Autonomic Nervous System: PSNS and SNS

• The autonomic nervous system (ANS) is divided into the parasympathetic (PSNS) and sympathetic (SNS) nervous systems.
  • PSNS is responsible for "rest and digest" functions.
  • SNS is responsible for "fight or flight" responses.
• Most organs receive input from both the PSNS and SNS.
• The PSNS and SNS generally mediate opposing responses in effector organs, acting as physiological antagonists.
  • Exceptions to this include the adrenal, lacrimal, sweat glands, pilomotor muscles, and blood vessel smooth muscle.

Anatomy of the ANS

• PSNS originates in the cranial and sacral spinal cord.
• SNS originates in the thoracic and lumbar spinal cord. Both systems consist of a two-neuron system, involving pre- and postganglionic fibers.
• Ganglia are aggregations of cell bodies of postganglionic neurons.

Sympathetic Nervous System (SNS)

• Ganglia are located near the spinal cord.
• Preganglionic fibers are short, and postganglionic fibers are long.
• One preganglionic neuron synapses with many postganglionic neurons.
• The SNS elicits a rapid, widespread response.

Parasympathetic Nervous System (PSNS)

• Ganglia are located close to or within the target tissue. Preganglionic fibers are long, and postganglionic fibers are short.
• One preganglionic neuron synapses with one postganglionic neuron.

Communication in the ANS

• Autonomic nerves are classified based on the neurotransmitter they release.
• Acetylcholine (ACh) was the first neurotransmitter identified.
  • It regulates both branches of the autonomic nervous system.
• Cholinergic neurons release ACh.
• Norepinephrine (NE) is typically released in tissues receiving sympathetic innervation.
  • Most postganglionic SNS neurons release NE.
• The adrenal gland secretes epinephrine (EP).
  • Neurons that release epinephrine are referred to as adrenergic.
  • Epinephrine is also known as adrenaline.

Autonomic Receptors: Cholinergic

• Muscarinic receptors (M1, M2, M3, M4, M5): Organs innervated by the PSNS primarily have M2 and M3 receptors.
  • Heart receptors are M2.
  • Endothelial cells have M3 and M5 receptors that can be activated by drugs, though they don't receive direct transmitter input.
  • Sweat glands innervated by cholinergic SNS fibers have M3 receptors.
  • The CNS contains all subtypes of muscarinic receptors.
• Nicotinic receptors (Nn, Nm):
  • Nn (neuronal) receptors are found in all ganglia (PSNS and SNS).
  • Nm (muscle) receptors are found on skeletal muscles (somatic nervous system).

Autonomic Receptors: Adrenergic

• Found in organs innervated by the SNS and CSNS
• Location and subtype determine tissue response
• Alpha receptors (α1, α2)
  • α1 cause constriction in blood vessels and smooth muscle contractions.
  • α1 receptors are activated by NE (norepinephrine) and EP (epinephrine).
• Beta receptors (β1, β2, β3)
  • β1 is activated by NE/EP in the heart.
  • β2 is selectively activated by EP but not NE (requires high levels of EP).
    • EP >>> NE for activation of β2 receptors.

Tonic Activity and Balance

• Most tissues receive input from both the PSNS and SNS, acting as physiological antagonists.
• Autonomic drugs, stress, and environmental input can alter the balance of neurotransmission.

Cholinergic Transmission

• Acetylcholine (ACh) synthesis: Synthesized by the enzyme choline acetyltransferase (ChAT).
• ACh degradation: Degraded by the enzyme acetylcholinesterase (AChE).
• ACh activates:
  • Muscarinic receptors (M1, M2, M3, M4, M5):
    • G protein-coupled receptors.
    • M1,M3,M5 increase IP3, DAG = stimulatory.
    • M2,M4 decrease cAMP = inhibitory.
  • Nicotinic receptors (Nn, Nm):
    • Ion channels = stimulatory.

Adrenergic Transmission

• Synthesis: A three-step process involving:
  • Tyrosine hydroxylase
  • Dopa decarboxylase
  • Dopamine β-hydroxylase
• Termination:
  • Re-uptake
  • Diffusion away from the synapse
• Metabolism:
  • Monoamine oxidase (MAO)
  • Catechol-O-methyl transferase (COMT)

Adrenergic Transmission Details

• Dopamine is transported into synaptic vesicles and converted to NE by β-hydroxylase.
• Epinephrine is secreted by the adrenal medulla, circulating via the blood to various tissues.
• All adrenoceptors are linked to G-protein second messenger systems.
  • α1 receptors function similarly to M1, M3, and M5 receptors: constriction, activation.
  • α2 receptors function similarly to M2 and M4 receptors: relaxation.
  • β1, β2, β3 receptors increase cAMP.

Beta Receptor Effects

β1: Heart; increase rate and force of contraction. β2: Smooth muscle cells; relaxation, found in blood vessels (supplying skeletal muscle), bronchial tree, uterine, GI, and bladder walls. β3: Fat cells; increases lipolysis.

Effects of Direct-Acting Receptor Agonists on Cardiovascular System

• Heart
  • M2 receptors: Decrease heart rate.
  • β1 receptors: Increase heart rate.
• Blood vessels (most)
  • M3 receptors: Vasodilation (relaxation).
  • α1 receptors: Vasoconstriction (activation).
• Blood vessels (skeletal muscle)
  • β2 receptors: Vasodilation (relaxation).
  • Only NE (norepinephrine) is released, not adrenal epinephrine.

Other Receptor Effects

• M3 receptors cause contraction, increasing activity and secretion (activation).
• β2 receptors cause relaxation of smooth muscle (relaxation).
• α1 receptors cause constriction of sphincters (activation).

Autonomic Drugs

• Autonomic transmission can be inhibited or stimulated by chemicals that affect neurotransmitter:
  • Synthesis
  • Storage
  • Release
  • Receptor activation
  • Re-uptake or inactivation

Cholinergic Drug Actions

• Acetylcholine: activates muscarinic and nicotinic receptors, susceptible to AChE.
• Bethanechol, Muscarine, Pilocarpine: activate muscarinic receptors.
• Nicotine: activates nicotinic receptors.

Indirect-Acting Agonists (AChE Inhibitors)

• Physostigmine, Endothiophate
• Intermediate and long-acting

Antagonists

• Atropine: antagonist for muscarinic receptors.
• Trimethaphan: antagonist for nicotinic neuronal receptors.
• D-tubocurarine: antagonist for nicotinic muscle receptors.

Direct Receptor Agonists

• Esters of Choline
  • Acetylcholine: M and N receptors.
  • Bethanechol: only M receptors.
  • Not absorbed/distributed well.
• Alkaloids
  • Muscarine: muscarinic receptors.
  • Nicotine: nicotinic receptors.
  • Pilocarpine: muscarinic receptors.
  • Absorbed and distributed well, even in the CNS.

Cholinergic Receptor Agonists

• Most clinically used agonists are not receptor subtype selective.
• Muscarinic receptor activation
  • Responses are the same as PSNS activation.
  • Affects sweat glands.
  • Causes endothelial-derived relaxation of blood vessels, even without ACh release.
• Nicotinic receptor activation
  • Activates PSNS and SNS.
  • Causes skeletal muscle contraction; nicotine initially stimulates, then blocks.
  • M3: smooth muscles.
  • M2: heart.
• Pilocarpine eye drops treat glaucoma by activating M3 receptors on the ciliary muscle, causing contraction and widening the canal for fluid drainage, which increases the drainage of aqueous humor out of the eye.
• Systemic Circulation Effects of Pilocarpine
  • Heart: Activation of M2 receptors decreases rate and force of contractions.
  • Blood vessels: Activation of M3 receptors on endothelial cells stimulate the endothelia, causing relaxation of blood vessels vasodilation and increase in EDRH (Endothelium-derived relaxing factor)
  • Bronchi: Activation of M3 stimulates the smooth muscle, that line the bronchi, activates M3 on bronchial smooth muscle and mucous glands causing Bronchoconstriction and increase in secretion.

Nicotinic Receptor Agonists

• Activates PSNS and SNS.
• Causes skeletal muscle contraction.
• Stimulates nicotinic receptors in CNS.

Nicotine Activation

• Activates both PSNS and SNS (Nn) at ganglia, increasing ACh and NE in tissue and adrenal gland.
• In most organ systems (PSNS is dominant): When both systems are activated, the PSNS response is observed.
  • Example: Nicotine and GI tract increase smooth muscle contraction, motility, and gland secretion.
• Tissues with no PSNS input: SNS response only.
  • SNS response in blood vessels: α1 = vasoconstriction (organs and skin)=Contract, β1 = vasodilation (skeletal muscle)=Relax
  • Vascular bed with α1 > vascular bed with β2; therefore, the net effect is vasoconstriction.
• Heart: Increases heart rate.

Indirect-Acting Cholinomimetics

• Inhibitors bind to acetylcholinesterase (AChE) at different levels (some are irreversible).
• Reduce ACh hydrolysis, increasing local ACh concentration, amplifying the effect on ACh.
• The drug-enzyme complex determines duration of action AChE inhibitor.

Reversible Inhibitors

• Carbamate ester (physostigmine)
  • Covalent bond between drug and AChE is somewhat resistant to hydration (Step 2 of hydrolysis).
  • T1/2 = 30 minutes to 6 hours.
  • Poor absorption and distribution (except for physostigmine).

Irreversible Inhibitors

• Organophosphate (echothiophate)
  • Covalent bond between drug and AChE phosphate stabilizes the bond.
  • T1/2 = days to weeks.
  • Absorbed and distributed well (even in the CNS).
  • Action: Amplification of endogenous ACh.
  • Effects are similar to direct-acting cholinomimetic drugs (only where ACh is released).

Increased ACh

• At PSNS and SNS ganglia, tissues innervated by autonomic ACh-releasing neurons, at skeletal muscle, and in CNS.
• MOST tissues SNS, increase ACh at ganglia vs PSNS increase ACh at ganglia and increase ACh at effector cell
• PSNS effect observed: Increase ACh; ganglia and tissue.
• Pilocarpine- Activates M2 receptors in the heart: decreases rate and force of contraction. Activates M3 and M5 receptors on endothelial cells: increases EDRF in endothelial cells. EDRF (Endothelium-derived relaxing factor) diffuses into smooth muscle: dilation of blood vessels.
• Nicotine Activates Nn (neurons) at PSNS and SNS ganglia and the adrenal gland.
  • Blood vessels (SNS): Increases NE and EP, α1 vasoconstriction (organs and skin)=Activation, β2 vasodilation (skeletal muscle)=Relaxation. Heart = Heart: increases rate and force of contraction β1.
• Physostigmine-Inhibits AChE: increases ACh at ganglia and adrenal gland activates Nn stimulates PSNS and SNS.
  • Blood vessels Physostigmine: SNS, α1 vasoconstriction (organs and skin), β2 vasodilation (skeletal muscle).
  • Heart Physostigmine: Increases SNS and PSNS input, increases ACh in the heart due to AChE inhibition decreases the rate and force of contraction.

Toxicities Associated with Muscarinic Agonists

• Mushroom (genus Inocybe) contain high level of muscarine; pilocarpine overdose.
  • Ingestion results results in symptoms of muscarinic excess.
  • Activation of muscarinic receptors in tissues/organs innervated by PSNS, sweat glands + blood vessels (EDRF), CNS (Excitation).
  • Symptoms of Muscarinic excess (DUMBELS):
    • Diarrhea: activation of M3 on smooth muscles the GI tract, which causes contractions.
    • Urination: muscarinic receptors that line the bladder wall cause contractions of bladder wall.
    • Miosis: pupil constriction.
    • Bradycardia: contraction of smooth muscle where M3 receptors are.
    • Bronchoconstriction: contraction of bronchi.
    • Excitation (CNS)
    • Lacrimation: M3 receptor activated gland secretion increases.
    • Sweating and salivation: M3 receptor activated gland secretion increases.
    • M3 most parts of the body VS M2 heart ONLY VS brain all muscarinic receptors

Atropine

• Has an equal affinity for M receptor subtypes.
• Well-absorbed and distributed, also in the CNS.
• Dilated pupils are achieved through eye drops.

Ganglionic Blockers: Trimethaphan (blocks Nn subunit)

• Used for hypertensive crisis or dissecting aortic aneurysm (rarely used clinically).
• Not often used due to nicotinic receptors in both PSNS and CNS.

Neuromuscular (Nm) Blockers: D-Tubocurarine (in Amazon frog)

• Used in surgical procedures to reduce skeletal muscle contraction.
  • A mechanism used by hunters.

Glaucoma = Increased Ocular Pressure

• Treatment: pilocarpine, physostigmine, echothiophate
• These drugs decrease ocular pressure through drainage out of the eye by opening the canal and contracting the ciliary muscle activating M3 muscles. How do these act differently
• Pilocarpine works as muscarinic direct agonists that Binds/activates M3 while physostigmine inhibits AChE increases ACh and M3
• Therefore in glaucoma avoid muscarinic receptors antagonists like atropine that inhibit M3

Bethanechol

• A 38-year-old female with difficulty urinating (bladder atony) gets a subcutaneous injection of bethanechol.
  • M3 is in the bladder and contracts the smooth muscle that allows urination bethanechol is direct muscarinic agonists so it can be used.
• Muscarinic agonist activates M3 receptors on bladder smooth muscle, causes contractions and increase of urination, alongside multiple drugs that could be used like muscarinic pilocarpine, increase levels of ACh

Sympathomimetic Drugs

• Norepinephrine and Amphetamine
  • Presence of -OH groups in Norepinephrine = catecholaime
    • Absence of 1 or both -OH decrease potency at adrenergic receptors
    • Increase susceptibility to COMT
  • Addition of a group α-carbon resistant to MAO
  • Addition of a group on the amino end alters receptor infinity

Direct Acting Agonists

• Mixed Norepinephrine α1=α2, β1>>β2 (Needs very high concentration to activate β2)
• Epinephrine α1=α2, β1=β2 ( Binds to all do to methyl groups)
• ALPHA Phenylephrine α1>>α2 VS Clonidine α1>α2 VS Yohimbine α1β2
• BETA Propranolol β1=β2 VS Butoxamine β2>>>β1
• In most organs SNS & PSNS are physiological antagonists, therefore adrenergic antagonists have the same effect as PSNS activation
• EYE
  • Block α1, constriction of pupil -Blocks β2 and β1, decrease production of aqueous humor
• HEART
  • Blocks β1, decreases heart rate and force of contraction
• BARORECEPTOR REFLEX RESPONSE
  • Beta-blockers inhibition β1, decrease heart rate and force, Baroreceptors detect decrease BP, decrease PSNS and increase SNS vasoconstriction via α1
  • Alpha blockers inhibition of α1 in blood vessels and vasodilation, baroreceptors detect decrease BP, decrease PSNS, increase SNS increased heart rate via β1
• Bronchi
  • Block β2 for bronchonstriction
• Smooth Muscle wall OF ORGAN β2 Vs Sphincter SMOOTH MUSCLE α1
• GI tract
  • Blocks β2, increase motility
  • Blocks α2, increases ACh release and increases motility
  • Blocks α1, relaxes sphincter
• Urinary bladder
  • Blocks β2, contracts
  • Blocks α1, relaxes sphincter