Epinephrine

• ( R) - ( -)- adrenaline
• L- epinephrine
• (R) -1 - (3,4 -dihydroxyphenyl ) -2 - ( N-methylamino ) ethanol
• IUPAC: (R) -4 - [1- hydroxy-2- (methylamino ) ethyl] benzene -1 ,2 -diol
• (R) -4 - (1- hydroxy-2- (methylamino ) ethyl ) catechol

• 51-43-4 (base)
• 51-42-3 ( tartrate)
• 55-31-2 (hydrochloride)

• A01AD01
• B02BC09
• C01CA24
• R01AA14
• R03AA01
• S01EA01

White solid

• Neurotransmitter
• Hormone

• 211-212 ° C ( base)
• 147-152 ° C ( tartrate)

8.6

• Readily soluble in aqueous mineral acids and alkalis
• Insoluble in water (180 mg · l-1 at 25 ° C), chloroform, ethanol, diethyl ether, acetone

Risk

0.10 mg · kg -1 ( LD50, dog, i.v.)

Template: Infobox chemical / molecular formula search available

Adrenaline (Latin ad, ' ren and Latin, kidney ' to ), also Epinephrine ( INN) (Greek epi, on ' and gr nephros, kidney ') called, is one in the adrenal medulla formed and in stressful situations into the blood undistributed hormone. As a stress hormone adrenaline mediates an increase in heart rate, a rise in blood pressure, an extension of the bronchioles, rapid deployment of energy reserves from fat breakdown (lipolysis ) and the release and biosynthesis of glucose. It also regulates the blood flow ( centralization ) and the gastrointestinal activity ( inhibition). In the central nervous system as a neurotransmitter adrenaline is in adrenergic neurons (nerve cells) before. Adrenaline mediated its effects via activation of G- protein-coupled receptors, the adrenergic receptors.

• 3.1 Cardiovascular system
• 3.2 Smooth muscle, respiratory, gastrointestinal tract, urinary bladder
• 3.3 Mobilization of energy reserves
• 3.4 Central Nervous System
• 3.5 Other Effects

• 4.1 synthesis
• 4.2 stability

• 5.1 Areas of application 5.1.1 Emergency Medicine
• 5.1.2 Respiratory Diseases
• 5.1.3 Local vasoconstriction
• 5.1.4 antidote

Discovery history

The first indication of a occurring in the adrenal medulla and from there released into the bloodstream substance that could be stained with iron ( III ) chloride, found in 1856, the French physiologist Alfred Vulpian. That this substance extraordinary pharmacological properties had to have, presented 1893/94 the practitioner George Oliver and the physiologist Edward Albert Schäfer fixed. The same succeeded in 1895 the Polish physiologist Napoleon Cybulski and Władysław Szymonowicz.

John Jacob Abel, who in 1897 tried to isolate the substance that gave her the name " epinephrine ". Inspired by his works was a Japanese- American chemist Takamine Jokichi it is purely and left them by the company Parke, Davis & Co. sell " adrenaline " under the name. Although Abel epinephrine later when it became an artifact of the isolation, the name epinephrine is used to this day synonymous with adrenaline. In 1904 was followed by the chemical synthesis.

Adrenaline was the first hormone that is produced purely and its structure was determined. Adrenaline further research led to the other two endogenous catecholamines norepinephrine and dopamine.

Biosynthesis and degradation

Biosynthesis

The biosynthesis of adrenaline is based on the α - amino acids L- tyrosine or L-phenylalanine. These are hydroxylated to L- DOPA. After a decarboxylation to the biologically active dopamine done an enantioselective hydroxylation of norepinephrine, which can be released from the adrenal medulla also acts as a transmitter and beyond in sympathetic neurons. The N- methylation of norepinephrine finally delivers the adrenaline. The normal concentration of adrenaline in the blood is less than 100 ng / l (500 pmol / l).

Regulation of the biosynthesis

The biosynthesis and release of adrenaline can be controlled by neural stimuli by hormones or drugs. Neural stimulation promotes the conversion of L-tyrosine to L- dopa and dopamine to noradrenaline. Cortisol, the hormone of the adrenal cortex, promotes the subsequent conversion of norepinephrine to epinephrine.

The adrenaline production can also be regulated by a negative feedback mechanism. Increasing adrenaline levels are negatively fed back to the L- tyrosine formation at elevated adrenaline levels so the L- tyrosine formation is slowed down.

Reduction

Adrenaline is degraded relatively quickly after its release. Thus, the plasma half-life after intravenous administration of epinephrine is only one to three minutes. On the decomposition of adrenalin, the enzymes catechol-O- methyltransferase ( COMT) and monoamine oxidase (MAO ) are particularly involved. The O- methylation ( COMT) formed primary metabolite metanephrine (see metanephrines ) already has no significant biological activity more. Through further, in particular oxidative metabolic processes involving the monoamine oxidase metabolism to a VMA and 3- methoxy-4- hydroxyphenylethylenglykol ( MOPEG ) is possible. These metabolites are excreted in conjugated (eg as sulfates ) and unconjugated form in the urine.

Effects

Adrenaline is a stress hormone and as such creates the conditions for the rapid provision of energy reserves that will ensure survival in dangerous situations ( fight or flight ). These effects are mediated by the activation of sub-cellular level, the G protein-coupled adrenoreceptors.

Cardiovascular system

Of particular importance is the effect of adrenaline on the cardiovascular system. These include, inter alia, the increase in the central blood volume, which is done by contraction of small blood vessels, particularly in the skin and in the kidneys, through the activation of α1 -adrenoceptors. At the same time, a β2 - adrenoceptor -mediated expansion and central blood vessels that supply the muscle is observed.

Activation of β1 - adrenergic receptors leads to an increased heart rate (positive chronotropic effect ), an accelerated conduction (positive dromotropic effect ), increased contractility (positive inotropic effect ) and a reduction of the threshold (positive bathmotrope effect). These effects improve the cardiac output and contribute to the constriction of small blood vessels to increase blood pressure in. After pretreatment with alpha - blockers, however, adrenaline leads to a paradoxical, used therapeutically lowering blood pressure (epinephrine reversal). Also very low dose epinephrine (< 0.1 mcg / kg ) may have a slight decrease in blood pressure effect, which is explained by a selective activation of β2 -adrenoceptors of blood vessels.

Chronically elevated adrenaline levels are associated with cardiac hypertrophy.

Smooth muscle, respiratory, gastrointestinal tract, urinary bladder

In addition to the above function to the cardiovascular system is an increase in respiration and a temporary inactivation of unneeded processes, such as digestion, in the context of the stress hormone adrenaline function of meaning. Adrenaline via an activation of β -adrenoceptors to a relaxation of the smooth muscles. This has, for example, immobilization of the gastrointestinal tract (inhibition of peristalsis) and a bronchodilator for relief of breathing as a result of ( β2 -adrenoceptors ). Also on β2 -adrenoceptors can adrenaline cause a relaxation of the uterus of pregnant women. On the other hand, adrenaline in organs that predominantly express α1 - adrenoceptors mediate contraction of smooth muscles. As epinephrine leads to a contraction of the sphincter of the bladder.

Mobilization of energy reserves

The release of adrenaline from the adrenal glands leads to a mobilization of endogenous energy sources by increasing fat breakdown (lipolysis ). This lipolysis catalyzed by a β -adrenoceptor -mediated (mainly β3 -adrenoceptors ) activation of hormone-sensitive lipase. Similarly, an increase in adrenaline levels to a release and regeneration of glucose and thus to an increase in blood sugar levels ( β2 -adrenoceptors ). This effect is increased by α2 -adrenoceptor mediated inhibition of insulin production and the β -adrenoceptor - mediated release of glucagon. In the muscle, it comes by adrenaline to increased glucose uptake. Epinephrine also leads to an increase in energy expenditure (mainly β2 -adrenoceptors ).

Central Nervous System

Observed central nervous effects as a stress hormone be regarded as a reflex, as in the adrenal gland adrenaline formed the blood -brain barrier can not happen. Notwithstanding the locally produced adrenaline could be detected as a neurotransmitter in certain neurons of the central nervous system. These neurons are found especially in the area reticularis superficialis ventrolateralis. The function of these adrenergic neurons is not yet known, but a role is discussed in the central regulation of blood pressure and the baroreceptor reflex. The central nervous system includes the stressor true, then the hypothalamus is active and activates the sympathetic nervous system. Its stimulating effect on the adrenal medulla causes the release of adrenaline and noradrenaline.

Other effects

As a result of adrenaline release or a local application of adrenaline sweating, goose bumps ( Pilomotorischer reflex) and pupil dilation ( mydriasis) can be observed. In addition, you get a dry mouth. Adrenaline is also involved in blood coagulation and fibrinolysis.

Chemistry

Adrenaline, chemically (R) -1 - (3,4 -dihydroxyphenyl ) -2 - (N -methylamino ) ethanol, belongs to the group of catecholamines, which also includes norepinephrine and dopamine. The active form ( eutomer ) of adrenalin has stereochemically an (R ) configuration [(R) - adrenaline or (-)- adrenaline]. (R)- adrenaline is about 20 - to 50 - times more potent than (S)- epinephrine.

Synthesis

For the synthesis of adrenaline, several methods are described in the literature. The classical synthesis procedure involves three steps: catechol ( 1) is acylated with chloroacetyl chloride (2) to 3,4- dihydroxy- ω - chloroacetophenone (3). The reaction corresponds indirectly to the Friedel -Crafts acylation, the preferred route leads nevertheless on the ester intermediate, thereby closing a Fries rearrangement with. Amination of Chloracetophenons with methylamine yields the adrenalone (4); subsequent reduction yields racemic epinephrine (5). The racemate resolution is possible by means of ( 2R, 3R)- tartaric acid.

Alternatively, you can also 3,4- Dimethoxybenzaldehyde react with cyanide to cyanohydrin whose oxidation then provides a Nitriloketon. By catalytic reduction creates a aminoketone whose gentle N- methylation then provides the secondary amine. Hydrolysis of Phenyletherfunktionen, reduction and resolution then you get to the adrenaline.

Stability

Like all catecholamines adrenaline is sensitive to oxidation. An oxidation product of adrenaline is adrenochrome. For the oxidation can be used silver (I ) oxide ( Ag2O ). The oxidation of adrenaline can also be catalyzed in aqueous solution by trace amounts of iron and iodide ions. Antioxidants, such as ascorbic acid and sodium metabisulfite can slow down the formation of adrenochrome. The oxidation rate is also on the pH of the solution dependent. As a stability optimum applies a slightly acidic pH.

Adrenaline as a drug

Areas of application

In medicine, adrenaline is mainly used as an emergency medicine in cardiopulmonary resuscitation in cardiac arrest and Anaphylactic shock. It is available on prescription and in various forms.

Emergency Medicine

For use in emergency medicine epinephrine intravenously alternatively intraosseous or very rare intracardiac. In the current recommendations of the European Resuscitation Council, the administration of adrenaline during resuscitation as a standard is recommended, although no placebo-controlled study in humans exist that prove a survival advantage through the use of adrenaline.

Another main area of ​​application of adrenaline in medicine is the circulatory shock, such as anaphylactic reaction or sepsis. The treatment of anaphylactic reactions and shock is also via intravenous administration of adrenaline. If in acute shock process no venous access can be created, it can also be administered by intramuscular adrenaline. For patients with severe allergic reactions in the past ( eg threat of asphyxiation due to swelling of the vocal cords ( glottis ) ) adrenaline -filled syringes are available, which can then be applied by the person concerned after allergen exposure with incipient symptoms themselves.

For use in cardiopulmonary resuscitation and shock the bloodstream are centralizing effects of epinephrine in the foreground. In conclusion, activation of α1 -adrenoceptors constriction of small blood vessels in the skin and in the kidneys is achieved while large central blood vessels to widen. In this way, adrenaline is designed to increase coronary and cerebral perfusion pressure.

Respiratory diseases

For use as adjunctive therapy in acute laryngitis subglottica ( " croup " ) Adrenaline is available as a solution for inhalation ( InfectoKrupp Inhal ® ) are available. By 2002, epinephrine - containing inhalation products were also approved for the acute treatment of bronchial asthma in Germany. With the entry into force of the CFC ban but these were taken off the market. The use of other inhaled adrenaline preparations for acute treatment of asthmatic symptoms is therefore outside the regulatory drug approval and corresponds to an off- label use.

The use of epinephrine for respiratory diseases based on its bronchienrelaxierenden effect that is mediated via activation of β2 -adrenoceptors. However, systemic side effects after absorption must be taken into account.

Local vasoconstriction

Epinephrine can be still used for local vasoconstriction in bleeding. Thus, this substance is also used as an addition to local anesthetics vasoconstrictive to prevent its removal, and thus to prolong its effectiveness.

The vasoconstrictor effect is also used to close cuts in boxing. This vasoconstrictive effect is due to activation of α1 -adrenoceptors of small blood vessels in the skin and in the muscle tissue and its subsequent constriction.

Antidote

Epinephrine is the drug of second choice for beta-blocker poisoning and can be used if no specific β - agonist is available. However, there is also no regulatory drug approval for this emergency use; the application corresponds to an off- label use.

Side effects

The side effects of epinephrine are similar to its main effects and due to its importance as a stress hormone. Epinephrine leads to a contraction of small blood vessels, in particular the skin and the kidney, is connected to a blood pressure increase and, in particular for topical application, isolated necrosis. Upon systemic application are cardiac side effects, such as heart failure, angina pectoris, myocardial infarction, tachycardia arrhythmia, to the ventricular and cardiac arrest in the foreground. Therefore, its application is partially controversial. The systemic administration of adrenaline may further include a rise in blood sugar levels (hyperglycemia ), a lowering of potassium levels (hypokalemia), metabolic acidosis and a decrease in the concentration of magnesium ( hypomagnesemia ) have the result. Furthermore, can be observed mydriasis, Miktionsschwierigkeiten, salivation, sweating at the same time feeling cold in the extremities, nausea, vomiting, dizziness and headache. As a mental side effects through the use of adrenaline restlessness, nervousness, anxiety, hallucinations, convulsions may occur up to psychosis.

Interactions

Some inhalation anesthetics that sensitize the heart to catecholamines, lead to an increased effect of adrenaline on the heart and thus to an increased risk of heart failure, angina pectoris attacks, heart attacks and tachycardic arrhythmia.

The effects and side effects of epinephrine may also (Nor ) epinephrine release are enhanced by inhibition of adrenaline degradation or increased. This is particularly with concomitant use of MAO inhibitors, levodopa, to observe L- thyroxine, theophylline, tricyclic antidepressants and reserpine.

Adrenaline, in turn, inhibits the blood pressure lowering effect of alpha blockers and the cardiac effects of beta-blockers. Since adrenaline leads to a rise in blood sugar levels, the effect of oral antidiabetic agents is reduced.

Dosage

Adrenaline is administered intravenously as a solution. Typically, the concentration of 1 mg / ml in an ampoule (0.1% referred to as epinephrine solution or epinephrine solution 1:1000 ). Depending on the application, it is common to dilute 1:10 with 0.9% sodium chloride solution ( 0.01 % strength then called epinephrine or adrenaline solution 1:10,000 solution). The resuscitation dose is 1 mg every 3-5 minutes. In the endobronchial application (deprecated) is usually diluted 3:10 with 0.9% sodium chloride solution.

Trade names by dosage form

Ampoules ( injection)

• Epinephrine (D)
• Epinephrine 1:1000 InfectoPharm (D)
• And generic (A, CH)

Auto-injectors ( solution for injection in pre-filled pen )

• EpiPen (A, CH)
• Fastjekt (D)
• Jext (D, A, CH, NL, DK, E, I, FIN, N, SLO, S, UK)
• Anapen (D, A, CH) - Lincoln Medical Limited called on 5 June 2012 back all yet durable batches because of possible non-discharge of adrenaline.

Inhalation Solution

• InfectoKrupp Inhal (D)