Introduction to the Autonomic Nervous System

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Introduction to the Autonomic Nervous System

• Ed Bilsky, Ph.D.
• Department of Pharmacology
• University of New England

Phone [phone], x2707 E-mail ebilsky_at_une.edu
2
Autonomic Nervous System

• A largely autonomous system that monitors and
  controls internal body functions to maintain
  homeostasis and meet the organisms demands
• cardiac output
• blood volume and pressure
• digestive processes
• Contains both afferent and efferent components,
  along with integrating centers
• Drugs which modify the function of the autonomic
  nervous system can be used therapeutically for
  many disease states

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Autonomic Nervous System

• There are two efferent divisions that act
  antagonistically to each other
• allows for a greater degree of control over
  various processes than one system would allow
• Sympathetic branch (fight or flight)
• increased cardiac output
• redirection of blood flow from GI system and skin
  to skeletal muscle
• Parasympathetic branch (rest and maintenance)
• decreased cardiac output
• increased GI motility and secretions

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Autonomic Nervous System

• Divisions of the ANS use a two neuron system
• Preganglionic neuron
• cell bodies in the spinal cord
• nerves terminate in ganglion
• Postganglionic neuron
• cell bodies in the ganglion
• nerves terminate on effector organs including
  smooth muscle and cardiac muscle

Ganglion aggregation of nerve cells in the
peripheral nervous system
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Autonomic Nervous System

• Preganglionic Cell Locations
• Sympathetic
• thoracic spinal cord
• lumbar spinal cord
• Parasympathetic
• cranial nerves (CN III, VII, IX, X)
• sacral spinal cord

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Neurotransmitters of the ANS

• Two primary neurotransmitters in the ANS
• Acetylcholine
• preganglionic cells of the parasympathetic and
  sympathetic branches
• postganglionic cells of the parasympathetic
  branch
• some postganglionic cells of the sympathetic
  branch
• Norepinephrine
• most postganglionic cells of the sympathetic
  branch

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Neurotransmitters of the ANS
cranial parasympathetic nerves
visceral effectors
Ach
Ach
visceral effectors
NE
Ach
sympathetic (thoracolumbar) nerves
visceral effectors
NE
Ach
visceral effector organs
sacral parasympathetic nerves
Ach
Ach
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Neuromodulators of the ANS

• There are numerous other substances found in
  cholinergic and noradrenergic neurons, as well as
  other neurons of the ANS
• These substances may modulate the actions of the
  primary neurotransmitters or have functions of
  their own
• Examples
• Substance P
• CGRP
• serotonin
• VIP
• CCK

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Primary Receptors of the ANS
Adrenergic
Cholinergic
?1
?2
?3
?1
?2
Muscarinic M1 M2 M3
Nicotinic NN NM
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Cholinergic Receptors

• Receptor Primary Locations Main Biochemical
  Effects
• M1 sympathetic post-ganglionic neurons,
  formation of IP3 and DAG --gt
• CNS neurons increased intracellular Ca2
• M2 myocardium, smooth muscle inhibition of
  adenylyl cyclase
• open K channels
• M3 vessels (smooth muscle/endothelial),
  formation of IP3 and DAG --gt
• exocrine glands increased intracellular Ca2
• NN postganglionic neurons increased Na
  conductance --gt
• depolarization of neuron
• NM neuromuscular junction increased Na
  conductance --gt
• initiation of muscle contraction

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Adrenergic Receptors

• Receptor Primary Locations Main Biochemical
  Effects
• ?1 smooth muscle formation of IP3 and DAG --gt
• increased intracellular Ca2
• ?2 presynaptic nerve terminals inhibition of
  adenylyl cyclase --gt
• platelets, lipocytes, smooth muscle
  decreased cAMP
• ?1 cardiac muscle, lipocytes, CNS stimulation of
  adenylyl cyclase --gt
• presynaptic ANS nerve terminals increased
  cAMP
• ?2 smooth muscle, cardiac muscle stimulation of
  adenylyl cyclase --gt
• increased cAMP
• ?3 lipocytes stimulation of adenylyl cyclase --gt
• increased cAMP

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Neurotransmission

• Four Major Steps
• 1. Synthesis and Storage of the neurotransmitter
  in the presynaptic neuron
• 2. Release of the neurotransmitter into the
  synaptic cleft
• 3. Interaction of the neurotransmitter with
  receptors on the post-synaptic cell
• 4. Termination of the synaptic actions of the
  neurotransmitter

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Synthesis and Storage

• Acetylcholine example
• The precursor choline is transported into
  cholinergic nerve terminals
• hemicholinums can block the transporter --gt
  decreased synthesis of ACh
• Once synthesized, acetylcholine is transported
  into vesicles for storage
• vesamicol can block the vesicular transporter,
  decreasing stores of releasable ACh
• Because of the ubiquitous nature of
  acetylcholine, these drugs are not used in
  clinical pharmacology

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Release of Neurotransmitter
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Release

• Acetycholine example
• Botulinum toxins are among the most potent
  pharmacological agents known
• The various botulinum toxins are produced by
  distinct strains of Clostridium botulinum
• The light chain of the protein exerts a
  metalloprotease effect that cleaves proteins
  involved in exocytosis
• SNAP-25
• syntaxin
• VAMP-1 and 2

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Clinical Correlate

• Intramuscular injections of botulinum toxin type
  A are the most effective treatment for focal
  dystonia and may be used in a limited form in
  patients with segmental or generalized dystonia
• Treatment is necessary every 3 to 5 months in
  most patients, and this therapy has been used
  safely in some patients for more than 15 years
• some patients develop resistance to the clinical
  response, and antibodies to the A toxin may
  develop
• if the dose is limited to less than 300 U per
  procedure and the treatment is given no more
  frequently than every 3 months, the risk of
  immunoresistance is minimized

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Interaction of Neurotransmitters with Receptors
Na
ACh
Ligand-gated channel
Agonist
G-protein regulated
Opioid
receptor
G protein
complex
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Termination of Neurotransmitter Effect
Enzymatic breakdown of neurotransmitter
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Acetylcholinesterase

• Acetylcholinesterase (AChE) is one of only a few
  enzymes that have obtained near catalytic
  perfection
• the rate of hydrolysis is close to the rate of
  diffusion to the active site
• a single enzyme can hydrolyze 14,000 ACh
  molecules/second
• Blockade of acetylcholinesterase will rapidly
  increase synaptic levels of acetylcholine
• neostigmine-reversible inhibitor
• sarin, malathion-irreversible inhibitors

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Termination of Neurotransmitter Effect
Reuptake of neurotransmitter
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Reuptake of Catecholamines

• Dopamine and norepinephrine are inactivated
  primarily via reuptake
• specific transporters that transport the
  catecholamines back into the presynaptic terminal
• The effects of cocaine and amphetamine are
  mediated in part through the dopamine transporter

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Cholinomimetic Drugs

• Ed Bilsky, Ph.D.
• Department of Pharmacology
• University of New England

Phone [phone], x2707 E-mail ebilsky_at_une.edu
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Drugs that Increase Cholinergic Activity

• Cholinergic agonists
• muscarinic agonists (pilocarpine)
• nicotinic agonists (nicotine)
• Inhibitors of acetylcholinesterase
• reversible inhibitors (neostigmine)
• irreversible inhibitors (nerve gas, insecticides)

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Direct Acting Cholinomimetics

• Structure
• Major differences exist between drugs in this
  class
• The choline esters have quaternary structures
  that possess positive charges (e.g., bethanechol)
• water soluble
• Other agents do not have have a charge (e.g.,
  pilocarpine)
• There is a strong stereoselective binding
  requirement for the muscarinic receptor
• (S)-bethanechol gtgt (R)-bethanechol

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Direct Acting Cholinomimetics

• Pharmacokinetics
• The quaternary amines are poorly absorbed and
  poorly distributed into the CNS compared to the
  tertiary amines
• bethanechol versus pilocarpine
• Some of these compounds are more resistant to
  cholinesterases than others
• bethanechol gtgt acetylcholine
• Modification of the structure can influence the
  affinity of the drug for muscarinic and nicotinic
  receptors
• bethanechol versus acetylcholine

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Direct Acting Cholinomimetics

• Pharmacodynamics
• Muscarinic receptors are coupled to G-proteins
  that activate phospholipase C (M1 and M3) or
  inhibit adenylyl cylase (M2)
• increased production of IP3 and DAG, decreased
  levels of cAMP
• These second messengers produce a number of
  intracellular effects
• increase intracellular Ca2 levels and activation
  of protein kinase C
• opening of K channels --gt hyperpolarization of
  the cell
• Activation of nicotinic receptors produces an
  influx of Na ions and depolarization of the cell
  --gt action potential

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Organ System Effects

• Cardiovascular system
• Primary effects of muscarinic agonists are a
  decrease in peripheral resistance and changes in
  heart rate
• Direct effects of the heart include
• increased K current in atrial muscle, SA and AV
  nodes
• decreased Ca2 current in cardiac cells
• a reduction in hyperpolarization-activated
  current that underlies diastolic depolarization
• net effect is to slow the pace maker cells and
  decrease atrial contractility
• the ventricles are less densely innervated than
  the atrial tissue

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Organ System Effects

• Cardiovascular system (continued)
• The direct effects of muscarinic agonists on the
  heart are usually opposed by reflex sympathetic
  discharge
• elicited by the fall in blood pressure
• Muscarinic agonists can produce marked
  vasodilation
• generation of EDRF from endothelial cells (NO
  main contributor)
• Respiratory system
• Muscarinic agonists produce smooth muscle
  contraction and stimulate secretion in the
  bronchial tree
• can aggravate symptoms associated with asthma

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Organ System Effects

• Genitourinary tract
• Stimulation of muscarinic receptors increases
  tone of the detrusor muscle and relaxes the
  trigone and sphincter muscles of the bladder
• promotes voiding of urine
• No major effects on uterine contractility

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Organ System Effects

• Eye
• muscarinic stimulation leads to contraction of
  the smooth muscle of the iris sphincter and of
  the cilliary muscle
• responsible for miosis and accomodation,
  respectively
• Both effects promote the outflow of aqueous humor
• decreases intraoccular pressure
• Miscellaneous secretory glands
• muscarinic agonists stimulate the secretory
  activity of sweat, lacrimal and nasopharyngeal
  glands

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Organ System Effects

• CNS effects
• The CNS contains both muscarinic and nicotinic
  receptors
• Nicotine has important effects on the brainstem
  and cortex
• stimulant type effects, addiction liability
• high doses can cause tremor and convulsions
• Muscarinic receptors play a role in movement,
  cognition, learning and memory, and vestibular
  function
• potential therapeutic applications to CNS
  diseases, though side-effects limit the clinical
  use of these agents

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Organ System Effects

• PNS effects
• Activation of nicotinic receptors produces action
  potentials in post-ganglionic nerves of the ANS
• The activation of both branches of the ANS
  results in complex effects on the organism
• cardiovascular effects are primarily
  sympathomimetic
• GI and genitourinary effects primarily
  parasympathomimetic
• Neuromuscular junction
• nicotine receptors initiate muscle action
  potentials
• fasciculations to strong contractions of an
  entire muscle possible
• can produce depolarization blockade

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Indirect Acting Cholinomimetics

• Structure
• Three major classes of compounds
• simple alcohols bearing quaternary ammonium group
• carbamic acid esters of alcohols bearing
  quaternary or tertiary ammonium groups
• organic derivatives of phosphoric acid
  (organophosphates)
• Pharmacokinetics
• The quaternary derivatives are poorly absorbed
  and poorly distributed into the CNS compared to
  the tertiary amines
• physostigmine gt neostigmine
• Differences in insecticide absorption and
  metabolism can affect the safety of these
  products
• malathion metabolized quickly in mammals and
  birds, not insects

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Indirect Acting Cholinomimetics

• Pharmacodynamics
• The affinity of the drug to acetycholinesterase
  determines the duration of action
• edrophonium and related quaternary alcohols
  interact weakly (electrostatic and hydrogen
  bonds) --gt 2-10 min interaction
• carbamate esters (e.g., neostigmine) form
  covalent bonds --gt 30 min to 6 hr interactions
• organophospahtes can form very strong covalent
  bonds that are basically irreversible --gt
  hundreds of hours
• An aging process can strengthen the
  organophosphate bonds making treatment of nerve
  gas poisoning very difficult to manage

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Organ System Effects

• Cardiovascular system
• These drugs exert negative chronotropic,
  inotropic and dromotropic effects on the heart
  --gt decreased CO
• Limited effects on the vasculature
• Net effect of moderate doses is modest
  bradycardia and a fall in CO, with only minimal
  effects on blood pressure
• higher doses produce marked bradycardia and
  hypotension
• Respiratory, GI and GU systems
• Similar to effects produced by direct acting
  agents

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Organ System Effects

• Neuromuscular junction
• Low (therapeutic) doses prolong and intensify the
  effects of physiologically released acetylcholine
• Higher doses can lead to muscle fibrillation and
  fasiculations of an entire motor unit

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Therapeutic Applications Myasthenia Gravis

• Myasthenia gravis is an autoimmune disorder that
  attacks the nicotinic ACh receptors at the
  neuromuscular junction
• leads to profound muscle weakness
• Acetylcholinesterase inhibitors increase the
  amount of acetylcholine in the neuromuscular
  junction
• neostigmine is frequently used for this disorder
• If muscarinic side-effects are prominent,
  anticholinergics can be administered (e.g.,
  atropine)
• tolerance usually occurs to the muscarinic
  side-effects
• Why are the direct acting cholinomimetics not
  used for myasthenia gravis?

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Therapeutic Applications Reversal of NMB

• By increasing levels of acetylcholine in the NMJ,
  the compounds are able to facilitate recovery
  from competitive neuromuscular blockade
• restores neuromuscular transmission
• Edrophonium has a more rapid onset of action than
  neostigmine, and shorter duration of action
• Neostigmine is preferable to other agents when
  gt90 twitch depression is to be antagonized

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Therapeutic Applications Glaucoma

• Constriction of the ciliary body promotes aqueous
  humor outflow --gt decreased intraoccular pressure
• Direct and indirect cholinomimetics can be used
  to treat glaucoma
• pilocarpine is the most commonly used agent
• typically formulated as eye drops

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Therapeutic Applications Atonic GI/GU

• The smooth muscle of the GI and GU systems can
  show depressed activity in certain states
• post-operative ileus
• congenital megacolon
• Bethanechol and neostigmine are the most widely
  used agents
• increases secretion and motility in the G.I.
  tract
• can be given orally or by injection

These agents can not be used if there is a
mechanical obstruction of the GI or urinary tract
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Therapeutic Applications Other Uses

• Physostigmine is rarely used for reversing the
  effects of anticholinergic poisoning
• has many side-effects of its own that are
  difficult to control
• The use of edrophonium for treating
  supraventricular tachyarrhythmias has been
  discontinued
• newer agents that act at adenosine receptors and
  calcium channels have replaced its use in this
  condition

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Anticholinergics

• Neuromuscular receptor antagonists
• Tubocurarine (nicotinic antagonist)
• Ganglionic receptor antagonists
• hexamethonium
• Muscarinic receptor antagonists
• atropine and scopolamine (belladonna alkaloids)
• pirenzepine

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Anticholinergics

• Structure
• Atropine is the prototypic drug in this class
• found in Atropa belladonna (deadly nightshade)
  and Datura stramonium (Jimson Weed)
• tertiary amine structure allows passage across
  the BBB
• Other drug classes possess anticholinergic
  activity by virtue of their similar chemical
  structures
• many antihistamines, antipsychotics and
  antidepressants
• Anticholinergics that are quaternary amines have
  been developed for limiting CNS effects
• ipratropium for asthma
• propantheline for GI use

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Anticholinergics

• Pharmacokinetics
• The quaternary amines are poorly absorbed from
  the GI tract and poorly distributed into the CNS
  compared to the tertiary amines
• atropine gtgt propantheline
• Metabolism is drug specific
• atropine has a relatively short half-life, with
  the majority of the drug being eliminated in the
  urine unchanged, some metabolism in the urine
  (hydrolysis and conjugation)

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Anticholinergics

• Pharmacodynamics
• Atropine produces reversible blockade of
  muscarinic receptors
• very selective for muscarinic receptors
• does not differentiate between M1, M2 and M3
  receptors
• Other anticholinergics possess subtype selective
  profiles
• pirenzepine M1 gt M2 gt M3

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Organ System Effects

• CNS
• Clinical doses of atropine typically produce
  minimal CNS effects
• scopolamine has greater CNS effects (sedation,
  amnesia)
• higher doses of these agents can produce
  hallucinations
• Blockade of muscarinic receptors has been used to
  treat tremors associated with Parkinsons disease
• newer agents have replaced anticholinergics as a
  primary treatment, sometimes used as an adjunct
• Vestibular disturbances, especially motion
  sickness, appears to be mediated by CNS
  muscarinic receptors
• scopolamine can be given orally or by transdermal
  patch

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Organ System Effects

• Eye
• Tertiary anticholinergics produced marked
  mydriasis due to unopposed sympathetic activity
• Decreased contraction of the ciliary muscle
  produces cycloplegia and a loss of accommodation
• These effects are useful for certain
  ophthalmology procedures
• contraindicated in patients with glaucoma
• Cardiovascular effects
• Moderate doses have pronounced effects on the SA
  node to increase heart rate
• low doses can cause bradycardia due to
  presynaptic muscarinic receptor blockade

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Organ System Effects

• Respiratory system
• Blockade of muscarinic receptors in the bronchial
  tree produces bronchodilation and decreased
  secretions
• Older class of agents used for treating asthma
• largely replaced in the treatment of asthma by
  beta-2 agonists
• Ipratropium is sometimes used in asthma and COPD
  as an inhalational drug
• decreased systemic distribution compared to
  atropine
• Anticholinergics can decrease secretions during
  intubation procedure and during the delivery of
  volatile anesthetics

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Organ System Effects

• GI effects
• Decreases secretions and motility in the GI
  system
• dry mouth and constipation are frequent
  side-effects
• infrequently used for treating peptic ulcer and
  diarrhea
• better agents available that have produce less
  side-effects
• selective M1 blockers are being developed
  (pirenzepine)
• Decreases spasms of the bladder and ureters is
  useful in treating some inflammatory conditions
  where incontinence is a problem (M3 antagonists)
• Sweat glands
• thermoregulatory sweating is inhibited by
  atropine
• sympathetic nervous system effect
• Large doses of atropine may increase body
  temperature in adults
• infants and children are much more sensitive to
  this effect

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Cholinergic poisoning

• A number of insecticides and nerve gasses can
  produce cholinergic toxicity
• Many of the signs and symptoms can be reversed by
  administering atropine
• There are several compounds that can hydrolyze
  the phosphoryalted acetylcholinesterase and
  reverse organic phosphate poisoning
• need to be administered soon after the exposure
• pralidoxine (PAM) regenerates the
  acetycholinesterase
• Atropine can be used to treat certain types of
  mushroom poisoning (Inocybe genus and others)

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Anticholinergic poisoning

• High doses of belladonna alkaloids can produce
  their own toxic syndrome
• dry as a bone, blind as a bat, red as a beet, mad
  as a hatter
• Typically associated with accidental poisoning in
  people seeking the hallucinogenic actions of the
  drug
• long-lasting agitation and delerium
• Overdose is typically treated symptomatically due
  to problems with the antidotes (physostigmine)
• temperature control and diazepam for seizures

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Ganglion Blocking Agents

• The lack of specificity with these agents limits
  their clinical use
• hexamethonium and others are used in preclinical
  research
• The specific response elicited depends on the
  predominant ANS innervation
• cycloplegia and loss of accommodation and usually
  dilation of the pupil
• cardiovascular effects include significant
  hypotension
• marked decrease in GI activity and loss of sexual
  function
• These compounds (e.g., trimethaphan) were once
  used to treat malignant hyperthermia
• replaced by other drugs (e.g., nitroprusside)