1. Pharmacology of Autonomic Nervous System
Munir Gharaibeh, MD, PhD, MHPE
Pharmacology of Autonomic Nervous System

2. Anatomic and neurotransmitter features of autonomic and somatic motor nerves.

3. Anatomy of the Autonomic Nervous System
Sites of Origins
Length of Preganglionic and Postganglionic neurons.
Ratio of preganglionic: postganglionic

5. Direct Effects of Autonomic Nerve Activity on some Organs Systems
Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

6. Direct Effects of Autonomic of Nerve Activity on some Organs Systems
Direct Effects of Autonomic of Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

7. Direct Effects of Autonomic Nerve Activity on some Organs Systems
Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

8. Direct Effects of Autonomic Nerve Activity on some Organs Systems
Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

9. Direct Effects of Autonomic Nerve Activity on some Organs Systems
Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical

10. Direct Effects of Autonomic Nerve Activity on some Organs Systems
Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical

13. Steps in Autonomic Transmission: Effect of Drugs

14. Steps in Autonomic Transmission: Effect of Drugs

15. 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
Munir Gharaibeh

16. Schematic illustration of a generalized cholinergic junction

17. 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.
Munir Gharaibeh

18. 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.
Munir Gharaibeh

19. Nicotinic transmission at the skeletal neuromuscular junction
Munir Gharaibeh

20. 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.

21. Diagram of the intestinal wall and some of the circuitry of the enteric nervous system.

22. 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

23. Cholinergic Receptors

24. The major groups of cholinoceptor-activating drugs, receptors, and target tissues.

25. 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.

26. Cholinergic Agonists or Parasympathomimetcs
Choline Esters.
Alkaloids.
Cholinesterase Inhibitors or Anticholinesterases.
Munir Gharaibeh

27. 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.
Munir Gharaibeh

28. Carbachol: not used clinically because of nicotinic activity
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.

29. Molecular structures of four choline esters

30. 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 M receptors.
used topically in glaucoma.
Nicotine
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31. 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 brain’s 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.

32. Varnicline(Chantix) Partial nicotinic agonist.
Highly effective in supporting smoking cessation.
May be associated with psychiatric symptoms, including suicidal ideation.

33. Structures of some cholinomimetic alkaloids

34. 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
Munir Gharaibeh

35. 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

38. 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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39. 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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40. 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.
Munir Gharaibeh