How do cholinergics (cholinergic agents) work?

Mechanism of Action of Cholinergic Agents

Cholinergic agents work by mimicking or enhancing the effects of acetylcholine (ACh) at cholinergic receptors—either by directly activating nicotinic and muscarinic receptors or by inhibiting acetylcholinesterase to increase ACh availability at synapses. 1

Acetylcholine Synthesis and Release

• Acetylcholine is synthesized by choline acetyltransferase (ChAT) from acetylcoenzyme A and choline, occurring in both neuronal (pre-ganglionic autonomic fibers and post-ganglionic parasympathetic fibers) and non-neuronal cells. 2

• This synthesis occurs not only in the nervous system but also in non-neuronal tissues, establishing ACh as both a neurotransmitter and a "cytotransmitter" with widespread physiological roles. 2

Receptor-Mediated Mechanisms

Cholinergic drugs exert their effects through two major receptor families:

Muscarinic Receptor Activation

• Muscarinic receptor agonists bind to G protein-coupled muscarinic ACh receptors (mAChRs), triggering intracellular signaling cascades that modulate neuronal excitability, glandular secretion, and smooth muscle contraction. 3

• In the airways, parasympathetic activity through released acetylcholine at motor nerve endings is responsible for both resting bronchomotor tone and bronchoconstrictive responses. 4

• Muscarinic stimulation causes increased glandular secretion and vasodilation, particularly sinusoidal engorgement contributing to nasal congestion. 4

• In the bladder, muscarinic receptor stimulation results in detrusor smooth muscle contraction, facilitating bladder emptying. 4

Nicotinic Receptor Activation

• Nicotinic ACh receptors (nAChRs) are cys-loop ligand-gated ion channels that, when activated by ACh or nicotinic agonists, allow rapid influx of cations (primarily sodium and calcium), causing neuronal depolarization. 3

• Alpha7-like nAChRs produce rapidly desensitizing currents (blocked by methyllycaconitine), while alpha4beta2-like nAChRs produce slowly decaying currents (blocked by dihydro-beta-erythroidine). 5

• In the cerebral cortex, nicotinic receptor activation in interneurons can relay both inhibitory and disinhibitory signals to pyramidal neurons, thereby modulating neuronal circuit activity. 5

• Nicotinic agonists increase the amplitude of excitatory postsynaptic potentials mediated by non-NMDA glutamate receptors through presynaptic mechanisms, enhancing synaptic transmission. 6

Cholinesterase Inhibition

• Cholinesterase inhibitors increase acetylcholine availability at synapses by preventing its enzymatic breakdown, prolonging and enhancing cholinergic neurotransmission. 1

• This mechanism is particularly relevant in the central nervous system where cholinergic synapses are highly concentrated in the thalamus, striatum, limbic system, and neocortex, regions critical for memory, learning, and attention. 1

Tissue-Specific Effects

Respiratory System

• Vagal-mediated cholinergic tone controls airway smooth muscle through stimulation of cough receptors in central airways and irritant receptors in peripheral airways. 4

• Anticholinergic agents like ipratropium bromide block muscarinic receptors locally on nasal mucosa, reducing glandular secretion and rhinorrhea without significantly affecting systemic anticholinergic effects due to poor systemic absorption (only 7% absorbed). 4

Ocular System

• Cholinergic agonists (pilocarpine, cevimeline) bind to muscarinic receptors on lacrimal and salivary glands, stimulating secretion to improve tear production in severe dry eye, particularly in Sjögren's syndrome. 4

• The miotic effect of pilocarpine (pupillary constriction) may contribute to improved visual symptoms through enhanced depth of focus. 4

Central Nervous System

• Cholinergic transmission in the hippocampus, arising from the medial septum and diagonal band of Broca, activates both nAChRs and mAChRs to regulate synaptic communication and induce oscillations important for cognitive function. 3

• Presynaptic nicotinic receptors located in preterminal axon segments and presynaptic terminals of interneurons can trigger GABAergic postsynaptic currents when activated by ACh. 5

Clinical Implications

• The non-neuronal cholinergic system comprises ACh, ChAT, acetylcholinesterase, and nicotinic/muscarinic receptors outside the nervous system, expanding therapeutic applications beyond neurotransmission. 2

• Cholinergic drugs modulate excitatory synaptic transmission at dendritic sites through presynaptic mechanisms rather than direct postsynaptic effects on membrane potential or input resistance. 6

• Common side effects of systemic cholinergic agonists include excessive sweating (>40% with pilocarpine), dry mouth, urinary retention, blurred vision, dilated pupils, and sedation due to widespread muscarinic receptor distribution. 4