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Chapter: Biochemical Pharmacology : Drugs that act on sodium and potassium channels

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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.

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 function-ally distinct parts that frequently exert antagonistic effects on their target organs. These are referred to as the sympa-thetic and the parasympathetic system, respectively. Figure 7.6 depicts some essential features. The parasympathet-ic system, for the most part, emerges from the central ner-vous system at the level of the medulla oblongata, which is the lowermost part of the brain. These neurons reach some nerve centers in the periphery, which are named gan-glia (singular: ganglion), where they trigger activity in sec-ondary 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 pe-ripheral 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 readi-ly accessible to drugs that do not cross the blood brain bar-rier.

 

The target tissues that are controlled by the secondary neurons (the ones originating in the ganglia) include:

 

     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 7.6 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 re-ceptors found in the neuromuscular synapse 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 tar-get tissues. They are mostly found in parasympathetic synapses, but they also occur in the sympathetically in-nervated sweat glands.

 

     Adrenergic receptors are always related to sympathet-ic activity, either within synapses (as shown here), or diffusely distributed and by responding to circulat-ing epinephrine.

 

     Dopamine D1 receptors are less widespread than adren-ergic receptors. One prominent occurrence is in the kid-ney arteries. Accordingly, dopamine and related ago-nists 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 parasympathet-ic system, or vice versa. Examples are found in table 7.1. Among the parasympathetic responses listed there, we find stimulation of smooth muscle in the bronchi, and relax-ation of smooth muscle in the arterioles; both are mediat-ed by muscarinic acetylcholine receptors (cf. Figure 7.6). Here, we have an example of diverse effector mechanisms triggered from similar receptors. Similarly, the adrener-gic 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 re-ceptors. nicotinic type as well. However, the subtype is different, and therefore selective drug action is possible.

 

     Muscarinic acetylcholine receptors occur in the tar-get tissues. They are mostly found in parasympathetic synapses, but they also occur in the sympathetically in-nervated sweat glands.

 

     Adrenergic receptors are always related to sympathet-ic activity, either within synapses (as shown here), or diffusely distributed and by responding to circulat-ing epinephrine.

 

     Dopamine D1 receptors are less widespread than adren-ergic receptors. One prominent occurrence is in the kid-ney arteries. Accordingly, dopamine and related ago-nists 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 parasympathet-ic system, or vice versa. Examples are found in table 7.1. Among the parasympathetic responses listed there, we find stimulation of smooth muscle in the bronchi, and relax-ation of smooth muscle in the arterioles; both are mediat-ed by muscarinic acetylcholine receptors (cf. Figure 7.6). Here, we have an example of diverse effector mechanisms triggered from similar receptors. Similarly, the adrener-gic 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 re-ceptors.


A `take-home' message from table 7.1 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 7.1), we can easily understand several applications of drugs that cause synaptic stimula-tion 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 cor-rect this.

 

     As we have seen, drugs that block α-adrenergic re-ceptors (e.g., phenoxybenzamine) will help to lower the resistance in arterioles and therefore reduce blood pressure.

 

     Blockers of β1-adrenoceptors help to reduce the work-load of the heart, but they sometimes slow down the generation or propagation of excitation too much, re-sulting in slow and occasionally irregular heartbeat.

 

Drugs that stimulate β2-adrenoceptors will help to di-late the bronchi (by reducing the smooth muscle tone there) will be useful in asthma, which basically con-sists 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 ipratropi-um bromide10.

 

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.11

 

Table 7.1 also lists the effects of sympathetic and parasym-pathetic stimuli on the pupil of the eye pupil (this had been omitted from Figure 7.6, which is incomplete in many ways). In the case of the pupil, the antagonism between sympathetic and parasympathetic system is due not to an-tagonistic innervation of the same target cells but of two antagonistic muscles, the dilatator and the sphincter mus-cles of the iris, respectively (Figure 7.7). While the auto-nomic control of the iris is not overwhelmingly important in applied pharmacotherapy, 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.

 



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