Basic principles of drugs acting on the ANS and description of drugs acting on the cholinergic system

1. Drugs acting on the Autonomic
Nervous System-1
Dr. M. Ahsan (MBBS, MD)

2. Learning Outcomes….
By the end of the lecture, the students must be able to:
Describe the organization of autonomic nervous system
Describe cholinergic transmission
Classify cholinergic and anticholinergic drugs
Describe the mechanism of action, uses and adverse effects of
cholinergic and anticholinergic drugs

3. Organization of the Peripheral Nervous
System
Peripheral
nervous system
Efferent
division
Autonomic
system
Somatic system
Afferent
division
Enteric
Parasympathetic
Sympathetic
Involved in voluntary control
Involved in involuntary
control of vital functions

4. Autonomic nervous system (ANS)
• The autonomic nervous system is also called the visceral, vegetative, or
involuntary nervous system
widely distributed throughout the body
regulates autonomic functions that occur without conscious control
• In the periphery, it consists of nerves, ganglia, and plexuses that innervate
the heart, blood vessels, glands, other visceral organs, and smooth muscle
in various tissues

5. Anatomy of the ANS
The ANS carries nerve impulses
from the CNS through the pre-
ganglionic and post-ganglionic
fibres
Brainstem or
spinal cord
Cell body
Preganglionic fibre
Postganglionic fibre
Ganglion
Ganglionic
transmission
Neuroeffector
transmission
Effector organ

6. Division of ANS
The ANS is divided into:
Sympathetic nervous system
Parasympathetic nervous system

7. Sympathetic nervous system
• The preganglionic neurons originate from thoracic and lumbar regions
of the spinal cord (T1 to L2)
• The preganglionic fibres synapse in two chains of ganglia located
parallel to the spinal cord
• The postganglionic fibres extend from the ganglia and to tissues they
innervate and regulate
The adrenal medulla, like the sympathetic ganglion, receives pre-ganglionic fibres.
Ach is released from the pre-ganglionic terminal.
On stimulation, adrenal medulla releases epinephrine (adrenaline) and small amounts of
norepinephrine (noradrenaline)

8. Parasympathetic nervous system
• The parasympathetic preganglionic fibres arise from cranial nerves III
(oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus)
• Parasympathetic fibres also originate from sacral region (S2 to S4) of
the spinal cord
• These fibres synapse in ganglia located near or on the effector organ
• Thus, preganglionic fibres are long and postganglionic fibres are short
• Acetylcholine is the neurotransmitter of parasympathetic system

9. Drugs acting on the ANS
Drugs acting on
ANS
Those acting on
receptors activated
by ACh
Cholinergic drugs
Cholinergic
antagonists
Those acting on
receptors activated
by NE or Epi
Adrenergic agonist
Adrenergic
antagonists

10. Neurotransmission in ANS

11. Cholinergic transmission
Acetylcholine (ACh) is a major neurohumoral transmitter at:
adrenal medulla
autonomic ganglia (sympathetic and parasympathetic),
postganglionic parasympathetic fibres,
postganglionic sympathetic fibres to sweat gland
 neuromuscular junction (NMJ)

12. Synthesis, storage & destruction of ACh
• ACh is synthesized in the cholinergic nerve endings and stored in
vesicles.
AChE
ACh
N M
Choline
Acetate
Ch
ACh
ChAT
M
-

13. Synthesis and
release of
acetylcholine from
the cholinergic
neuron

14. Cholinergic receptors
They can be of 2 types
Muscarinic (M) Nicotinic (N)
M 1
M 2
M 3
M 4
M 5
NM
NN
 Ganglia
 Adrenal
medulla
 Skeletal muscle
 Postganglionic
cholinergic fibres
 Few postganglionic
sympathetic fibres

15. Muscarinic receptors
• G-protein coupled receptors
• Selectively stimulated by ‘muscarine’ and blocked by ‘atropine’.

16. Muscarinic receptorsM1
Major role in
gastric secretion
and relaxation
of lower
esophageal
sphincter (LES)
Plays role in
learning and
memory
M2
Cardiac
muscarinic
receptors are
predominantly
M2
Mediate vagal
bradycardia
M3
Visceral smooth
muscle
contraction and
glandular
secretions are
elicited through
M3 receptors
Mediates
vasodilatation
through EDRF
release
M4
Involved in
transmitter
release in
certain areas of
the brain
M5
Facilitates
dopamine
release and
mediate reward
behaviour

17. Muscarinic receptors

18. Nicotinic receptors
• Selectively activated by ‘nicotine’ and blocked by ‘tubocrurarine’.
• Functions as a ligand-gated Na channel

19. Cholinergic drugs
I. Direct acting Cholinergic agonists
• Choline esters
Acetylcholine
Methacholine
Carbachol
Bethanechol
• Alkaloids
Muscarine
Nicotine
Pilocarpine
II. Indirect-acting cholinergic agonists:
Anticholinesterases
• Reversible
Edrophonium, Neostigmine, Physostigmine,
Pyridostigmine
Rivastigmine, Donepezil, Tacrine, Galantamine
• Irreversible
Organophosphates:
Dyflos, Echothiophate, Malathion, Diazinon,
Tabun, Sarin, Soman
Carbamates:
Carbaryl, Propoxur

20. Direct acting cholinergic agonists
• Direct-acting cholinergic agonists mimic the effects of ACh by binding
directly to cholinoceptors (muscarinic or nicotinic).
All of the direct-acting cholinergic drugs have a longer duration of action
than ACh.
The more therapeutically useful drugs (pilocarpine and
bethanechol) preferentially bind to muscarinic receptors and are
sometimes referred to as muscarinic agents.

21. Acetylcholine
• ACh lacks therapeutic importance:
 multiple actions….both muscarinic and nicotinic.. (leading to diffuse
effects)
rapidly inactivated by the cholinesterases.
• ACh has both muscarinic and nicotinic activity.

22. Actions of ACh
• A. Muscarinic actions:
 Heart: Decrease in heart rate and cardiac output
Blood vessels: Causes vasodilation and lowering of blood pressure
Smooth muscle: stimulates intestinal motility, increases tone of detrusor
urination
Glands: increases salivary and bronchial secretion
Eye: causes ciliary muscle contraction for near vision, constricts pupillae
sphincter muscle, causing miosis (marked constriction of the pupil)

23. Actions of ACh
• B. Nicotinic actions:
Autonomic ganglia
Skeletal muscle
CNS actions

24. Cholinergic agonist: adverse effects

25. Uses
Bethanecol:
• It is used to stimulate the atonic bladder (postpartum/ postoperative/
spinal cord injury),
• Neurogenic bladder
• Congenital megacolon

26. Uses
Pilocarpine:
Ophthalmic uses: Topical pilocarpine is
used for:
Glaucoma
Drug of choice for emergency lowering of
intraocular pressure
Miotic action of pilocarpine is used for
reversing mydriasis due to atropine
Other uses:
Oral pilocarpine promotes salivation in
patients with xerostomia
Sjogren syndrome

27. Indirect-acting cholinergic agonist:
Anticholinesterases
• Acetylcholinesterase (AChE) is an
enzyme that specifically cleaves ACh
to acetate and choline and, thus,
terminates its actions.
• Inhibitors of AChE result in
accumulation of ACh in the synaptic
space
• Therefore, these drugs can provoke a
response at:
 all cholinoceptors (M and N)
NMJ
brain

28. Reversible anticholinesterase
• Anti-AChE with tertiary amino N are lipid soluble. Eg: Physostigmine
• Anti-AChE with quarternary amino N are non- lipid soluble/ polar.
Eg: Neostigmine
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Rivastigmine
Donepezil

29. Reversible anticholinesterases: Uses
• As miotics – a. glaucoma
b. to reverse effect
of mydriatics
c. to prevent
formation of
adhesions
between iris and
lens/cornea
• Myasthenia gravis
• Postoperative paralytic ileus
• Urinary retention
• Postoperative decurarisation
• Atropine poisoning
• Cobra poisoning
• Alzheimers disease

30. Myasthenia gravis
• Myasthenia gravis is an autoimmune disorder
affecting about 1 in 10,000 population,
• Antibodies develop against nicotinic receptors
(Nm) at the muscle endplate
• There is reduction in number of Nm receptors
to 1/3 of normal or less
• This results in weakness and easy fatigability
on repeated activity, with recovery after rest.
• The eyelid, external ocular, facial and
pharyngeal muscles are generally involved
first. Later, limb and respiratory muscles get
affected.

31. Myasthenia gravis
• Treatment:
Neostigmine 15 mg orally every 6 hrs
Corticosteroids (Prednisolone)
Other immunosuppressants
Thymectomy
Plasmapheresis
Atropine can be added for unwanted muscarinic side-effects
Edrophonium is a short acting AChE
inhibitor.
It is used in the diagnosis of myasthenia
gravis
 TENSILON test: IV injection of
edrophonium causes a rapid increase in
muscle strength in patients of
myasthenia gravis

32. Irreversible anticholinesterase
• Synthetic organophosphate compounds bind covalently to AChE and inhibit
it irreversibly
• This result in long-lasting increase in ACh at sites where it is released.
• These drugs are extremely toxic and were developed by the military as
nerve agents
• Compounds such as parathion and malathion, are used as insecticides.
Organophosphate nerve gas,
sarin, is used as agents of
chemical warfare

33. Anticholinesterase poisoning
• It can be accidental/ suicidal/ homicidal
• Toxicity with these agents is manifested as nicotinic and muscarinic signs
and symptoms
• Signs/Symptoms:
Irritation of eye, lacrimation, salivation, sweating, copious
tracheobronchial secretions, miosis, blurring of vision, bronchospasm,
breathlessness, colic, involuntary defecation/urination
Fall in BP, bradycardia or tachycardia, cardiac arrhythmias, vascular
collapse
Muscular fasciculations
Irritability, disorientation, tremor, convulsions, coma, death
Irreversible AChE inhibitors
are common insecticides.

34. Anticholinesterase poisoning
Treatment:
1. Termination of exposure
2. Maintain patent airway, positive pressure ventilation
3. Supportive measure: maintain temperature, BP, hydration and
control of convulsions
4. Specific antidote:
Atropine: 2mg iv every 10 min till signs of atropinisation occur
Reactivation of AChE with Oximes: Pralidoxime .. 1-2 g iv slowly

35. Pralidoxime
• Pralidoxime can reactivate inhibited AChE
• It acts as an antidote for organophosphorus insecticides
and nerve gases, but must be administered IV within
minutes of exposure
• It is ineffective after “aging” of the enzyme

36. Summary of cholinergic agonists

37. Anticholinergic drugs
• Drugs that block the action of ACh on muscarinic receptors (M)
They are also called ‘antimuscarinic drugs‘ or ‘parasympatholytics’
Drugs that block the action of Ach on nicotinic receptors (N):
 Ganglion blockers (block Nn)
 Neuromuscular blockers (block Nm)

38. Classification
Natural alkaloids
• Atropine
• Hyoscine
(scopolamine)
Semisynthetic
derivatives
• Atropine methonitrate
• Homatropine
• Hyoscine butyl bromide
• Ipratropium bromide
• Tiotropium bromide
Synthetic
compounds
• Glycopyrrolate
• Pirenzepine
• Cyclopentolate
• Tropicamide
• Oxybutynin
• Flavoxate
• Trihexphenidyl
• Procyclidine
Show selectivity for certain
types of muscarinic receptors

39. Synthetic compounds
Antisecretory-antispasmodics
Propantheline Dicyclomine
Oxyphenonium Valethamate
Glycopyrrolate Pirenzepine
Mydriatics
Cyclopentolate
Tropicamide
Vesicoselective
Oxybutinin Flavoxate
Tolterodine Darifenacin
Solifenacin
Antiparkinsonian
Trihexphenidyl
Procyclidine
Biperiden

40. Atropine
• Atropine is a tertiary amine
belladonna alkaloid
• It binds competitively to muscarinic
receptors (M) and prevents ACh from
binding to those sites
• Atropine acts both centrally and
peripherally
• Its actions last about 4 hours (except
eyes: action may last for days)

41. Anticholinergic drugs: Actions
Eye:
Atropine blocks muscarinic
receptors in the eye, resulting in:
mydriasis (dilation of the pupil)
unresponsiveness to light and
cycloplegia (inability to focus for
near vision)
In patients with angle-closure
glaucoma, intraocular pressure
may rise dangerously

42. Anticholinergic drugs: Actions
Smooth muscles:
Atropine and its congeners block M3 receptors in gut: atropine and
scopolamine are potent antispasmodic drugs
Causes bronchodilation and reduces airway resistance
Has a relaxant action on ureter and urinary bladder

43. Anticholinergic drugs: Actions
Secretions:
Block M3 receptors in the sweat, salivary, tracheobronchial and lacrimal
glands:
can cause rise in body temperature
produce dryness of mouth (xerostomia) and eyes
Used as pre-anaesthetic medication
Pirenzepine blocks M1 receptors on gastric glands (reduces acid secretion)

44. Anticholinergic drugs: Actions
CVS:
Tachycardia: High doses of atropine block M2 receptors on SA node
At low doses, M1 autoreceptors are blocked  increase Ach  decreased
hear rate (transient action)
CNS:
Hyoscine (scopolamine) depresses vestibular excitation: antimotion
sickness property
Blockage of cholinergic activity in basal ganglia: suppresses tremor and
rigidity of Parkinsonism
High doses cause excitation, restlessness, hallucination, delirium and coma

45. Uses of anticholinergic drugs
• Preanesthetic
medication
• Pulmonary
embolism
Antisecretory
• Intestinal colic & abd cramps
• Renal colic
• Nervous, functional & drug
induced diarrhoea
• To relieve urinary frequency &
urgency
• Dysmenorrhoea
Antispasmodic
• Inhaled ipratropium
bromide and
tiotropium is
effective in
asthmatic bronchitis
& COPD
Bronchodilator

46. Uses of anticholinergic drugs
• Diagnostic use:
for refraction
testing
• Therapeutic use:
to counter
mioticsMydriatic and
cycloplegic
• Sinus
bradycardia in
some cases of
MI and in
digitalis toxicity
Cardiac
vagolytic
• Parkinsonism
• Motion sickness
Central action
To antagonize muscarinic action of poisons:
*Anti-ChE *Early mushroom poisoning

47. Adverse effects
• Dry mouth, difficulty in swallowing and talking
• Dry, flushed and hot skin, fever
• Difficulty in micturition
• Constipation
• Dilated pupils, photophobia, blurring of vision
• Palpitation
• Excitement, delirium, visual hallucinations
• Cardiovascular and respiratory depression
The clinical picture of a high
(toxic) dose of atropine may be
remembered by an old
mnemonic device that
summarizes the symptoms:
Red as a beet, Dry as a bone,
Blind
as a bat, Hot as firestone, and
Mad as a hatter.

48. Atropine: Adverse effects and
contraindications
In patients with narrow irido-corneal
angle, acute congestive glaucoma can
be precipitated
Use with caution
in elderly males

49. Thank you

50. References
• Goodman & Gillman’s: The Pharmacological Basis of Therapeutics,
13th edition. New York: McGraw-Hill, 2018
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.

51. Summary:
General outline
of Autonomic
nervous system