ANS Pharmacology: Cholinergic Antagonists & Anatomy

• Drugs Affecting The Autonomic Nervous System (ANS) is covered
• These notes are from ANS Pharmacology, Lecture 1 and 2,
• By Dr. Hiwa K. Saaed, College of Pharmacy, University of Sulaimani
• Notes are from the academic year 2024-2025

Cholinergic Antagonists

• Atropine
• Scopolamine

Anatomy of The Nervous System (NS)

• The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system
• The central nervous system (CNS) includes the brain and spinal cord
• CNS processes sensory input and initiates responses
• Peripheral nervous system is the neuronal tissue outside the CNS

Afferent and Efferent Divisions

• Afferent division transmits sensory input to the CNS and modifies motor output through the reflex arc
• Efferent division carries motor signals from the CNS to the body
• The efferent division is divided into two major functional subdivisions: somatic and autonomic nervous systems

Somatic System

• One motor neuron innervates the skeletal muscles
• Somatic System controls voluntary (consciously) functions; movement, respiration, and posture
• Responses are generally faster than in the ANS

Autonomic Nervous System (ANS)

• Also known as the visceral, vegetative, involuntary nervous system
• Regulates subconscious physiological functions, heart rate (HR), blood pressure (BP), and the activities of the gastrointestinal (GIT) and genitourinary (GUT) systems
• Divided into the sympathetic and parasympathetic nervous systems

Sympathetic and Parasympathetic Nervous Systems

• Parasympathetic (PANS) dominates during sleep and controls the "rest and digest" functions
• Acetylcholine (ACh). is the main neurotransmitter
• Sympathetic (SANS) dominates during activity controlling the "fight or flight" response
• Epinephrine & Norepinephrine are the main neurotransmitters

Enteric Nervous System (ENS)

• The enteric nervous system(ENS) is considered the "brain of the gut"
• It functions autonomously but communicates with the PANS and SANS
• ENS receives sensory input from the GIT and sends motor output
• This regulates digestive functions via both the PANS and SANS
• The Myenteric plexus (plexus of Auerbach) and the Submucous plexus (plexus of Meissner) form part of this autonomous nervous system

Location of Ganglia

• The Efferent ANS transmits impulses via a preganglionic (myelinated) fiber from the CNS and a postganglionic (nonmyelinated) fiber to the effector
• Sympathetic & parasympathetic NS have ganglia (relay stations), unlike the somatic system
• The adrenal medulla receives only preganglionic fibers
• When stimulated by ACh, it secretes epinephrine & lesser amounts of norepinephrine into the blood.

Parasympathetic Division

• Originates in the craniosacral region
• Preganglionic fibers arise from specific cranial nerve nuclei including CN III (oculomotor), CN VII (facial), CN IX (glossopharyngeal), and CN X (vagus, covering 90% of preganglionic fibers),
• Also from region (S2-S4) of the spinal cord.
• Fibers synapse in ganglia close to the effector organ
• Preganglionic fibers are long, postganglionic ones are short
• One-to-one connection exists between the preganglionic and postganglionic neurons, enabling discrete response

Sympathetic Division

• Originates in thoracolumbar region
• The preganglionic fibers arise from the Thoracic (T1-T12)
• Lumbar (L1-L2) of the spinal cord, and if confirmed, the Sacral (S2-S4) segments of the cord.
• Two cord-like chains of ganglia synapse close to and in parallel on each side of the spinal cord.
• preganglionic fibers are short, and the postganglionic ones are long.
• preganglionic fibers are highly branched, enabling a single preganglionic neuron to activate multiple postganglionic neurons

Neurotransmitter Aspects of The ANS

• All preganglionic fibers of ANS are cholinergic
• All parasympathetic postganglionic fibers are cholinergic
• Few sympathetic postganglionic fibers are cholinergic (i.e. sweat gland)
• All somatic fibers to skeletal muscle are cholinergic

Adrenergic Neurons

• Most sympathetic postganglionic fibers release norepinephrine and are adrenergic
• Some peripheral sympathetic fibers release dopamine and are dopaminergic.
• The adrenal medulla releases EP (~85%) and a lesser amount of NEP (15%) into the blood.

Functions of the ANS - Sympathetic Nervous System

• Sympathetic nervous system remains remains active even at rest
• Dominates under stress (e.g., trauma, pain, fear, hypoglycemia, cold, or exercise), triggering the fight-or-flight response
• Enhances energy and metabolism, increasing heart rate, BP, blood sugar, and bronchodilation, redirecting blood flow to skeletal muscles

Functions of the ANS - Parasympathetic Nervous System

• Regulates "rest and digest" functions, maintaining essential bodily processes and conserving energy
• Promotes Digestion and waste elimination
• Vasodilation in the skin and Bradycardia (decreased heart rate) and increased saliva and digestive secretion
• Bronchoconstriction and Bladder contraction for urination

ANS Dual Innervation

• Most organs are innervated
• Despite this dual innervation, one system usually predominates in controlling the activity of an organ

Opposite Effects

• Myocardium: Sympathetic causes Tachycardia Parasympathetic causes Bradycardia Intestinal smooth muscle: Sympathetic causes Decreased Motility Parasympathetic causes Increased Motility Pupil muscles of iris: Sympathetic causes Mydriasis (radial muscle) while Parasympathetic causes Miosis (circular muscle)

Sympathetic one division Control

The following can be innervated by one division of ANS include

• Blood vessels: Constriction
• Sweat glands: Increased Secretion
• Ciliary Muscle Accommodation reflex

Parasympathetic one division Control

• Stomach & Pancreas: Increased Secretion

Parasympathetic Receptors

• Muscarinic (M1 to M5)
• Nicotinic (Nn, Nm)

Sympathetic Receptors

• Alpha (α1, α2),
• Beta (β₁ to β 3),

Ciliary Epithelium B₁ Activation

• Stimulates aqueous humor production and maintains intraocular pressure for proper light focus.

Iris a₁ Activation

• Contraction here results in pupil dilation (mydriasis).

• NE (α, β) for sympathetic response (stress) to enhance production of aqueous humor and cause Pup dilation

Ciliary Muscle (ACh to M Receptors)

Contraction relaxes tension on lens and accommodates vision Pulls on trabecular meshwork and Opens Canal of Schlemm to facilitate fluid drainage

Iris Sphincter (ACh to M Receptors)

Contracts to constrict pupil (miosis)

• Pupil constriction and Aqueous humor drainage occurs due to parasympathetic response

Lungs - ANS Control

• Sympathetic (SANS)
• B₂ receptor activation leads to bronchodilation & ↓ airway secretions
• Parasympathetic (PANS)
• ACh stimulates M receptors, causing bronchoconstriction & ↑ airway secretions.

Heart

• Sympathetic (β₁): ↑ HR, contractility, AV conduction, and cardiac output
• Parasympathetic (M): SA nodal firing, AV node conduction, and cardiac output

Blood Vessels - ANS Control

• Blood vessels express α, β, dopamine (DA), histamine and M receptors
• Sympathetic- NE (α₁, α₂, β₁), and epinephrine (α₁, α₂, β₁, β₂) and dopamine (DA) are released. Vasoconstriction with a₁ occurs in arterioles, ↑ pressure, directs flow to organs
• Vasodilation using β₂ expands skeletal muscle vessels, ↑ blood flow for the BP

Dopamine (DA) Effects and Mechanisms

• Concentration-dependent effects through three different mechanisms:

1. Low dose DA: Stimulates D₁ receptors, dilates the renal artery kidney perfusion
2. Mid-dose DA: Stimulates β₂ receptors, dilates skeletal muscle blood vessels systemic resistance
3. High dose DA: Stimulates a₁ receptors, causes vasoconstriction blood pressure Renal artery dilation occurs with all doses to support increased kidney perfusion

GI ANS Control

• Very complex
• Parasympathetic (M): ↑ Motility,↓ Sphincter tone, ↑ Secretions
• Sympathetic (α, β): ↓ Motility, ↑ Sphincter tone,↓ Secretions
• Dopamine (DA): ↑ Motility,↓ Sphincter tone, ↑ Secretions
• Opioids: Motility, Sphincter tone, Secretions Constipation

Bladder Control

• Parasympathetic (M receptors): Stimulates bladder and relaxes internal sphincter (Micturition Reflex).
• Sympathetic (a receptors): Inhibits bladder contraction, and contracts internal sphincter.

Autonomic Receptor Organs

• Ganglia of the Parasympathetic NS
• M₁: gastric parietal cells
• M2: cardiac cells and smooth muscle
• M3: bladder, exocrine gland, and smooth muscle
• The M1-M5 subtypes are present on neurons

Actions of the muscarinic receptors

• M1: Gq; Increased inositol phosphates (IP3) and diacylglycerol (DAG); Depolarization, decreased K+ conductance
• M2: Gi; decreased cAMP, calcium channels, and increased K+ conductance Mostly inhibitory (responsible for the vagal inhibition of the heart)
• M3: Gq; Increased inositol phosphates (IP3) and DAG, and intracellular calcium Mostly exitatory (stimulation of glandular secretion, viscera contraction)
• M1, M3, & M5: → Gq protein → Phospholipase C activation PIP2 hydrolysis IP3 & DAG formation ↑ Intracellular Ca2+
• M2: Gi protein Adenylyl cyclase inhibition K+ conductance

Nicotinic Receptors NM NN

• CNS, Adrenal Medulla, Autonomic Ganglia & Neuromuscular Junction
• They are Ligand-gated ion channels.
• Binding of two Ach molecules elicits a conformational change that allows the entry of Na+ ions.

Cholinergic Neurotransmission

1. Synthesis of ACh
2. Storage and release of ACh
3. Binding
4. Degradation of ACh
5. Recycling of choline