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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/30 00:53:17」(JST)

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Isoprenaline (INN) or isoproterenol (USAN) (trade names Medihaler-Iso and Isuprel) is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. In humans, it is a non-selective β adrenoreceptor agonist and TAAR1 agonist that is structurally similar to epinephrine (adrenaline).^[1]^[2]

Uses

Its primary use is for bradycardia or heart block. By activating β₁ adrenergic receptor in the heart, it induces positive chronotropic, dromotropic, and inotropic effects.^[2]

It can be used as an inhaled aerosol to treat asthma, although this is currently a rare treatment.^[2] Although it activates all beta adrenergic receptors, it works in a similar fashion to selective β₂ adrenergic agonists, e.g. salbutamol, by relaxing the airways to increase airflow.

It is also supplied in ampoules under the brand name Isuprel for injection and in sublingual pill form for treatment of asthma, chronic bronchitis and emphysema.

Used with caution, it can also be used to treat torsades de pointes by acquired defect, in conjunction with overdrive pacing and magnesium sulfate.

Pharmacology

Isoprenaline is a β₁ and β₂ adrenoreceptor agonist which was commonly used to treat asthma before the more widespread use of salbutamol, which has more selective effects on the airways. Its agonist effects at TAAR1 provide it with a pharmacodynamic effects that resemble those of the endogenous trace amines, like tyramine,^[1] although its short half-life prevents it from producing persistent psychoactive effects from TAAR1 activation in the central nervous system. Its route of administration is either intravenous, oral, intranasal, subcutaneous, or intramuscular, depending on use. The plasma half-life for isoprenaline is approximately two minutes.

Isoprenaline's effects on the cardiovascular system (non-selective) relate to its actions on cardiac β₁ receptors and β₂ receptors on smooth muscle within the tunica media of arterioles. Isoprenaline has positive inotropic and chronotropic effects on the heart. β₂ adrenoceptor 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 β₂ receptors' vasodilation.

The adverse effects of isoprenaline are also related to the drug's cardiovascular effects. Isoprenaline can produce tachycardia (an elevated heart rate), which predisposes patients to cardiac arrhythmias.

Warnings and contraindications

Isoprenaline should not be administered to patients with myocardial ischemia.

According to Code of Federal Regulations (CFR) Title 21 Section 201.305, use of isoprenaline has been regulated by mandating the inclusion of the following warning label: "Occasional patients have been reported to develop severe paradoxical airway resistance with repeated, excessive use of isoprenaline inhalation preparations. The cause of this refractory state is unknown. It is advisable that in such instances the use of this preparation be discontinued immediately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn. Deaths have been reported following excessive use of isoprenaline inhalation preparations and the exact cause is unknown. Cardiac arrest was noted in several instances"

Structure-activity relationship

The isopropylamine group in isoprenaline makes it selective for β receptors. The free catechol hydroxy groups keep it susceptible to enzymatic metabolism.^[3]

History

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.^[4]

Synthesis

Isoprenaline synthesis^[5]^[6]

Colterol

Friedel-Crafts acylation of catechol 1 with chloroacetyl chloride 2 leads to chloroketone 3. Displacement of halogen with isopropylamine gives aminoketone; hydrogenation over platinum reduces the carbonyl group to give racemic isoproterenol 4.

If instead of the isopropyl there is a tert-butyl group then the compound is called colterol. The p-cresoyl diester of the catechol is called bitolterol. It is a prodrug of colterol.^[7]

References

^ ^a ^b Kleinau G, Pratzka J, Nürnberg D, Grüters A, Führer-Sakel D, Krude H, Köhrle J, Schöneberg T, Biebermann H (October 2011). "Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists". PLoS ONE 6 (10): e27073. doi:10.1371/journal.pone.0027073. PMC 3205048. PMID 22073124.
"Table 1: EC₅₀ values of different agonists at hTAAR1, hADRB1 and hADRB2."
^ ^a ^b ^c Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. p. 5. ISBN 1-59541-101-1.
^ Medicinal Chemistry of Adrenergics and Cholinergics
^ Pierce, Neil and Hensley, Michael J. (1998). "Epidemiologic Studies of Beta Agonists and Asthma Deaths" (PDF). Epidemiologic Studies 20 (2).
^ G. Schening, O. Thomae, DE 723278 (1942).
^ G. Schening, O. Thomae, U.S. Patent 2,308,232 (1943).
^ Walker, Susannah B.; Kradjan, Wayne A.; Bierman, C. Warren (6 May 1985). "Bitolterol Mesylate: A Beta-adrenergic Agent; Chemistry, Pharmacokinetics, Pharmacodynamics, Adverse Effects and Clinical Efficacy in Asthma". Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 5 (3): 127–137. doi:10.1002/j.1875-9114.1985.tb03410.x. PMID 3895171. |access-date= requires |url= (help)

UpToDate Contents

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English Journal

Differential expression and regulation of anti-hypertrophic genes Npr1 and Npr2 during β-adrenergic receptor activation-induced hypertrophic growth in rats.

Manivasagam S1, Subramanian V1, Tumala A1, Vellaichamy E2.
Molecular and cellular endocrinology.Mol Cell Endocrinol.2016 Sep 15;433:117-29. doi: 10.1016/j.mce.2016.06.010. Epub 2016 Jun 6.
We sought to determine the effect of chronic activation of β-adrenergic receptor (β-AR) on the left ventricular (LV) expression profile of Npr1 and Npr2 (coding for NPR-A and NPR-B, respectively) genes, and the functional activity of these receptors in adult Wistar rat hearts. The Npr1 gene expres
PMID 27283501

Protective effects of Astragalus polysaccharides against endothelial dysfunction in hypertrophic rats induced by isoproterenol.

Han R1, Tang F2, Lu M2, Xu C2, Hu J2, Mei M2, Wang H3.
International immunopharmacology.Int Immunopharmacol.2016 Sep;38:306-12. doi: 10.1016/j.intimp.2016.06.014. Epub 2016 Jun 22.
Astragalus polysaccharide (APS) is an important bioactive component extracted from Chinese herb Astragalus membranaceus. It has been widely used in treatment of cardiovascular diseases. We have previously reported that APS could inhibit isoproterenol-induced cardiac hypertrophy. The present study wa
PMID 27344039

Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway.

Huang Z1, Nan C2, Wang H3, Su Q1, Xue W1, Chen Y1, Shan X1, Duan J4, Chen G1, Tao W5.
International immunopharmacology.Int Immunopharmacol.2016 Sep;38:186-93. doi: 10.1016/j.intimp.2016.05.025. Epub 2016 Jun 8.
Crocetin ester (CE) is the active ingredient of Crocus sativus L. stigmas and Gardenia jasminoides Ellis fruit. The main purpose of the present study was to investigate the protective effect of CE on isoproterenol (ISO)-induced acute myocardial ischemia (AMI) through Rho/ROCK/NF-κB pathway and expl
PMID 27285672

Japanese Journal

Potential Antiarrhythmic Effect of Methyl 3,4,5-Trimethoxycinnamate, a Bioactive Substance from Roots of Polygalae Radix: Suppression of Triggered Activities in Rabbit Myocytes

Biological and Pharmaceutical Bulletin 36(2), 238-244, 2013
NAID 130002480757

Role of Sphingosine-1-Phosphate in β-adrenoceptor Desensitization via Ca2+ Sensitization in Airway Smooth Muscle

Allergology International 61(2), 311-322, 2012
NAID 130004477126

Alpha Lipoic Acid Treatment Improved Endothelium-dependent Relaxation in Diabetic Rat Aorta

YAKUGAKU ZASSHI 131(5), 739-744, 2011
NAID 130000678856

Related Pictures

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★リンクテーブル★

リンク元	「isoproterenol sulfate」「dl-isoproterenol hydrochloride」
拡張検索	「isoprenaline sulfate」「dl-isoprenaline hydrochloride」「l-isoprenaline hydrochloride」

「isoproterenol sulfate」

Isoprenaline
Systematic (IUPAC) name
	(RS)-4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol
Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a601236
Pregnancy; category	C;
Routes of; administration	Inhalation (80–120 μg)
Legal status
Legal status	℞ (Prescription only);
Pharmacokinetic data
Biological half-life	~2 minutes
Identifiers
CAS Number	7683-59-2
ATC code	C01CA02 (WHO) R03AB02 (WHO); R03CB01 (WHO)
PubChem	CID 3779
IUPHAR/BPS	536
DrugBank	DB01064
ChemSpider	3647
UNII	L628TT009W
KEGG	D08090
ChEMBL	CHEMBL434
Chemical data
Formula	C11H17NO3
Molar mass	211.258 g/mol
	SMILES Oc1ccc(cc1O)C(O)CNC(C)C ;
	InChI 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 ; Key:JWZZKOKVBUJMES-UHFFFAOYSA-N ;
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