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THE DOPAMINERGIC SYSTEM

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Dopamine is one of several endogenous catecholamines that serve as neurotransmitters within the central and autonomic (sympathetic) nervous systems. Dopamine is synthesized in neurons of the central nervous system, particularly the substantia nigra and the ventral tegmental area, and the adrenal medulla. Dopamine is derived from its precursor, l-dihydroxyphenylalanine (l-DOPA), by the enzyme DOPA decarboxylase. Dopamine then becomes a precursor in the synthesis of norepinephrine and epinephrine, two very important catecholamines. It does not cross the blood-brain barrier. Endogenous dopamine has a half-life of one minute. It is rapidly metabolized into inactive metabolites by the enzymes monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT). Homovanillic acid, the primary metabolite, is excreted into the urine.

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Of the five known subtypes of peripheral dopamine (DA) receptors, DA1 and DA2 receptors are physiologically most important. Vascular DA1 receptors are located on the smooth muscle of most arterial circulations (especially mesenteric, renal, and coronary) and mediate vasodilation through adenylate cyclase signal transduction pathways. These effects are greatest in the renal vasculature. Stimulation of the DA1 receptor increases vasodilation, renal blood flow distribution, and glomerular filtration rates. DA1 receptors in the renal proximal tubules also mediate natriuresis (by inhibiting the Na+/H+ exchanger and Na+/K+ ATPase pump) and diuresis. The DA2 receptor is located on the presynaptic terminal of postganglionic sympathetic neurons and autonomic ganglia. Like alpha-2 adrenergic receptors, stimulation of the DA2 receptor inhibits the release of norepinephrine from presynaptic vesicles.

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The dopaminergic system has multiple roles in the central and autonomic nervous systems. In the brain, dopamine has important functions related to mood, behavior, reward, learning and memory, and attention. Central dopamine receptors (DA2) may mediate nausea and vomiting. In systemic circulation, dopamine has an integral role in endogenous vasodilation, natriuresis, and the maintenance of normal blood pressure. It particularly helps to improve blood flow through the renal and splanchnic circulations. Dopamine can also bind to alpha and beta adrenergic receptors to promote inotropy and vasoconstriction.

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Dopamine Receptor Agonists

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A. Synthetic Dopamine
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Exogenous dopamine can be used as a vasopressor to treat severe hypotension in vasodilatory shock states like sepsis, and as an inotrope in low cardiac output states. It can supplement normal circulatory function in situations of induced hypertension, such as for the treatment of cerebral vasospasm after subarachnoid hemorrhage. Since dopamine cannot cross the blood-brain barrier, synthetic dopamine will not affect the central nervous system. When used in dosages to support blood pressure and cardiac output, dopamine, like any vasopressor, may become harmful. Tachycardia combined with vasoconstriction can decrease oxygen delivery, increase myocardial oxygen demand, and may trigger myocardial ischemia.

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Synthetic dopamine is administered in a continuous intravenous infusion without a loading dose. The physiologic effects are dose-dependent. At low doses (1-3 μg/kg/min), dopamine stimulates the DA1 receptors. The net effect is dilation of the ...

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