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Organization of the Nervous System

• The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system (PNS).
• The PNS has afferent and efferent divisions.
• The efferent division includes the autonomic and somatic systems.
• The autonomic system is further divided into the enteric, parasympathetic, and sympathetic systems.

Sympathetic vs. Parasympathetic Nervous Systems

• The sympathetic nervous system originates from spinal cord segments T1-L2 (thoracolumbar).
• The parasympathetic nervous system originates from cranial nerves III, VII, IX, and X, and spinal cord segments S2-S4 (craniosacral).
• Sympathetic ganglia are paravertebral and collateral while parasympathetic ganglia are terminal and located near effector organs.
• Preganglionic fibers are short in the sympathetic and long in the parasympathetic system.
• Postganglionic fibers are long in the sympathetic and short in the parasympathetic system.
• The sympathetic system involves mass activation, affecting all effector organs simultaneously.
• The parasympathetic system involves separate stimulation of nerves.
• Norepinephrine(except sweat glands) is the primary neurotransmitter released by postganglionic sympathetic nerves.
• Acetylcholine (ACh) is the neurotransmitter released by postganglionic parasympathetic nerves.
• The sympathetic system supports fight or flight (exercise, excitement, emergencies).
• The parasympathetic system supports rest and digest via digestion, defecation, and diuresis.

Adrenergic Receptors

• Adrenergic receptors are present in target tissue cells.
• They are stimulated by norepinephrine from sympathetic nerve endings and epinephrine from the adrenal medulla.
• Types of adrenergic receptors include alpha (α) and beta (β) subtypes:
• Alpha receptors have two subtypes: α1 and α2.
• Beta receptors have three subtypes: β1, β2, and β3.
• Alpha-1 (α1) receptors contract smooth muscles vasoconstricting all blood vessels except coronaries and skeletal muscle vessels.
• Beta-1 (β1) receptors are present in the heart and increase heart functions.
• Beta-2 (β2) receptors relax smooth muscles in the digestive tract, bronchioles, and uterus.
• Beta-3 (β3) receptors are in adipose tissue and the urinary bladder.
• Alpa1 adrenergic receptors are located on:
• Smooth muscle of blood vessels of the skin and splanchnic regions, causing vasoconstriction resulting in decreased blood flow
• The gastrointestinal and bladder sphincters, causing contraction and slowing passage of food and urine.
• The radial muscle of the iris in the eye, resulting in dilation of the pupil.
• Alpha-2 (α2) adrenergic receptors are on sympathetic presynaptic nerve terminals and mediate negative feedback control, which decreases blood pressure.
• Beta-1 (β1) adrenergic receptors are located on:
• The sinoatrial (SA) node, increasing heart rate.
• The artioventricular (AV) node, increasing conduction velocity
• Atrial and ventricular muscles increasing force of contraction
• Kidney, increasing renin release, increasing blood volume, thus increasing blood pressure
• Beta-2 (β2) adrenergic receptors are located on:
• Smooth muscle of blood vessels in skeletal muscle & coronaries, causing vasodilation and increased blood flow.
• Bronchioles, causing bronchodilation.
• Walls of the GI tract and uterus causing relaxation.
• Beta-3 (β3) adrenergic receptors are located on:
• Adipose tissues, increasing lipolysis.
• Urinary bladder, causing relaxation.

Cholinergic Receptors

• Cholinergic receptors are stimulated by acetylcholine (ACh) which is released from:
• Somatic nerve endings
• Preganglionic nerve endings
• Postganglionic parasympathetic nerve endings
• Postganglionic sympathetic nerve endings that lead to sweat glands
• Types of cholinergic receptors include:
• Nicotinic receptors
• Muscarinic receptors M1, M2, and M3.

Nicotinic Receptors

• Nicotinic receptors are located in ganglia of the sympathetic and parasympathetic nerves, in adrenal medulla and at the neuromuscular junction.
• Stimulation in Ganglia of the sympathetic and parasympathetic nerves and in the Adrenal medulla causes excitation
• Stimulation at Neuromuscular junction causes contraction of skeletal muscle

Muscarinic Receptors

• Muscarinic receptors are located in the CNS, gastric parietal cells, heart, and smooth muscle and glands.
• Muscarinic M1 receptors are located in CNS and gastric parietal cells which stimulates:
• Gastric acid secretion in the tomach
• CNS stimulatory effect in brain.
• A deficiency in can cause dementia & Alzheimer.
• Muscarinic M2 receptors are located in the heart; stimulation causes:
• Decreased heartrate on the sinoatrial (SA) node
• Decreased conduction velocity in the atrioventricular (AV) node
• Decreased force of contraction in only the Atrial muscle
• M3 Cholinergic receptors are located in glands and smooth muscle stimulation causes:
• Bronchioles bronchoconstriction.
• Walls of the GI tract and the bladder contration and increase motility
• GI and bladder sphincters relaxation
• Lactimal and salivary glands, the GI tract, and the pancreas secretion
• Circular muscle of the iris in the eye its constriction.

Autonomic Nervous System Pharmacology

• Autonomic pharmacology studies drugs that affect the autonomic nervous system (ANS).
• The ANS regulates involuntary physiological functions and is divided into the sympathetic and parasympathetic nervous systems.
• Each system has distinct neurotransmitters and receptors.

A-Cholinergic Transmission

• Synthesis: Choline transported into neuron, converted to acetylcholine (ACh) by choline acetyltransferase (ChAT) with Acetyl-CoA. Inhibitors: Hemicholiniums (block CHT).
• Storage: ACh transported into vesicles via vesicle-associated transporter (VAT). Inhibitors: Vesamicol (blocks VAT).
• Release: Action potential, leading to Ca2+ influx and vesicle fusion with membrane via SNARE proteins. Inhibitors: Botulinum toxin (cleaves SNARES).
• Termination: Acetylcholinesterase (AChE) degrades ACh into choline and acetate. Inhibitors: AChE inhibitors (e.g., neostigmine, donepezil).

B-Adrenergic Transmission

• Synthesis: Tyrosine is converted to dopa, then dopamine, and finally to norepinephrine. Key Players: Tyrosine hydroxylase, dopa decarboxylase, dopamine β-hydroxylase. Inhibitors: Metyrosine (inhibits tyrosine hydroxylase).
• Storage: Norepinephrine stored in vesicles via vesicular monoamine transporter (VMAT). VMAT is the Key Player. Reserpine (blocks VMAT) is the inhibitor.
• Release: Triggered by Ca2+ influx and vesicle fusion. SNARE proteins, N-type Ca2+ channels are the Key Players. Inhibitors: Guanethidine, bretylium (inhibit release).
• Termination: Norepinephrine reabsorbed by the norepinephrine transporter (NET) or degraded. NET, MAO, COMT are the Key Players. Cocaine, antidepressants (block NET) are the inhibitors.

Role of the CNS in Autonomic Function Control

• The ANS requires sensory input from peripheral structures to monitor the body's internal state.
• Sensory feedback is sent as afferent impulses to CNS centers, including the hypothalamus, medulla oblongata, and spinal cord.
• These centers process feedback and send efferent impulses via the ANS to regulate functions.
• Most afferent impulses translate into involuntary reflex responses
• A drop in blood pressure triggers baroreceptors in the heart, aortic arch, and carotid sinuses, sending fewer signals to cardiovascular centers in the brain.
• This triggers increased sympathetic output (heart and vasculature) and decreased parasympathetic output (heart).
• The resulting compensatory rise in blood pressure/heart rate is the baroreceptor reflex, which maintains blood-pressure stability.

Definitions of Drug Categories

• Sympathomimetics stimulate sympathetic nervous system actions by mimicking norepinephrine/epinephrine, directly activating adrenergic(α and β) receptors (e.g., epinephrine, albuterol), increase NE or inhibit NE breakdown (e.g., amphetamines, cocaine, MAO inhibitors).
• Parasympathomimetics stimulate parasympathetic nervous system actions by mimicking ACh, directly activating muscarinic/nicotinic receptors (e.g. pilocarpine, bethanechol), inhibit acetylcholinesterase (AChE) to increase ACh (e.g., neostigmine, physostigmine).
• Sympatholytics inhibit sympathetic nervous system actions by blocking adrenergic activity. They directly block adrenergic receptors to decrease NE release or synthesis.
• Parasympatholytics inhibit parasympathetic nervous system actions by blocking cholinergic activity by directly blocking muscarinic/nicotinic receptors.
• Parasympatholytics inhibit ACTH Release.