Anatomy of the Autonomic Nervous System (ANS)

Anatomy of the ANS

• The nervous system is divided into central and peripheral nervous systems
• The peripheral nervous system includes the somatic and autonomic nervous systems, controlling voluntary and involuntary functions, respectively
• The ANS is the major involuntary portion of the nervous system, responsible for automatic functions like heart rate, blood pressure, and gastrointestinal/genitourinary functions
• The ANS is divided into parasympathetic (craniosacral) and sympathetic (thoracolumbar) subcategories
• Autonomic nerves are composed of preganglionic and postganglionic neuron systems based on their location relative to ganglia
• Preganglionic neurons have their cell bodies in the spinal cord or brain
• Postganglionic neurons send axons directly to effector organs (peripheral involuntary visceral organs)
• Autonomic innervation includes a myelinated preganglionic fiber forming a synapse with the cell body of a non-myelinated post-ganglionic fiber
• A synapse is a structure formed by the close connection of a neuron with another neuron or effector cells
• Both parasympathetic (PANS) and sympathetic (SANS) have ganglia between the CNS and end organs, unlike the somatic system
• SANS ganglia lie in paraventral chains adjacent to the vertebral column
• Most PANS ganglia are located in the organs they innervate

ANS Receptor Types and Neurotransmitters

• Nɴ (ganglionic nicotinic) receptors are on cell bodies in ganglia of both PANS and SANS, and in the adrenal medulla
• Nᴍ (endplate nicotinic) receptors are on the skeletal muscle motor endplate innervated by somatic motor nerves
• M₁₋₃ (muscarinic) receptors are on all organs/tissues innervated by postganglionic nerves of the PANS and on thermoregulatory sweat glands innervated by the SANS
• The major receptor types include ganglionic nicotinic (Nɴ), endplate nicotinic (Nᴍ), muscarinic (M₁₋₃), and adrenergic receptors (α₁, α₂, β₁, β₂)
• Acetylcholine (ACh) is the neurotransmitter at all N receptors and M receptors innervated by postganglionic PANS fibers/thermoregulatory sweat glands innervated by the SANS
• Norepinephrine (NE) is the neurotransmitter at adrenoreceptors innervated by the SANS
• NE and epinephrine (E) are released from the adrenal medulla
• Dopamine (DA) receptor activation leads to vasodilation in some vascular beds

Neurotransmitters in Detail

• Neurotransmitters are chemical messengers that enable neurotransmission across a chemical synapse
• Acetylcholine (ACh) functions at both nicotinic and muscarinic receptors in innervated tissues, and is used in direct transmission from the CNS
• Postganglionic transmission in the SANS may use organ-specific transmitters
• Norepinephrine (NE) is the neurotransmitter at most adrenoceptors in the organs, including cardiac and smooth muscle
• Dopamine (DA) activates D1 receptors, which causes vasodilation in renal and mesenteric vascular beds
• Epinephrine (E) from the adrenal medulla activates most adrenoceptors and is transported in the blood

Cholinergic System and Transmission

• Acetylcholine (ACh) is the main neurotransmitter in the cholinergic system
• Neurons that synthesize, store, and release ACh are called cholinergic neurons
• Sites of ACh and noradrenaline (NA) release in the PNS include preganglionic fibers of both sympathetic and parasympathetic systems, postganglionic fibers of the parasympathetic system, sympathetic postganglionic fibers supplying sweat glands, nerve fibers supplying the adrenal medulla, and motor nerves

Effects of Sympathetic and Parasympathetic Stimulation

• Sympathetic stimulation increases heart rate and force of contraction
• Parasympathetic stimulation decreases heart rate and force of contraction
• Sympathetic stimulation causes mydriasis (pupil dilation)
• Parasympathetic stimulation causes miosis (pupil constriction)
• Sympathetic stimulation causes bronchodilation, while parasympathetic causes bronchospasm
• Sympathetic stimulation decreases GI motility and increases sphincter tone
• Parasympathetic stimulation increases GI motility and relaxes sphincters

Synthesis and Breakdown of Acetylcholine

• Choline enters the cholinergic neuron via carrier-mediated transport and reacts with acetyl-CoA via choline acetyltransferase (ChAT) to form ACh
• ACh is stored in storage vesicles and released into the synaptic cleft when an action potential reaches nerve terminals
• Released ACh interacts with cholinergic receptors on effector cells
• In the synaptic cleft, ACh is rapidly hydrolyzed by acetylcholinesterase (AChE) enzyme

Cholinesterases and Cholinergic Receptors

• Acetylcholine is rapidly hydrolyzed into choline and acetic acid by cholinesterase
• True cholinesterase (AChE) is found in cholinergic neurons, ganglia, RBCs, and the neuromuscular junction (NMJ); it rapidly hydrolyzes ACh and choline esters like methacholine
• Pseudocholinesterase (butyrylcholinesterase) is found in plasma, liver, and glial cells; it acts on various esters (including ACh) but does not hydrolyze methacholine
• Cholinergic receptors are divided into muscarinic and nicotinic types
• Muscarinic receptors (M1-M5) are G-protein-coupled and regulate intracellular second messengers

Muscarinic Receptor Subtypes

• M₁ receptors are located in the gastric glands, autonomic ganglia, and CNS
• M₂ receptors are located in the heart
• M₃ receptors are located in smooth muscles, exocrine glands, and endothelial cells
• Nicotinic receptors are divided into Nɴ and Nᴍ subtypes
• Activation of nicotinic receptors directly opens ion channels and causes depolarization of the membrane

Characteristics of Muscarinic and Nicotinic Receptor Subtypes

• M₁ and M₃ promote glandular secretion and smooth muscle contraction
• M₂ has a depressant effect on the heart
• Nɴ causes depolarization
• Nᴍ causes skeletal muscle contraction

Cholinergic Agents: Cholinergic Agonists (Cholinomimetics, Parasympathomimetics)

• Acetylcholine is a quaternary ammonium compound that is rapidly hydrolyzed by cholinesterases, limiting its therapeutic use
• It must be given intravenously to study its pharmacological actions because a large amount of the drug is destroyed by pseudocholinesterase in the blood

Classification of Cholinergic Agonists

• Directly acting cholinergic are split into choline esters (acetylcholine, bethanechol, carbachol) and alkaloids (pilocarpine, muscarine)
• Indirectly acting cholinergic agonists-anticholinesterases that is are either reversible (physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepezil, galantamine, carbaryl, propoxur) or irreversible (organophosphorus compounds like parathion, malathion, sarin, soman, tabun, dyflos, echothiophate)

Cholinergic Drugs

• Cholinergic drugs promote the action of the neurotransmitter acetylcholine
• These drugs are also called parasympathomimetic drugs
• Cholinergic agonists mimic the action of acetylcholine
• Anticholinesterase drugs inhibit the destruction of acetylcholine at cholinergic receptor sites
• Direct-acting drugs bind to and activate muscarinic or nicotinic receptors while esters of choline (methacholine, carbachol, betanechol) and cholinergic alkaloids (pilocarpine, muscarine, arecoline, nicotine)
• Indirect-acting drugs inhibit acetylcholinesterase enzyme where these are either reversible (neostigmine, physostigmine, edrophonium) or irreversible (organophosphate compounds like echothiophate)
• Nicotinic actions are produced by stimulating all autonomic ganglia and the NMJ while muscarinic actions are produced at postganglionic cholinergic nerve endings
• Acetylcholine (ACh) functions as a neurotransmitter at all cholinergic sites but has limited therapeutic use due to its pharmacokinetic properties

Pharmacokinetics of Acetylcholine

• Acetylcholine is poorly absorbed from the gastric mucosa and is ineffective when given orally
• It should be administered parenterally
• Blood ACh is rapidly hydrolyzed by cholinesterase into acetic acid and choline

Pharmacodynamics of Acetylcholine

• Acetylcholine has nicotinic and muscarinic actions
• Muscarinic actions are of main interest and include the following cardiovascular effects: a slower heart rate and vasodilation, which leads to a drop in blood pressure It also has the following GIT effects: the tone and motility of the GI tract are stimulated but the sphincters will be relaxed
• It also effects the urinary tract by stimulating the detrusor muscle and relaxes the internal urethral sphincter causing an evacuation of the bladder

Other Effects include..

• Bronchioles: Increased bronchial secretion and brings about bronchoconstriction
• Eye: Miosis (pupil constriction) and accommodates near objects through stimulation of the constrictor pupillae and ciliary muscles

Exocrine glands:

• Stimulates salivary, gastric, bronchial, lacrimal, and sweat gland secretions
• Synthetic Choline Esters (methacholine, carbachol, and bethanechol) have longer durations of action
• It also produces effective when administered orally as well as parenterally, and more selective in action
• Cholinergic Alkaloids
• Those with chiefly nicotinic actions include nicotine, lobeline etc.
• Those with chiefly muscarinic actions include muscarine, pilocarpine, etc

Anticholinesterase Drugs

• Inhibits choliesteraterase, the enzyme responsible for acetylchoine which results from hydrolysis of ACh
• ACh accumulates in both muscarinic and nicotinic areas which produces colinergic effects
• The common cholinesterase inhibitors are split into three categories
  • Simple Alcohols eg Endrophonium
  • Carbamate related.eg Neostigmine and Physostigmine
  • Organic Derivatives of Phosphates: e.g., isofluorophate, echothiophate

Physostigmine

• It is completely absorbed from the gastrointestinal tract and it can cross the blood-brain barrier as it is hightly distributed
• It increases and prolongs acetylcholine action however doesnt effect the cholinergic receptors

Organophosphates

• Organophosphates e.g echothiopate irreversibly binds to cholinesterase thus making hydrolysis ineffective
• Treats galucoma, however parathion and malethion are used in insectacides which increases the mortality rate
• Occupational Hazards e.g. Spraying Insecticides, suicidal atempts

Anticholinergic Agents

• Anticholinergic blocks that action of the colinergic duets which include antimuscarinic and antinicotininc agents
• These drugs inhibit the receptor medium action in the heart CNS organs and execrine glands, atropine and scopolamine are examples
• Anticholinergics agents is split into two groups:
  • Antinicotinics (ganglion blockers e.g hexamethonium, trimethaphan
  • Antimuscarinics tertiary amines muscarnic eg atropine, scopolamine, tropicamide

Atropine

• Atrophine in found in the plant artopa belladonna and functions as a marcrininic antagoniscts
• Athropine compettitively binds to ACh which decreases its effect
• The efffects are the oposite to ach

Organs that are effected include:

• CNS - lower doses can produce sedation and higher doses can result in hallucinations
• Eyes - Relaxation of the contriction. and cyclopegia which is ability to lack accomodation
• CVS - blocks the vagal parasympathetic which results in tachycardia and vasoconstriction
• Respiratory system - reduction of secretions and bronchodialation
• Relaxes smoot muscle of the uterter and bladder

What happens to atropine

• Over doses progressive is is due to M blockers in the medications.
• Treated via physostigmine as it acts an antidote

Synthic artopine

• Synthic artopine derrives have less side effects, those grouups include;
  • Mydartic - e.g Homatropine
  • Antiseccretory - propantheline and hyoscine
  • Antiparkisionian eg Benztropine, Trihexyphenidyl
  • Bronchiall astham eg iprotropium
  • those decreasing bladder acitvie eg Oxybutymin

Ganglionic Blockers

• Efffects the autonomic ganglia to produce complex effetcs

Skeletal Muscle Relaxants

• The skeletal muscle relaxants decrease skeletal muscle tone by peripheral or central action
• skeletal muscle relaxants are categorised into; - centrally acting are Diazepan and Gabapention drugs acting on NMJ - peripherally acting drugs directly that are non depolarising

Key information on Skeletal Musice

• Neuromuscular blockers are water saulable and administered intravenously. and broken down in the liver
• the PH the duration of the PH inreases during the block
• Hypothetmia - potencates the blocking
• Mynsathenia Gravis - PAtients are extremly sensitive to this.
• Aminoglycoside antibiotics - Presynatic blockers
• inhalational Anaesthetics - increase the efffect The skeletal muscle relaxants decrease skeletal muscle tone by peripheral or central action
• succinylcholine provides muscle relaxation during short procedures
• Treats Tetanus and statuses epilepticus that cant be controlled by other drugs