The Parasympathetic Nervous System

The Parasympathetic Nervous System

The parasympathetic nervous system (PNS or cholinergic system):

Acetylcholine is the major transmitter of the parasympathetic nervous system, but is also the transmitter at the ganglia of both the sympathetic and sympathetic nervous systems and the somatic nervous system.  Cholinergic nerves are also present within the CNS.  For this reason, drugs that modulate cholinergic neurotransmission can potentially produce a range of effects. Fewer responses are achieved by using drugs which act more selectively at muscarinic or nicotinic receptors. 

The steps involved in cholinergic neurotransmission are outlined below and further information is provided here.

There are two subtypes of acetylcholine receptors in the autonomic nervous system.  They are outlined here.  Nicotinic receptors are present at the ganglia of both the sympathetic and parasympathetic arms of the ANS as well as on the adrenal medulla.  Muscarinic receptors are activated by ACh released by the postganglionic parasympathetic nerves and thus mediate the actions of the parasympathetic nervous system.  In addition, muscarinic receptors mediate the actions of the sympathetic cholinergic nerves (e.g. sweating).

Drugs affecting cholinergic neurotransmission

Drugs affecting synthesis, storage or release of acetylcholine

Synthesis of acetylcholine is dependent on uptake of its immediate precursor, choline which is then metabolized to acetylcholine via a single step catalyzed by choline acetyltransferase (CAT).  Hemicholinium competes with choline for the choline transporter, resulting in inhibition of acetylcholine synthesis. Once synthesized, acetylcholine is taken up via a specific active transport mechanism and stored within synaptic vesicles.  This transport is inhibited by vesamicol.  Both hemicholinium and vesamicol lead to depletion of acetylcholine levels within the nerve terminal, and while not useful as therapeutics, have been used as experimental tools to study the physiological roles of cholinergic nerves. 

Exocytotic release of acetylcholine is triggered by an action potential arriving at the nerve terminal leading to an influx of Ca2+.  This release is inhibited by the neurotoxins, botulinum toxin and β-bungarotoxin.  Botulinum toxin acts to inhibit the docking of the synaptic vesicle with the membrane of nerve terminal and therefore interferes with the release of acetylcholine from all cholinergic nerves.  Some selectivity can be achieved by administering via local injection to the required site of action.  Botulinum toxin (Botox) injections cause localized effects, including muscle paralysis to reduce wrinkles and decreased sweating in conditions such as hyperhidrosis.  

Drugs affecting the termination of action of acetylcholine

The action of acetylcholine is terminated rapidly due to its metabolism by acetylcholinesterase (AChE) enzymes present within cholinergic neuroeffector and synaptic junctions.  AChE is also present in cholinergic nerve terminals and a related enzyme, butyrylcholinesterase (BuChE, or pseudocholinesterase) is found within the plasma. While AChE is quite specific for acetylcholine, BuChE has broader substrate specificity and is involved in the metabolism of some therapeutics, including suxamethonium.  Genetic variants of BuChE, associated with decreased enzymic activity, are associated with clinically relevant increases in the duration of activity of these drugs.

Inhibition of cholinesterase enzymes accounts for the effects organophosphate nerve gases (e.g. sarin) and insecticides (e.g. malathion).  The symptoms of organophosphate poisoning include over activity of the parasympathetic nervous system (“DUMBBELS”*); stimulation followed by inhibition of nicotinic receptors at autonomic ganglia and on the skeletal muscle; and stimulation of cholinergic receptors in the CNS.

*DUMBBELLS: Diarrhoea, Urination, Miosis, Bradycardia,Bronchoconstriction, Emesis, Lacrimation, Salivation

Cholinesterase inhibitors (or anticholinesterases) used therapeutically are classified according to their duration of action and may be long acting and irreversible (e.g. ecothiopate), medium-duration (e.g. physostigmine) or short-acting (e.g. edrophonium). Therapeutic uses of anticholinesterases include:

  • the diagnosis (e.g. edrophonium) and treatment (e.g. neostigmine; physostigmine; pyridostigmine) of myasthenia gravis, an autoimmune disease associated with a reduced number of functional skeletal muscle nicotinic receptors
  • slowing the progression of Alzheimer’s disease, a neurodegenerative condition associated with a loss of cholinergic neurons in the CNS (e.g. donepezil, rivastigmine)
  • the treatment of glaucoma (e.g. ecothiopate, physostigmine )

A good review of the actions of anticholinesterases; their mechanisms of action, effects and therapeutic uses.  It also includes information about specific anticholinesterases in use.

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Drugs affecting acetylcholine receptors

Drugs acting at ganglion nicotinic receptors

As the same receptors are present at the ganglia of both the sympathetic and parasympathetic arms of the ANS, they cannot be differentiated pharmacologically.  Being ionotropic receptors, overstimulation can lead to depolarization blockade.  Thus, there is the potential for both agonists and antagonists to inhibit ganglionic neurotransmission.  Although ganglion blocking drugs have been used in the past in the treatment of hypertension, they are now considered clinically obsolete.

Drugs acting at muscarinic receptors

While subtypes of muscarinic receptors have been identified, the homogeneity of the orthosteric binding site at all subtypes means that there are few drugs which show selectivity for one subtype over others.

Muscarinic receptor agonists

 Agonists of muscarinic receptors mimic the actions of the parasympathetic nervous system.  These include:

  • a decrease in heart rate and in atrial contraction
  • indirect vasodilatation due to stimulation of NO from vascular endothelial cells
  • contraction of smooth muscle of the gastrointestinal tract along with relaxation of the sphincters
  • stimulation of exocrine glands leading to gastric acid secretion, salivation, lacrimation and sweating
  • contraction of the detrusor muscle and relaxation of the bladder sphincters, leading to urination
  • constriction of the pupil and the ciliary muscle of the eye, leading to miosis and decreased intraocular pressure

The effects of muscarinic agonists will depend on their duration of action (which can be determined by their susceptibility to breakdown by cholinesterases), their selectivity for muscarinic receptors over nicotinic receptors and their selectivity for the various muscarinic receptor subtypes.   For example, ACh is of no use as a therapeutic, due to its rapid breakdown and ability to stimulate all cholinoreceptor subtypes.  In contrast, bethanechol shows limited selectivity for M3 receptors and is not susceptible to hydrolysis by cholinesterase.  It is used to in some situations to stimulate gastrointestinal motility or bladder emptying.   Muscarinic agonists are also used in opthamology to cause pupil constriction and/or decrease intraocular pressure. 

Muscarinic receptor antagonists

Muscarinic receptor antagonists oppose the actions of the parasympathetic nervous system.  Examples of antagonists include atropine and hyoscine (scopolamine) which are found in the plants Atropa belladonna and Datura stramonium.  Ingestion of these antagonists can cause a range of peripheral (flushing, dry mouth, blurred vision, dilated pupils, tachycardia, urinary retention, constipation and hyperthermia) and central (confusion, hallucinations agitation, coma and convulsions) effects.  Synthetic and semi-synthetic antagonists have been developed and these differ in their pharmacokinetics (duration of action and distribution) and selectivity for the muscarinic receptor subtypes.  Therapeutic uses of muscarinic antagonists include:

  • to cause pupil dilation to facilitate eye examinations (e.g. atropine; tropicamide)
  • to cause relaxation of bronchial smooth muscle in COPD (e.g. ipratropium)
  • to decrease gastric motility (e.g. hyoscine)
  • to decrease bladder emptying (e.g. oxybutynin)

The involvement of muscarinic receptors in vomiting and emesis provides the rationale for the use of muscarinic antagonists to prevent motion sickness.

A set of slides that covers some basic background to the muscarinic receptors and the actions of muscarinic agonists and antagonists, for those beginning pharmacology.

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