Autonomic Pharmacology: Sympathetic and Parasympathetic Systems

Core Review

Organization of the Autonomic Nervous System

The autonomic nervous system (ANS) controls involuntary visceral functions including heart rate, blood pressure, respiration, digestion, glandular secretion, and pupil diameter. It has two anatomically and functionally distinct divisions that generally act in opposition:

Parasympathetic Nervous System (Craniosacral, "Rest and Digest")

The parasympathetic system conserves energy, promotes digestion, and maintains basal bodily functions. It is tonically active at rest.

Anatomy:

• Preganglionic neurons: Cell bodies in the brainstem (CN III, VII, IX, X) and sacral spinal cord (S2-S4)
• Long preganglionic fibers, short postganglionic fibers
• Ganglia located near or within the target organ

For dental relevance, the key parasympathetic pathways are:

• CN VII → chorda tympani → submandibular ganglion → submandibular and sublingual salivary glands
• CN VII → greater petrosal nerve → pterygopalatine ganglion → lacrimal gland, nasal/palatal glands
• CN IX → lesser petrosal nerve → otic ganglion → parotid gland

Neurotransmitter and receptors:

• Preganglionic: Acetylcholine (ACh) acting on NICOTINIC (Nn) receptors on postganglionic neurons
• Postganglionic: Acetylcholine (ACh) acting on MUSCARINIC (M1-M5) receptors on target organs

Muscarinic receptor subtypes relevant to dentistry:

• M1: CNS, autonomic ganglia, gastric parietal cells
• M2: Heart — decreases heart rate (negative chronotropic effect), decreases AV conduction velocity
• M3: Smooth muscle contraction, glandular secretion — THE receptor mediating salivary secretion. M3 activation → copious, watery (serous) saliva. Also mediates bronchoconstriction, GI smooth muscle contraction, and pupillary constriction (miosis).
• M4, M5: CNS

Parasympathetic effects on oral/dental structures:

• Increased salivary secretion (M3) — watery, enzyme-rich
• Minimal direct effect on blood vessels in the head and neck (parasympathetic vasodilation is less prominent than sympathetic vasoconstriction)

Sympathetic Nervous System (Thoracolumbar, "Fight or Flight")

The sympathetic system prepares the body for stress, exercise, and emergencies. It increases heart rate, blood pressure, and blood flow to skeletal muscle while diverting flow from non-essential organs.

Anatomy:

• Preganglionic neurons: Cell bodies in T1-L2 spinal cord (intermediolateral cell column)
• Short preganglionic fibers, long postganglionic fibers
• Ganglia in the paravertebral sympathetic chain or prevertebral ganglia
• Exception: The adrenal medulla is a modified sympathetic ganglion (preganglionic fibers synapse directly on chromaffin cells, which release epinephrine [80%] and norepinephrine [20%] into the bloodstream)

Neurotransmitters and receptors:

• Preganglionic: ACh → nicotinic (Nn) receptors on postganglionic neurons
• Postganglionic (most): Norepinephrine (NE) → adrenergic receptors (α1, α2, β1, β2, β3)
• Exception: Sweat glands (sympathetic cholinergic — ACh at M3 receptors) and renal vascular smooth muscle (dopamine at D1 receptors)
• Adrenal medulla: Epinephrine and norepinephrine released into bloodstream → systemic adrenergic activation

Adrenergic receptor subtypes:

Sympathetic effects on oral/dental structures:

• Vasoconstriction of oral blood vessels (α1) — used therapeutically in LA with vasoconstrictors
• Production of small volumes of viscous, protein-rich saliva (β-adrenergic, minor role)
• Pupillary dilation (mydriasis — α1)
• Decreased GI motility

Comparison: Parasympathetic vs. Sympathetic

Cholinergic Pharmacology

Direct-acting cholinergic agonists (parasympathomimetics):

• Pilocarpine: Muscarinic agonist. Used as a sialagogue to stimulate salivary flow in xerostomia (Sjögren's syndrome, radiation-induced xerostomia). May cause sweating, bradycardia, bronchoconstriction, GI cramps.
• Bethanechol: Muscarinic agonist. Primarily used for urinary retention.

Cholinesterase inhibitors (indirect cholinergic agonists): Increase ACh by inhibiting acetylcholinesterase.

• Physostigmine: Reversible inhibitor, crosses blood-brain barrier
• Neostigmine: Reversible inhibitor, does NOT cross BBB (quaternary amine). Used for myasthenia gravis.

Anticholinergics (parasympatholytics): Block muscarinic receptors.

• Atropine: Prototype muscarinic antagonist. Produces tachycardia, xerostomia, mydriasis, decreased GI motility, urinary retention.
• Scopolamine: Similar to atropine, crosses BBB (used for motion sickness)
• Glycopyrrolate: Quaternary amine — does NOT cross BBB. Used perioperatively to reduce salivary and respiratory secretions.

Dental relevance of anticholinergics:

• XEROSTOMIA is the most common and clinically significant oral side effect. Any drug with anticholinergic activity can cause dry mouth by blocking M3 receptors on salivary glands.
• Many commonly prescribed medications have anticholinergic properties (see Xerostomia topic)
• Atropine-like effects: "Hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter" (hyperthermia, mydriasis, xerostomia, flushing, CNS effects)

Adrenergic Pharmacology

Adrenergic agonists (sympathomimetics):

Epinephrine (adrenaline): Endogenous catecholamine. Non-selective — activates α1, α2, β1, β2.

• Used in local anesthetic cartridges as a vasoconstrictor (typically 1:50,000, 1:80,000, 1:100,000, or 1:200,000 concentration)
• α1 vasoconstriction → reduced bleeding, reduced systemic absorption of LA, prolonged duration of anesthesia
• β1 → increased heart rate, contractility → caution in patients with cardiovascular disease
• β2 → bronchodilation (therapeutic in anaphylaxis)
• Clinical considerations for epinephrine in LA: Patients with significant cardiovascular disease (unstable angina, recent MI, uncontrolled hypertension, severe arrhythmias) may require reduced epinephrine or epinephrine-free LA. However, the small amounts in dental cartridges are generally safe for most patients with stable cardiovascular disease. ASA and AHA guidelines generally support the use of epinephrine-containing LA in stable cardiovascular patients with appropriate aspiration technique and limitation of dose.

Norepinephrine (noradrenaline, levarterenol): Primarily α1 (potent vasoconstrictor) with some β1 (no β2). Used as a vasopressor in shock. Levonordefrin is a synthetic analogue used in some dental LA formulations.

Adrenergic antagonists:

• Alpha blockers: Prazosin, terazosin, doxazosin → vasodilation, used for hypertension and BPH. Can cause orthostatic hypotension.
• Beta blockers: See Cardiovascular Medications topic. Propranolol (non-selective), metoprolol (β1 selective), atenolol (β1 selective).
• Non-selective beta blockers: Block both β1 (heart) and β2 (bronchodilation) → caution in asthmatics (can cause bronchospasm). Also block β2 vasodilation → theoretically, unopposed α1 vasoconstriction with epinephrine administration. This interaction is clinically debated — most authorities consider epinephrine in dental LA safe with beta blockers in routine doses, but caution is warranted with high epinephrine doses.

Autonomic Control of Salivary Secretion

The primary stimulus for salivary secretion is PARASYMPATHETIC (M3 muscarinic receptors). This explains why anticholinergic drugs are the most common cause of medication-induced xerostomia.

Parasympathetic stimulation: ACh → M3 receptors on salivary acinar and ductal cells → activation of phospholipase C → IP3 → increased intracellular Ca2+ → secretion of copious, watery saliva (serous). This is the primary mechanism.

Sympathetic stimulation: NE → β-adrenergic receptors on acinar cells → activation of adenylyl cyclase → cAMP → secretion of small volumes of protein-rich, viscous saliva. Sympathetic stimulation is a minor contributor under physiological conditions.

Clinical consequence: Blockade of M3 receptors by anticholinergic drugs → profoundly reduced salivary flow (xerostomia). Beta blockers do NOT cause significant xerostomia by blocking adrenergic receptors — most xerostomia from cardiovascular drugs is due to other mechanisms or concomitant anticholinergic effects.

Clinical Application

Understanding autonomic pharmacology is essential for:

1. Interpreting medication lists: Identifying drugs with anticholinergic properties that contribute to xerostomia, caries risk, and oral candidiasis
2. Safe use of vasoconstrictors: Balancing the need for hemostasis and prolonged anesthesia against the risk of cardiovascular adverse effects
3. Managing medical emergencies: Epinephrine is the drug of choice for anaphylaxis (β2 bronchodilation + α1 vasoconstriction); atropine for symptomatic bradycardia
4. Understanding drug interactions: Beta blocker + epinephrine → theoretical unopposed α1 vasoconstriction (hypertensive response); MAO inhibitors + epinephrine → theoretical potentiation

Common Traps

• Thinking beta blockers cause xerostomia by blocking sympathetic salivary stimulation — the primary driver of salivary flow is PARASYMPATHETIC (cholinergic). Beta blockers rarely cause significant xerostomia by themselves (other antihypertensives and the anticholinergic properties of some drugs are the major culprits)
• Confusing nicotinic (Nn = neuronal ganglionic, Nm = neuromuscular junction) and muscarinic receptors — postganglionic parasympathetic effects are MUSCARINIC
• Forgetting that the adrenal medulla releases epinephrine (80%) and NE (20%) and is a modified sympathetic ganglion
• Thinking all anticholinergic effects are CNS-mediated — glycopyrrolate is a quaternary amine that does NOT cross the BBB but still causes xerostomia