Which part of your nervous system is most responsible for activating you in an emergency?

Postganglionic parasympathetic dysfunction—tonic pupil

A tonic pupil is large and reacts poorly to light and slowly to near stimuli. After distance refixation, it exhibits a slow, tonic redilation (Fig. 17.4), which transiently reverses the anisocoria, making the tonic pupil smaller, because the normal pupil quickly redilates whereas the tonic pupil does not (seeFig. 17.4, D). In the ophthalmology office, evaluation of a tonic pupil at the slit lamp reveals segmental constriction of some portions of the pupil and absent constriction of other portions. Denervation supersensitivity can occur with parasympathetic denervation of the iris sphincter muscle. As a result, instillation of a dilute solution of pilocarpine, the cholinergic agent, can be used to confirm the diagnosis (Fig. 17.5; seeTable 17.1). A 0.1% solution is often suggested, but false-positive results may be more frequent than with a more dilute solution (Leavitt et al., 2002). Dilute pilocarpine will constrict the tonic pupil but not a normal pupil or a dilated pupil from pharmacological stimulation. Dilute pilocarpine is not commercially available and must be prepared by dilution with preservative-free normal saline.

Tonic pupils result from damage to the intraorbital ciliary ganglion or short ciliary nerves from a variety of etiologies, including focal infectious (herpes zoster, syphilis) or noninfectious (giant cell arteritis) inflammation (Prasad et al., 2009), malignant infiltration, paraneoplastic processes (Horta et al., 2012), and trauma. Tonic pupils may also be seen as a component of a systemic autonomic neuropathy (seeChapter 107) (Bremner and Smith, 2006; Yamashita et al., 2010), Guillain-Barré syndrome or its Miller Fisher variant (Kaymakamzade et al., 2013), and botulism. Perhaps the most common and most easily recognizable tonic pupil is the benign Adie pupil, which often presents with acute painless enlargement of the pupil and may be accompanied by complaints of photophobia and blurred near vision due to involvement of fibers traveling to the ciliary body for lens accommodation. In 80% of patients, the condition is unilateral. It is most common in healthy young women and is thought to be due to a viral ciliary ganglionitis. Additional examination findings may include decreased corneal sensation and, in the Holmes-Adie syndrome, decreased deep tendon reflexes (Kelly-Sell and Liu, 2011). The affected pupil tends to become smaller with time and can sometimes become smaller than the unaffected pupil. Ross syndrome is the triad of tonic pupils, hyporeflexia, and segmental anhidrosis (Ross, 1958). It is unclear whether this syndrome is a variant of the Holmes-Adie syndrome or a mechanistically distinct disorder, but impaired sweating is the distinguishing feature (Nolano et al., 2006). Harlequin syndrome, in which there is asymmetrical impairment of facial flushing to thermal or emotional stress, may also occur in patients with tonic pupils and hyporeflexia, although Horner syndrome is more common (Bremner and Smith, 2008).

Parasympathetic Nervous System

The parasympathetic nervous system is composed mainly of the cranial and sacral spinal nerves. The preganglionic neurons, arising from either the brain or sacral spinal cord, synapse with just a few postganglionic neurons which are located in or near the effector organ (muscle or gland). The parasympathetic nervous system is responsible for the body's rest and digestion response when the body is relaxed, resting, or feeding. It basically undoes the work of sympathetic division after a stressful situation. The parasympathetic nervous system decreases respiration and heart rate and increases digestion. Stimulation of the parasympathetic nervous system results in:

Construction of pupils

Decreased heart rate and blood pressure

Constriction of bronchial muscles

Increase in digestion

Increased production of saliva and mucus

Increase in urine secretion

Sympathetic and Parasympathetic Innervation

Isolated fetal cardiac tissue has a lower threshold of response to the inotropic effects of norepinephrine than adult cardiac tissue and is more sensitive to norepinephrine throughout the dose-response curves.16 Because isoproterenol, a direct β-adrenergic agonist that is not taken up and stored in sympathetic nerves, has similar effects on fetal and adult myocardium, the supersensitivity of fetal myocardium to norepinephrine is probably the result of incomplete development of sympathetic innervation in fetal myocardium. Myocardial concentrations of norepinephrine in the fetus within several weeks of term are significantly lower than in newborn animals, and activity of tyrosine hydroxylase, the intraneuronal enzyme responsible for the first transformation in catecholamine biosynthesis, is also reduced.16 In contrast, adrenal gland tyrosine hydroxylase activity at the same gestational age is not suppressed, possibly because the decrease in myocardial activity is related to delayed sympathetic innervation rather than to a generalized immaturity.

Monoamine oxidase, the enzyme responsible for oxidative deamination of norepinephrine, is also present in lower concentrations in the fetal heart than in the adult. Histochemical evaluation of the development of sympathetic innervation using the monoamine fluorescence technique has further substantiated the delayed development of sympathetic innervation of the fetal myocardium. At term, sympathetic innervation is incomplete. Patterns of staining indicate a progression of innervation, starting at the area of the sinoatrial node and progressing toward the left ventricular apex.25,26

Although sympathetic nervous innervation appears to begin developing in the fetal heart by about 0.55 of term, β-adrenergic receptors seem to be present much earlier and can be stimulated by appropriate agonists before 0.4 of term.27 Before about 0.55 of term (80 days of gestation in the lamb), fetal myocardium may be affected by circulating catecholamines, but local reflex activity through the sympathetic nervous system is not likely to play a major role in circulatory regulation.

Vagal stimulation at about 0.85 of term produces bradycardia. Administration of atropine at 0.55 of term produces a modest increase in fetal heart rate,28 indicating that vagal innervation is present by this stage of development. Histochemical staining for acetylcholinesterase in close-to-term fetuses has shown that the concentrations of this enzyme, which is responsible for metabolism of acetylcholine, are similar to concentrations found in adults.

The Parasympathetic Nervous System

The parasympathetic nervous system is responsible for energy building, food digestion, and assimilation. It functions to restore homeostasis and is active when the body is at rest and recuperating. It causes a decrease in the heart rate, stimulates the normal peristaltic smooth muscle movement of the intestines, and promotes the secretion of all digestive juices and tropic (tissue building) hormones. A person can be in parasympathetic override (dominance), which would contribute to lethargy, loss of normal motivation, and depression.

Many people have an underactive parasympathetic nervous system and an overactive sympathetic nervous system. One of the primary benefits of massage that is given in a relaxing manner is the stimulation of the parasympathetic nervous system. This induces a state of relaxation and promotes the healing and rejuvenation functions of the parasympathetic nervous system, which supports homeostasis.

Parasympathetic Nervous System

Although the role of the parasympathetic nervous system in the control of ureteral peristalsis has not been well defined, muscarinic cholinergic receptors have been demonstrated in the ureter of a number of species including the human (Hernández et al., 1993;Latifpour et al., 1989, 1990;Sakamoto et al., 2006). There are five cloned muscarinic subtypes: M1 to M5. The excitatory muscarinic receptors, M1, M3, and M5, work through an excitatory G protein, Gq, and increase intracellular calcium by generating 1-, 4-, 5-trisphosphate (IP3) and 1-, 2-DG. The inhibitory muscarinic receptors, M2 and M4, work through an inhibitory G protein, Gi, with inhibition of adenylyl cyclase (van Koppen and Kaiser, 2003;Wu et al., 2000). Carbachol induced contractile responses are primarily mediated via the M3 receptor subtype (Tomiyama et al., 2003b). It has been suggested that M2 receptor activation may inhibit smooth muscle relaxation that results from activation of adenylyl cyclase (Hegde et al., 1997). There is a higher density of M2 than M3 muscarinic receptors in the human ureter (Sakamoto et al., 2006).

Acetylcholinesterase-positive nerve fibers have been demonstrated in the equine ureter (Prieto et al., 1994). The cholinergic innervation is especially rich in the distal and intravesical ureter (Hernández et al., 1993). Furthermore, ACh has been shown to be released from isolated guinea pig, rabbit, and human ureters in response to electric field stimulation (Del Tacca, 1978), and this release is inhibited by the neural poison tetrodotoxin. These data suggest, but do not prove, that the parasympathetic nervous system has at least a modulatory role in the control of ureteral activity.

The prototypic cholinergic agonist is ACh, which serves as the neurotransmitter at (1) neuromuscular junctions of somatic motor nerves (nicotinic sites); (2) preganglionic parasympathetic and sympathetic neuroeffector junctions (nicotinic sites); and (3) postganglionic parasympathetic neuroeffector sites (muscarinic sites). ACh synthesis involves

Acetyl CoA+Choline→acetyltransferasecholineACh

where CoA is coenzyme A. The ACh is stored in vesicles within the synaptic terminal; its release depends on the influx of Ca2+ into the terminal, which presumably causes vesicle fusion with the presynaptic terminal membrane, thereby expelling ACh into the synaptic cleft. ACh subsequently is hydrolyzed by acetylcholinesterase. The muscarinic effects of cholinergic agonists can be blocked by atropine. The effects of nicotinic agonists can be blocked by nondepolarizing ganglionic blocking agents or by high concentrations of the nicotinic agonist, which may cause ganglionic blockade by desensitization of receptor sites after an initial period of ganglionic stimulation.

The parasympathetic nervous system

The parasympathetic nervous system acts like the opposite of an emergency system. Increased activity of this system is associated with “vegetative” behaviors, such as sleeping and digesting. The parasympathetic nervous system is responsible for the unconscious regulation of salivation, lacrimation, urination, digestion, and defecation (acronym SLUDD) [16].

Most of the nerves of the parasympathetic nervous system come from the brain stem and some from sacral spinal cord. Acetylcholine is the chemical messenger released from both the preganglionic and the postganglionic parasympathetic fibers. Ganglia of parasympathetic nervous system are located nearby the target organs. Acetylcholine binds to nicotinic receptors on the cell bodies of the postganglionic nerves, whereas receptors in the target organs are muscarinic.

Stimulation of the vagus nerve increases smooth muscle tone and secretion of stomach acid and digestive hormones. Vagal stimulation also decreases heart rate and the force of cardiac contraction.

Most of parasympathetic nervous fibers are afferents. Therefore, they carry information to the brain, such as those from baroreceptors in the wall of the carotid artery and the aorta.

In the lower part of the parasympathetic nervous system are nerves from the bottom level of the spinal cord, the sacral spinal cord. These nerves travel to the lower gastrointestinal tract, urinary bladder, and genital organs [1,7,11,14–16].

Autonomic Stimulation

The parasympathetic nervous system stimulates an increase in alimentary glandular secretion. The glossopharyngeal and vagus parasympathetic nerves innervate glands of the upper tract; these include the salivary glands, esophageal glands, gastric glands, pancreas, and Brunner's glands in the duodenum. Glands in the large intestine also receive parasympathetic innervation. Other glands of the gut secrete in response to local neural and hormonal stimuli rather than as a result of nerve innervation.

Sympathetic stimulation to alimentary tract glandular secretion is less straightforward than parasympathetic stimulation. Sympathetic stimulation has a dual effect, causing a slight increase in glandular secretion if stimulated alone, but with preexisting parasympathetic or hormonal stimulation, sympathetic stimulation reduces secretions. This results from vasoconstriction of blood vessels that supply the glands.52

Anticholinergic Agents

The parasympathetic nervous system provides substantial control of airway tone in health and disease. Potential mechanisms by which cholinergic pathways contribute to asthma pathophysiology include bronchoconstriction through increased vagal tone, increased reflex bronchoconstriction due to stimulation of airway sensory receptors, and increased acetylcholine release induced by inflammatory mediators.63 Patients with asthma experience lesser degrees of bronchodilation with anticholinergic agents (such as atropine and ipratropium bromide) than with beta-agonists. There is presently no indication for anticholinergic agents as a component for long-term asthma control. Evidence supports the use of ipratropium bromide in conjunction with inhaled beta-agonists in the emergency department during acute exacerbations of asthma in children,64,65 as the addition of ipratropium has been shown to decrease rates of hospitalization64 and duration of time in the emergency department.65 This effect is most evident in patients with very severe exacerbations.

b Pharmacokinetics

The parasympathetic nervous system is widely distributed and has multiple actions. MRAs with systemic activity produce many unwanted side effects, such as tachycardia, dysrhythmias, dry mouth, blurred vision, and confusion. MRA activity confined to the lung is optimal; inhalation therapy with minimal absorption is ideal.

Atropine (the prototypic muscarinic antagonist) and hyoscine may decrease airway resistance and attenuate airway reactivity when given parenterally or when inhaled, but systemic side effects have limited their use specifically as bronchodilators.

Ipratropium bromide is a quaternary ammonium derivative of tropane and is positively charged at physiologic pH. It is poorly absorbed from the lungs (<1%), does not readily cross the blood-brain barrier, and can be administered by inhalation at high dose and with minimal systemic side effects.245,246 This and similar agents have slow onset times, up to 90 minutes.247,248 Tiotropium, although not licensed for use in asthma, has a long duration of action, up to a week.104

Parasympathetic Nervous System

The parasympathetic nervous system is composed of cells located in the brain stem and the sacral region of the spinal cord, and for this reason it has been referred to as the craniosacral system. The cranial preganglionic neurons project to the cranial nerves (CNs) with autonomic activity: III, VII, IX, and X. Unlike the sympathetic nervous system, the parasympathetic postganglionic neurons are located near end-organ systems, resulting in long preganglionic axons and relatively short postganglionic axons (Benarroch, 2007).

The brain stem nuclei involved in CN parasympathetic innervation include the following. (1) CN III: Preganglionic neurons from the Edinger-Westphal nucleus extend down the oculomotor nerve and synapse at the orbital ciliary ganglion, where postganglionic neurons extend to the ciliary muscles and iris, resulting in accommodation and pupillary constriction. (2) CN VII: Pontine preganglionic fibers from the superior salivatory nucleus extend down the facial nerve to the pterygopalatine ganglion, with postganglionic fibers extending to the lacrimal gland (tear production) and the cranial vasculature (resulting in vasodilation). Pontine preganglionic fibers also extend to the submandibular ganglion, with postganglionic fibers continuing on to the salivary glands (resulting in salivation). (3) CN IX: Medullary preganglionic fibers from the inferior salivatory nucleus extend down the glossopharyngeal nerve to the otic ganglion, where postganglionic fibers continue on to the parotid gland (resulting in salivation). (4) CN X: By far the largest parasympathetic output, the preganglionic fibers from the dorsal motor nucleus of the vagus and the ventrolateral portion of the nucleus ambiguus extend down the vagus nerve to various ganglia. The fibers extending from the dorsal motor nucleus of the vagus provide input to the gastrointestinal tract (enteric system, described in more detail later), the respiratory tract, and some cardiac input, whereas fibers extending from the nucleus ambiguus extend primarily to the heart. The primary response to vagal activation is cardiac inhibition, visceromotor activation, and salivation (Benarroch, 2007).

Sacral parasympathetic output begins in the lateral gray matter of segments S2–S3, with preganglionic fibers extending down the ventral roots to the splanchnic nerves. The parasympathetic fibers extend to the colon, bladder, and sexual organs. The Onuf nucleus innervates the rectal and urethral sphincters and the pelvic floor. Selective denervation of the Onuf nucleus in Parkinson disease enables differentiation (in some cases) from multiple system atrophy, although this has not been found to be widely reproduced (Palace, Chandiramani, & Fowler, 1997).

The overall effect achieved with activation of the sacral parasympathetic system results is urination (relaxation of the bladder sphincter with simultaneous contraction of the detrusor muscle to facilitate micturition), defecation (relaxation of the rectal sphincter with increased peristalsis), and penile erection (ejaculation is mediated via sympathetic innervation). Unlike the sympathetic nervous system, the parasympathetic nervous system uses acetylcholine for both preganglionic and postganglionic neural transmission.