PANS CHOLINERGICS

• Parasympathetic Autonomic Nervous System (PANS)


  Rest and digest, activities of relaxation
• Neurotransmitter - Acetylcholine (ACh)


  Endogenous substance created by the body
• Acetylcholine biosynthesis


  1. Choline + Acetyl CoA

  2. Enzyme: choline acetyltransferase (ChAT) in phase 2 conjugation reaction
• Acetylcholine storage


  Vesicles at nerve endings of parasympathetic nerves, except on sympathetic nerves connected to sweat glands
• Acetylcholine receptors


  • Muscarinic (M)
  • Nicotinic (N)
• Muscarinic (M) receptors


  • Located on smooth and cardiac muscles
  • M1 - Neural, except parietal cells in stomach
  • M2 - Cardiac
  • M3 - Glandular and Smooth Muscles
  • M4 and M5 - CNS (unknown functions)

  
• Nicotinic receptors


  • Located on skeletal muscle neuromuscular junction
• If unsure what receptor, assume M3
• Perspiration only happens after the event/activity, except during emergencies when palms and soles will sweat due to sympathetic nerve connection
• OLINE (ACH)


  Endogenous substance – created by body
• Biosynthesis of ACh


  1. Choline + Acetyl CoA

  2. Enzyme: choline acetyltransferase (ChAT) in phase 2 conjugation reaction
• Storage of ACh


  • Vesicles at nerve endings of parasympathetic nerves except on sympathetic nerves connected to sweat glands

  
• Perspiration


  Only happens after the event/activity, except during an emergency when the palms and soles will sweat due to being connected to sympathetic nerves
• ACh Receptors


  • Muscarinic (M)
  • Nicotinic (N)
• Muscarinic (M) Receptors


  • M1 - Neural
  • M2 - Cardiac
  • M3 - Glandular and Smooth Muscles
  • M4 and M5 - CNS (unknown functions)
• Nicotinic Receptors


  • Muscles - skeletal neuromuscular junction
  • Ganglionic - transmission at sympathetic and parasympathetic region
  • CNS - brain
• Nicotinic receptors in CNS

  • Stimulant effect → faster thought process
  • 25 yrs above → peak thought process – complete myelination of neurons
• ACh created from Acetyl CoA + choline through the enzyme choline acetyltransferase
• ACh will be stored inside vesicles of parasympathetic nerves, in the end terminals of axons

  
• Release of ACh

  1. During action potential, Na ions will enter the cell while K ions will exit

  2. Voltage-gated Ca channels will open to allow Ca ions to go inside the cell, push the vesicles towards the end of the axon, and increase the permeability of the vesicles to release ACh
• Breakdown of ACh


  1. ACh binds to receptor → effect

  2. When effect of ACh is done, it will be broken down back into acetyl CoA and choline by the enzyme acetylcholinesterase

  3. Once broken down, it can be recycled by the axon, taken back by the NT transporters until the cycle starts again
• PANS Effects


  • Dilatation, diaphoresis (sweating)
  • Urination
  • Muscle contraction, miosis
  • Bowel movement
  • Excretion
  • Lacrimation
  • Salivation
• Mnemonic for PANS effects


  When it is painful to hold on – let go
• Effects of ACh on the Heart

  • Negative chronotropy (↓HR) on SA node
  • Negative inotropy (↓Force of contraction) on atrial muscle
  • Negative bathmotropy (↓Electrical excitability) on AV node
  • No effect on ventricular muscle

  
• All cardiac effects decrease cardiac output – amount of blood ejected per min – ↓BP
• Cardiac effects of ACh are a correcting mechanism for SANS
• Effects of ACh on Blood Vessels

  • No effect on arteries (coronary, muscle, viscera, skin, brain)
  • Dilatation of erectile tissue near hair follicles and salivary glands
  • No effect on veins
• Dilatation of erectile tissue and salivary glands


  Provides the necessary fluid to produce sebum and saliva
• Effects of ACh on Visceral Organs

  • Bronchial muscles - Constriction
  • Bronchial glands - Secretion of mucus
  • Gastrointestinal smooth muscle - Peristalsis
  • Gastrointestinal sphincters - Dilatation
  • Gastrointestinal glands - Secretion
  • Uterus - Variable
  • Penis - Erection
  • Urinary bladder detrusor - Contraction
  • Urinary bladder sphincter - Relaxation
  • Pupil - Constriction
  • Ciliary muscle - Relaxation
  • Salivary glands - Secretion
  • Lacrimal glands - Secretion
  • No effect on skin, kidneys, liver
• Peristalsis


  The movement of food or debris towards the stomach up until the rectum
• Gastrointestinal sphincters


  • M3 receptors are only found on the internal anal sphincter (involuntary)
  • Activation of ACh on M3 receptors of internal anal sphincter → sphincter will dilate/open → allowing defecation to occur
  • The contraction of the external anal sphincter is somatic (controlled/voluntary)
  • Kegel's exercise – The contraction and relaxation of the external anal sphincter and urethral sphincters
• Gastrointestinal glands


  • Activating the M3 receptors causes the secretion of mucus on the lumen of the stomach, protecting it against acid
  • Also allows secretion of gastric acid
  • Parietal cells (M1) – Produces gastric acid needed for digestion
  • M1 receptors have to be activated by ACh with histamine (H2) receptors and gastrin receptors for acids to be released
• Penis erection


  • M3 receptors are located in the ischiocavernosus and bulbospongiosus or bulbocavernosus muscles
  • Two of these muscles are needed to contract in order for blood to flow and maintain penile erection
  • Dilation of arteries on the penis → filling of blood → penile erection
  • Psychological aspect of erection can involve lust
  • Physiological aspect shows how it can occur with or without external stimulation
• Urinary bladder


  • M3 receptors are found on the detrusor muscle and internal urethral sphincter muscle
  • Activation of M3 receptor in detrusor muscles → contraction → urine is pushed towards urethra
  • Activation of M3 in the internal urethral sphincter → relaxation → urine is able to flow
  • The detrusor muscle surrounds the whole urinary bladder while the internal u.s. is circular around the bladder neck
  • External urethral sphincter – Somatic and can be controlled, allows inhibition of urination
  • Diuresis – Increased production and removal of urine
• Eyes


  • M3 receptors are found on the pupillary muscle and ciliary or radial muscles
  • Pupillary – Activation of M3 by ACh → miosis (constriction of pupils)
  • Miosis accommodates near vision – A mechanism in order to see clearly within a short distance or around 2 ft
  • Constriction of pupils limits light exposure entering the eyes and prevents damage of the optic nerves
  • Ciliary muscle – ACh activation of M3 → relaxes and also accommodates miosis

  
• Effects of ACh on Skin and Glands

  • No effects on sweat glands and pilomotor muscle
  • Salivary gland - Secretion
  • Lacrimal gland - Secretion
  • No effect on kidneys and liver
• Salivary glands


  • M3 receptors are responsible for salivation or secretion of saliva
  • The stimulation from food through sight, scent or sound leads to saliva production
  • Mastication (chewing) – The mechanical movement in the mouth that is prepared and lubricated by saliva
  • Saliva is also needed to dissolve food components attributed to flavor
• Lacrimal glands


  • Used to moisten the eyes
  • Tears are needed to clear the eyes from debris that contaminate it
  • Tears can be excreted towards the sides of the eyes
  • Excessive tears can end up passing through the nasolacrimal duct, causing the resemblance of a runny nose

  
• Drugs Acting on PANS

  • Direct Acting MOA: Occupies the M/N Receptors (Choline esters, Alkaloids)
  • Indirect Acting/Acetylcholinesterase Inhibitor MOA: Reversibly/irreversibly inhibit the AChase enzyme (Metoclopramide derivatives, Alcohol (ROH) derivatives, Carbamates, Organophosphates)
• Direct Acting Cholinomimetics


  Have an affinity to muscarinic or nicotinic receptors, can mimic the effect that endogenous ACh has