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Adrenoceptor-Activating & Other Sympathomimetic Drugs - Brian B. Hoffman, MD

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Introduction

The sympathetic nervous system is an important regulator of the activities of organs such as the heart and peripheral vasculature, especially in responses to stress (see Chapter 6). The ultimate effects of sympathetic stimulation are mediated by release from nerve terminals of norepinephrine that serves to activate the adrenoceptors on postsynaptic sites. Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues; in other words, epinephrine acts as a hormone. Drugs that mimic the actions of epinephrine or norepinephrine¾sympathomimetic drugs¾would be expected to have a wide range of effects. An understanding of the pharmacology of these agents is thus a logical extension of what we know about the physiologic role of the catecholamines.

The Mode & Spectrum of Action of Sympathomimetic Drugs

Like the cholinomimetic drugs, the sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (eg, norepinephrine and epinephrine) act by a direct mode; that is, they directly interact with and activate adrenoceptors. Others act indirectly; their actions are dependent on the release of endogenous catecholamines. These indirect agents may have either of two different mechanisms: (1) displacement of stored catecholamines from the adrenergic nerve ending (eg, amphetamine and tyramine) or (2) inhibition of reuptake of catecholamines already released (eg, cocaine and tricyclic antidepressants). Some drugs have both direct and indirect actions. Both types of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to some or all of the characteristic effects of endogenous catecholamines. The selectivity of different sympathomimetics for various types of adrenoceptors is discussed below.

I. BASIC PHARMACOLOGY OF SYMPATHOMIMETIC DRUGS

IDENTIFICATION OF ADRENOCEPTORS

Introduction

The effort to understand the molecular mechanisms by which catecholamines act has a long and rich history. A great conceptual debt is owed to the work done by John Langley and Paul Ehrlich 100 years ago in developing the hypothesis that drugs have their effects by interacting with specific "receptive" substances. Raymond Ahlquist in 1948 rationalized a large body of observations by his conjecture that catecholamines acted via two principal receptors. He termed these receptors a and b. Alpha receptors are those that have the comparative potencies epinephrine ³ norepinephrine >> isoproterenol. Beta receptors have the comparative potencies isoproterenol > epinephrine ³ norepinephrine. Ahlquist's hypothesis was dramatically confirmed by the development of drugs that selectively antagonize b receptors but not a receptors (see Chapter 10). More recent evidence suggests that a receptors comprise two major families. At present, therefore, it appears appropriate to classify adrenoceptors into three major groups, namely, b, a1, and a2 receptors. Each of these major groups of receptors also has three subtypes. Considerable effort has been expended in elucidating structure-function relationships that determine ligand binding properties and the molecular signaling characteristics of the various adrenergic receptors.

A. BETA ADRENOCEPTORS
Soon after the demonstration of separate a and b receptors, it was found that there were at least two subtypes of b receptors, designated b1 and b2. These subtypes are operationally defined by their affinities for epinephrine and norepinephrine: b1 receptors have approximately equal affinity for epinephrine and norepinephrine, whereas b2 receptors have a higher affinity for epinephrine than for norepinephrine. Subsequently, b3 receptors were identified as a novel and distinct third b-adrenoceptor subtype. These receptor types are listed in Table 9-1.

B. ALPHA ADRENOCEPTORS
Following the demonstration of the b subtypes, two major groups of a receptors were found: a1 and a2. These receptors were originally identified with antagonist drugs that distinguished between a1 and a2 receptors. For example, a adrenoceptors were identified in a variety of tissues by measuring the binding of radiolabeled antagonist compounds that are considered to have a high affinity for these receptors, eg, dihydroergocryptine (a1 and a2), prazosin (a1), and yohimbine (a2). These radioligands were used to measure the number of receptors in tissues and to determine the affinity (by displacement of the radiolabeled ligand) of other drugs that interact with the receptors.

The concept of subtypes within the a1 group emerged out of pharmacologic experiments that demonstrated complex shapes of agonist dose-response curves of smooth muscle contraction as well as differences in antagonist affinities in inhibiting contractile responses in various tissues. These experiments demonstrated the existence of two subtypes of a1 receptor that could be distinguished on the basis of their reversible affinities for a variety of drugs and experimental compounds. A third a1-receptor subtype was subsequently identified by molecular cloning techniques. These a1 receptors are termed a1A, a1B, and a1D receptors. There is evidence that the a1A receptor has splice variants. A major current area of investigation is determining the importance of each of these various subtypes in mediating a1-receptor responses in a variety of organs.

The hypothesis that there are subtypes of a2 receptors emerged from pharmacologic experiments and molecular cloning. It is now known that there are three subtypes of a2 receptors, termed a2A, a2B, and a2C, which are products of distinct genes.

C. DOPAMINE RECEPTORS
The endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9-1). These receptors are distinct from a and b receptors and are particularly important in the brain (see Chapters 21 and 29) and in the splanchnic and renal vasculature. There is now considerable evidence for the existence of at least five subtypes of dopamine receptors. Pharmacologically distinct dopamine receptor subtypes, termed D1 and D2, have been known for some time. Molecular cloning has identified several distinct genes encoding each of these subtypes. Further complexity occurs because of the presence of introns within the coding region of the D2-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D4 human receptor gene. The terminology of the various subtypes is D1, D2, D3, D4, and D5. They comprise two D1-like receptors (D1 and D5) and three D2-like (D2, D3, and D4). These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs (see Chapter 29).

Receptor Selectivity

Examples of clinically useful sympathomimetic agonists that are relatively selective for a1-, a2-, and b-adrenoceptor subgroups are compared with some nonselective agents in Table 9-2. Selectivity means that a drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. For example, norepinephrine preferentially activates b1 receptors compared with b2 receptors. However, selectivity is not usually absolute (nearly absolute selectivity has been termed "specificity"), and at higher concentrations related classes of receptor may also interact with the drug. As a result, the "numeric" subclassification of adrenoceptors is clinically important mainly for drugs that have relatively marked selectivity. Given interpatient variations in drug kinetics and dynamics, the extent of a drug's selectivity should be kept in mind if this property is viewed as clinically important in the treatment of an individual patient.

The exact number of adrenoceptor subtypes that are actually expressed in human tissues is uncertain, but expression of subtypes has been demonstrated in tissues in which the physiologic or pharmacologic importance of the subtype is not yet known. These results suggest the possibility of designing novel drugs to exploit the expression of a particular receptor subtype in a single target tissue. For example, determining which blood vessels express which subtypes of a1 and a2 receptors could lead to design of drugs having selectivity for certain vascular beds such as the splanchnic or coronary vessels. Similarly, there has been extensive investigation into the a1-receptor subtypes mediating pharmacologic responses in the human prostate (see Box: Receptor Selectivity and Physiologic Functions of Adrenoceptor Subtypes).

RECEPTOR SELECTIVITY AND PHYSIOLOGIC FUNCTIONS OF ADRENOCEPTOR SUBTYPES: LESSONS FROM KNOCKOUT MICE

Since pharmacologic tools used to evaluate the function of adrenoceptor subtypes have some limitations, a number of knockout mice have been developed with one or more adrenoceptor genes subjected to loss of function mutations, as described in Chapter 1 (see Box: Pharmacology & Genetics). These models have their own complexities and extrapolations from mice to humans may be uncertain. Nonetheless, these studies have yielded some novel insights. For example, a-adrenoceptor subtypes play an important role in cardiac responses, the a2A-adrenoceptor subtype is critical in transducing the effects of a2 agonists on blood pressure control, and b1 receptors play a predominant role in directly increasing heart rate in mouse heart.

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