Autonomic Nervous System

• The autonomic nervous system (ANS) controls involuntary/visceral functions like heartbeat, blood pressure, and digestion.

Types of Nerves

• Preganglionic nerves are myelinated, while postganglionic nerves are non-myelinated.

Types of ANS

• The sympathetic nervous system (SNS) is associated with "fight or flight" responses.
• The parasympathetic nervous system (PSNS) is linked to "rest and digest" functions.

Sympathetic vs. Parasympathetic Effects

• SNS functions in emergencies while PSNS functions in relaxed conditions.
• SNS increases heart rate; PSNS decreases it.
• SNS dilates bronchi; PSNS constricts them.
• SNS dilates pupils (mydriasis); PSNS constricts them (miosis).
• SNS relaxes the bladder, reducing the urge to urinate; PSNS constricts the bladder, increasing urination.
• SNS reduces stomach acid secretion; PSNS increases it.
• SNS relaxes the intestine, PSNS frequent defecation
• SNS induces lipolysis; PSNS facilitates lipogenesis.
• SNS causes ejaculation; PSNS enables erection.

Relevant Anatomy

• SNS: Adrenergic, has thoracolumbar outflow (T1-L2) and small preganglionic nerves with long postganglionic nerves.
• PSNS: Cholinergic, has cranio-sacral outflow (cranial nerves 3, 7, 9, 10 and S1-S4) with long preganglionic nerves and short postganglionic nerves.

Neurotransmitters and Receptors

• Both SNS and PSNS use acetylcholine as the preganglionic neurotransmitter
• Postganglionic receptors are nicotinic neuronal receptors.
• SNS postganglionic neurotransmitters are norepinephrine, (primarily) and dopamine (minor, in kidney/GIT)
• PSNS postganglionic neurotransmitter is acetylcholine with muscarinic and nicotinic end organ receptors.
• SNS effects are produced by catecholamines (epinephrine, norepinephrine, dopamine)
• PSNS effects are produced only by acetylcholine.
• Some post-ganglionic nerves release acetylcholine, called sympathetic cholinergic nerves, innervating sweat glands and blood vessels and have muscarinic receptors.

Acetylcholine Physiology

• Acetylcholine is synthesized from Acetyl CoA inside the neuron.
• Choline uptake from surroundings is a rate-limiting step.
• After depolarization, acetylcholine enters vesicles and is released after depolarization.
• Acetylcholine acts on postsynaptic neurons containing nicotinic and muscarinic receptors.
• Acetylcholine esterase (ACHE) degrades acetylcholine and end organs.
• Choline is then reuptaken into the neuron.

Acetylcholine Degradation

• Endogenous acetylcholine in the synapse gets degraded by ACHE.
• Exogenous acetylcholine (from drugs) in blood plasma is degraded by butyrylcholinesterase (BChE) or pseudocholinesterase (PChE).
• Anticholinesterase drugs inhibit ACHE/PACHE, increasing acetylcholine levels and parasympathetic activity.

Cholinergic Toxins

• Drugs that block sodium entry are Saxitoxin and Tetrodotoxin.
• Drugs inhibiting entry into vesicle: Vesamicol.
• Drugs inhibiting choline uptake: Hemicholinium.
• Drugs blocking calcium channels: Botulinum toxin.
• Black widow spider venom causes massive release of ACh.

Botulinum Toxin

• Inhibit acetylcholine release by blocking calcium channels
• Calcium-dependent SNARE protein is the underlying issue
• Source: Clostridium botulinum, a bacterial toxin with types A-H
• Type A> B is effective for humans and Type A-BTX-A is used as a drug.
• Modify the drug by adding lipids
• Onabotulinum Toxin A, Abobotilinum Toxin A, or Incobotilinium Toxin A
• It is the most lethal toxin to mankind; 1 mg can kill 1 million people
• Injections must produce action at the local site only
• Respiratory Paralysis prevent cause of death respiratory paralysis

Botulinum Toxin Uses

• BATS: Relieve Muscle spasticity (rigidity)
  • Blepharospasm
  • Achalasia
  • Torticollis/Wry neck
  • Squint
• Relieve migraine pain.
• Treat hyperhidrosis
• Cosmetic Procedures - Botox

Receptors of Acetylcholine

• Nicotinic (N): Iontropic receptors which conduct sodium to cause an excitatory action, pentameric rosette shape.
• Muscarinic (M): G-protein coupled receptors (GPCRs), also known as metabotropic receptors, seven transmembrane, serpentine, helical shaped.

Nicotinic Receptor Details

• Nn: Neurons (Ganglionic receptors). SNS releases Epinephrine & Norepinephrine; PSNS releases Acetylcholine; Adrenal medulla (gland) releases Epinephrine. Agonist: Nicotine. Antagonist Ganglionic blockers (Hexamethonium, Mecamylamine, Trimethaphan).
• Nm: Skeletal muscles, muscle contraction occurs following sodium entry into the muscle and depolarization, part of the somatic nervous system, and voluntary actions. Subunits: α, β, γ, δ, ε. Agonist: Nicotine. Non-depolarizing muscle relaxants block (Tubocurare, Atracurium, Vecuronium).

Muscarinic Receptor Details

• 5 types (M1-M5).
• M1, M3, M5: Gq type GPCR (Excitatory), increases Calcium.
• M2, M4: Gi type GPCR (Inhibitory), decreases Calcium.

Location of Muscarinic Receptors

• CNS: Predominantly M1 receptors, including the hippocampus (increases memory/cognition, targeted for Alzheimer's treatment) and basal ganglia (decrease dopamine levels, use anticholinergics to increase levels in Parkinson's disease).
• Periphery: M1 in the stomach (increases HCl production, use Oxotremorine for research) and M2 in the heart (reduces heart rate, inhibits SA/AV node, uses Methacholine).

M3

• Excitatory
• Glands, smooth muscles for bronchoconstriction, Vasoconstriction
• Nitric oxide (EDRF), which is associated with vasodilation

What Happens During Ach Administration

• Normal Vessels: Acetylcholine produces Nitric oxide to relax muscles for vasodilation.
• Damaged vessels: Acetylcholine causes M3 receptors on muscles contracts causing vasoconstriction

Effect of Acetylcholine in body

• DUMBBELSS
• Increase all secretions in the body
  • D: Diarrhea
  • U: Urination
  • M: Miosis
  • B: Bronchospasm
  • B: Bradycardia
  • E: Excitation/Seizures
  • L: Lacrimation
  • S: Salivation
  • S: Sweating