The Sympathetic Nervous System

The Sympathetic Nervous System

The sympathetic nervous (adrenergic) system:

Drugs can modulate the activity of the sympathetic nervous system by affecting the synthesis, storage, release or reuptake of noradrenaline, or its interaction with adrenoceptors.

A link to an animation showing the steps involved in the noradrenergic neurotransmission is provided here. This process involves:

  • synthesis of noradrenaline from its amino acid precursor (tyrosine)
  • storage of noradrenaline in synaptic vesicles within sympathetic nerve terminals
  • release of noradrenaline via exocytosis
  • diffusion of noradrenaline across the neuroeffector junction to activate adrenoceptors
  • termination of action via reuptake into nerve terminals (Uptake 1) or uptake into extraneuronal tissues (Uptake 2)

Drugs affecting synthesis, storage, release or removal of noradrenaline

Drugs which affect the synthesis or storage of noradrenaline will affect all sympathetic nerves, thereby causing a diverse range of effects.  In addition, because there is an overlap in the mechanisms involved in the synthesis, storage, release and removal of noradrenaline, adrenaline and dopamine, drugs which affect noradrenergic neurotransmission will have similar effects on adrenergic and dopaminergic nerurotransmission in the periphery and the CNS.  Drugs which target noradrenaline synthesis and storage, therefore, have limited value as therapeutics.

Drugs can affect the release of noradrenaline by:

  • affecting the available stores of noradrenaline in the sympathetic nerve terminals. Stores of noradrenaline within the nerve terminal can be affected by changes in metabolism e.g. by inhibition of the main metabolic pathway via monoamine oxidase (MAO) or inhibiting catechol-O-methyltransferase (COMT).  However, because reuptake rather than metabolism is the major mechanism for terminating the action of noradrenaline in the peripheral nervous system, inhibition of MAO and/or COMT may have little effect on the responses to sympathetic nerve stimulation.
  • directly blocking release from the nerve terminal. Noradrenergic neurone blocking drugs, such as bretylium, can inhibit the release of noradrenaline from the nerve terminal.  Actions contributing to this effect include uptake into the nerve terminal and displacement of NA from the synaptic vesicles, along with a membrane stabilizing action.  The result of this is a decrease in the amount of noradrenaline released with each nerve stimulation.   While noradrenergic neurone blocking drugs were used in the treatment of hypertension, they had a number of adverse effects associated with effects on multiple sympathetically innervated organs and interference with cardiovascular reflexes.  They have been superseded by safer, more selective drugs.
  • causing release of noradrenaline from the nerve terminal. Indirectly acting sympathomimetics enter the nerve via the uptake process and trigger the release of noradrenaline.  This release is due to the indirectly acting sympathomimetic displacing noradrenaline from the synaptic vesicles into the cytoplasm and then out of the nerve terminal via the reverse action of the uptake  transporter.  Once in the neuroeffector junction, the noradrenaline can interact with adrenoceptors and produce effects similar to those seen with activation of the sympathetic nervous system (including increased blood pressure and increased heart rate). Amphetamine is an example of an indirectly acting sympathomimetic. 

As the major mechanism for terminating the action of noradrenaline released from sympathetic nerves is via reuptake into the nerve terminal (Uptake 1), inhibition of this transport system will result in potentiation of sympathetic activity.  Drugs such as cocaine act as Uptake 1 inhibitors.  Their stimulant effects and addictive potential are due to action within the CNS. 
 

An animation that illustrates the synthesis, storage and release of noradrenaline from sympathetic nerve endings.

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Drugs which affect the synthesis or storage of noradrenaline will affect all sympathetic nerves, thereby causing a diverse range of effects.  In addition, because there is an overlap in the mechanisms involved in the synthesis, storage, release and removal of noradrenaline, adrenaline and dopamine, drugs which affect noradrenergic neurotransmission will have similar effects on adrenergic and dopaminergic nerurotransmission in the periphery and the CNS.  Drugs which target noradrenaline synthesis and storage, therefore, have limited value as therapeutics.

Drugs can affect the release of noradrenaline by:

  • affecting the available stores of noradrenaline in the sympathetic nerve terminals. Stores of noradrenaline within the nerve terminal can be affected by changes in metabolism e.g. by inhibition of the main metabolic pathway via monoamine oxidase (MAO) or inhibiting catechol-O-methyltransferase (COMT).  However, because reuptake rather than metabolism is the major mechanism for terminating the action of noradrenaline in the peripheral nervous system, inhibition of MAO and/or COMT may have little effect on the responses to sympathetic nerve stimulation.
  • directly blocking release from the nerve terminal. Noradrenergic neurone blocking drugs, such as bretylium, can inhibit the release of noradrenaline from the nerve terminal.  Actions contributing to this effect include uptake into the nerve terminal and displacement of NA from the synaptic vesicles, along with a membrane stabilizing action.  The result of this is a decrease in the amount of noradrenaline released with each nerve stimulation.   While noradrenergic neurone blocking drugs were used in the treatment of hypertension, they had a number of adverse effects associated with effects on multiple sympathetically innervated organs and interference with cardiovascular reflexes.  They have been superseded by safer, more selective drugs.
  • causing release of noradrenaline from the nerve terminal. Indirectly acting sympathomimetics enter the nerve via the uptake process and trigger the release of noradrenaline.  This release is due to the indirectly acting sympathomimetic displacing noradrenaline from the synaptic vesicles into the cytoplasm and then out of the nerve terminal via the reverse action of the uptake  transporter.  Once in the neuroeffector junction, the noradrenaline can interact with adrenoceptors and produce effects similar to those seen with activation of the sympathetic nervous system (including increased blood pressure and increased heart rate). Amphetamine is an example of an indirectly acting sympathomimetic. 

As the major mechanism for terminating the action of noradrenaline released from sympathetic nerves is via reuptake into the nerve terminal (Uptake 1), inhibition of this transport system will result in potentiation of sympathetic activity.  Drugs such as cocaine act as Uptake 1 inhibitors.  Their stimulant effects and addictive potential are due to action within the CNS. 
 

This is a series of videos of mini lectures in adrenergic pharmacology.  The videos are well paced and with easy to follow slides.  Included at the end are some challenge questions. 

Average: 4.2 (6 votes)

Drugs interacting directly with adrenoceptors

An overview of the receptors of the Sympathetic Nervous system is provided here and further information about the actions associated with these receptors and their potential as therapeutic targets is available here

Drugs that directly interact with adrenoceptors can act as agonists (thereby mimicking some of the actions of the sympathetic nervous system) or antagonists (blocking the effects of sympathetic activation).  The actions of these drugs will be dependent on their selectivity profile for the different adrenoceptor subtypes as well as their interaction with removal systems (e.g. uptake 1; metabolism by monoamine oxidase (MAO)/catechol-O-methyltransferase (COMT).

For example, adrenaline can activate all adrenoceptor subtypes so will stimulate β1-adrenoceptors to increase the rate and force of cardiac contraction, cause vasoconstriction in the viscera and skin via stimulation of a1-adrenoceptors, but vasodilatation in skeletal muscle vascular beds due to stimulation of β2- adrenoceptors. Activation of β2- adrenoceptors in the lungs results in bronchodilation.  These effects together make adrenaline useful treatment for the treatment of anaphylactic shock.  However, adrenaline must be given via injection as it is not orally active and has a short half life.

Examples of therapeutic uses of drugs acting at adrenoceptors are given in the table below.

Some therapeutic actions of drugs acting at adrenoceptors.

Action

Effect

Therapeutic use

Examples

α-adrenoceptors
α1- adrenoceptor agonists vasoconstriction nasal decongestants, ocular decongestants phenylephrine
α2-adrenoceptor antagonists decrease intraocular pressure treatment of glaucoma clonidine
α1-adrenoceptor antagonists vasodilation antihypertensives prazosin; terazosin
relaxation of bladder neck and prostate symptomatic treatment of Benign Prostatic Hyperplasia terazosin; tamsulosin (uroselective)
ß-adrenoceptors
ßadrenoceptors agonists bronchodilatation treatment of asthma salbutamol (albuterol)
ßadrenoceptors agonists relaxation of uterine smooth muscle delay pre-term labour terbutaline
ß1-adrenoceptor antagonists

decrease cardiac activity & decrease blood pressure

antihypertensives atenolol

This website provides information about alpha and beta adrenoceptors – including subtypes, location, function and transduction mechanisms.

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An overview of the receptors of the Sympathetic Nervous system is provided here and further information about the actions associated with these receptors and their potential as therapeutic targets is available here

Drugs that directly interact with adrenoceptors can act as agonists (thereby mimicking some of the actions of the sympathetic nervous system) or antagonists (blocking the effects of sympathetic activation).  The actions of these drugs will be dependent on their selectivity profile for the different adrenoceptor subtypes as well as their interaction with removal systems (e.g. uptake 1; metabolism by monoamine oxidase (MAO)/catechol-O-methyltransferase (COMT).

For example, adrenaline can activate all adrenoceptor subtypes so will stimulate β1-adrenoceptors to increase the rate and force of cardiac contraction, cause vasoconstriction in the viscera and skin via stimulation of a1-adrenoceptors, but vasodilatation in skeletal muscle vascular beds due to stimulation of β2- adrenoceptors. Activation of β2- adrenoceptors in the lungs results in bronchodilation.  These effects together make adrenaline useful treatment for the treatment of anaphylactic shock.  However, adrenaline must be given via injection as it is not orally active and has a short half life.

Examples of therapeutic uses of drugs acting at adrenoceptors are given in the table below.

Some therapeutic actions of drugs acting at adrenoceptors.

Action

Effect

Therapeutic use

Examples

α-adrenoceptors
α1- adrenoceptor agonists vasoconstriction nasal decongestants, ocular decongestants phenylephrine
α2-adrenoceptor antagonists decrease intraocular pressure treatment of glaucoma clonidine
α1-adrenoceptor antagonists vasodilation antihypertensives prazosin; terazosin
relaxation of bladder neck and prostate symptomatic treatment of Benign Prostatic Hyperplasia terazosin; tamsulosin (uroselective)
ß-adrenoceptors
ßadrenoceptors agonists bronchodilatation treatment of asthma salbutamol (albuterol)
ßadrenoceptors agonists relaxation of uterine smooth muscle delay pre-term labour terbutaline
ß1-adrenoceptor antagonists

decrease cardiac activity & decrease blood pressure

antihypertensives atenolol

This is a series of videos of mini lectures in adrenergic pharmacology.  The videos are well paced and with easy to follow slides.  Included at the end are some challenge questions. 

Average: 4.2 (6 votes)