Neuropharmacology: Acetylcholine Functions

Autonomic Nervous System

• The autonomic nervous system is a part of the peripheral nervous system that controls involuntary functions.
• Cholinergic and adrenergic drugs act by either stimulating or blocking receptors in the autonomic nervous system.
• Cholinergic drugs act on receptors activated by acetylcholine.

Cholinergic Agonists and the Parasympathetic System

• Cholinergic drugs, discussed in this chapter, act on receptors activated by acetylcholine.
• Cholinergic and adrenergic drugs influence the autonomic nervous system by stimulating or blocking receptors.
• Cholinomimetic drugs (cholinergic) have subgroups like direct-acting (muscarinic, nicotinic, alkaloids, and choline esters) and indirect-acting (organophosphates, carbamates, and edrophonium).

Parasympathetic System—The Cholinergic Neuron

• Preganglionic fibers terminating in the adrenal medulla, autonomic ganglia (parasympathetic and sympathetic), and postganglionic fibers of the parasympathetic division release acetylcholine as a neurotransmitter.
• Cholinergic neurons innervate somatic muscles and play a crucial role in the central nervous system (CNS).
• Alzheimer's disease involves significant loss of cholinergic neurons in the temporal lobe and entorhinal cortex; treatments often use acetylcholinesterase inhibitors.

Neurotransmission at Cholinergic Neurons

• Neurotransmission in cholinergic neurons involves six steps: synthesis, storage, release, binding to the receptor, degradation, and recycling of choline.
• Acetylcholine synthesis involves transporting choline from the extracellular fluid into the cholinergic neuron's cytoplasm using an energy-dependent carrier system.
• Acetylcholine is packaged into presynaptic vesicles by active transport coupled to the efflux of protons; mature vesicles contain ATP.

Release of Acetylcholine

• An action potential, propagated by voltage-sensitive sodium channels, causes voltage-sensitive calcium channels to open on the presynaptic membrane.
• Elevated intracellular calcium levels promote the fusion of synaptic vesicles with the cell membrane, releasing their contents into the synaptic space.
• Botulinum toxin blocks this release, while black widow spider venom causes all acetylcholine in synaptic vesicles to empty into the synaptic gap.

Binding to the Receptor

• Acetylcholine released diffuses across the synaptic space, binding to postsynaptic muscarinic or nicotinic receptors on the target cell or presynaptic receptors of the releasing neuron.
• Postsynaptic cholinergic receptors on effector organs are of two types: muscarinic and nicotinic.

Degradation of Acetylcholine

• The signal at the post-junctional effector site is rapidly terminated by acetylcholinesterase, which cleaves acetylcholine into choline and acetate in the synaptic cleft.

Recycling of Choline

• Choline is recaptured by a sodium-coupled, high-affinity uptake system, transported back into the neuron, and acetylated into acetylcholine, stored until a subsequent action potential.
• Butyrylcholinesterase (sometimes called pseudocholinesterase) is found in the plasma but plays a minor role in terminating acetylcholine's effect.

Cholinergic Receptors (Cholinoceptors)

• Cholinergic receptors are categorized as muscarinic and nicotinic, differing in their responses to various agents.

Muscarinic Receptors

• Muscarinic receptors bind acetylcholine and recognize muscarine (found in certain poisonous mushrooms).
• Muscarinic receptors have five subclasses(M1, M2, M3, M4, and M5); only certain receptors (M1, M2, and M3) are functionally characterized.
• Muscarinic receptors are found on ganglia of the autonomic nervous system, the heart, smooth muscle, brain regions and exocrine glands.
• M1 receptors are found in gastric parietal cells; M2 receptors in cardiac cells and smooth muscle; M3 receptors in the bladder, exocrine glands, and smooth muscle.

Mechanisms of Acetylcholine Signal Transduction

• Activated M1 and M3 receptors interact with Gq protein, leading to phosphatidylinositol-4,5-bisphosphate hydrolysis. Hydrolysis forms diacylglycerol (DAG) and inositol that increase intracellular Ca2+.
• Increased intracellular Ca2+ modulates enzymes, causing hyperpolarization, secretion, or contraction.
• Conversely, activation of M2 receptors (Gi protein) stimulates an effect on the heart that results in decreased rate and force of contraction.

Muscarinic Agonists and Antagonists

• Pirenzepine, a tricyclic anticholinergic drug, shows high selectivity for M1 receptors and is used to treat gastric mucosa, but it can induce reflex tachycardia in the heart.
• The effectiveness of pirenzepine as an alternative to proton pump inhibitors for gastric ulcers is questionable.
• Darifenacin is a competitive muscarinic receptor antagonist; it has a high affinity for the M3 receptor and is used to treat overactive bladder.

Indirect-Acting Cholinergic Agonists (Anticholinesterases)

• Anticholinesterase inhibitors indirectly increase acetylcholine in the synaptic space.
• Physostigmine, naturally found in plants, is a tertiary amine with intermediate duration of action and acts as a substrate for acetylcholinesterase, causing a carbamoylated intermediate that inhibits acetylcholinesterase. It can be used to reverse the effects of anticholinergic drugs (e.g., atropine)
• Neostigmine is a synthetic carbamic acid analog of physostigmine, a quaternary amine. This makes it not enter CNS; its duration of action is 30 minutes to 2 hours.
• Pyridostigmine and ambenomium are cholinesterase inhibitors used in the chronic management of myasthenia gravis.

Echothiophate

• Echothiophate is an organophosphate, inhibiting acetylcholinesterase by a covalent bond.
• It can be used to treat glaucoma.

Pralidoxime

• Pralidoxime is used to reactivate acetylcholinesterase.

Acetylcholine

• Acetylcholine is a quaternary ammonium compound and cannot penetrate membranes. It is a neurotransmitter in the parasympathetic and somatic nerves and autonomic ganglia, but due to its multiple actions and rapid inactivation is not therapeutically important.
• Its actions include decreasing heart rate and cardiac output (negative chronotropy).

Decrease in Blood Pressure

• Acetylcholine causes vasodilation and lowers BP by activating M3 receptors on endothelial cells. This leads to nitric oxide production (EDRF) from arginine. This nitric oxide then relaxes vascular smooth muscle, which leads to vasodilation.
• Atropine blocks these receptors and avoids this vasodilation.

Other Actions

• Acetylcholine in the gastrointestinal tract stimulates intestinal secretions and motility, increases salivary secretions, and increases the tone of detrusor urina muscle.
• It's involved in ciliary muscle contraction for near vision and pupillary constriction (miosis).
• Bethanechol structurally resembles acetylcholine, not hydrolyzed by acetylcholinesterase, is a cholinergic agonist with effects on the GI tract and bladder.

Carbachol

• Carbachol has both muscarinic and nicotinic actions.
• It's an ester of carbamic acid, a weak substrate for acetylcholinesterase, and biotransformed by other esterases more slowly.

Cholinergic Agonists: Therapeutic Uses

• Carbachol: Used in eyes as a miotic (reduces intraocular pressure).
• Bethanechol: Used to increase intestinal motility and bladder tone; for atonic bladder and Mega colon.
• Pilocarpine: Used ophthalmologically; most potent secretagogue (stimulates sweat, tears, and saliva) and one of the most potent stimulators of secretions.

Cholinergic Agonist Summary

• Pilocarpine, bethanechol, and carbachol are direct-acting cholinergic agonists.
• Physostigmine, neostigmine, and pyridostigmine are indirect-acting cholinergic agonists (anticholinesterases).
• Many other cholinergic agonists have different durations of action and uses.

Cholinergic Antagonists

• Antagonists block cholinoceptors, inhibiting receptor-mediated intracellular effects.
• Ganglionic blockers show preference for nicotinic receptors in autonomic ganglia.
• Neuromuscular blocking agents are used as adjuvants in surgery, often block selectively and reversibly the transmission of efferent impulses to skeletal muscle, allowing relaxation.

Antimuscarinic Agents

• Common examples include atropine, scopolamine, and others. They block muscarinic receptors in various parts of the body, reducing functions like salivation, sweating, and gastrointestinal motility.
• They are beneficial for many conditions but have some limitations.

Atropine

• Atropine blocks cholinergic activity, producing mydriasis, cycloplegia, and preventing near vision.
• It reduces gastric motility, but HCl production is unaffected; not used to treat ulcers.
• It's also utilized topically in eyes for ophthalmic examinations to dilate pupils.

Scopolamine

• Scopolamine has similar effects to atropine but also affects the central nervous system.
• It is crucial in motion sickness prevention and also for sedation.

Ipratropium

• Ipratropium is a quaternary ammonium compound, useful for asthma and COPD management (used in preventing wheezing and reduced breathing).

Tropicamide and Cyclopentolate

• Tropicamide and cyclopentolate are used ophthalmologically to produce mydriasis and cycloplegia, but both have a shorter duration of action. There are better options than atropine in certain applications.

Ganglionic Blockers

• Ganglionic blockers act on nicotinic receptors in sympathetic and parasympathetic ganglia.
• Clinical use of ganglionic blockers is limited due to complex side effects.
• The effects aren't predictable or selective.

Nicotine

• Nicotine, found in cigarette smoke, is not therapeutically beneficial and is harmful.
• At low doses, it stimulates autonomic ganglia and, at high doses, causes paralysis.
• It affects both sympathetic and parasympathetic ganglia, increasing blood pressure, heart rate, and motility.

Mecamylamine

• Mecamylamine is a potent oral antihypertensive agent.
• This drug blocks nicotinic receptors at the ganglia to reduce sympathetic stimulation which decreases blood pressure.
• It is also used for situations that involve emergency and high-blood pressure.

Neuromuscular Blocking Agents

• These agents block cholinergic transmission between motor nerve endings and nicotinic receptors on the neuromuscular end plates.
• They are structural analogs of acetylcholine, acting as competitive antagonists (nondepolarizing type) or agonists (depolarizing type).
• They are helpful in surgery for producing muscle relaxation without using higher anesthetic doses.

Non-depolarizing Blockers

• Curare was the first drug to be proven capable of blocking the skeletal neuromuscular junction and later Tubocurarine was purified in the early 1940s.
• Low doses of non-depolarizing blockers prevent acetylcholine binding, inhibiting depolarization, and muscular contraction.
• High doses block ion channels at the end plate, further reducing nerve transmission.
• Agents such as vecuronium and rocuronium are preferred due to their faster on/off time compared to tubocurarine or atracurium.

Mechanism of Action of Non-depolarizing Blockers

• Primarily, nondepolarizing neuromuscular blocking drugs interact with nicotinic receptors to prevent acetylcholine binding.
• This will prevent depolarization and inhibits muscle contractions.
• The effects can be reversed by increasing the amount of acetylcholine in the synaptic gap such as administering anticholinesterase inhibitors.

Mechanism of Action of Depolarizing Agents

• Succinylcholine is a depolarizing agent that attaches to the nicotinic receptor, mimicking acetylcholine to depolarize the junction initially.
• Repeated depolarization eventually leads to resistance and a flaccid paralysis.
• The actions of succinylcholine are halted because the drug is rapidly broken down via cholinesterase.

Therapeutic Uses of Neuromuscular Blocking Agents

• These agents are helpful in surgery for muscle relaxation during anesthesia, and facilitating intubation.
• They are also useful in electroconvulsive shock treatment.

Adverse Effects of Neuromuscular Blocking Agents

• Hyperthermia: Halothane with succinylcholine increase the risk of malignant hyperthermia in genetically susceptible individuals. Treatment involves rapidly cooling and administering dantrolene to reduce heat production in muscle cells.
• Apnea: Succinylcholine can cause prolonged apnea in patients with genetic deficiency in plasma cholinesterase.

General Summary Notes

• Cholinergic agonists can stimulate or mimic the action of acetylcholine at cholinergic receptors.
• Cholinergic antagonists block or inhibit the action of acetylcholine at these receptors, and this can affect all systems affected by acetylcholine.

Test your knowledge on the functions and mechanisms of acetylcholine in the nervous system. This quiz covers topics such as presynaptic vesicles, cholinergic receptors, and the effects of drugs like botulinum toxin. Challenge yourself with questions about its role in various physiological processes.