Autonomic Pharmacology

Autonomic Pharmacology

Autonomic pharmacology is the study of how drugs interact with the autonomic nervous system. The autonomic nervous system plays an important role in the control of the internal organs including the heart, lungs, gastrointestinal tract and vasculature.  Drugs which target the autonomic nervous system are, therefore, useful in the treatment of a range of conditions such as hypertension; gastrointestinal disturbances and asthma.  An understanding of how drugs can interact with the autonomic nervous system allows us to appreciate the therapeutic uses of these drugs, and to predict their likely adverse effects.

ANS Part I: Introduction and anatomy

There is only one nervous system, but for ease of description it is traditionally divided into the central nervous system (CNS) comprising the brain and spinal cord and peripheral nervous system (PNS) that conveys information from the CNS to the organs and tissues of the body and vice versa. By convention, those neurone cell bodies and their associated axons (or fibres) that conduct action potentials from the CNS to the periphery are termed efferents, whereas those that relay information in the opposite direction are known as afferents. Broadly, efferents send command signals directed towards the effectors of the body, such as muscles (skeletal, cardiac and smooth) and exocrine and endocrine glands.

The afferents and associated structures act as sensors of the internal and external environments, constantly providing the information essential to maintain homeostasis by the modulation of appropriate efferents. The autonomic nervous system (ANS) influences the activity of many body systems including digestion, respiration and circulation.  Information about the internal and external environments is fed via afferent nerves to regions in the hypothalamus and the medulla, which control the activity of the autonomic nerves supplying the internal organs such as the heart, the blood vessels, the gastrointestinal system, lungs, endocrine and exocrine glands. At a relatively simply level, such regulation occurs via a reflex arc, typically polysynaptic, that often, but not invariably, involves the CNS. Numerous activities of the gut, such as peristalsis, are important examples of reflex control mediated by microcircuits that are independent of CNS participation. More generally a physiological variable, such as arterial blood pressure, is: (i) detected by sensory afferents; (ii) compared with a desired set point by a comparator within a co-ordinating centre of the the CNS and (iii) any deviation between the set point and measured variable (an error) is then minimised by adjustment of the activity of the efferents supplying the effector organs controlling that variable (e.g. heart rate and force of contraction, resistance of arterioles to blood flow) (Figure 1).  A multitude of physiological processes are regulated by negative feedback, as exemplified in the neuronal control of arterial blood pressure mentioned above.

Moreover, an array of ‘mundane, or house-keeping’, activities that are indispensable to life occurs without conscious awareness (e.g. when asleep). Such constant, subconscious, monitoring and corrective action is one of the fundamental tasks of the autonomic (‘self-regulating’) nervous system (ANS).

 

What is the ANS? How is it defined?

John Newport Langley (1921), in a classic text (‘The Autonomic Nervous System’), summarised the ANS in a way that is rather difficult to improve upon, without resorting to ‘nit-picking’ with the benefit of hindsight:

‘’The autonomic nervous system consists of nerve cells and nerve fibres, by means of which efferent impulses pass to tissues other than multi-nuclear striated muscle.’’

Langley’s definition, in the clearest of terms, emphasises the vast territory of autonomic control: it is the CNS motor output to the whole body, other than skeletal, otherwise termed  voluntary (multi-nuclear striated) muscle, the latter being innervated directly by efferent motor fibres termed α- and g- motor neurones (or motoneurones) that are part of the somatic nervous system. Langley’s (1921) definition does not include sensory (afferent) fibres that innervate the blood vessels and hollow organs (viscera) of the body. Although essential to autonomic control (such as the regulation of arterial blood pressure touched upon above), there has been considerable debate about whether all such afferents should properly be regarded as components of the ANS (a complexity clearly appreciated by Langley). For example, the activity of some visceral afferents that are nociceptive in function can undoubtedly evoke intense awareness (the pain of cardiac ischaemia being a prime example). For our purposes, we will ignore what for students might seem the largely distracting (and confusing!) semantics and simply appreciate the vital role of afferent input in autonomic control, whether arising from the viscera, or elsewhere. Indeed, ‘sensory’ input can be non-neuronal, as exemplified by numerous inflammatory mediators that influence autonomic output.

The ANS comprises both CNS and peripheral components. Within the brain, higher level autonomic control primarily involves cortical areas and subcortical nuclei of the hypothalamus and brainstem that will not, with the exception of the latter, be discussed in detail here. Functions essential to human health and life that are regulated by the ANS include:

  • contraction and relaxation of vascular and visceral smooth muscle, thus affecting mechanical activity in virtually all of the systems of the body (e.g. cardiovascular, gastrointestinal, respiratory, reproductive, urinary)
  • the heartbeat (e.g. cardiac rate, force and electrical activity)
  • all exocrine gland secretions (e.g. lacrimation, sweating, gastric acid, exocrine pancreas) and many endocrine secretions (e.g. endocrine pancreas, adrenal medulla, liver)
  • all aspects of metabolism (e.g. in the liver, skeletal muscle, adipose tissue)
  • modulation of the function of immune organs and cells (e.g. mast cells, lymph nodes)

The pioneering studies of the motor ANS conducted over a century ago divided it in to two, or three, subdivisions:

  • sympathetic (the fright, fight and flight system)
  • parasympathetic (the rest and digest system)
  • (although it can be argued that this ‘little brain of the gut’, comprising more than 100 million neurones in man, is separate from the ANS). This might be justified by the fact that many activities of the gut do not require extrinsic neuronal input for their co-ordination and execution.

As described in other sections, there is a firm anatomical and also functional rationale to such a classification but there has been an unfortunate tendency to extend this to a parody, or polarisation, of function. Thus, it is common to read that the sympathetic division (originally named because it acts ‘in sympathy’ with the emotions) is the mediator of ‘fight, or flight’ reactions when the organism is confronted with danger, or other extremely stressful situation (a Pharmacology exam?). The parasympathetic division is often associated with ‘rest, or digest’ activities (or plain idleness!). A further extension is that the sympathetic and parasympathetic divisions are physiological opponents with one, or the other, dominant in particular situations. Generally, this is quite misleading (a simple objection being that many organs are not innervated by both sympathetic and parasympathetic fibres) as we will explore in sections devoted to the sympathetic and parasympathetic divisions of the ANS. For now, note that whilst sub-divisions are convenient ‘labels’ for ease of description, there is functionally one ANS and it is the integrated activity of all of its components in association with the somatic nervous system and neuroendocrine system that is indispensable to homeostasis and survival.

A summary of the actions of the autonomic nervous system can be found at: Merck Manuals.

 

Anatomy of the ANS

The parasympathetic and sympathetic nervous systems each consist of two nerves – a preganglionic nerve which has its cell body within the CNS; and a postganglionic nerve which innervates the effector tissue. Shown in schematically in Figure 2 below.

Preganglionic nerves of the sympathetic nervous system leave the CNS in the thoracolumbar regions of the spinal cord and synapse with the postganglionic fibres in prevertebral and paravertebral ganglia adjacent to the spinal cord.  The long postganglionic fibres run from these ganglia to the effector organs.

The parasympathetic preganglionic nerve fibres exit the spinal cord via the cranial nerves and the sacral regions of the spinal cord.  The parasympathetic ganglia are located within the effector organs and the postganglionic fibres of the parasympathetic nervous system are, therefore, much shorter than those of the sympathetic system. 

 

Elizabeth Davis, John Peters

This 23 slide Powerpoint presentation is intended to introduce the reader to the function of the autonomic nervous system (ANS). Specific areas that are covered include: the basic organization of the motor ANS and its components; the sympathetic and parasympathetic outflows from the central nervous system (CNS) to peripheral organs: the basics of neurochemical neurotransmission within the motor ANS including key neurotransmitters and receptor types; important selected activities of the motor ANS and finally some misconceptions regarding the ANS that even the beginner should be aware of.

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ANS Part II: Receptors, transmitters and drugs

The two principal (or 'classical') small transmitter molecules used by neurons of the motor ANS are acetylcholine (ACh) and noradrenaline (NA). Many others, some of which will be mentioned in other sections [e.g. adenosine triphosphate (ATP), nitric oxide (NO) and numerous peptides], act as co-transmitters, or modulators. See Figure 1 below.

The key facts, which are summarised in Box 1, are:

  • all preganglionic neurones, sympathetic and parasympathetic, are cholinergic, meaning that they synthesise and release ACh as their primary transmitter. Thus, fast synaptic neurotransmission at the autonomic ganglia is always mediated by ACh.
  • all postganglionic neuronescommunicate with their effector targets by chemical transmission at neuroeffector junctions. The latter are generally not regarded as conventional synapses because they lack structural elements of, for example, the best studied synapse, that of the skeletal neuromuscular junction. Moreover, each axon has sites of transmitter release from multiple swellings, known as varicosities, which occur along its distal portion, giving a 'string of pearls' appearance. The distance between the varicosity and postjunctional membrane, through which transmitter must diffuse, varies greatly between the innervated tissues (the extremes being 20 nm to 1-2 µm) and is generally much wider than the cleft at a synapse such as the skeletal neuromuscular junction (~ 30 nm).
  • parasympathetic postganglionic neurones are mainly cholinergic, releasing ACh at the neuroeffector junction. In some instances a gas, nitric oxide (NO) may subserve neurotransmission.
  • sympathetic postganglionic postganglionic neurones are largely adrenergic, meaning that they synthesise and release NA as their primary transmitter. It should be noted that that NA is also known as norepinephrine (NE), particularly in North America. Fortunately, 'norepinephrinergic' (which is an abomination to Pharmacologists!) is not used as an alternative nomenclature to adrenergic. ATP is frequently released with NA as a co-transmitter. A minority of sympathetic postganglionic neurones, such as those innervating eccrine sweat glands, are cholinergic.
  • As is generally the case in chemical neurotransmission, the release of either ACh, or NA, from presynaptic or prejunctional sites is triggered by the arrival of an action potential. The latter evokes membrane depolarization that in turn opens voltage-activated calcium-selective ion channels that allow influx of Ca2+. The resultant local increase in intracellular Ca2+ concentration causes vesicles in which the transmitter is stored to fuse with the presynaptic/prejunctional membrane liberating the transmitter to activate postsynaptic/postjunctional receptors. Such release of transmitters from vesicles in response to Ca2+ is known as exocytosis.
  • The most important receptors through which the autonomic transmitters act, at least from the perspective of current therapeutic agents, are cholinoceptors and adrenoceptors that are activated by ACh and NA (or adrenaline), respectively. Still others to be introduced in other sections mediate the effects of co-transmitters and modulators of the ANS. Nitric oxide has the distinction of acting via an enzyme (soluble guanylyl cyclase), rather than a receptor.
  • The cholinoceptors are fundamentally classed as nicotinic, which are ligand-gated ion channels (LGICs), or muscarinic which are G-protein-coupled receptors (GPCRs). This nomenclature is rooted deeply in the history of Pharmacology, the plant alkaloids nicotine and muscarine being the earliest studied selective agonists of nicotinic and muscarinic cholinoceptors, respectively. A large number of antagonists, some of which are of past, or current, therapeutic importance are also strongly selective between skeletal neuromuscular junction nicotinic (e.g. vecuronium), ganglionic nicotinic (e.g. hexamethonium) and muscarinic (e.g. atropine) cholinoceptors.
  • Both nicotinic and muscarinic receptors exist as multiple subtypes. The structural underpinnings of such diversity will be mentioned in other sections, but for now it is sufficient to note that the nicotinic receptors of the ganglia and skeletal neuromuscular junction, which many Physiology texts unhelpfully (and in violation of NC-IUPHAR nomenclature recommendations!) denote NN (or N2) and NM (or N1) respectively, are pharmacologically distinct which is of clinical importance). For example, a very common task of the anaesthetist is to reversibly block the nicotinic receptors of the skeletal neuromuscular junction to achieve controlled paralysis without perturbing transmission through the ganglia by blocking ganglionic nicotinic receptors. Muscarinic receptors exist as five subtypes: M1, M2, M3, M4and M5 with differing tissue/organ locations and hence physiological functions. Efforts to develop clinically useful subtype-selective antagonists of muscarinic receptors, which we will see is a highly desirable goal, have thus far met with limited success, largely due to the structural conservation of the orthosteric site to which the transmitter, ACh, binds. Pirenzepine and solifenacin are examples of antagonists with marginal selectivity for M1 and M3 receptors, respectively, whilst atropine (above) is non-selective.

Adrenoceptors also exist as numerous subclasses. A fundamental distinction is between α- and β-adrenoceptors, first made by careful study of the rank order of potency of agonists including NA, A and isoprenaline (aka isoproterenol), a synthetic agent. Subsequently, α1-, α2-, β1-, β2- and β3-adrenoceptors have been characterised structurally and pharmacologically. Such receptors have distinct tissue/organ locations (e.g. β1 - cardiac nodes and muscle; β2 - airway smooth muscle) and drugs that selectively activate (e.g. salbutamol, aka albuterol - a β2 agonist) and block (e.g. atenolol - a β1 antagonist) adrenoceptor subtypes are some of the most important and frequently used drugs in medicine.

Box 1. Comparison of the Sympathetic and Parasympathetic Divisions of the Motor Autonomic Nervous System
  Sympathetic Parasympathetic

Location of preganglionic neurone cell body

Thoracolumbar spinal cord

Brainstem, sacral spinal cord

Length of preganglionic fibre and fibre class

Short, mostly motor B-myelinated

Long, mostly motor B-myelinated

Principal transmitter of preganglionic neurones and receptor of postganglionic neurones

Acetylcholine (ACh), ganglionic nicotinic cholinoceptor

Acetylcholine (ACh), ganglionic nicotinic cholinoceptor

Location of autonomic ganglia

Prevertebral as sympathetic chains on either side of the spinal cord and paravertebral within the abdomen

Discrete ganglia within the head, pelvic ganglia, or intramural ganglia within walls of target organs

Length of postganglionic fibre and fibre class

Long, motor C-unmyelinated

Short, motor C-unmyelinated

Principal transmitter of postganglionic neurones and receptor on post-junctional cells

noradrenaline (NA) (occasionally ACh), α- and β-adrenoceptors and their subclasses (occasionally muscarinic cholinoceptors)

acetylcholine (ACh), muscarinic cholinoceptors

Established co-transmitters, or modulators*

adenosine triphosphate (ATP), neuropeptide Y

nitric oxide (NO), vasoactive intestinal peptide (VIP)

Examples of receptor agonists mimicking neuroeffector transmission that are in clinical use**

phenylephrine1-adrenoceptor selective)
adrenaline (non-selective)
salbutamol2-adrenoceptor selective)
salmeterol2-adrenoceptor selective)
mirabegron3-adrenoceptor selective)

bethanechol (muscarinic, non-selective)
cevimeline (muscarinic M3, selective)

Examples of receptor antagonists blocking neuroeffector transmission that are in clinical use**

doxazosin1-adrenoceptor selective)
tamsulosin1-adrenceptor selective)
propranolol (β-adrenoceptor selective)

atenolol1-adrenocptor selective)

atropine (muscarinic, non-selective)
ipratropium (muscarinic, non-selective)
oxybutynin (muscarinic, non-selective)
solifenacin (muscarinic M3, marginally selective)

* Neurotransmission mediated by transmitters other than ACh and NA is termed non-adrenergic non-cholinergic (NANC) and includes nitrergic (NO), purinergic (e.g. ATP) and peptidergic (numerous peptides, including VIP).

**Only a few exemplar drugs are listed. A more comprehensive listing is given in sections on the sympathetic and parasympathetic nervous systems.

An overview of the transmitters and receptors of the ANS is available here.

While acetylcholine and noradrenaline are considered the major transmitters of the autonomic nervous system, non-adrenergic, non-cholinergic (“NANC”) nerves which release transmitters such as nitric oxide (NO) and ATP have also been identified. These NANC transmitters are co-localised and released with the main transmitter and may act to modulate its action or act as co-transmitters, contributing to the response seen with nerve activation.  Indeed in some tissues, the NANC transmitter may be the major transmitter (for example nitric oxide (NO) in the male genitourinary tract).

Pharmacologic modulation of the ANS

Drugs can modulate the activity of the autonomic nervous system by interacting at a number of different sites and the range of effects caused will vary depending on how many systems will be affected.  As mentioned above, drugs which interfere with ganglionic transmission will affect the outflow of both the sympathetic and parasympathetic systems.  However, drugs which target the receptors in the effector tissues, particularly if they are selective for subtypes of receptors, will have the greatest selectivity and fewer unwanted effects.

 

Elizabeth Davis, John Peters

This 23 slide Powerpoint presentation is intended to introduce the reader to the function of the autonomic nervous system (ANS). Specific areas that are covered include: the basic organization of the motor ANS and its components; the sympathetic and parasympathetic outflows from the central nervous system (CNS) to peripheral organs: the basics of neurochemical neurotransmission within the motor ANS including key neurotransmitters and receptor types; important selected activities of the motor ANS and finally some misconceptions regarding the ANS that even the beginner should be aware of.

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