The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. Others, which will be dealt with in Chapter 7, block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons. This chapter describes agents that either directly or indirectly stimulate adrenoceptors (Figure 6.1).
Figure 6.1. Summary of adrenergic agonists.
Agents marked with an asterisk (*) are catecholamines.
The Adrenergic Neuron
Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs (Figure 6.2).
Figure 6.2. Sites of actions of adrenergic agonists.
Neurotransmission at adrenergic neurons
Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons (see p. 47), except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure 6.3).
Figure 6.3. Synthesis and release of norepinephrine from the adrenergic neuron.
(MAO = monoamine oxidase.)
Synthesis of norepinephrine
Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.1 This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron.
Storage of norepinephrine in vesicles
Dopamine is then transported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine (see p. 96). Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine ?-hydroxylase. [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP) and ?-hydroxylase as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells along with norepinephrine. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation.
Release of norepinephrine
An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. Drugs such as guanethidine block this release (see p. 96).
Binding to receptors
Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system2 and the phosphatidylinositol cycle3 to transduce the signal into an effect. Norepinephrine also binds to presynaptic receptors that modulate the release of the neurotransmitter.
Removal of norepinephrine
Norepinephrine may 1) diffuse out of the synaptic space and enter the general circulation, 2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium- or potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure 6.3). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects.
Potential fates of recaptured norepinephrine
Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool in the cytoplasm. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in urine as vanillylmandelic acid, metanephrine, and normetanephrine.
Adrenergic receptors (adrenoceptors)
In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated ? and ?, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes has revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.
?1 and ?2 Receptors
The ?-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 6.4). For ? receptors, the rank order of potency is epinephrine ? norepinephrine >> isoproterenol. The ?-adrenoceptors are subdivided into two subgroups, ?1 and ?2, based on their affinities for ? agonists and blocking drugs. For example, the ?1 receptors have a higher affinity for phenylephrine than do the ?2 receptors. Conversely, the drug clonidine selectively binds to ?2 receptors and has less effect on ?1 receptors.
Figure 6.4. Types of adrenergic receptors.
These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects, originally designated as ?-adrenergic, involving constriction of smooth muscle. Activation of ?1 receptors initiates a series of reactions through the G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell (Figure 6.5).
Figure 6.5. Second messengers mediate the effects of ? receptors.
DAG = diacylglycerol; IP3 = inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate.
These receptors, which are located primarily on presynaptic nerve endings and on other cells, such as the ? cell of the pancreas and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the ?1 receptors. A portion of the released norepinephrine “circles back” and reacts with ?2 receptors on the neuronal membrane (see Figure 6.5). The stimulation of the ?2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron.
This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance, these receptors are acting as inhibitory autoreceptors.] ?2 receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances, these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to ?1 receptors, the effects of binding at ?2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.
The ?1 and ?2 receptors are further divided into ?1A, ?1B, ?1C, and ?1D and into ?2A, ?2B, and ?2C. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective ?1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets ?1A receptors found primarily in the urinary tract and prostate gland.
? receptors exhibit a set of responses different from those of the ? receptors. These are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine (see Figure 6.4). For ? receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. The ?-adrenoceptors can be subdivided into three major subgroups, ?1, ?2, and ?3, based on their affinities for adrenergic agonists and antagonists, although several others have been identified by gene cloning. [Note: It is known that ?3 receptors are involved in lipolysis, but their role in other specific reactions is not known].
?1 receptors have approximately equal affinities for epinephrine and norepinephrine, whereas ?2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of ?2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three ? receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell.
Distribution of receptors
Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. For example, tissues such as the vasculature to skeletal muscle have both ?1 and ?2 receptors, but the ?2 receptors predominate. Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors. For example, the heart contains predominantly ?1 receptors.
Characteristic responses mediated by adrenoceptors
It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one type of receptor. Figure 6.6 summarizes the most prominent effects mediated by the adrenoceptors. As a generalization, stimulation of ?1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of ?1 receptors characteristically causes cardiac stimulation, whereas stimulation of ?2 receptors produces vasodilation (in skeletal vascular beds) and smooth muscle relaxation.
Figure 6.6. Major effects mediated by ? and ? adrenoceptors.
Desensitization of receptors
Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon: 1) sequestration of the receptors so that they are unavailable for interaction with the ligand; 2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis, and 3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase ? or ?-adrenergic receptor kinase.
Characteristics of Adrenergic Agonists
Most of the adrenergic drugs are derivatives of ?-phenylethylamine (Figure 6.7). Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities to differentiate between ? and ? receptors and to penetrate the CNS. Two important structural features of these drugs are 1) the number and location of OH substitutions on the benzene ring and 2) the nature of the substituent on the amino nitrogen.
Figure 6.7. Structures of several important adrenergic agonists.
Drugs containing the catechol ring are shown in yellow.
Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. These compounds share the following properties:
Drugs that are catechol derivatives (with ?OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating ? or ? receptors.
Not only are the catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, but they are also metabolized in other tissues. For example, COMT is in the gut wall, and MAO is in the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and they are ineffective when administered orally because of inactivation.
Poor penetration into the CNS
Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS.
Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. Phenylephrine, which is an analog of epinephrine, has only a single ?OH at position 3 on the benzene ring, whereas ephedrine lacks hydroxyls on the ring but has a methyl substitution at the ?-carbon. These are poor substrates for MAO and, thus, show a prolonged duration of action, because MAO is an important route of detoxification. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. [Note: Ephedrine and amphetamine may act indirectly by causing the release of stored catecholamines.]
Substitutions on the amine nitrogen
The nature and bulk of the substituent on the amine nitrogen is important in determining the ? selectivity of the adrenergic agonist. For example, epinephrine, with a ?CH3 substituent on the amine nitrogen, is more potent at ? receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol, which has an isopropyl substituent ?CH(CH3)2 on the amine nitrogen (see Figure 6.7), is a strong ? agonist with little ? activity (see Figure 6.4).
Mechanism of action of the adrenergic agonists
These drugs act directly on ? or ? receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla (Figure 6.8). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine.
Figure 6.8. Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.
These agents, which include amphetamine, cocaine, and tyramine, may block the uptake of norepinephrine (uptake blockers) or are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (see Figure 6.8). As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the ? or ? receptors. Examples of uptake blockers and agents that cause norepinephrine release include cocaine and amphetamines, respectively.
Some agonists, such as ephedrine and its stereoisomer, pseudoephedrine, have the capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron (see Figure 6.8).