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.
Side effects of isoprenaline include tachycardia, palpitation, and , among others.
Isoprenaline was one of the first synthetic sympathomimetic and was the first selective β-adrenergic receptor agonist.
Medical uses
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 can be administered, for
bronchospasm occurring during
anesthesia, and as an
adjunct therapy in the treatment of hypovolemic shock,
septic shock, low
cardiac output (
hypoperfusion) states, congestive heart failure, and cardiogenic shock.
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.
Isoprenaline is used in the acute management of bradycardia, though not in the chronic treatment of bradycardia.
Historically, it was used to treat asthma via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations.
Available forms
Many formulations of isoprenaline appear to have been discontinued in the
United States and many other countries.
In the United States, it remains available only as an injectable solution.
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.
Contraindications
It should not be used in people with
(except in special circumstances),
or
heart block caused by
digitalis poisoning, ventricular arrhythmias which require inotropic therapy, or with
angina.
Side effects
Side effects of isoprenaline may include
nervousness,
headache,
dizziness,
nausea,
blurred vision,
tachycardia,
palpitations,
angina, Adams-Stokes attacks,
pulmonary edema,
hypertension,
hypotension, ventricular arrhythmias,
, difficulty breathing,
sweating, mild
,
weakness, flushing, and
pallor.
Isoprenaline has been reported to cause insulin resistance leading to diabetic ketoacidosis.
Overdose
Overdose of isoprenaline may produce effects including
tachycardia,
,
,
angina,
hypotension,
hypertension, and myocardial necrosis.
Pharmacology
Pharmacodynamics
Isoprenaline is a β
1- and β
2-adrenergic receptor
full agonist and has almost no activity at the α-adrenergic receptors at lower concentrations.
It has similar affinity for the β
1- and β
2-adrenergic receptors.
At higher concentrations, isoprenaline can also evoke responses mediated by α-adrenergic receptors.
Its agonist effects at the trace amine-associated receptor 1 (TAAR1) additionally provide it with
pharmacodynamic effects that resemble those of the endogenous
, like
tyramine.
Isoprenaline's effects on the cardiovascular system (non-selective) relate to its actions on heart β1-adrenergic receptors and β2-adrenergic receptors on smooth muscle within the tunica media of . Isoprenaline has positive inotropic and chronotropic effects on the heart. β2-Adrenergic receptor stimulation in arteriole smooth muscle induces vasodilation. Its inotropic and chronotropic effects elevate systole blood pressure, while its vasodilatory effects tend to lower diastole blood pressure. The overall effect is to decrease mean arterial pressure due to the vasodilation caused by β2-adrenergic receptor activation.
The isopropylamine group in isoprenaline makes it selective for β-adrenergic receptors.
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.
Pharmacokinetics
Absorption
Data on the absorption of isoprenaline are limited.
Oral isoprenaline is well-absorbed but is subject to strong first-pass metabolism
and is approximately 1,000times less potent than intravenous administration.
Hence, its oral
bioavailability is very low.
Another study suggested that its oral bioavailability, based on
pharmacodynamic activity via different routes, was slightly less than 4%.
Distribution
Isoprenaline is minimally able to cross the blood–brain barrier and hence is a peripherally selective drug.
This is attributed to its high
hydrophilicity.
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%.
The plasma protein binding of isoprenaline is 68.8 ± 1.2%.
Metabolism
Isoprenaline is
metabolism by catechol
O-methyltransferase (COMT) and conjugation by
sulfation.
It does not appear to be
glucuronidation.
There is very large interindividual variability in the sulfation of isoprenaline.
The free
catechol hydroxyl groups keep it susceptible to enzymatic metabolism.
The drug is a poor substrate for monoamine oxidase (MAO) and is not metabolized by this enzyme.
This is in contrast to
epinephrine and
norepinephrine.
Isoprenaline is much more strongly metabolized and conjugated with oral administration than with intravenous administration.
Its
metabolite 3-
O-methylisoprenaline, formed by COMT, is active as a weak
beta blocker.
Elimination
Isoprenaline is
excretion primarily in the
urine, as
sulfate conjugates.
It is excreted 59 to 107% in urine and 12 to 27% in
feces.
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.
The elimination half-life of isoprenaline by intravenous administration is approximately 2.5 to 5minutes.
Chemistry
Isoprenaline, also known as
N-isopropyl-3,4,β-trihydroxyphenethylamine or as
N-isopropylnorepinephrine, is a substituted phenethylamine and synthetic
catecholamine derivative.
It is the
N-
isopropyl analogue of
norepinephrine (3,4,β-trihydroxyphenethylamine) and
epinephrine (3,4,β-trihydroxy-
N-methylphenethylamine).
Isoprenaline is a small-molecule compound with the molecular formula C11H17NO3 and a molecular weight of 211.26g/mol.
Isoprenaline is used pharmaceutically as the hydrochloride and sulfate salts.
Isoprenaline is a racemic mixture of levorotatory and dextrorotatory .
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.
History
Isoprenaline was discovered in 1940
and was developed in the 1940s.
It was first approved for medical use in 1947 in the United States.
Isoprenaline was one of the first synthetic
sympathomimetic , was the first selective β-adrenergic receptor agonist, and was the first major sympathomimetic agent devoid of
vasopressor effects.
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.
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).
Society and culture
Names
Isoprenaline is the major
generic term of the drug and its , , and .
is its
Italian language generic name and its .
and
isoprenaline sulfate are its in the case of the
hydrochloride and
sulfate salts, respectively.
is another important synonym of the drug.
is its and in the case of the hydrochloride salt and
isoproterenol sulfate is its and in the case of the sulfate salt.
Other synonyms of the drug include
isopropylnorepinephrine,
isopropylnoradrenaline, and
isopropydine.
It is additionally known by the former developmental code name
WIN-5162.
Isoprenaline has been marketed under many brand names worldwide.
