Pharmacology of Autonomic Nervous System

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Pharmacology of Autonomic Nervous System

• Munir Gharaibeh, MD, PhD, MHPE
• mgharaib_at_ju.edu.jo

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Anatomic and neurotransmitter features of
autonomic and somatic motor nerves.
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Anatomy of the Autonomic Nervous System

• Sites of Origins
• Length of Preganglionic and Postganglionic
  neurons.
• Ratio of preganglionic postganglionic

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Direct Effects of Autonomic Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical.
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Direct Effects of Autonomic of Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical.
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Direct Effects of Autonomic Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical.
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Direct Effects of Autonomic Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical.
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Direct Effects of Autonomic Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical
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Direct Effects of Autonomic Nerve Activity on
some Organs Systems. Drug effects are similar but
not identical
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Steps in Autonomic Transmission Effect of Drugs
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Steps in Autonomic Transmission Effect of Drugs
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Effects of Sympathetic and Parasympathetic
Activity
Function Sympathetic Parasympathetic
Heart rate Increased Slowed
Blood vessels Constricted Dilated
Stomach and intestine Decreased activity and secretions Increased activity and secretions
Salivary and bronchial glands Decreased secretion Increased secretion
Urinary bladder Body relaxed, sphincter constricted Body contracted, sphincter relaxed
Bronchial muscle Relaxed Contracted
Blood sugar Raised
Eye Pupils dilated Pupils constricted, accommodation for near vision
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Schematic illustration of a generalized
cholinergic junction
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Life Cycle of Acetylcholine

• Choline is transported into the presynaptic nerve
  terminal by a sodium-dependent choline
  transporter (ChT). This transporter can be
  inhibited by hemicholinium drugs.
• In the cytoplasm, acetylcholine is synthesized
  from choline and acetyl Co-A (AcCoA) by the
  enzyme choline acetyltransferase (ChAT).
• Acetylcholine is then transported into the
  storage vesicle by a second carrier, the
  vesicle-associated transporter (VAT), which can
  be inhibited by vesamicol.
• Peptides (P), adenosine triphosphate (ATP), and
  proteoglycan are also stored in the vesicle.

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Life Cycle of Acetylcholine

• Release of transmitter occurs when
  voltage-sensitive calcium channels in the
  terminal membrane are opened, allowing an influx
  of calcium. The resulting increase in
  intracellular calcium causes fusion of vesicles
  with the surface membrane and exocytotic
  expulsion of acetylcholine and cotransmitters
  into the junctional cleft. This step can be
  blocked by botulinum toxin.
• Acetylcholine's action is terminated by
  metabolism by the enzyme acetylcholinesterase.
• Receptors on the presynaptic nerve ending
  modulate transmitter release.

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Nicotinic transmission at the skeletal
neuromuscular junction
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Nicotinic transmission at the skeletal
neuromuscular junction

• ACh released from the motor nerve terminal
  interacts with subunits of the pentameric
  nicotinic receptor to open it, allowing Na
  influx to produce an excitatory postsynaptic
  potential (EPSP).
• The EPSP depolarizes the muscle membrane,
  generating an action potential, and triggering
  contraction. Acetylcholinesterase (AChE) in the
  extracellular matrix hydrolyzes ACh.

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Diagram of the intestinal wall and some of the
circuitry of the enteric nervous system.
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Diagram of the intestinal wall and some of the
circuitry of the enteric nervous system (ENS).

• The ENS receives input from both the sympathetic
  and the parasympathetic systems and sends
  afferent impulses to sympathetic ganglia and to
  the central nervous system.
• Many transmitter or neuromodulator substances
  have been identified in the ENS.
• AC absorptive cell
• CM circular muscle layer
• EC enterochromaffin cell
• EN excitatory neuron
• EPAN extrinsic primary afferent neuron
• IN inhibitory neuron
• IPAN intrinsic primary afferent neuron
• LM longitudinal muscle layer
• MP myenteric plexus
• NP neuropeptides
• SC secretory cell
• SMP submucosal plexus

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Cholinergic Receptors
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The major groups of cholinoceptor-activating
drugs, receptors, and target tissues.
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Cholinergic Agonists or Parasympathomimetcs

• Definition
• Drugs which produce effects similar to those
  observed during the stimulation of postganglionic
  parasympathetic nerve fibers or have actions
  similar to acetylcholine.

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Cholinergic Agonists or Parasympathomimetcs

• Choline Esters.
• Alkaloids.
• Cholinesterase Inhibitors or Anticholinesterases.

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Cholinergic Agonists or Parasympathomimetcs

• Choline Esters
• Acetylcholine
• Naturally released ACh from the cholinergic nerve
  endings.
• Very short acting because of rapid hydrolysis by
  AChase enzyme.
• Used only in experimentation.

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• Methacholine
• Used in in the diagnosis of bronchial asthma
  Methacholine Challenge
• Carbachol not used clinically because of
  nicotinic activity
• Bethanechol
• Works mainly on M3( smooth muscles and glands),
  but weak at M2, so minimal cardiac effects.
• Synthetic, long acting, used orally or s.c..
• Used in gastric and bladder atony, when there is
  no obstruction.
• Causes flushing, sweating, colic.

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Molecular structures of four choline esters
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Cholinergic Agonists or Parasympathomimetcs

• Choline Esters.
• Alkaloids produce similar actions to ACH but
  inconsistent
• Muscarine present in some species of mushroom
  (Amanita muscaria), can cause poisoning.
• Pilocarpine
• not hydrolyzed by cholinesterase
• works mainly on M3 receptors.
• used topically in glaucoma.
• Nicotine

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Nicotine

• Uses Non medical use( smoking and as an
  insecticide) and medical use in smoking cessation
• Kinetics
• Rapidly absorbed through skin, lungs, and gut
• For smoking cessation, used orally as a gum or
  topically as a patch.
• Works on the ganglia, parasympathetic,
  sympathetic, motor end plate, CNS).
• Dependence due to activation of nicotinic
  receptors on neurons in the brains dopaminergic
  reward pathway(venrtal tegument area).
• Nm stimulation can lead to fasiculations,
  spasms, and depolarizing blockade.
• Nn stimulation can lead to
• High heart rate
• Vsoconstriction
• High gastric motility and secretions.
• Increased respiratory rate, due to chemoreceptor
  activation.
• Medullary emetic chemoreceptor stimulation, so
  nausea and vomiting.

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Varnicline(Chantix)

• Partial nicotinic agonist.
• Highly effective in supporting smoking cessation.
• May be associated with psychiatric symptoms,
  including suicidal ideation.

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Structures of some cholinomimetic alkaloids
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Cholinergic Agonists or Parasympathomimetcs

• Choline Esters.
• Alkaloids.
• Cholinesterase Inhibitors or Anticholinesterases
• Reversible
• Alcohols e.g. Edrophonium
• Carbamic acid esters e.g. Neostigmine, Carbaryl.
• Irreversible( Organophosphates) e.g.
  Echothiophtae, Soman, Malathion

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Cholinest Cholinesterase Inhibitors or
Anticholinesterases erase Inhibitors or
Anticholinesterases

• Mechanism of Action
• Inhibit cholinesterase enzyme leading to
  accumulation of acetylcholine at neuromuscular
  junctions and synapses

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Organophosphate Poisoning

• Very potent agricultural insecticides and lethal
  war weapons.
• Very easily absorbed through all parts of the
  skin.
• Inhibit the enzyme and cause accumulation of ACh
  at all sites.

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Organophosphate Poisoning
Tissue or System Effects
Skin Sweating
Visual Lacrimation, miosis, blurring, spasm
Digestive Salivation, increased secretions, tone, and motility (cramps, vomiting, diarrhea, and defecation)
Urinary Frequency and incontinence
Respiratory Increased secretions, bronchoconstriction, weakness of muscles
Skeletal muscle Fasiculation, weakness, paralysis
Cardivascular Bradycardia, decreased cardiac output, hypotension.
CNS Tremor, anxiety, restlessness, confusion, convulsions, coma

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Treatment of Organophosphate Poisoning

• Stop the exposure, wash extensively, very lipid
  soluble.
• Atropine, a parasympatholytic drug, in very large
  doses, until the appearance of Atropine
  Poisoning.
• Pralidoxime, when given very early after the
  poisoning, can regenerate the enzyme.

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