7.5 Overview of the autonomic nervous system
It was stated at the beginning that the peripheral autonomic system has a prominent place as a site of drug action. We will now look at the organization of this system, and at the distribution of transmitter receptors within it. This will enable us to understand the effects of drugs acting upon this system and rationales behind their usage.
The autonomic nervous system consists of two functionally distinct parts that frequently exert antagonistic effects on their target organs. These are referred to as the sympathetic and the parasympathetic system, respectively. Figure 7.5-1 depicts some essential features. The parasympathetic system, for the most part, emerges from the central nervous system at the level of the medulla oblongata, which is the lowermost part of the brain1. These neurons reach some nerve centers in the periphery, which are named ganglia (singular: ganglion), where they trigger activity in secondary neurons that in turn reach out to the target organs. The sympathetic system mostly emerges at the thoracic portion of the spinal cord. It too has relay neurons in peripheral ganglia (which are connected with each other in the so-called 'sympathetic chains', located on either side of the spine). The parasympathetic and sympathetic ganglia are outside the central nervous system, and therefore readily accessible to drugs that do not cross the blood brain barrier.
- Secretory cells in various glands, both exocrine and endocrine;
- Heart conduction system and muscle cells;
- Smooth muscle cells in in the intestine, other hollow organs (bronchi, urinary tract, sexual organs, etc.) and in the blood vessels.
Figure 7.5-1 also shows the major types of neurotransmitter receptors found within the autonomic nervous system:
- The nicotinic acetylcholine receptor occurs in both the sympathetic and the parasympathetic ganglia. The receptors found in the neuromuscular synapse 2 are of the nicotinic type as well. However, the subtype is different, and therefore selective drug action is possible.
- Muscarinic acetylcholine receptors occur in the target tissues. They are mostly found in parasympathetic synapses, but they also occur in the sympathetically innervated sweat glands.
- Adrenergic receptors are always related to sympathetic activity, either within synapses (as shown here), or diffusely distributed and by responding to circulating epinephrine.
- Dopamine D1 receptors are less widespread than adrenergic receptors. One prominent occurrence is in the kidney arteries. Accordingly, dopamine and related agonists are being used in intensive care treatment of acute kidney failure to improve kidney perfusion.
Very commonly, a target tissue will be stimulated by the sympathetic system and inhibited by the parasympathetic system, or vice versa. Examples are found in table 7.5-1. Among the parasympathetic responses listed there, we find stimulation of smooth muscle in the bronchi, and relaxation of smooth muscle in the arterioles; both are mediated by muscarinic acetylcholine receptors (cf. Figure 7.5-1). Here, we have an example of diverse effector mechanisms triggered from similar receptors. Similarly, the adrenergic receptors can operate different intracellular switches as needed. These different effector mechanisms are covered in some more detail in the chapter on G protein-coupled receptors.
A 'take-home' message from table 7.5-1 is that, by and large, muscarinic receptors mediate the parasympathetic effects, whereas the sympathetic ones are mediated by adrenergic receptors.
From the effects of the autonomic nervous system on the various target organs (table 7.5-1), we can easily understand several applications of drugs that cause synaptic stimulation or inhibition:
- In patients having undergone abdominal surgery, quite frequently the activity of the intestine is sluggish. Drugs that stimulate muscarinic receptors will help to correct this.
- As we have seen, drugs that block α-adrenergic receptors (e.g., phenoxybenzamine) will help to lower the resistance in arterioles and therefore reduce blood pressure.
- Blockers of β1-adrenoceptors help to reduce the workload of the heart, but they sometimes slow down the generation or propagation of excitation too much, resulting in slow and occasionally irregular heartbeat.
- Drugs that stimulate β2-adrenoceptors will help to dilate the bronchi (by reducing the smooth muscle tone there) will be useful in asthma, which basically consists in impeded air flow due to a spastic narrowing of the bronchi.
- If the effect of β2 agonists in asthma proves insufficient, one additional therapeutic option is to add a drug that will inhibit the cholinergic (parasympathetic) stimulation of the bronchial smooth muscle, such as ipratropium bromide3.
A peculiar element within the autonomic nervous system is the medulla (inner part) of the adrenal gland . This is the site of production for epinephrine and norepinephrine that are released into the circulation. It is directly controlled by cholinergic neurons emerging from the spinal cord, so it assumes the place of a sympathetic ganglion. In fact, the cells in the adrenal medulla are of neural origin – they are nerve cells turned gland cells. In contrast, the cortex (outer part) of the adrenal gland) is a 'proper' gland tissue not of neural but mesodermal origin. The endocrine (hormonal) and the neural system are not as cleanly separated as our neat abstractions suggest. 4
Table 7.5-1 also lists the effects of sympathetic and parasympathetic stimuli on the pupil of the eye pupil (this had been omitted from Figure 7.5-1, which is incomplete in many ways). In the case of the pupil, the antagonism between sympathetic and parasympathetic system is due not to antagonistic innervation of the same target cells but of two antagonistic muscles, the dilatator and the sphincter muscles of the iris, respectively (Figure 7.5-2). While the autonomic control of the iris is not overwhelmingly important in applied pharmacotherapy5, it is a very useful diagnostic marker. E.g., in poisoning with drugs that induce or amplify cholinergic action we will see a pronounced narrowing of the pupil. This is called 'miosis' in doctors' speak; widening (observed e.g. with cocaine) is 'mydriasis'. One of the glorious things about medicine is the profusion of cryptic names for simple things.
1: The higher parts of the brain have been disregarded, which I consider to be in accord with general UW practice.
2: Within the skeletal muscle. These neurons – the α-motoneurons – are not part of the autonomic but of the somatic system.
3: Other options are concerned with the suppression of the allergic / inflammatory process that trigger the bronchial constriction in the first place.
4: Another case in point is the hypophyseal gland, which like the adrenal gland combines entodermal and neural gland cells in one organ; both cell types secrete peptide hormones into the circulation.
5: Drugs that widen the pupil (e.g., atropine) are, however, used by ophthalmologists in diagnostic procedures. An additional effect of atropine is to relax the ciliary muscle, which modifies the shape of the lens to switch focus between far and near. Relaxation of the ciliary muscle, then, facilitates 'objective' measurement of the eyes' refractive properties, undisturbed by the patients' attempts to adjust the focus.