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Drugs acting on the autonomic nervous system 1
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
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
-
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
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
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
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)
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
Choline is taken up by an energy-dependent carrier, Na-choline co-trantansporter (rate limiting step)
Choline acetyl-transferase catalyzes the reaction of choline with acetyl CoA to form Ach
Ach is stored in pre-synaptic vesicles by active transport (along with ATP and proteoglycans)
When action potential arrives calcium influx fusion of synaptic vesicle with the cell membrane release of Ach
ACh released in the synaptic space binds to cholinergic receptor biological response
Acetylcholinesterase cleaves Ach to choline and acetate (termination of action)
Choline is transported back to the pre-synaptic neuron
Muscarine is an alkaloid in certain poisonous mushrooms
Nicotine is an alkaloid found in tobacco and other plants
Ach hyperpolarized the nodal node and decreases HR – bradycardia
At AV node and Purkinje fibres, refractory period is increased – conduction is slowed, PR interval increases, AV block can be produced
Force of contraction is also reduced
All blood vessles are dilated. Fall in BP and flushing (esp in blush area)…..M3 receptors are present on vascular endothelium …vasodilatation is due to release of EDRF
Smooth muscles in most organs are contracted (M3)…Tone and peristalsis in Git increases and sphincters relax --- abdominal cramps and evacuation of bowel
Peristalsis of ureter increases. Detrusor contracts , triogone and sphinter relaxes ….voiding of urine
Glands: secretion increases…..tracheobronchial and gastric
Eye: contraction of circular muscle of iris ---- miosis
Nicotinic actions: Ganglia: seen at higher doses. High dose of Ach after atropine causes tachycardia and rise in BP
Skeletal muscle: contraction of fibre
CNS: Ach does not penetrate BBB….direct inj-- Produces arousal
Diaphoresis = profuse sweating
Bethanecol:
MOA: Strong muscarinic action; lacks nicotinic action
Stimulates detrusor muscle of bladder, while trigone and sphincter are relaxed stimulates urination
Action is persistent: bethanecol is resistant to cholinesterases
Oral pilocarpine is the most potent stimulator of secretions such as sweat, tears, and saliva.
The drug is beneficial in patients with xerostomia resulting from irradiation of the head and neck.
Sjogren syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine
Cevimeline is a muscarinic agonist that seems to preferentially activate M1 and M3 receptors on lacrimal and salivary gland epithelia. The drug has a long-lasting sialogogic action and may have fewer side effects and better patient compliance than pilocarpine. The usual dose is 30 mg three times daily.
Glaucoma: Applied topically to the eye, pilocarpine produces rapid miosis, contraction of ciliary muscles, and spasm of accommodation .
It is extremely effective in opening the trabecular meshwork around the Schlemm canal, causing an immediate drop in intraocular pressure because of increased drainage of aqueous humor
Edrophonium has a short duration of action (10-20 mins) due to rapid renal elimination
It is a quartenary amine and its actions are limited to the periphery
Excess dose of edrophonium can cause cholinergic crisis: atropine is the antidote
The most clinically useful agents are selective blockers of muscarinic receptors. They are commonly known as anticholinergic agents, antimuscarinic agents or parasympatholytics.
A second group of drugs, the ganglionic blockers, shows a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia. Clinically, they
are the least important of the cholinergic antagonists.
A third family of compounds, the neuromuscular-blocking agents (mostly nicotinic antagonists), interfere with transmission of efferent impulses to skeletal
muscles. These agents are used as skeletal muscle relaxant adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures.
Atropine blocks muscarinic receptors in the salivary glands, producing dryness of the mouth (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature, which can be dangerous in children and the elderly.]
Atropine produces divergent effects on the cardiovascular system, depending on the dose. At low doses, the predominant effect is a slight decrease in heart rate. This effect results from blockade of the M1 receptors on the inhibitory prejunctional (or presynaptic) neurons, thus permitting increased ACh release. Higher doses of atropine cause a progressive increase in heart rate by blocking the M2 receptors on the sinoatrial node.
Tiotropium is administered once daily, a major advantage over ipratropium, which requires dosing up to four times daily.