Understanding Autonomic Pharmacology: A Short Essay (Part 1 of 2)

by: Archimedes O. Bayquen, RPh, MPH

The autonomic nervous system (ANS) has been described many years ago as a division of the peripheral nervous system. It is subdivided into Parasympathetic (Rest and Digest, Conservative and Restorative function) and the Sympathetic (fight, flight, fright, stress response). The Enteric Nervous system is also a division of the ANS consisting of Myenteric or Auerbach plexus and submucous/Meissner’s plexus. The ANS is involuntary, automatic, unconscious response. Think of whenever you breathe and whenever your heart is beating. You don’t utilize your conscious control to initiate and sustain their function as they do their job independently without your control even when you are at sleep.Most of the organs in our body are dually innervated by both branches. Only very few are not—worth mentioning are the sympathetic cholinergic sweat glands in the skin and the blood vessels. Let us very briefly take a look at how these two systems differ.

In terms of spinal roots of origin, the SANS occupies Thoracic (from 1^st to 12^th) segments of the spinal cord with paravertebral chains lying along the spinal column and some along the anterior aspect of the abdominal aorta as its location of ganglia. Its preganglionic fibers are short while its postganglionic fibers are long. This is in contrast to the PANS, which originates in Cranial nerves 3, 7, 9 and 10 as well as the sacral segments of the spinal cord. Its ganglia are located mostly in the organs innervated, more distant from the spinal cord. Its preganglionic fibers are long while its postganglionic fiber are short as it is located nearer the effector organ.

The effect brought about by stimulating the sympathetic nervous system is mostly described as fight, flight, fright, stress reaction. Think of when a dinosaur is going to eat you so you have to run for your life or when an emergency fire is taking place. Your pupils are dilated, heart rate increases, blood vessels constrict as more blood are delivered in the skeletal muscles. The bronchi dilate to deliver more oxygen to the lungs and the bladder and anal sphincter contracts to prevent micturition and defecation respectively. The GIT walls and bladder walls relax at the same time as digestion and urination is not needed in these circumstances. You also need a lot of energy to run away from predators, so your glucose level increases through lipolysis, gluconeogenesis and glycolysis. The alpha and beta receptors are associated with SANS.

On the contrary, in parasympathetic there is an overall restorative, conservative, rest and digest action. As you are fully rested, the eyes constrict leading to myosis. The heart rate is decrease and blood pressure is at its low. Heart contractility likewise diminishes as there is no need for better circulation. The bronchi constricts as oxygen is not a major requirement when someone is at peace. There is however a marked increased in peristaltic activity where the stomach, intestines and gut are fully activated for digestion to take place. This is primarily associated with Muscarinic and Nicotinic receptors.

The Parasympathomimetics/ Cholinomimetics/ Parasympathetic Agonists

Acetylcholine is the major neurotransmitter in all autonomic ganglia at the synapses between parasympathetic postganglionic neurons and their effector cells. For a discussion on the synthesis up to release of acetylcholine, please refer to the Katzung Pharmacology reference.

There are two classes of drugs in this category—the direct acting (Nicotinic or Muscarinic) and the indirect acting (Short, Intermediate, Long acting).  Direct acting drugs can be chemically classified as choline esters or alkaloids. These drugs directly interact with muscarinic (subtypes 1 thru 5) selectively or non-selectively and/or to nicotinic (Nm and Nn) either selectively or non-selectively as well. Examples of choline esters include betanechol and carbachol whereas Pilocarpine, verenicline, succinylcholine, nicotine belong to alkaloid. 

The indirect acting drugs are further classified according to their chemical structure which affects its duration of action so that edrophonium (alcohol derivative) is very short acting which can only therapeutically exert its activity within 5-10 minutes. The intermediate acting carbamates include neostigmine, physostigmine and pyridostigmine. Of importance is pyridostigmine which is a tertirary amine and can then cross the blood brain barrier thereby reversing the CNS effect of atropine when given as an antidote. The organophosphates are the longest acting which include parathion, malathion and the neurologic warfare substances sarin, tabun and soman. They are primarily used as insecticide without clinical usefulness. However, rivastigmine, galantamine, donepazil and tacrine, indirect acting cholinomimetics were once used for Alzheimer’s disease.

The Cholinoceptor Blockers/ Antagonists/ Cholinolytics/ Prasympatholytics/ Parasympathetic Blockers/ Antagonists

This family of drugs can be divided as antimuscarinic or antinicotinic. Drugs acting as antinicotinic can be further classified as either ganglionic blockers or neuromuscular blockers. Their organ effect is opposite of that of cholinomimetics so you would expect cycloplegia, mydriasis, increased heart rate, decrease salivation and decreased gland secretions.

Atropine is the classical prototypical drug in this category. Although, it has no antinicotinic activity, it is a nonselective muscarinic blocker. This is naturally derived from a pant source, Atropa belladonna which is believed to be utilized by Cleopatra to dilate her pupil thus giving her that beautiful wide eyes. Its chemical property renders this drug to be absorbed in the CNS as it is lipophilic enough to cross the blood brain barrier. Other drugs belonging to this category which has many therapeutic usefulness include scopolamine, hyoscine, pirenzepine, telenzepine, darifenacine, benztropine, dicyclomine, ipratoropium, tiotropium, trospium and the like.

As a chemical antagonist to organophosphate, pralidoxime is parenterally given as antidote to indirect acting parasympathomimetic organophosphate poisoning. This is only effective when the insecticide has not yet aged and thus administration during its early stage of intoxication is necessary to be effective. The antinicotinic ganglion blockers like hexamethonium, trimethaphan and mecamylamine block all autonomic effects and has no practical application in clinical situations except for board exam question purposes.