Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:           Cardiac stimulants, excluding cardiac glycosides: adrenergic and dopaminergic agents.
ATC code:                            C01C A

Epinephrine (aAdrenaline) is a sympathomimetic amine. It has vasoconstrictor, positive chronotropic and inotropic, bronchodilator and hyperglycaemic activity.

Mechanism of action
Adrenaline acts by binding to its (α and β) receptors on a large number of body systems: cardiovascular, bronchial, gastrointestinal, renal, uterine, ocular, nervous system, metabolism and blood composition. Although some of these actions have no therapeutic application, they should be borne in mind as they may be related to the occurrence of adverse effects.

Pharmacodynamic effects

Actions on the cardiovascular system
The effects depend on the route of administration and the dose.
Effects on blood pressure
Adrenaline causes an increase in blood pressure due to its positive inotropic, positive chronotropic and vasoconstrictor actions. Low doses of adrenaline (0.1 μg/kg) may cause blood pressure to fall because β2 receptors, which cause vasodilation, are more sensitive to adrenaline. The pulse rate at first accelerates but, as the blood pressure rises, is slowed by compensatory vagal discharge.

Vascular effects
Adrenaline causes vasoconstriction mainly of precapillary sphincters and smaller arterioles, although it also affects the veins and large arteries. Adrenaline administration decreases cutaneous blood flow.

Cardiac effects
Adrenaline is a very potent cardiac stimulant. It acts directly on the β1 receptors of the myocardium, increasing the heart rate and rhythm. The myocardium is more excitable, systole is shorter and cardiac contraction is more forceful, cardiac output is enhanced and the work of the heart and its oxygen consumption are also markedly increased. In addition, adrenaline causes an increase in coronary circulation.

Action on the bronchial system
Adrenaline acts on β2 receptors, causing relaxation of the smooth muscle, and on α receptors, contracting the vessels of the bronchial mucosa, thereby decreasing congestion and oedema.
Adrenaline acts via cyclic AMP, which activates a kinase chain, and by inhibiting degranulation of mast cells.

Action on the gastrointestinal tract
Catecholamines have depressant effects on the gastrointestinal muscles (β1 and α effects).

Action on the kidney and urinary tract
Adrenaline causes a marked reduction in renal blood flow (vasoconstriction of the afferent and efferent glomerular arterioles, α effect), while the volume of glomerular filtrate is unchanged.
Urine volume is generally unchanged. Adrenaline relaxes the (detrusor) muscle of the bladder and contracts the sphincter, and may therefore contribute to retention of urine in the bladder.

Action on the uterus
During the last month of pregnancy and during labour, adrenaline inhibits uterine tone and contractions.

Action on the eye
Adrenaline produces mydriasis (stimulation of the radial fibres of the iris, α effect) and has the property of decreasing intraocular pressure in normal individuals and especially in glaucoma.

Action on the nervous system

Adrenaline can cause restlessness and apprehension due rather to the occurrence of tachycardia or palpitations than to direct action on the central nervous system.
Adrenaline is able to facilitate neuromuscular junction transmission.

Metabolic actions
Adrenaline causes a large number of changes in metabolism.

The injection of adrenaline produces hyperglycaemia (and sometimes glycosuria). It inhibits the secretion of insulin and increases the secretion of glucagon. Muscle glycogen is also converted into lactic acid, which passes into the blood, thereby increasing the blood lactate level.

Furthermore, adrenaline increases the concentration of free fatty acids in blood by stimulating β1 receptors in adipocytes. The calorigenic action of adrenaline (increase in metabolism) is reflected by an increase of 20-30% in oxygen consumption after administration of the usual doses.

Actions on blood composition
Adrenaline can reduce circulating plasma volume and therefore increase erythrocyte and plasma protein concentrations. This effect has been observed in the presence of shock, haemorrhage, hypotension and anaesthesia.
In addition, it produces a decrease in the number of eosinophils in the circulating blood and causes aggregation of blood platelets.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
When administered by intravenous injection, bioavailability is 100%.
After subcutaneous administration of adrenaline, a relatively slow absorption process takes place. This can be accelerated by massage at the injection site. Adrenaline reaches detectable systemic levels 5-10 minutes after subcutaneous administration and the peak plasma concentration in 20-40 minutes. Absorption is faster and more active after intramuscular administration.
Adrenaline does not act when administered by ingestion or sublingually.

Distribution

Injected adrenaline disappears rapidly from the circulation with an extremely short half-life of approximately 20 seconds. It is distributed to all tissues, especially the heart, liver, kidney and spleen, but only very small amounts reach the brain due to difficulty crossing the blood-brain barrier.
Catecholamines are taken up by nerve endings by active transport and form deposits or pools.
There are two types of uptake: neuronal uptake (mainly in organs with extensive sympathetic innervation, such as the heart, vessels and spleen, occurring with low concentrations of catecholamines and by active transport), and extraneuronal uptake (especially in organs such as the liver, kidney, intestine and heart which have a high content of the enzyme catechol-O- methyltransferase, which rapidly inactivates catecholamines, as a result of which they are metabolised rather than stored).

Metabolism or biotransformation

Catecholamines are metabolised mainly by two enzymes, catechol-O-methyltransferase (extraneuronal) and monoamine oxidase (intraneuronal), which lead to their inactivation with 
the formation mainly of vanillylmandelic acid. These processes take place to a large extent in the liver. The transformations of adrenaline lead to its pharmacological inactivation.

Elimination
Adrenaline and its metabolites are excreted mainly in the urine. The metabolites found in greatest quantity are conjugated metanephrine (around 40%) and vanillylmandelic acid (another 40%). Small amounts of free metanephrine, dihydroxymandelic acid, methoxyhydroxyphenylglycol and unchanged adrenaline (around 5% of the administered dose) are also eliminated.

Fifty per cent of the administered dose is excreted in 6 hours and the rest in 18 hours, and very small amounts are excreted in the faeces.
In patients with phaeochromocytoma, adrenaline is eliminated in the urine in much larger amounts than in healthy subjects.