Adrenoceptor Agonists



Adrenoceptor Agonists



Classification of Adrenoceptor Agonists





aAlso fenoterol (BEROTEC), formoterol (FORADIL), arformoterol (BROVANA), levalbuterol (XOPENEX), pirbuterol (MAXAIR), salmeterol (SEREVENT), and terbutaline.


bAlso brimonidine (ALPHAGAN).


cAlso dexmedetomidine (PRECEDEX).





Adrenoceptors


Adrenoceptors were originally classified as α-adrenoceptors or β-adrenoceptors based on the relative potency of adrenoceptor agonists in different tissues. For example, epinephrine and norepinephrine are more potent than isoproterenol at adrenoceptors in smooth muscle, and these were designated α-adrenoceptors, whereas isoproterenol is more potent than epinephrine and norepinephrine at adrenoceptors in cardiac tissue and these receptors were called β-adrenoceptors.


As shown in Table 8-1 and Figure 8-1, subtypes of α- and β-adrenoceptors have been identified on the basis of several criteria, including differences in signal transduction and physiologic effects and differences in agonist affinity for different receptors. The receptor subtypes have been cloned and their molecular structures determined.



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FIGURE 8-1 Primary tissue locations of α-adrenoceptors and β-adrenoceptors. Whereas α1– and β2-adrenoceptors are primarily located in smooth muscle, β1-adrenoceptors are predominantly found in cardiac tissue. Some α2-adrenoceptors are located on sympathetic neurons, where they produce feedback inhibition of neurotransmitter release. Other α2– and β2-adrenoceptors are located in blood platelets and a variety of organ tissues. The α- and β-adrenoceptors are also found in the central nervous system.


α-Adrenoceptors


The α-adrenoceptors can be differentiated on the basis of their location and function. The α1-adrenoceptors are primarily located in smooth muscle at sympathetic neuroeffector junctions, but these receptors are also found in exocrine glands and in the central nervous system. Three main subtypes of α1-adrenoceptors have been identified (α1A, α1B, and α1D), but the functional roles of these receptors have not been clearly established. The α2-adrenoceptors are widely distributed in presynaptic neurons, various tissues, and blood platelets (see Fig. 8-1), and subtypes of these receptors have also been identified.


The α1-adrenoceptors mediate contraction of vascular smooth muscle, the iris dilator muscle, and smooth muscle in the lower urinary tract (bladder, urethra, and prostate) and other tissues. The α2-adrenoceptors located on sympathetic postganglionic neurons serve as autoreceptors whose activation leads to feedback inhibition of norepinephrine release from nerve terminals. The α2-receptors are also found in blood platelets and in ocular, adipose, intestinal, hepatic, renal, and endocrine tissue. In blood platelets, α2-receptors mediate platelet aggregation. In the pancreas, α2-receptors mediate the inhibition of insulin secretion that occurs when the sympathetic nervous system is activated.



β-Adrenoceptors


Table 8-1 summarizes the effects of three subtypes of β-adrenoceptors.


Activation of β1-adrenoceptors produces cardiac stimulation, leading to a positive chronotropic effect (increased heart rate), a positive inotropic effect (increased contractility), and a positive dromotropic effect (increased cardiac impulse conduction velocity). Activation of β1 receptors also increases renin secretion from renal juxtaglomerular cells.


The β2-adrenoceptors mediate relaxation of bronchial, uterine, and vascular smooth muscle (see Fig. 11-3). In skeletal muscle, β2 receptors mediate potassium uptake. In the liver, they mediate glycogenolysis (breakdown of glycogen and release of glucose), which increases the glucose concentration in the blood. Whereas epinephrine and norepinephrine are equally potent at β1-receptors in cardiac tissue, epinephrine is more potent than norepinephrine at β2-receptors in smooth muscle.


A third class of β-adrenoceptors known as β3-adrenoceptors has been recently characterized. These receptors appear to mediate lipolysis (breakdown of triglycerides in adipose tissue), thermogenesis in skeletal muscle, uterine relaxation, and other effects. Selective agonists have been identified but not yet developed for clinical use.





Signal Transduction


The adrenergic and dopamine receptors are guanine nucleotide binding protein–coupled receptors (GPCRs) that are located in cell membranes of target tissues.


Activation of α1-adrenoceptors is coupled with activation of phospholipase C, which catalyzes the release of inositol triphosphate (IP3) from membrane phospholipids. In smooth muscle, IP3 stimulates the release of calcium from the sarcoplasmic reticulum, leading to muscle contraction. By this action, α1-adrenoceptor agonists cause vasoconstriction and increase blood pressure. In exocrine glands, formation of IP3 leads to calcium release and gland secretion.


Activation of α2-adrenoceptors leads to inhibition of adenylyl cyclase and decreased levels of cyclic adenosine monophosphate (cAMP) in sympathetic neurons and other tissues. This action reduces aqueous humor secretion in the eye and elicits the other effects of α2-adrenoceptor agonists. Activation of D2-receptors also reduces cAMP formation.


Activation of β-adrenoceptors and D1 receptors leads to stimulation of adenylyl cyclase and an increase in the levels of cAMP in cardiac tissue and smooth muscle. cAMP activates protein kinase A, which phosphorylates other proteins and enzymes. The cellular response depends on the specific proteins that are phosphorylated in each tissue. In cardiac tissue, calcium channels are phosphorylated, thereby augmenting calcium influx and cardiac contractility. In smooth muscle, cAMP produces muscle relaxation via effects on multiple targets; including potassium channels, calcium channels, and myosin light chain kinase (see Fig. 11-3).



Classification of Adrenoceptor Agonists


The adrenoceptor agonists mimic the effect of sympathetic nervous system stimulation and are sometimes called sympathomimetic drugs. These drugs are divided into three groups based on their mode of action. The direct-acting agonists bind and activate adrenoceptors. As shown in Figure 8-2, the indirect-acting agonists increase the stimulation of adrenoceptors by increasing the concentration of norepinephrine at sympathetic neuroeffector junctions in one of two ways. Cocaine inhibits the catecholamine transporter located in the plasma membrane of the presynaptic sympathetic neuron and thereby decreases the neuronal reuptake of norepinephrine and increases its synaptic concentration. Amphetamine and related drugs are transported into the sympathetic nerve terminal by the catecholamine transporter. Once inside the sympathetic neuron, amphetamines inhibit the storage of norepinephrine by neuronal vesicles. This increases the cytoplasmic concentration of norepinephrine, leading to reverse transport of norepinephrine into the synapse by the catecholamine transporter. The mixed-acting agonists (e.g., ephedrine) have both direct and indirect actions.


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FIGURE 8-2 Mechanisms of indirect-acting and direct-acting adrenoceptor agonists. Cocaine blocks norepinephrine reuptake by the catecholamine transporter. Amphetamine inhibits the storage of norepinephrine by neuronal vesicles, leading to reverse transport of norepinephrine into the synapse by the catecholamine transporter. Direct-acting agonists bind to and activate adrenoceptors. α, α-Adrenoceptor; β, β-adrenoceptor; NE, norepinephrine.



Catecholamines


The naturally occurring catecholamines include norepinephrine, an endogenous sympathetic neurotransmitter; epinephrine, the principal hormone of the adrenal medulla; and dopamine, a neurotransmitter and the precursor to norepinephrine and epinephrine. Synthetic catecholamines include isoproterenol and dobutamine.



General Properties



Chemistry and Pharmacokinetics

Each catecholamine consists of the catechol moiety and an ethylamine side chain (Fig. 8-3). The catecholamines are rapidly inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), enzymes found in the gut, liver, and other tissues. For this reason, these drugs have low oral bioavailabilities and short plasma half-lives, and they must be administered parenterally when a systemic action is required (such as in the treatment of anaphylactic shock).


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FIGURE 8-3 Structures of selected adrenoceptor agonists. Catecholamines contain the catechol moiety and an ethylamine side chain. The amine nitrogen substitution (R2) determines the relative affinity for α- and β-adrenoceptors, with larger substitutions (e.g., in isoproterenol and dobutamine) decreasing the affinity for α-adrenoceptors and increasing the affinity for β-adrenoceptors. Note that dopamine has an even higher affinity for dopamine D1 receptors than for adrenoceptors.


Mechanisms and Effects

As shown in Figure 8-3 and Table 8-2, the various catecholamines differ in their affinities and specificities for receptors. The size of the alkyl substitution on the amine nitrogen (R2) determines the relative affinity for α- and β-adrenoceptors. Drugs with a large alkyl group (e.g., isoproterenol) have greater affinity for β-adrenoceptors than do drugs with a small alkyl group (e.g., epinephrine). Epinephrine is a potent agonist at all α- and β-adrenoceptors. Norepinephrine differs from epinephrine only in that it has greater affinity for β1-adrenoceptors than for β2-adrenoceptors. Because of this difference, norepinephrine constricts all blood vessels, whereas epinephrine constricts some blood vessels but dilates others. Isoproterenol is a selective β1– and β2-adrenoceptor agonist because it has little affinity for α-receptors. Dobutamine primarily stimulates β1-receptors, with smaller effects on β2– and α-receptors. Dopamine activates D1 receptors, β1-receptors, and α-receptors. Unlike the other catecholamines, dopamine also stimulates the release of norepinephrine from sympathetic neurons. For this reason, dopamine is both a direct-acting and an indirect-acting receptor agonist.



TABLE 8-2


Pharmacologic Effects and Clinical Uses of Adrenoceptor Agonists






















































































DRUG PHARMACOLOGIC EFFECT (AND RECEPTOR) CLINICAL USE
Direct-Acting Catecholamines
Dobutamine Cardiac stimulation (β1) and vasodilation (β2) Cardiogenic shock, acute heart failure, and cardiac stimulation during heart surgery
Dopamine* Renal vasodilation (D1), cardiac stimulation (β1), and increased blood pressure (β1 and α1) Cardiogenic shock, septic shock, heart failure, and adjunct to fluid administration in hypovolemic shock
Epinephrine Vasoconstriction and increased blood pressure (α1), cardiac stimulation (β1), and bronchodilation (β2) Anaphylactic shock, cardiac arrest, ventricular fibrillation, reduction in bleeding during surgery, and prolongation of the action of local anesthetics
Isoproterenol Cardiac stimulation (β1) and bronchodilation (β2) Atrioventricular block and bradycardia
Norepinephrine Vasoconstriction and increased blood pressure (α1) Hypotension and shock
Direct-Acting Noncatecholamines
Albuterol Bronchodilation (β2) Asthma
Apraclonidine Decreased aqueous humor formation (α2) Short-term control of intraocular pressure
Clonidine Decreased sympathetic outflow from central nervous system (α2 and imidazoline) Hypertension, opioid dependence
Dexmedetomidine Sedation (α2) Adjunct to anesthesia
Midodrine Vasoconstriction (α1) Orthostatic hypotension
Oxymetazoline Vasoconstriction (α1) Nasal and ocular decongestion
Phenylephrine Vasoconstriction, increased blood pressure, and mydriasis (α1) Nasal and ocular decongestion, mydriasis, maintenance of blood pressure, and treatment of shock
Terbutaline Bronchodilation (β2) Asthma, premature labor
Indirect-Acting Agents
Amphetamine Increase in norepinephrine release, central nervous system stimulation Narcolepsy, attention-deficit disorder
Cocaine Inhibition of norepinephrine uptake Local anesthesia
Mixed-Acting Agents  
Ephedrine Vasoconstriction (α1) Nasal decongestion
Pseudoephedrine Vasoconstriction (α1) Nasal decongestion
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Adrenoceptor Agonists

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