Metaraminol was first discovered in 1951. It is a mixed-acting sympathomimetic amine—indirectly releasing noradrenaline (norepinephrine) and directly activating α-adrenoceptors. It has prominent direct effects activating α1-adrenoceptors on vascular, postganglionic, sympathetic nerve terminals (causing vasoconstriction) and is also is an indirectly-acting agent that stimulates the release of noradrenaline (norepinephrine). The release of noradrenaline (norepinephrine) from sympathetic nerves in the heart acts on β1-adrenoceptors and has a positive inotropic effect while the peripheral vascular effects will increase the vasoconstriction. Some β2-adrenergic-mediated vasodilation via the release of adrenaline (epinephrine) from the adrenal medulla occurs with metaraminol, but α effects predominate. The accumulation of metaraminol and its metabolites as false-transmitters in the presynaptic sympathetic ganglion can produce a persistent reduction in the content of noradrenaline (norepinephrine) at functionally critical sites.
The key factor in the response of any cell or organ to sympathomimetic amines is the density and proportion of α- and β-adrenoceptors. For example, noradrenaline (norepinephrine) has relatively little capacity to increase bronchial airflow, since the receptors in bronchial smooth muscle are largely of the β2 subtype. In contrast, isoprenaline and adrenaline (epinephrine) are potent bronchodilators. Cutaneous blood vessels physiologically express almost exclusively α-adrenoceptors; thus, noradrenaline (norepinephrine)and adrenaline (epinephrine) cause constriction of such vessels, whereas isoprenaline has negligible effect. The smooth muscle of blood vessels that supply skeletal muscles has both β2 and α receptors; activation of β2-adrenoceptors causes vasodilation and stimulation of α-adrenoceptors constricts these vessels. In such vessels, the threshold concentration for activation of β2-adrenoceptors by adrenaline (epinephrine) is lower than that for α-adrenoceptors, but when both types of receptors are activated at high concentrations of adrenaline (epinephrine), the response to α-adrenoceptors predominates.
Physiological concentrations of adrenaline (epinephrine) primarily cause vasodilation. Blood flow to skeletal muscles is increased by therapeutic doses of adrenaline (epinephrine). This is due in part to a powerful β2-mediated vasodilator action that is only partially counterbalanced by a vasoconstrictor action on the α receptors that also are present in the vascular bed. If an α-adrenoceptor antagonist is also given, the vasodilation in muscle is more pronounced, the total peripheral resistance is decreased, and the mean blood pressure falls. In the presence of significant α-adrenoceptor antagonist activity, unopposed β2-adrenoceptor activity produces a fall in blood pressure instead of the expected rise. This is the well-described adrenaline (epinephrine) reversal phenomenon.
Unlike adrenaline, small doses of noradrenaline do not cause vasodilation or lower blood pressure, since the blood vessels of skeletal muscle constrict rather than dilate; α-adrenoceptor antagonists, therefore, may decrease or even abolish the pressor effects but do not cause significant reversal (i.e. hypotension).
Indirectly-acting amines like metaraminol are taken up into sympathetic nerve terminals and storage vesicles, where they replace noradrenaline (norepinephrine) in the storage complex. They must be substrates of both the noradrenaline (norepinephrine) plasma-membrane transporter and the vesicular monoamine transporter (VMAT; responsible for transport into the presynaptic storage vesicles) to produce effective increases in synaptic noradrenaline (norepinephrine). In a study of indirectly acting sympathomimetic amines, the degree of noradrenaline (norepinephrine) release correlated directly with their afﬁnity for the noradrenaline (norepinephrine) transporter. Phenylethylamines that lack a β-hydroxyl group are retained there poorly, but β-hydroxylated phenylethylamines (metaraminol) and compounds that subsequently become hydroxylated in the synaptic vesicle by dopamine β-hydroxylase (metaraminol to octopamine) are retained in the synaptic vesicle for relatively extended periods of time. Such substances can produce a persistent diminution in the content of noradrenaline (norepinephrine) at functionally critical sites.
When the nerve is stimulated, the contents of a relatively constant number of synaptic vesicles are released by exocytosis. If these vesicles contain phenylethylamines that are less potent thannoradrenaline (norepinephrine), activation of postsynaptic α- and β-adrenoceptors will be diminished. This phenomenon is the explanation for the period of hypotension that is often seen after ceasing a metaraminol infusion. Consequently, restarting the metaraminol in this clinical situation is exactly the wrong thing to do.
Basic autonomic pharmacology teaches us that the adrenal medulla is effectively a post-ganglionic nerve in the sympathetic nervous system. Stimulation of the preganglionic nerve releases acetylcholine which acts on the postsynaptic adrenal medulla to release adrenaline (epinephrine) (and noradrenaline [norepinephrine]). The same mechanisms by which the indirectly acting agents provoke noradrenaline (norepinephrine) release from sympathetic postganglionic nerves are, not surprisingly, those that result in the release of both noradrenaline (norepinephrine) and adrenaline (epinephrine) from the adrenal medulla. Both the noradrenaline (norepinephrine) transporter and VMAT are found in the adrenal medulla.
Putting this all together, metaraminol (and any other indirectly acting or mixed sympathomimetic agent) causes the release of adrenaline (epinephrine) from the adrenal medulla in the same way it causes noradrenaline (norepinephrine) release from sympathetic nerves. The amount of extra circulating adrenaline (epinephrine) is likely to be less than therapeutic doses of adrenaline (epinephrine). Nevertheless, in the context of extensive α-adrenoceptor blockade from one or more drugs taken in overdose, metaraminol will certainly have its pressor effect reduced and may even produce hypotension. While any hypotension is unlikely to be as severe as is seen with adrenaline (epinephrine), it makes metaraminol a poor choice as pressor agent in this situation.