Pharmacology - An Illustrated Review
4. The Peripheral Nervous System
The peripheral nervous system (PNS) is composed of afferent and efferent neurons that lie outside the brain and spinal cord. It regulates and coordinates body physiology in conjunction with the endocrine system. The actions of the PNS are mediated by neurotransmitters acting on a diverse array of receptors at effector organs. Pharmacological agents act on the efferent nerves of the PNS by either mimicking or blocking the effects of these neurotransmitters.
4.1 Divisions of the Peripheral Nervous System
Autonomic Nervous System
Efferent neurons of the autonomic nervous system (ANS) innervate the viscera and are responsible for involuntary homeostatic control of the organs. The ANS is subdivided into the sympathetic and parasympathetic nervous systems, which are summarized in Table 4.1. The relative innervations of target organs by each subdivision are depicted in Fig. 4.1.
Table 4.1 Summary of the Divisions of the Autonomic Nervous System
Region of spinal cord from which preganglionic neurons emerge
Cranial and sacral
— Cell bodies of preganglionic neurons are in the midbrain, pons, and medulla giving rise to the autonomic components of cranial nerves III, VII, IX, and X
— Cell bodies of preganglionic neurons are in S2-S4
— Cell bodies of preganglionic neurons are in T1-L3
Length of preganglionic neurons
Length of postganglionic neurons
Location of ganglia
Near target organs
Sympathetic chain ganglia (located parallel to the spinal cord on both sides)
Abdominal prevertebral ganglia
Neurotransmitters and receptors
Preganglionic neurons release acetylcholine, which acts at nicotinic receptors.
Postganglionic neurons release acetylcholine, which acts at muscarinic receptors.
Preganglionic neurons release acetylcholine, which acts at nicotinic receptors.
Postganglionic neurons release norepinephrine, which acts at adrenergic receptors.
Principally concerned with maintenance, conservation, and protection of body resources (anabolic).
Principally involved with expenditure of body resources or energy (catabolic).
A functioning parasympathetic system is necessary to sustain life as it maintains essential bodily functions.
Parasympathetic nerves can act in isolation from the system as a whole, producing discrete effects at specific end organs.
The sympathetic system is not strictly necessary to maintain life.
It is capable of a mass response, the emergency “flight or fight response.” The neuronal basis of this widespread response lies in the wide divergence of preganglionic axons within the sympathetic chain ganglia.
Fig. 4.1 The autonomic nervous system (ANS).
The ANS comprises a parasympathetic division and a sympathetic division. Parasympathetic preganglionic neurons arise in the cranial and sacral region of the spinal cord and are relatively long compared with the parasympathetic postganglionic neurons. Sympathetic preganglionic neurons arise in the thoracolumbar region of the spinal cord and are relatively short compared to sympathetic postganglionic neurons.
Chapter 5 covers cholinergic agents and Chapter 6 covers adrenergic agents.
Somatic Nervous System
Efferent neurons of the somatic nervous system innervate skeletal muscle and are responsible for voluntary movements. The axons of these efferent neurons originate in the spinal cord and synapse directly on skeletal muscle.
Drugs that block nicotinic cholinergic receptors on skeletal muscle are covered in the section on “Depolarizing and Nondepolarizing Neuromuscular Blockers of Acetylcholine” in C hapter 5 (p. 49).
The efferent neurons of the parasympathetic, sympathetic, and somatic neurons are shown schematically in Fig. 4.2.
Fig. 4.2 Efferent neurons of the parasympathetic, sympathetic, and somatic nervous systems.
Postganglionic neurons that innervate sweat glands release ACh. (ACh, acetylcholine; NE, norepinephrine; EPI, epinephrine.)
Enteric Nervous System
Enteric neurons include the submucosal and myenteric plexuses in the gastrointestinal (GI) tract. This system possesses all the elements necessary for the short reflex regulation of GI functions, i.e., modification of motility and secretory activity by afferent and efferent nerves entirely within the GI tract. It is able to do this without modulation from the ANS, with the exception of the proximal esophagus and the external anal sphincter.
Nerve cells communicate with each other through the release of neurotransmitters from the presynaptic nerve terminal. The sequence of events that leads to the response of a postsynaptic neuron or effector organ is as follows:
– Presynaptic action potential
– Influx of Ca2+ into the nerve terminal
– Release of the neurotransmitter from the presynaptic terminal
– Neurotransmitter binds to the postsynaptic receptor.
– Transduction of the message to the ion channel
– Integration of signals from various inputs
– Postsynaptic response
Quadriplegia is caused by spinal cord injury at the level of the cervical spine. A ventilator may be required if the injury involves C3−C5, as these spinal nerves control the diaphragm (via the phrenic nerve), which is the major muscle that allows us to breathe. However, quadriplegic patients can survive because the cranial nerves (ANS preganglionic parasympathetic nerves) remain intact and can coordinate vital bodily functions despite the patient's having no voluntary control from below the level of injury.
Embryology of the adrenal gland
The adrenal cortex, which comprises 80% of the adrenal gland, is derived from mesothelium; the adrenal medulla, which comprises 20%, is derived from neural crest cells as are the neurons of the sympathetic nervous system. The adrenal medulla is innervated by preganglionic sympathetic nerves and is pharmacologically similar to a sympathetic ganglion. However, because the chromaffin cells of the adrenal medulla lack axons, the adrenal medulla responds to preganglionic secretion of acetylcholine by secreting the hormones epinephrine (and norepinephrine to a lesser extent) into the bloodstream.
Horner syndrome may occur due to an interruption of the sympathetic nerve supply to the face through a disease of or injury to the brainstem or thoracolumbar region of the spinal cord, for example, by stroke, tumors, carotid artery dissection (tearing of the lining of the artery), or spinal cord injury. It may also be idiopathic (cause not known). Horner syndrome causes miosis (pupillary constriction), enophthalmos (a sunken eye), ptosis (drooping of the upper eyelid), and anhydrosis (loss of sweating) on the affected side of the face. Treatment for Horner syndrome is directed at the underlying cause.
Disorders of CNS autonomic control
Disorders involving central autonomic control may manifest as hyperactivity (e.g., hypertension and arrhythmias) or as autonomic failure (e.g., orthostatic hypotension, impotence, or GI tract dysmotility). In general, autonomic hyperactivity tends to occur acutely, whereas autonomic failure is more typical of chronic neurodegenerative disease (e.g., multiple sclerosis).
4.2 Neurotransmitters of the Autonomic and Somatic Nervous Systems
Synthesis. The neurotransmitter acetylcholine (ACh) is synthesized in the nerve terminal from acetate, derived from acetyl coenzyme A, and choline. This reaction is catalyzed by the enzyme choline acetyltransferase. The uptake of choline is the rate-limiting step in acetylcholine synthesis (Fig. 4.3).
Storage and release. Acetylcholine is stored within vesicles in nerve terminals. An action potential causes Ca2+ influx through voltage-gated channels and the subsequent release of ACh into the synaptic cleft.
Degradation. The breakdown of acetylcholine to acetic acid and choline is rapid and occurs via the enzyme acetylcholinesterase. Acetylcholinesterase is located in neuronal membranes and red blood cells. Pseudocholinesterases (nonspecific) or butyrylcholinesterases, which are more widely distributed, can also hydrolyze acetylcholine.
Site of neurotransmission. ACh is the neurotransmitter released from the following types of neurons:
– Preganglionic neurons that innervate all autonomic (parasympathetic and sympathetic) ganglia
– Postganglionic parasympathetic neurons
– Somatic motor neurons that innervate the neuromuscular junction
– Neurons that innervate the adrenal medulla
– Postganglionic neurons that innervate sweat glands
Pantothenic acid (vitamin B5) is a precursor of coenzyme A (CoA). CoA participates in fatty acid synthesis and oxidation, as well as the oxidation of pyruvate in the citric acid cycle. A molecule of CoA that has an acetyl group is acetyl coenzyme A (acetyl CoA). Acetate, which is derived from acetyl CoA, combines with choline to form the neurotransmitter acetylcholine (ACh).
Fig. 4.3 Acetylcholine: release, effects, and degradation.
Acetylcholine is stored in vesicles in the axoplasm of presynaptic nerve terminals. These vesicles are anchored to a cytoskeletal network by the protein synapsin, thus allowing for the accumulation of vesicles near the presynaptic membrane while preventing fusion with the membrane. An action potential causes Ca2+ influx into the axoplasm through voltage-gated channels. Ca2+ then activates protein kinases that phosphorylate synapsin. This causes the vesicles to become free, fuse with the membrane, and release acetylcholine into the synaptic gap. Acetylcholine attaches to receptors on the postsynaptic membrane and exerts its effects. It is then hydrolyzed by acetylcholinesterase with reuptake of the choline component into the axoplasm.
Norepinephrine and Epinephrine
– Norepinephrine (NE) is synthesized in nerve terminals. Tyrosine is converted to dopa by tyrosine hydroxylase (rate-limiting step). Dopa is converted to dopamine by dopa decarboxylase and then dopamine is converted to norepinephrine by dopamine-β-hydroxylase.
— Epinephrine (EPI) (and a lesser amount of norepinephrine) is synthesized in the adrenal medulla. A cytoplasmic enzyme in the adrenal medulla (phenylethanolamine-n-methyltransferase) transfers a methyl group to norepinephrine to form epinephrine (Fig. 4.4).
Ascorbic acid redox reactions
Ascorbic acid (vitamin C) is involved in many processes in the body, including collagen and bile acid synthesis, activation of neuroendocrine hormones (e.g., gastrin, corticotropin-releasing hormone [CRH], and thyrotropin-releasing hormone [TRH]), iron absorption, and detoxification (via stimulation of cytochrome P-450 enzymes in the liver. Ascorbic acid is oxidized to dehydroascorbic acid via an extremely reactive intermediate, semidehydro-l-ascorbate. The hydrogen ions that are liberated in this oxidation are able to act as donors in hydroxylation reactions throughout the body (which accounts for some of its effects). One such reaction where this occurs is when ascorbic acid acts as a cofactor for dopamine-β-hydroxylase in the synthesis of norepinephrine and epinephrine.
Storage and release
– NE is stored in vesicles within nerve terminals. An action potential at the nerve terminal causes the influx of Ca2+ through voltage-gated channels and the subsequent release of NE into the synaptic cleft.
– EPI (80%) and NE (20%) are released from the adrenal medulla following sympathetic stimulation (via ACh).
Termination of action is primarily by reuptake (60−90%) into the nerve terminal. Secondary degradation is by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
Site of neurotransmission
– NE is the neurotransmitter released from postganglioinc sympathetic neurons (except sweat glands which release ACh).
Fig. 4.4 Synthesis and termination of norepinephrine and adrenergic transmission.
Postganglionic sympathetic nerve terminals possess varicosities that enable them to lie in close proximity to effector organs. Norepinephrine (NE) synthesis and storage in vesicles occurs in these varicosities. An action potential at the nerve terminal causes the influx of Ca2+ and the subsequent release of NE into the synaptic cleft. NE then binds to adrenergic receptors on effector organs, exerting a physiological effect. Note that NE has little effect on the β2-adrenergic receptors, whereas epinephrine, synthesized in the adrenal medulla, acts at all adrenergic receptors. Approximately 70% of NE is taken back up into the presynaptic nerve terminal and repackaged in vesicles or is inactivated by monoamine oxidase (MAO). In the heart, NE is inactivated by MAO or catechol-O-methyltransferase (COMT).
4.3 Neurotransmitter Receptors
There are two broad categories of neurotransmitter receptors in the ANS, cholinergic and adrenergic. The cholinergic receptors can be further broken down into two types, nicotinic and muscarinic receptors.
Nicotinic receptors are ligand-gated ion channels composed of five protein subunits that combine to form a functional receptor and ion pore. Ligand binding induces Na+ conductance. The two major subtypes are the muscle type and the neuronal type and they each have different subunit compositions:
– The muscle type is composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio in adults.
– The neuronal subtypes are homomeric or heteromeric combinations of 12 different nicotinic receptor subunits: α2 through α10 and β2 through β4.
– Autonomic ganglia
– Neuromuscular junction of somatic nerves and skeletal muscle
– Adrenal medulla
Muscarinic receptors are brain G protein-coupled receptors (see pages 21 to 23), which in turn transduce receptor activation by acetylcholine into various intracellular changes. There are five main subtypes of muscarinic receptors. Three primary ones (M1 to M3) will be considered here.
– M1 receptors are found in the CNS.
– M2 receptors are found in the heart.
– M3 receptors are found in smooth muscle and glands.
Signal transduction mechanism
– M1 and M3 couple to Gq: Gq activates phospholipase which increases DAG and IP3 (see page 23).
– M2 couples to Gi: Gi inhibits cAMP (see page 23).
Cholinergic nicotinic and muscarinic receptors are illustrated in Fig. 4.5.
Fig. 4.5 Acetylcholine receptors.
(A) The nicotinic receptor consists of five protein subunits. Binding of acetylcholine to the two α subunits is thought to change its conformation, allowing for the central pore to open and for the influx of ions into the cell. (B) The muscarinic receptor is coupled to intracellular G proteins, which may then transduce excitatory effects via phospholipase C or inhibitory/excitatory effects via adenylate cyclase.
Adrenergic receptors are G-protein coupled receptors (GPCRs). There are two main subtypes of adrenergic receptors, α and β.
– α1 are found on vascular smooth muscle.
– α2 are autoreceptors at presynaptic terminals of sympathetic neurons.
– β1 are found in cardiac muscle.
– β2 are found in the lung.
– β3 are found in adipose tissue.
Signal transduction mechanism
– α1 couples to Gq.
– α2 couples to Gi.
– β-receptors couple to Gs (see page 23).
Table 4.2 provides a summary of ANS receptors.
4.4 Physiologic Responses of the Autonomic Nervous System
Drugs that act on the ANS alter the physiological responses of the endogenous system. Understanding the normal sympathetic or parasympathetic responses of the various organs is important to understanding the actions of drugs that affect the ANS. Most organs receive dual innervation from both the sympathetic and parasympathetic divisions, which generally have opposing effects (Fig. 4.6).
Fig. 4.6 Physiological responses of the autonomic nervous system.
The effects of parasympathetic and sympathetic stimulation on organs throughout the body are shown. Many organs are innervated by both systems, with each having a different effect; however, an exception to this is blood vessels, which only receive innervation by sympathetic postganglionic neurons. (cAMP, cyclic adenosine monophosphate; CNS, central nervous system; DAG, diacylglycerol; IP3, inositol triphosphate; VIP, vasoactive intestinal polypeptide.)