Dopexamine

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Dopexamine
Dopexamine.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
  • 4-[2-({6-[(2-phenylethyl)amino]hexyl}amino)ethyl]benzene-1,2-diol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H32N2O2
Molar mass 356.510 g·mol−1
3D model (JSmol)
  • Oc1ccc(cc1O)CCNCCCCCCNCCc2ccccc2
  • InChI=1S/C22H32N2O2/c25-21-11-10-20(18-22(21)26)13-17-24-15-7-2-1-6-14-23-16-12-19-8-4-3-5-9-19/h3-5,8-11,18,23-26H,1-2,6-7,12-17H2 Yes check.svgY
  • Key:RYBJORHCUPVNMB-UHFFFAOYSA-N Yes check.svgY
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Dopexamine is a synthetic analogue of dopamine that is administered intravenously in hospitals to reduce exacerbations of heart failure and to treat heart failure following cardiac surgery. It is not used often, as more established drugs like epinephrine, dopamine, dobutamine, norepinephrine, and levosimendan work as well. It works by stimulating beta-2 adrenergic receptors and peripheral dopamine receptor D1 and dopamine receptor D2. It also inhibits the neuronal re-uptake of norepinephrine.

Contents

The most common adverse effects include fast heart beats and nausea.

It was discovered by scientists at Fisons, which licensed it to Ipsen in 1993, and Ipsen in turn licensed it to Élan in 1999. Ipsen licensed rights in North America and Japan to Circassia in 2008; the drug had never been approved in those countries. Dopexamine went off-patent in 2010.

Medical use

Dopexamine is used in hospitals as an inotropic agent to reduce exacerbations of heart failure and to treat heart failure following cardiac surgery. [1] [2] [3] It is administered intravenuously. [2]

As of 2010 dopexamine was not often administered in cardiac care because other, more well established drugs can accomplish the same effect, other such drugs include epinephrine, dopamine, dobutamine, norepinephrine, and levosimendan. [4]

It should not be used in people taking monoamine oxidase inhibitors, nor in people who have certain adrenal cancers, low platelet counts, or people with left ventricular outlet obstruction. [2]

It also should not be used in people with severe low blood pressure or reduced systemic vascular resistance. It should be used in caution in people with ischemic heart disease especially following heart attack or a recent episode of angina due to the risk of tachycardia. It should not be used in people with reduced blood volume. [2]

Safety in pregnant women has not been established. [2]

Adverse effects

Very common (greater than 10%) adverse effects include fast heart beats and nausea. [2] Common (between 1% and 10%) adverse effects include tremor, headache, transient low blood pressure, vomiting, increased sweating, sepsis, sinus and nodal slow heart beat, cardiac arrest, myocardial infarction, cardiac enzyme changes, non-specific ECG changes, high blood pressure, hemorrhage, respiratory failure, acute respiratory distress syndrome, pulmonary edema, pulmonary hypertension, and kidney failure. [2]

Like other β2-agonists, dopexamine lowers potassium levels and raises glucose levels, so there is a risk of exacerbating hypokalaemia or hyperglycaemia. [2]

People can develop drug tolerance to dopexamine if it is administered over a long period of time, as with other catecholamines. [2]

Dopexamine may potentiate the effects of other catecholamines like noradrenaline. Effects of depexamine may be suppressed by concomitant use with β2-adrenergic and dopamine receptor antagonists requires caution. [2]

Pharmacology

The half-life of IV dopexamine is 6–7 minutes in healthy adults and 11 minutes in patients with heart failure. [2]

Mechanism of action

Dopexamine stimulates beta-2 adrenergic receptors and peripheral dopamine receptor D1 and dopamine receptor D2. It also inhibits of neuronal re-uptake of norepinephrine (Uptake-1). These activities increase cardiac output and increase blood flow to peripheral vascular beds. [2] [3] It is not an α-adrenergic agonist, does not cause vasoconstriction, and is not a pressor agent. [2]

As of 2004 there was some controversy surrounding the mechanism of dopexamine. Some held that its local effects of increased tissue perfusion were due only to increased output from the heart, while others held that were direct peripheral effects. [5]

Chemistry

Dopexamine is a synthetic analogue of dopamine, a catecholamine. [3] Its formula may be stated 4-[2-[4[[6-[(2-phenylethy)amino]-hexyl]amino]ethyl]-1,2-benzenediol or 4-[2-[4[[6-(phenethylamino)hexyl]-amino]ethyl]pyrocatechol. [6]

Chinese manufacturers dominated the market for the active pharmaceutical ingredient as of 2015. [7]

History

Dopexamine was discovered by scientists at Fisons [8] [9] and Fisons received the USAN name dopexamine in 1985 for its compound, then called FPL 60278. [6]

The drug was marketed by 1992 [10] and by 1996 had been approved in several countries. [11]

Fisons licensed the rights to Ipsen in 1993, and Ipsen in turn licensed the rights to Elan in 1999. [8]

The patent on dopexamine was controlled by Elan when it expired in 2003. [12]

Dopexamine was approved for use in the European Union for treatment of symptoms related to heart failure in 2010. [2]

In 2008 the UK company Circassia acquired the US, Canadian, and Japanese marketing rights to dopexamine from Ipsen; at the time, the company said it was planning to develop a new formulation of dopexamine in combination with fluids delivered via IV fluids, looking to improve outcomes following surgery. [13] As of 2008 dopexamine had not been approved for any use in the US, Canada, or Japan. [13] A

Teva recalled batches of dopexamine in the UK in 2014 due to quality control issues by the manufacturer, Cephalon. [14]

Research

Use in sepsis has been explored in clinical trials, but use of an inotropic agent like dobutamine or dopexamine did not reduce mortality compared with norepinephrine or epinephrine. [15] Use of dopexamine may be harmful in sepsis [5]

Related Research Articles

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most people.

<span class="mw-page-title-main">Adrenergic receptor</span> Class of G protein-coupled receptors

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) antagonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

<span class="mw-page-title-main">Sympathomimetic drug</span> Substance that mimics effects of catecholamines

Sympathomimetic drugs are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart rate, force of cardiac contraction, and blood pressure. The primary endogenous agonists of the sympathetic nervous system are the catecholamines, which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

<span class="mw-page-title-main">Phenylephrine</span> Decongestant medication

Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among others, is a medication used as a decongestant for uncomplicated nasal congestion in the form of a nasal spray or oral tablet, to dilate the pupil, to increase blood pressure given intravenously in cases of low blood pressure, and to relieve hemorrhoids as a suppository. It can also be applied to the skin.

An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3, although there are more subtypes, and agonists vary in specificity between these receptors, and may be classified respectively. However, there are also other mechanisms of adrenergic agonism. Epinephrine and norepinephrine are endogenous and broad-spectrum. More selective agonists are more useful in pharmacology.

<span class="mw-page-title-main">Isoprenaline</span> Medication for slow heart rate

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, heart block, and rarely for asthma, among other indications. 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.

<span class="mw-page-title-main">Dobutamine</span> Medication which strengthens heart contractions

Dobutamine is a medication used in the treatment of cardiogenic shock and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection into a vein or intraosseous as a continuous infusion. The amount of medication needs to be adjusted to the desired effect. Onset of effects is generally seen within 2 minutes. It has a half-life of two minutes. This drug is generally only administered short term, although it may be used for longer periods to relieve symptoms of heart failure in patients awaiting heart transplantation.

<span class="mw-page-title-main">Beta-1 adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The beta-1 adrenergic receptor, also known as ADRB1, can refer to either the protein-encoding gene or one of the four adrenergic receptors. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" is more commonly used in the United Kingdom and the rest of the world, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

A cardiac stimulant is a drug which acts as a stimulant of the heart – e.g., via positive chronotropic action and/or inotropic action. They increase cardiac output.

<span class="mw-page-title-main">Adrenaline</span> Hormone and medication

Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions. It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an essential role in the fight-or-flight response by increasing blood flow to muscles, heart output by acting on the SA node, pupil dilation response, and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals, including humans, and some single-celled organisms. It has also been isolated from the plant Scoparia dulcis found in Northern Vietnam.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

Alpha blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

<span class="mw-page-title-main">Beta-adrenergic agonist</span> Medications that relax muscles of the airways

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.

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<span class="mw-page-title-main">Dopamine (medication)</span> Hormone used as a medication

Dopamine, sold under the brand name Intropin among others, is a medication most commonly used in the treatment of very low blood pressure, a slow heart rate that is causing symptoms, and, if epinephrine is not available, cardiac arrest. In newborn babies it continues to be the preferred treatment for very low blood pressure. In children epinephrine or norepinephrine is generally preferred while in adults norepinephrine is generally preferred for very low blood pressure. It is given intravenously or intraosseously as a continuous infusion. Effects typically begin within five minutes. Doses are then increased to effect.

<span class="mw-page-title-main">Angiotensin II (medication)</span> Medication for low blood pressure

Angiotensin II is a medication that is used to treat hypotension resulting from septic shock or other distributive shock. It is a synthetic vasoconstrictor peptide that is identical to human hormone angiotensin II and is marketed under the brand name Giapreza. The Food and Drug Administration approved the use of angiotensin II in December 2017 to treat low blood pressure resulting from septic shock.

References

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  13. 1 2 "Circassia gets rights to dopexamine from Ipsen". Pharma Times. 9 October 2008.
  14. "MHRA CLDA Company-Led Drug Alert - Dopacard 50mg/5ml Concentrate for Solution in 5ml vials - Cephalon UK Limited - CLDA (14)A/16". Track Regulatory. 15 September 2014.
  15. Oba Y, Lone NA (October 2014). "Mortality benefit of vasopressor and inotropic agents in septic shock: a Bayesian network meta-analysis of randomized controlled trials". Journal of Critical Care. 29 (5): 706–710. doi:10.1016/j.jcrc.2014.04.011. PMID   24857641.