Figure 101

Skeletal structure of catecholamines.

tors. Others are relatively selective. For example, isoproterenol has a high affinity for ß1- and ß2-adrenoceptors but a very low affinity for a-adrenoceptors; isoproterenol is considered a nearly pure ß-agonist. Norepinephrine has a high affinity for a- and ß1-adrenocep-tors but a relatively low affinity for ß2-receptors.

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenocep-tors. The interaction of compounds with these adreno-ceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains ß2-adrenoceptors, the response in this tissue elicited by the action of ß2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for ß2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for ß2-adrenoceptors and has relatively weak bronchiolar relaxing properties.

Adrenomimetic drugs can be divided into two major groups on the basis of their mechanism of action. Norepinephrine, epinephrine, and some closely related adrenomimetics produce responses in effector cells by directly stimulating a- or ß-adrenoceptors and are referred to as directly acting adrenomimetic drugs.

Many other adrenomimetic drugs, such as amphetamine, do not themselves interact with adrenoceptors, yet they produce sympathetic effects by releasing norepi-nephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells. These adrenomimetics are called indirectly acting adreno-mimetic drugs. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine.

An important characteristic of indirectly acting adrenomimetic drugs is that repeated injections or prolonged infusion can lead to tachyphylaxis (gradually diminished responses to repeated administration). This is a result of a gradually diminishing availability of re-leasable norepinephrine stores on repeated drug administration. The time frame of the tachyphylaxis will vary with individual agents.

The actions of many indirectly acting adreno-mimetic drugs are reduced or abolished by the prior administration of either cocaine or tricyclic antidepressant drugs (e.g., imipramine). These compounds can block the adrenergic neuronal transport system and thereby prevent the indirectly acting drug from being taken up into the nerve and reaching the norepinephrine storage vesicles. Lipophilic drugs (e.g., amphetamine), however, can enter nerves by diffusion and do not need membrane transport systems.

Destruction or surgical interruption of the adrener-gic nerves leading to an effector tissue renders indirectly acting adrenomimetic drugs ineffective because neuronal norepinephrine is no longer available for release since the nerves have degenerated. Also, patients being treated for hypertension with reserpine or guanethidine, which deplete the norepinephrine stores in adrenergic neurons (see Chapter 20), respond poorly to administration of indirectly acting adrenomimetic drugs.

Some adrenomimetic drugs act both directly and indirectly; that is, they release some norepinephrine from storage sites and also directly activate tissue receptors. Such drugs are called mixed-action adrenomimetics. However, most therapeutically important adreno-mimetic drugs in humans act either directly or indirectly.

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