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.

Introduction to the Autonomic Nervous System

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.

There are two main divisions of the autonomic nervous system - the parasympathetic nervous system (the rest and digest system) and the sympathetic nervous system (the fright, fight and flight system).  While some systems are innervated by only one division of the ANS, others are innervated by both the sympathetic and the parasympathetic systems, and they usually have opposing actions.

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.  

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. 

Transmitters and receptors of the ANS

The preganglionic nerves of both the sympathetic and parasympathetic nervous systems release the acetylcholine (ACh) which stimulates nicotinic receptors on the postganglionic nerve fibre.  Sympathetic nerves supplying the adrenal medulla also release ACh which acts on nicotinic receptors to cause release of adrenaline (epinephrine). Given the similarity in the transmitter and receptor involved in activating the postganglionic fibres of both divisions of the autonomic nervous system, drugs which act as ganglion stimulants or blockers produce a complex and sometimes unpredictable array of effects involving both divisions of the ANS. Such drugs therefore have limited value as therapeutics. 

The main transmitter released from the sympathetic postganglionic nerves is noradrenaline (norepinephrine).  Adrenaline (epinephrine), and to a lesser extent, noradrenaline is also released from the adrenal medulla following activation of the sympathetic nervous system.  Noradrenaline and adrenaline produce their effects by activating adrenoceptors.  Multiple subtypes of adrenoceptors (e.g. a1-, a2 -, β1 -, β2 ) have been identified and drugs which can show subtype selectivity have been developed to allow for a more targeted response.

Acetylcholine is the main transmitter released from the postganglionic nerves of the parasympathetic nervous system. ACh activates muscarinic receptors on the effector tissues innervated by these nerves.  While multiple subtypes of muscarinic receptors have been identified, the high degree of sequence similarity between these subtypes has hampered the development of subtype specific ligands.

Figure 1 below summarises the main transmitters of the ANS.

Figure 1: Major transmitters of the ANS

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.

 

 

 

A good overview of the anatomy and physiology of the autonomic nervous system (ANS) which includes a summary of some clinical conditions associated with dysfunction of the ANS.

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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.

There are two main divisions of the autonomic nervous system - the parasympathetic nervous system (the rest and digest system) and the sympathetic nervous system (the fright, fight and flight system).  While some systems are innervated by only one division of the ANS, others are innervated by both the sympathetic and the parasympathetic systems, and they usually have opposing actions.

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.  

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. 

Transmitters and receptors of the ANS

The preganglionic nerves of both the sympathetic and parasympathetic nervous systems release the acetylcholine (ACh) which stimulates nicotinic receptors on the postganglionic nerve fibre.  Sympathetic nerves supplying the adrenal medulla also release ACh which acts on nicotinic receptors to cause release of adrenaline (epinephrine). Given the similarity in the transmitter and receptor involved in activating the postganglionic fibres of both divisions of the autonomic nervous system, drugs which act as ganglion stimulants or blockers produce a complex and sometimes unpredictable array of effects involving both divisions of the ANS. Such drugs therefore have limited value as therapeutics. 

The main transmitter released from the sympathetic postganglionic nerves is noradrenaline (norepinephrine).  Adrenaline (epinephrine), and to a lesser extent, noradrenaline is also released from the adrenal medulla following activation of the sympathetic nervous system.  Noradrenaline and adrenaline produce their effects by activating adrenoceptors.  Multiple subtypes of adrenoceptors (e.g. a1-, a2 -, β1 -, β2 ) have been identified and drugs which can show subtype selectivity have been developed to allow for a more targeted response.

Acetylcholine is the main transmitter released from the postganglionic nerves of the parasympathetic nervous system. ACh activates muscarinic receptors on the effector tissues innervated by these nerves.  While multiple subtypes of muscarinic receptors have been identified, the high degree of sequence similarity between these subtypes has hampered the development of subtype specific ligands.

Figure 1 below summarises the main transmitters of the ANS.

Figure 1: Major transmitters of the ANS

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.

 

 

 

In this 6.5 minute video, the author diagrams the anatomy of the parasympathetic nervous system including pre- and post-ganglionic nerves, transmitters at the ganglia and organ systems.

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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.

There are two main divisions of the autonomic nervous system - the parasympathetic nervous system (the rest and digest system) and the sympathetic nervous system (the fright, fight and flight system).  While some systems are innervated by only one division of the ANS, others are innervated by both the sympathetic and the parasympathetic systems, and they usually have opposing actions.

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.  

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. 

Transmitters and receptors of the ANS

The preganglionic nerves of both the sympathetic and parasympathetic nervous systems release the acetylcholine (ACh) which stimulates nicotinic receptors on the postganglionic nerve fibre.  Sympathetic nerves supplying the adrenal medulla also release ACh which acts on nicotinic receptors to cause release of adrenaline (epinephrine). Given the similarity in the transmitter and receptor involved in activating the postganglionic fibres of both divisions of the autonomic nervous system, drugs which act as ganglion stimulants or blockers produce a complex and sometimes unpredictable array of effects involving both divisions of the ANS. Such drugs therefore have limited value as therapeutics. 

The main transmitter released from the sympathetic postganglionic nerves is noradrenaline (norepinephrine).  Adrenaline (epinephrine), and to a lesser extent, noradrenaline is also released from the adrenal medulla following activation of the sympathetic nervous system.  Noradrenaline and adrenaline produce their effects by activating adrenoceptors.  Multiple subtypes of adrenoceptors (e.g. a1-, a2 -, β1 -, β2 ) have been identified and drugs which can show subtype selectivity have been developed to allow for a more targeted response.

Acetylcholine is the main transmitter released from the postganglionic nerves of the parasympathetic nervous system. ACh activates muscarinic receptors on the effector tissues innervated by these nerves.  While multiple subtypes of muscarinic receptors have been identified, the high degree of sequence similarity between these subtypes has hampered the development of subtype specific ligands.

Figure 1 below summarises the main transmitters of the ANS.

Figure 1: Major transmitters of the ANS

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.

 

 

 

This 10 min video is a continuation of the discussion of the basic anatomy of the Autonomic Nervous System. The author reviews both sympathetic and parasympathetic anatomy and innervation of organs. The video concludes with an explanation of the mnemonic DUMBBELSS as a memory aid. This video is appropriate for early learners in pharmacology but it best viewed after students have a basic understanding of the ANS.

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