firstselectiveβ-adrenergic receptor agonist,and was the first major sympathomimetic agent devoid ofpressoreffects.[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 unintentionaloverdose: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 shortduration of actionand poororalactivity of isoprenaline led to the development of the much longer-acting and orally activeorciprenaline(metaproterenol).[40][7]

Society and culture

[edit]

Names

[edit]

Isoprenalineis the majorgeneric nameof the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name,andDCFTooltip Dénomination Commune Française.[35][1][36][2]Isoprenalinais itsItaliangeneric name and itsDCITTooltip Denominazione Comune Italiana.[1][2]Isoprenaline hydrochlorideandisoprenaline sulfateare itsBANMTooltip British Approved Namein the case of thehydrochlorideandsulfatesalts,respectively.[1]Isoproterenolis another important synonym of the drug.[35][1][2]Isoproterenol hydrochlorideis itsUSANTooltip United States Adopted NameandJANTooltip Japanese Accepted Namein the case of the hydrochloride salt andisoproterenol sulfateis itsUSANandJANin the case of the sulfate salt.[35][1][36][2]Other synonyms of the drug includeisopropylnorepinephrine,isopropylnoradrenaline,andisopropydine.[35][1][36][2]It is additionally known by the former developmental code nameWIN-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 acombination drugwithcromoglicic acidas Frenal Compositum, in combination withpronaseas Isopal P, and in combination withatropineas Stmerin D.[2]

References

[edit]
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