Physiology of the Parasympathetic Nervous System and the Pharmacology of Cholinomimetics and Anticholinergics

What is a neurotransmitter?

A chemical messenger that transmits signals across a synapse from one neuron to another.

What is the first characteristic of a neurotransmitter?

Neurotransmitter is endogenously synthesized in nerve terminals (e.g., Ach is synthesized from AcCoA and Choline).

Where are neurotransmitters stored?

Neurotransmitters are stored in vesicles in nerve endings.

What triggers neurotransmitter release?

An action potential (membrane depolarization) of the nerve ending results in opening VDCC and influx of Ca²⁺.

How do neurotransmitters get released from vesicles?

Vesicle fusion with the plasma membrane is facilitated by interactions between VAMPs and SNAPs.

What happens after neurotransmitter release?

Ach is released into the synapse and activates post-synaptic receptors.

How is neurotransmitter signaling terminated?

By degradation (e.g., Ach is degraded by acetylcholinesterase) or by reuptake into the releasing neuron.

What is EPSP?

Excitatory Post-Synaptic Potential, caused by depolarization of the post-synaptic neuronal membrane via Na⁺ or Ca²⁺ influx.

What is IPSP?

Inhibitory Post-Synaptic Potential, caused by hyperpolarization of the post-synaptic neuronal membrane via Cl⁻ influx or K⁺ efflux.

What are the two types of cholinergic receptors?

Muscarinic and nicotinic receptors.

What is the function of nicotinic cholinergic receptors?

They are ion channels allowing Na⁺ influx and K⁺ efflux, causing depolarization.

What is the function of muscarinic cholinergic receptors?

They activate G-proteins and second messenger systems for varied cellular responses.

Where are nicotinic receptors found in the autonomic system?

Adrenal medulla and postganglionic neurons.

Where are muscarinic receptors found in the parasympathetic system?

On effector organs such as glands and smooth muscle.

What is the role of Ach in skeletal muscle?

It binds to nicotinic receptors to facilitate muscle contraction.

What is a direct-acting cholinomimetic drug?

A drug that mimics the action of acetylcholine by directly stimulating cholinergic receptors.

What is the susceptibility of acetylcholine to cholinesterases?

Highly susceptible (+++).

What is the muscarinic activity of acetylcholine?

High activity in cardiovascular, G.I., urinary bladder, and eye (topical) effects (++).

What is the nicotinic activity of acetylcholine?

Moderate activity (++).

What is the susceptibility of methacholine to cholinesterases?

Low susceptibility (+).

What is the muscarinic activity of methacholine?

High activity (+++ in cardiovascular and urinary bladder).

What is the nicotinic activity of methacholine?

Low activity (+).

What is the susceptibility of carbachol to cholinesterases?

Resistant (-).

What is the muscarinic activity of carbachol?

High activity (+++ in G.I. and urinary bladder).

What is the nicotinic activity of carbachol?

High activity (+++).

What is the susceptibility of bethanechol to cholinesterases?

Resistant (-).

What is the muscarinic activity of bethanechol?

Moderate activity in G.I. and urinary bladder (+++).

What is the nicotinic activity of bethanechol?

Minimal activity (-).

What is the susceptibility of pilocarpine to cholinesterases?

Resistant (-).

What is the muscarinic activity of pilocarpine?

High activity (+++ in G.I. and urinary bladder).

What is the nicotinic activity of pilocarpine?

None (-).

What is xerostomia?

Dry mouth caused by Sjogren syndrome, radiation therapy, or other conditions.

Which drugs are used to treat xerostomia?

Pilocarpine and cevimeline.

What is postoperative ileus?

A condition involving impaired G.I. motility after surgery.

What are pharmacological interventions for postoperative ileus?

Cholinergic drugs like bethanechol, beta blockers like propranolol, and opioid receptor antagonists.

What is the MOA of indirect-acting cholinergic agonists?

Reversible inhibitors of acetylcholinesterase at the NMJ, autonomic ganglia, and cholinergic receptors at the end organ.

What happens when acetylcholinesterase is inhibited?

It prevents the breakdown of acetylcholine, increasing its concentration and prolonging its action.

What is Myasthenia Gravis?

An autoimmune disease affecting skeletal muscle neuromuscular junctions due to antibody formation against acetylcholine receptors (AchR).

What is the effect of indirect-acting cholinergic drugs in Myasthenia Gravis?

They prolong and intensify the action of physiologically-released acetylcholine at the NMJ.

What is the most commonly used drug for Myasthenia Gravis?

Pyridostigmine.

What causes the pathophysiology of Myasthenia Gravis?

Antibody formation against AchR on muscle end plates, leading to complement-mediated AchR destruction or functional blockade.

What are Neuromuscular Blockers (NMBs)?

Drugs that block neuromuscular transmission, used as paralyzing agents.

What are depolarizing blockers?

Drugs like succinylcholine (SC) that bind to Nm receptors, causing channel opening, brief contraction, and desensitization block due to lack of hydrolysis by acetylcholinesterase.

What are non-depolarizing blockers?

Receptor antagonists that prevent acetylcholine from binding to Nm receptors, such as atracurium, vecuronium, and rocuronium.

What is the pharmacological use of indirect-acting cholinomimetics in NMB reversal?

To reverse the effects of non-depolarizing NMBs by increasing acetylcholine levels to compete with blockers at the receptor.

How does succinylcholine cause desensitization block?

It remains bound to Nm receptors, preventing further action potentials and leading to muscle relaxation.

What is the difference between depolarizing and non-depolarizing NMBs?

Depolarizing NMBs activate receptors briefly before blocking, while non-depolarizing NMBs block receptors without activation.

What is anticholinergic toxidrome?

A condition caused by substances that block acetylcholine at muscarinic receptors, leading to symptoms such as dry skin, hallucinations, and urinary retention.

What are examples of substances causing anticholinergic toxidrome?

Diphenhydramine, tricyclic antidepressants, atropine, and Jimson weed.

What are the key symptoms of anticholinergic toxicity?

"Hot as a hare" (anhidrotic hyperthermia), "Mad as a hatter" (delirium, hallucinations), "Dry as a bone" (anhidrosis), "Red as a beet" (cutaneous vasodilation), "Full as a flask" (urinary retention), and absent bowel sounds.

What is the antidote for anticholinergic toxicity?

Physostigmine.

What is the typical effect of anticholinergics on vital signs?

Increase in temperature, heart rate, and pupil size; decreased bowel sounds and reflexes; dry skin.

What is organophosphate toxidrome?

A condition caused by organophosphates leading to muscarinic and nicotinic receptor overstimulation due to irreversible acetylcholinesterase inhibition.

What are the symptoms of muscarinic excess in organophosphate poisoning?

Chest tightness, lacrimation, bronchorrhea, abdominal cramps, diarrhea, nausea, vomiting, and miosis.

What are the symptoms of nicotinic excess in organophosphate poisoning?

Sporadic twitching, muscle fasciculations, and progressing to generalized weakness.

What is the mechanism of toxicity in organophosphate poisoning?

Irreversible inhibition of acetylcholinesterase, leading to accumulation of acetylcholine.

What is the antidote for organophosphate poisoning?

Pralidoxime (2-PAM) to regenerate acetylcholinesterase and atropine to block muscarinic effects.

What is organophosphate aging?

A chemical stabilization of the phosphate bond to acetylcholinesterase over time, preventing enzyme regeneration.

How does pralidoxime (2-PAM) work?

It binds to organophosphates and regenerates acetylcholinesterase if administered before aging occurs.

What are common organophosphate compounds?

Echothiophate, sarin, parathion, malathion, and paraoxon.

What is DuoDote®?

A combination of atropine and pralidoxime indicated for organophosphate and nerve gas poisoning.

What are the therapeutic uses of cholinergic antagonists?

Parkinson's disease, urinary incontinence, spastic GI disorders, motion sickness, COPD, decreasing secretions, and smoking cessation.

Which drugs are muscarinic blockers used for Parkinson's disease?

Trihexyphenidyl and benztropine.

What are the therapeutic uses of darifenacin, solifenacin, and oxybutynin?

Treatment of overactive urinary bladder.

What are the uses of atropine in clinical practice?

Treatment of spastic GI disorders, organophosphate poisoning, suppression of respiratory secretions prior to surgery, and bradycardia.

Which cholinergic antagonist is used to prevent motion sickness?

Scopolamine.

What are the general side effects of anticholinergic drugs?

Dry mouth, blurred vision, mydriasis, constipation, tachycardia, CNS effects like agitation or confusion, and increased dementia risk in the elderly.

Why should anticholinergics be used cautiously in patients with coronary artery disease?

Because they may cause tachycardia, increasing cardiac stress.

What is the main use of aclidinium and tiotropium?

Treatment of COPD.

Why might anticholinergic drugs increase the risk of dementia?

Some drugs cross the blood-brain barrier, causing CNS effects such as confusion, hallucination, or memory impairment.