HS1 - L25 Pharmacology of the Parasympathetic Nervous System

Functional Organisation of the Nervous System

• The nervous system is divided into two primary sections: the Central Nervous System (CNS) and the Peripheral Nervous System (PNS).
• Central Nervous System (CNS): Comprises the brain and the spinal cord.
• Peripheral Nervous System (PNS): Comprises the cranial and spinal nerves. It is further divided by function:
  • Motor Division (Efferent): Carries signals away from the CNS to effector organs.
  • Sensory Division (Afferent): Carries signals from receptors to the CNS.
• Motor Division Classifications:
  • Autonomic Nervous System (Involuntary): Regulates internal environments. Includes the Sympathetic, Parasympathetic, and Enteric nervous systems.
  • Somatic Nervous System (Voluntary): Controls skeletal muscle movement.

Anatomy and Projections of the Autonomic Nervous System

• Parasympathetic Projections: Originates from the midbrain, pons, medulla, and the sacral region of the spinal cord.
  • Oculomotor nerve (III): Targets the eye.
  • Facial nerve (VII) and Glossopharyngeal nerve (IX): Target lacrimal and salivary glands.
  • Vagus nerve (X): Targets the lungs, heart, liver, stomach, pancreas, and small intestine.
  • Sacral projections: Target the large intestine, rectum, bladder, and reproductive organs via the splanchnic nerve.
• Sympathetic Projections: Utilizes a paravertebral chain and specific ganglia.
  • Ganglia: Includes the superior cervical ganglion, stellate ganglion, celiac ganglion, superior mesenteric ganglion, and inferior mesenteric ganglion.
  • Adrenal Medulla: Functions as a modified ganglion, releasing adrenaline ($Ad$) and some noradrenaline ($NAd$) directly into the bloodstream.

Organisation of Sympathetic and Parasympathetic Pathways

• Parasympathetic Nervous System:
  • Path: CNS $\rightarrow$ Preganglionic fiber $\rightarrow$ Ganglion (Nicotinic receptors, $n$) $\rightarrow$ Postganglionic fiber $\rightarrow$ Effector organ (Muscarinic receptors, $m$).
  • Primary neurotransmitter at both the ganglion and effector organ is Acetylcholine ($ACh$).
• Sympathetic Nervous System:
  • Standard Path: CNS $\rightarrow$ Ganglion ($ACh$) $\rightarrow$ Effector organ ($NAd$).
  • Adrenal Path: CNS $\rightarrow$ Adrenal medulla ($ACh$) $\rightarrow$ Secretion of Adrenaline ($Ad$) and some $NAd$ into the blood to reach the effector organ.

The Life Cycle of Cholinergic Neurotransmission

There are six critical stages in the function of a cholinergic nerve:

1. Supply of transmitter precursor: Choline uptake.
2. Synthesis of transmitter: Formation of Acetylcholine ($ACh$).
3. Storage of transmitter: Packaging into synaptic vesicles.
4. Release of transmitter: Exocytosis triggered by calcium.
5. Inactivation of transmitter: Enzymatic degradation.
6. Feedback inhibition of release: Prejunctional receptor modulation.

Step 1: Supply

• Nerve cells cannot synthesize a sufficient amount of choline independently.
• Choline must be sourced from the blood, originating from the diet and the liver.
• Uptake into nerve endings occurs via a high-affinity carrier through a $Na^+$-dependent process.
• Hemicholinium:
  • Acts as a competitive inhibitor of the choline carrier.
  • Causes an activity-dependent block of cholinergic transmission by depleting $ACh$ stores.
  • It has no clinical use because its actions are too widespread throughout the body.

Step 2: Synthesis

• Synthesis occurs in the nerve cytoplasm and is catalyzed by the enzyme Choline Acetyltransferase (ChAT).
• Reaction: $\text{Choline} + \text{acetylCoA} \rightarrow \text{acetylcholine} + \text{CoA}$.
• Triethylcholine:
  • Can act as a substrate for ChAT.
  • Results in the formation of acetyltriethylcholine, which serves as a "false transmitter."
• ChAT inhibitors are not currently used in clinical practice.

Step 3: Storage

• $ACh$ is stored within synaptic vesicles maintained by an energy-dependent pump (Vesicular $ACh$ transporter).
• Vesamicol: Inhibits this pump, leading to the depletion of $ACh$ stores.
• False Transmitters:
  • The vesicular uptake mechanism is not highly specific.
  • Acetyltriethylcholine (produced from triethylcholine) can be taken up and stored.
  • Upon release, it has a significantly weaker effect on postsynaptic receptors than natural $ACh$.
  • This represents a unique drug action: providing a precursor that is converted into a less potent transmitter to reduce functional output.

Step 4: Release

• Release always requires the entry of $Ca^{2+}$ into the nerve ending.
• Release occurs through exocytosis, where the vesicle membrane fuses with the cell membrane.
• Pharmacological Modulation:
  • Black widow spider venom ($\alpha$-latrotoxin): Evokes massive release and subsequent depletion of vesicles.
  • Botulinum toxin: Blocks the release of $ACh$.
  • Clinical uses of Botulinum toxin: Blepharospasm, salivary drooling, axillary hyperhidrosis (excessive sweating), achalasia (oesophageal spasm), and cosmetic procedures. It is also classified as a biological warfare agent.

Step 5: Inactivation

• Diffusion of $ACh$ away from the cleft is generally not important unless cholinesterase is inhibited.
• The primary mechanism of removal is hydrolysis by tissue Acetylcholinesterase (AChE).
• Reaction: $\text{Acetylcholine} \rightarrow \text{acetate} + \text{choline}$.
• This reaction is non-reversible.
• Anticholinesterases: Drugs like neostigmine inhibit this process to prolong $ACh$ activity.

Step 6: Feedback and Regulation

Cholinergic nerves possess presynaptic (prejunctional) receptors that regulate neurotransmitter release:

• Muscarinic Autoinhibition: $ACh$ acting on muscarinic receptors ($mAChRs$) inhibits further release of $ACh$ (observed in the enteric nervous system).
• Nicotinic Modulation: $ACh$ acting on nicotinic receptors can increase release, though this is likely less functionally significant.
• Purinergic Regulation: ATP is co-released with $ACh$ and converted to adenosine, which inhibits release via $A_1$ receptors.
• Opioid Regulation: Morphine and other opioids inhibit release via $\mu$-receptors, which leads to side effects like constipation.
• Sympathetic Cross-Inhibition: Noradrenaline inhibits $ACh$ release via $\alpha_2$-adrenoceptors in certain tissues.

Muscarinic Receptors and Agonists

• Receptor Structure: Muscarinic receptors are G-protein coupled receptors characterized by 7 transmembrane segments.
• Agonist Potency Series: When cholinesterase is inhibited, the relative potency for agonists is: $\text{methacholine, muscarine} > \text{carbachol} \ggg \text{nicotine}$.
• Parasympathomimetics (Agonists):
  • $ACh$
  • Carbachol
  • Muscarine
  • Pilocarpine
  • Oxytremorine
• Physiological Effects of Agonists:
  • Cardiovascular: Decreased heart rate and cardiac output.
  • Smooth Muscle: Contraction of most smooth muscle; however, vascular smooth muscle dilates via the release of Endothelium-Derived Relaxing Factor (EDRF), which is Nitric Oxide (NO).
  • Exocrine Glands: Increased secretion, including sweating, lacrimation, salivation, and bronchial secretion.
• Clinical Uses: Glaucoma (topical application).
• Toxicology: Mushroom poisoning occurs through the ingestion of muscarine, a toxin found in certain mushroom species.

Muscarinic Antagonists

There are 5 subclasses of muscarinic receptors; three are of particular clinical importance:

• M1: Located in the stomach and salivary glands; Antagonist: Pirenzepine.
• M2: Located in the heart (cardiac); Antagonist: Gallamine.
• M3: Located in smooth muscle.
• Less Specific Antagonists: Atropine, hyoscine, and cyclopentolate.

Clinical Uses of Antimuscarinic Drugs

• Asthma: Ipratropium (bronchodilation).
• Bradycardia: Atropine (to increase heart rate).
• Gastrointestinal: Pirenzepine (to decrease gut motility and secretions).
• Surgical: Atropine (to decrease secretions and counteract the side effects of Acetylcholinesterase inhibitors/AChEI).
• Ophthalmic: Tropicamide (to dilate pupils).
• Urinary: Oxybutynin (to treat urinary incontinence).
• Motion Sickness: Hyoscine.