Overview
Drugs affecting the autonomic nervous system (ANS) are categorized based on the type of neuron they target. Cholinergic drugs, discussed in this and the following chapter, act on receptors activated by acetylcholine (Ach), while adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine. These drugs can either stimulate or block ANS receptors.
The Cholinergic Neuron
Preganglionic fibers terminating in the adrenal medulla, autonomic ganglia (both parasympathetic and sympathetic), and postganglionic fibers of the parasympathetic division use Ach as a neurotransmitter . Additionally, cholinergic neurons innervate sweat glands in the sympathetic division, somatic muscles, and play crucial roles in the central nervous system (CNS).
Neurotransmission at Cholinergic Neurons
Neurotransmission in cholinergic neurons involves six sequential steps:
1. Synthesis of Ach: Choline is transported from extracellular fluid into the cholinergic neuron’s cytoplasm by an energy-dependent carrier system that co-transports sodium. This uptake can be inhibited by hemicholinium. The rate-limiting step in Ach synthesis is the uptake of choline, which reacts with acetyl coenzyme A (AcCoA) under the catalysis of choline acetyltransferase.
2. Storage of Ach: Ach is packaged and stored in presynaptic vesicles by active transport. These vesicles also contain ATP and proteoglycan, which can modulate the effect of Ach.
3. Release of Ach: An action potential opens voltage-sensitive calcium channels on the presynaptic membrane, increasing intracellular calcium levels and causing synaptic vesicles to fuse with the cell membrane, releasing Ach into the synaptic space. This release can be blocked by botulinum toxin or induced by black widow spider venom.
4. Binding to the Receptor: Ach diffuses across the synaptic space and binds to postsynaptic receptors on the target cell, presynaptic receptors on the releasing neuron, or other presynaptic receptors. Postsynaptic receptors on effector organs are divided into muscarinic and nicotinic classes.
5. Degradation of Ach: Ach is rapidly broken down in the synaptic cleft by acetylcholinesterase (AChE) into choline and acetate, terminating the signal.
6. Recycling of Choline: Choline is taken back up by the neuron to be reused in Ach synthesis.
Muscarinic Receptors
Muscarinic receptors are G-protein-coupled receptors that recognize Ach and muscarine but have weak affinity for nicotine. There are five subclasses, but only M1, M2, and M3 are well characterized.
- Location: These receptors are found on autonomic effector organs like the heart, smooth muscle, brain, and exocrine glands. M1 receptors are found on gastric parietal cells, M2 on cardiac cells and smooth muscle, and M3 on the bladder, exocrine glands, and smooth muscle. Drugs targeting these receptors can preferentially affect these tissues but may also impact nicotinic receptors at high concentrations.
- Mechanism of Signal Transduction: Different mechanisms transmit the signal generated by Ach binding. Activation of M1 or M3 receptors changes the receptor’s shape, allowing it to interact with a G-protein that activates phospholipase C, leading to the production of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 increases intracellular calcium, influencing enzyme activity, secretion, or contraction, while DAG activates protein kinase C, which phosphorylates various proteins. Activation of M2 receptors in cardiac muscle inhibits adenylyl cyclase and increases potassium conductance, reducing heart rate and contraction force.
- Muscarinic Agonists: Pilocarpine, a nonselective muscarinic agonist, is used to treat xerostomia and glaucoma. Efforts are ongoing to develop agents targeting specific muscarinic receptor subtypes.
.
Nicotinic receptors
Nicotinic receptors bind to acetylcholine (Ach) and also recognize nicotine, but they have a low affinity for muscarine. These receptors are made up of five subunits and operate as ligand-gated ion channels (ionotropic receptors). When two Ach molecules bind to the receptor, it undergoes a conformational change that allows sodium ions to enter, leading to the depolarization of the target cell. Nicotine can activate these receptors at low concentrations but inhibits them at high concentrations. Nicotinic receptors are found in the central nervous system (CNS), adrenal medulla, autonomic ganglia, and at the neuromuscular junction (NMJ) in skeletal muscles. NMJ receptors are sometimes referred to as NM, while others are known as NN. The receptors in autonomic ganglia are different from those at the NMJ. For instance, ganglionic receptors are blocked by mecamylamine, whereas NMJ receptors are specifically restricted by atracurium.
Conclusion
Drugs that affect the autonomic nervous system (ANS) are classified based on their target receptors. Cholinergic drugs act on receptors activated by acetylcholine (Ach), while adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine. Cholinergic neurons utilize Ach and are found in various parts of the ANS, such as the adrenal medulla, autonomic ganglia, and parasympathetic division, as well as in sweat glands, somatic muscles, and the central nervous system (CNS).
Neurotransmission in cholinergic neurons follows a six-step process: synthesis, storage, release, binding, degradation, and recycling of Ach. Muscarinic receptors, which are G-protein-coupled, are primarily located on autonomic effector organs and have three well-characterized subclasses (M1, M2, M3) with distinct locations and mechanisms of action. Nicotinic receptors, composed of five subunits and functioning as ligand-gated ion channels, are activated by ACh and nicotine but not by muscarine. They are found in the CNS, adrenal medulla, autonomic ganglia, and neuromuscular junctions (NMJ). These receptors exhibit different sensitivities to specific blockers depending on their location, such as mecamylamine for ganglionic receptors and atracurium for NMJ receptors.
Understanding the distinct mechanisms and locations of cholinergic receptors (muscarinic and nicotinic) allows for the development of targeted drugs that can modulate various physiological responses by either stimulating or inhibiting these receptors.
