Systems Pharmacology

Sympathetic Nervous System

In the course of phylogeny an efficient control system evolved that enabled the functions of individual organs to be orchestrated in increasingly complex life forms and permitted rapid adaptation to changing environmental conditions. This regulatory system consists of the CNS (brain plus spinal cord) and two separate pathways for two-way communication with peripheral organs, viz., the somatic and the autonomic nervous systems. The somatic nervous system comprising extero- and interoceptive afferents, special sense organs, and motor efferents, serves to perceive external states and to target appropriate body movement (sensory perception: threat ^ response: flight or attack). The auto-nomic (vegetative) nervous system

(ANS), together with the endocrine system, controls the milieu interieur. It adjusts internal organ functions to the changing needs of the organism. Neural control permits very quick adaptation, whereas the endocrine system provides for a long-term regulation of functional states. The ANS operates largely beyond voluntary control; it functions autonomously. Its central components reside in the hypothalamus, brain stem, and spinal cord. The ANS also participates in the regulation of endocrine functions.

The ANS has sympathetic and parasympathetic branches. Both are made up of centrifugal (efferent) and centripetal (afferent) nerves. In many organs innervated by both branches, respective activation of the sympathetic and parasympathetic input evokes opposing responses.

In various disease states (organ malfunctions), drugs are employed with the intention of normalizing susceptible organ functions. To understand the biological effects of substances capable of inhibiting or exciting sympathetic or parasympathetic nerves, one must first envisage the functions subserved by the sympathetic and parasympathetic divisions (A, Responses to sympathetic activation). In simplistic terms, activation of the sympathetic division can be considered a means by which the body achieves a state of maximal work capacity as required in fight or flight situations.

In both cases, there is a need for vigorous activity of skeletal musculature. To ensure adequate supply of oxygen and nutrients, blood flow in skeletal muscle is increased; cardiac rate and contractility are enhanced, resulting in a larger blood volume being pumped into the circulation. Narrowing of splanchnic blood vessels diverts blood into vascular beds in muscle.

Because digestion of food in the intestinal tract is dispensable and only counterproductive, the propulsion of intestinal contents is slowed to the extent that peristalsis diminishes and sphinc-teric tonus increases. However, in order to increase nutrient supply to heart and musculature, glucose from the liver and free fatty acid from adipose tissue must be released into the blood. The bronchi are dilated, enabling tidal volume and alveolar oxygen uptake to be increased.

Sweat glands are also innervated by sympathetic fibers (wet palms due to excitement); however, these are exceptional as regards their neurotransmitter (ACh, p. 106).

Although the life styles of modern humans are different from those of hominid ancestors, biological functions have remained the same.

Sinoatrial Vegetative Stimulation

Structure of the Sympathetic Nervous System

The sympathetic preganglionic neurons (first neurons) project from the inter-mediolateral column of the spinal gray matter to the paired paravertebral ganglionic chain lying alongside the vertebral column and to unpaired prevertebral ganglia. These ganglia represent sites of synaptic contact between pre-ganglionic axons (1st neurons) and nerve cells (2nd neurons or sympathocy-tes) that emit postganglionic axons terminating on cells in various end organs. In addition, there are preganglion-ic neurons that project either to peripheral ganglia in end organs or to the adrenal medulla.

Sympathetic Transmitter Substances

Whereas acetylcholine (see p. 98) serves as the chemical transmitter at ganglionic synapses between first and second neurons, norepinephrine (= noradrenaline) is the mediator at synapses of the second neuron (B). This second neuron does not synapse with only a single cell in the effector organ; rather, it branches out, each branch making en passant contacts with several cells. At these junctions the nerve axons form enlargements (varicosities) resembling beads on a string. Thus, excitation of the neuron leads to activation of a larger aggregate of effector cells, although the action of released norepi-nephrine may be confined to the region of each junction. Excitation of pregan-glionic neurons innervating the adrenal medulla causes a liberation of acetyl-choline. This, in turn, elicits a secretion of epinephrine (= adrenaline) into the blood, by which it is distributed to body tissues as a hormone (A).

Adrenergic Synapse converted via two intermediate steps to dopamine, which is taken up into the vesicles and there converted to norepi-nephrine by dopamine-p-hydroxylase. When stimulated electrically, the sympathetic nerve discharges the contents of part of its vesicles, including norepi-nephrine, into the extracellular space. Liberated norepinephrine reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of presynaptic a2-receptors inhibits norepinephrine release. By this negative feedback, release can be regulated.

The effect of released norepineph-rine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-O- methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid).

The liver is richly endowed with COMT and MAO; it therefore contributes significantly to the degradation of circulating norepinephrine and epi-nephrine. The end product of the combined actions of MAO and COMT is van-illylmandelic acid.

Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 |im in diameter). In the axoplasm, L-tyrosine is Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Phenyl NephrineVaricosities Noradrenaline
B. Second neuron of sympathetic system, varicosity, norepinephrine release

Adrenoceptor Subtypes and Catecholamine Actions

Adrenoceptors fall into three major groups, designated ai, a2, and p, within each of which further subtypes can be distinguished pharmacologically. The different adrenoceptors are differentially distributed according to region and tissue. Agonists at adrenoceptors (direct sympathomimetics) mimic the actions of the naturally occurring cate-cholamines, norepinephrine and epinephrine, and are used for various therapeutic effects.

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca2+ via activation of the inositol tris-phosphate (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. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction; via the latter, p2-receptors mediate va-sodilation, particularly in skeletal muscle — an effect that has little therapeutic use.

Vasoconstriction. Local application of a-sympathomimetics can be employed in infiltration anesthesia (p. 204) or for nasal decongestion (naphazoline, tetra-hydrozoline, xylometazoline; pp. 90, 324). Systemically administered epi-nephrine is important in the treatment of anaphylactic shock for combating hypotension.

Bronchodilation. p2-Adrenocep-tor-mediated bronchodilation (e.g., with terbutaline, fenoterol, or salbutamol) plays an essential part in the treatment of bronchial asthma (p. 328).

Tocolysis. The uterine relaxant effect of p2-adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation with a resultant drop in systemic blood pressure results in reflex tachycardia, which is also due in part to the Pi-stimulant action of these drugs.

Cardiostimulation. By stimulating P1-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of shortening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostimulant effect of P-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest. Use of p-sympathomimetics in heart failure carries the risk of cardiac arrhythmias.

Metabolic effects. P-Receptors mediate increased conversion of glycogen to glucose (glycogenolysis) 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 p3-receptors), which then enter the blood (C). The metabolic effects of catechola-mines are not amenable to therapeutic use.

Effects Local Anesthetics ThiemeHow Epinephrine And Norepi EffectHow Epinephrine And Norepi Effect

Structure - Activity Relationships of Sympathomimetics

Due to its equally high affinity for all a-and p-receptors, epinephrine does not permit selective activation of a particular receptor subtype. Like most cate-cholamines, it is also unsuitable for oral administration (catechol is a trivial name for o-hydroxyphenol). Norepi-nephrine differs from epinephrine by its high affinity for a-receptors and low affinity for p2-receptors. In contrast, isoproterenol has high affinity for p-recep-tors, but virtually none for a-receptors (A).

norepinephrine ^ a, P1 epinephrine ^ a, Pi, p2 isoproterenol ^ Pi, P2

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 phenylethylamine structure. The side chain p-hydroxyl group confers affinity for a- and P-receptors. Substitution on the amino group reduces affinity for a-receptors, but increases it for p-re-ceptors (exception: a-agonist phenyl-ephrine), with optimal affinity being seen after the introduction of only one isopropyl group. Increasing the bulk of the amino substituent favors affinity for P2-receptors (e.g., fenoterol, salbutamol). Both hydroxyl groups on the aromatic nucleus contribute to affinity; high activity at a-receptors is associated with hydroxyl groups at the 3 and 4 positions. Affinity for p-receptors is preserved in congeners bearing hydroxyl groups at positions 3 and 5 (orciprena-line, terbutaline, fenoterol).

The hydroxyl groups of catechol-amines are responsible for the very low lipophilicity of these substances. Polarity is increased at physiological pH due to protonation of the amino group. Deletion of one or all hydroxyl groups improves membrane penetrability at the intestinal mucosa-blood and the blood-brain barriers. Accordingly, these non-

catecholamine congeners can be given orally and can exert CNS actions; however, this structural change entails a loss in affinity.

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. 88).

An altered position of aromatic hy-droxyl groups (e.g., in orciprenaline, fe-noterol, or terbutaline) or their substitution (e.g., salbutamol) protects against inactivation by COMT (p. 82). In-droduction of a small alkyl residue at the carbon atom adjacent to the amino group (ephedrine, methamphetamine) confers resistance to degradation by MAO (p. 80), as does replacement on the amino groups of the methyl residue with larger substituents (e.g., ethyl in etilefrine). Accordingly, the congeners are less subject to presystemic inactiva-tion.

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 affinity 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 affinity must be accepted (etilefrine).

Norepinephrine

CX a

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    How CatecholOmethylTransferase Inhibitors (COMT) works?
    7 years ago

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