Catecholamines and sympathomimetic drugs are classified as direct, indirect, or mixed acting. Direct-acting agents act directly on one or more of the adrenergic receptors. Indirect-acting drugs increase the availability of norepinephrine (NE) or epinephrine (Epi) to stimulate adrenergic receptors (by releasing or displacing NE from sympathetic nerve varicosities [e.g., amphetamine]; by blocking the transport of NE into sympathetic neurons [e.g., cocaine]; or by blocking the metabolizing enzymes, MAO [e.g.,pargyline] or COMT [e.g., entacapone]). Drugs that indirectly release NE and also directly activate receptors are referred to as mixed-acting sympathomimetic drugs (e.g., ephedrine). The classification is not absolute and activities may overlap; prototypical drugs are listed in Figure 10-1.
b-phenylethylamine, a benzene ring with an ethylamine side chain, may be viewed as a parent structure for sympathomimetic amines (Table 10-1). NE, Epi, dopamine (DA), isoproterenol, and a few other agents have hydroxyl groups substituted at positions 3 and 4 of the benzene ring. Since o-dihydroxybenzene is also known as catechol, sympathomimetic amines with these hydroxyl substitutions in the aromatic ring are termed catecholamines. Many directly acting sympathomimetic drugs influence both a and b receptors, but the ratio of activities varies among drugs in a continuous spectrum from predominantly a activity (phenylephrine) to predominantly b activity (iso-proterenol). Maximal a and b activity depends on the presence of hydroxyl groups on positions 3 and 4. The response to noncatecholamines is partly determined by their capacity to release NE from storage sites. Phenylethylamines that lack hydroxyl groups on the ring and the b-hydroxyl group on the side chain act almost exclusively by causing the release of NE from sympathetic nerve terminals. Unsubstituted or alkyl-substituted compounds cross the blood—brain barrier more readily and have more central activity. Thus, ephedrine, amphetamine, and methampheta-mine exhibit considerable CNS activity, and the absence of polar hydroxyl groups results in a loss of direct sympathomimetic activity.
Catecholamines have only a brief duration of action and are ineffective when administered orally because they are rapidly inactivated in the intestinal mucosa and the liver (see Chapter 6). Compounds without one or both hydroxyl substituents are not substrates for COMT, and their oral effectiveness and duration of action are enhanced. Substitution on the a-carbon blocks oxidative deamination by MAO, prolonging the duration of action of noncatecholamines. Thus, the duration of action of ephedrine and amphetamine is measured in hours rather than minutes. Substitution of an —OH on the b carbon generally decreases actions within the CNS (largely by reducing lipid solubility) but greatly enhances agonist activity at both a and b adrenergic receptors.
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