Adrenoceptor Subtypes and Catecholamine Actions

The biological effects of epinephrine and norepinephrine are mediated by nine different adrenoceptors (α1A,B,D, α2A,B,C, β1, β2, β3). To date, only the classification into α1, α2, β1 and β2 receptors has therapeutic relevance.

Smooth Muscle Effects

The opposing effects on smooth muscle (A) of α- and β-adrenoceptor activation are due to differences in signal transduction. α1-Re- ceptor stimulation leads to intracellular release of Ca2+ via activation of the inositol trisphosphate (IP3) pathway. In concert with the protein calmodulin, Ca2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin († vasoconstriction). α2-Adrenocep- tors can also elicit a contraction of smooth muscle cells by activating phospholipase C (PLC) via the βγ-subunits of G1 proteins.

cAMP inhibits activation of myosin kinase. Via stimulatory G-proteins (Gs), β2-receptors mediate an increase in cAMP production († vasodilation).

Vasoconstriction induced by local application of α-sympathomimetics can be employed in infiltration anesthesia (p.204) or for nasal decongestion (naphazoline, tetrahydrozoline, xylometazoline; p.94, 336, 338). Systemically administered epinephrine is important in the treatment of anaphylactic shock and cardiac arrest.

Bronchodilation. β2-Adrenoceptor-medi- ated bronchodilation plays an essential part in the treatment of bronchial asthma and chronic obstructive lung disease (p.340). For this purpose, β2-agonists are usually given by inhalation; preferred agents being those with low oral bioavailability and low risk of systemic unwanted effects (e.g., fenoterol, salbutamol, terbutaline).

Tocolysis. The uterine relaxant effect of β2- adrenoceptor agonists, such as fenoterol, can be used to prevent premature labor. β2-Vaso- dilation in the mother with an imminent drop in systemic blood pressure results in reflex tachycardia, which is also due in part to the β1-stimulant action of these drugs.

Cardiostimulation

By stimulating β-receptors, and hence cAMP production, catecholamines augment all heart functions including systolic force, velocity of myocyte shortening, sinoatrial rate, conduction velocity, and excitability. In pacemaker fibers, cAMP-gated channels (“pacemaker channels”) are activated, whereby diastolic depolarization is hastened and the firing threshold for the action potential is reached sooner (B). cAMP activates protein kinase A, which phosphorylates different Ca2+ transport proteins. In this way, contraction of heart muscle cells is accelerated, as more Ca2+ enters the cell from the extracellular space via L-type Ca2+ channels and release of Ca2+ from the sarcoplasmic reticulum (via ryanodine receptors, RyR) is augmented. Faster relaxation of heart muscle cells is effected by phosphorylation of troponin and phospholamban.

In acute heart failure or cardiac arrest, β- mimetics are used as a short-term emergency measure; in chronic failure they are not indicated.

Metabolic Effects

Via cAMP, β2-receptors mediate increased conversion of glycogen to glucose (glycoge- nolysis) in both liver and skeletal muscle. From the liver, glucose is released into the blood. In adipose tissue, triglycerides are hydrolyzed to fatty acids (lipolysis mediated by β2- and β3-receptors), which then enter the blood.

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Structure–Activity Relationships of Sympathomimetics

Owing to its equally high af nity for all α- and β-receptors, epinephrine does not permit selective activation of a particular receptor subtype. Like most catecholamines, it is also unsuitable for oral administration (catechole is a trivial name for o-hydroxyphe- nol). Norepinephrine differs from epinephrine by its high af nity for α-receptors and low af nity for β2-receptors. The converse holds true for the synthetic substance, isoproterenol (isoprenaline) (A).

Knowledge of structure–activity relationships has permitted the synthesis of sympathomimetics that display a high degree of selectivity at adrenoceptor subtypes.

Direct-acting sympathomimetics (i.e. adrenoceptor agonists) typically share a phenlethylamine structure. The side chain β- hydroxyl group confers af nity for α- and β- receptors. Substitution on the amino group reduces af nity for α-receptors, but increases it for β-receptors (exception: α-ago- nist phenylephrine), with optimal af nity being seen after the introduction of only one isopropyl group. Increasing the bulk of amino substituents favors af nity for β2-re- ceptors (e.g., fenoterol, salbutamol). Both hydroxyl groups on the aromatic nucleus contribute to af nity; high activity at α-re- ceptorsisassociated withhydroxylgroupsat the 3 and 4 positions. Af nity for β-receptors is preserved in congeners bearing hydroxyl groups at positions 3 and 5 (orciprenaline, terbutaline, fenoterol).

The hydroxyl groups of catecholamines are responsible for the very low lipophilicity of these substances. Polarity is increased at physiological pH owing to protonation of the amino group. Deletion of one or all hydroxyl groups improves the membrane penetrability at the intestinal mucosa–blood barrier and the blood–brain barrier. Accordingly,

these noncatecholamine congeners can be given orally and can exert CNS actions; however, this structural change entails a loss in af nity.

Absence of one or both aromatic hydroxyl groups is associated with an increase in indirect sympathomimetic activity, denoting the ability of a substance to release norepinephrine from its neuronal stores without exerting an agonist action at the adrenoceptor (p.92).

A change in position of aromatic hydroxyl groups (e.g., in orciprenaline, fenoterol, or terbutaline) or their substitution (e.g., salbutamol) protects against inactivation by COMT (p.87). Introduction of a small alkyl residue at the carbon atom adjacent to the amino group (ephedrine, methamphetamine) confersresistance to degradation by MAO(p.87); replacement on the amino groups of the methyl residue with larger substituents (e.g., ethyl in etilefrine) impedes deamination by MAO. Accordingly, the congeners are less subject to presystemic inactivation.

Since structural requirements for high affinity on the one hand and oral applicability on the other do not match, choosing a sympathomimetic is a matter of compromise. If the high af nity of epinephrine is to be exploited, absorbability from the intestine must be foregone (epinephrine, isoprenaline). If good bioavailability with oral administration is desired, losses in receptor af nity must be accepted (etilefrine).