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cholinergic receptors


ÿþEditors: Finkel, Richard; Clark, Michelle A.; Cubeddu, Luigi X. 

Title: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition 

Copyright ©2009 Lippincott Williams & Wilkins 

> Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System > Chapter 4 - Cholinergic Agonists 

Chapter 4 

Cholinergic Agonists 

I. Overview 

Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on receptors that are activated by acetylcholine. The second group⬠ the adrenergic drugs (discussed in Chapters 6 and 7)⬠ act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the autonomic nervous system. Figure 4.1 summarizes the cholinergic agonists discussed in this chapter. 


Figure 4.1 Summary of cholinergic agonists.

II. The Cholinergic Neuron 

The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division use acetylcholine as a neurotransmitter (Figure 4.2). In addition, cholinergic neurons innervate the muscles of the somatic system and also play an important role in the central nervous system (CNS). [Note: Patients with Alzheimer's disease have a significant loss of cholinergic neurons in the temporal lobe and entorhinal cortex. Most of the drugs available to treat the disease are acetylcholinesterase inhibitors (see p. 102).] 

A. Neurotransmission at cholinergic neurons 

Neurotransmission in cholinergic neurons involves sequential six steps. The first four⬠ synthesis, storage, release, and binding of acetylcholine to a receptor⬠ are followed by the fifth step, degradation of the neurotransmitter in the synaptic gap (that is, the space between the nerve endings and adjacent receptors located on nerves or effector organs), and the sixth step, the recycling of choline (Figure 4.3). 

Synthesis of acetylcholine: Choline is transported from the extra-cellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium and that can be inhibited by the drug hemicholinium. [Note: Choline has a quaternary nitrogen and carries a permanent positive charge, and thus, cannot diffuse through the membrane.] The uptake of choline is the rate-limiting step in acetylcholine synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form acetylcholine⬠ an ester⬠ in the cytosol. Acetyl CoA is derived from the mitochondria and is produced by the Krebs cycle and fatty acid oxidation. 


Storage of acetylcholine in vesicles: The acetylcholine is packaged into presynaptic vesicles by an active transport process coupled to the efflux of protons. The mature vesicle contains not only acetylcholine but also adenosine triphosphate (ATP) and proteoglycan. [Note: ATP has been suggested to be a cotransmitter acting at prejunctional purinergic receptors to inhibit the release of acetylcholine or norepinephrine.] Cotransmission from autonomic neurons is the rule rather than the exception. This means that most synaptic vesicles will contain the primary neurotransmitter, here acetylcholine, as well as a cotransmitter that will increase or decrease the effect of the primary neurotransmitter. The neurotransmitters in vesicles will appear as bead-like structures, known as varicosities, along the nerve terminal of the presynaptic neuron. 

Release of acetylcholine: When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic space. This release can be blocked by botulinum toxin. In  


contrast, the toxin in black widow spider venom causes all the acetylcholine stored in synaptic vesicles to empty into the synaptic gap. 


Figure 4.2 Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems.

Binding to the receptor: Acetylcholine released from the synaptic vesicles diffuses across the synaptic space, and it binds to either of two postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the acetylcholine. The postsynaptic cholinergic receptors on the surface of the effector organs are divided into two classes⬠ muscarinic and nicotinic. (see Figure 4.2 and p. 46). Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells as mediated by second-messenger molecules (see p. 27 and below).

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