The document provides a comprehensive overview of autonomic pharmacology, detailing the nervous system's organization and the function of the autonomic nervous system (ANS) including cholinergic and adrenergic neurotransmission. It describes the actions of various cholinergic drugs, such as agonists and anticholinesterase agents, their effects on muscarinic and nicotinic receptors, and their clinical applications in conditions like glaucoma, myasthenia gravis, and Alzheimer's disease. Additionally, it discusses toxicity associated with cholinergic agents and the mechanisms underlying drug interactions with the autonomic system.

1. Introduction to Autonomic Pharmacology

3. Nervous system
Peripheral nervous
system
Central nervous
system
Efferent
division
Afferent
division
Autonomic
system
Somatic
system
Enteric
Parasympathatic
Sympathatic

4. Anatomy of the ANS
• The ANS carries nerve impulses from the CNS to the effector organs by way
of two types of efferent neurons:
– The preganglionic neurons (cell bodies are located within the CNS): emerge
from the brainstem or spinal cord and make a synaptic connection in ganglia
– The postganglionic neurons (cell bodies originating in the ganglion): generally
nonmyelinated and terminates on effector organs, such as smooth muscles of
the viscera, cardiac muscle, and the exocrine glands

5. Brainstem or
spinal cord
Preganglionic
neuron
Ganglionic transmitter
Postganglionic
neuron
Neuroeffector transmitter
Effector organ
Anatomy of the ANS

6. Neurotransmitter chemistry of the autonomic nervous system
• The ANS can be divided into two groups based on the primary
neurotransmitter released:
• Cholinergic: if transmission is mediated by acetylcholine
• Adrenergic: if transmission is mediated by norepinephrine or epinephrine

7. Effector organ
M receptor
Sympathatic
Neuromuscular junction
NM receptor
Adrenal
medulla
Ganglionic
transmittion
Neuroeffector
transmittion
Parasympathatic
Sympathatic innervation of
adrenal medulla
Somatic
Effector organ
α or β Adrenergic receptor
NN receptor
NN receptor
NN receptor
Acetylcholine
Norepinephrine

8. Cholinergic transmission
• Acetylcholine mediates the transmission of nerve impulses across:
– All preganglionic efferent in both the sympathatic & parasympathatic systems
– The somatic motor fibres to the skeletal muscles
– Postsynaptic parasympathatic fibres
– Postsynaptic sympathatic innervation of sweat glands

9. Action Potential
Na+
Ca 2+
Acetylcholinesterase
Presynaptic neuron
Postsynaptic target
Nicotinic
Receptor
Muscarinic
Receptor
Choline
Choline
Na+
Acetyl CoA
+ Acetylcholine
Choline
Acetyltransferase
H+
ACH
ACh
Choline Acetate
Neurotransmission at cholinergic neurons
Neurotransmission at adrenergic neurons involves : synthesis, storage, release, and
receptor binding of Ach, followed by removal of the neurotransmitter from the
synaptic gap

10. Adrenergic transmission
• Norepinephrine mediates the transmission of nerve impulses across most
postganglionic sympathatic fibres

11. Action Potential
Na+
Neurotransmission at adrenergic neurons
Neurotransmission at adrenergic neurons involves : synthesis, storage, release, and receptor
binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic
gap
Presynaptic neuron
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake
Na+
, Cl-
NE
NE
NE
NE


NE
MAO

12. Overview
• Drugs affecting the ANS are divided into two groups according to the
type of neuron involved in the mechanism of action:
• The cholinergic drugs: they act on receptors that are activated by
acetylcholine (Ach)
• The adrenergic drugs: they act on receptors that are activated by
norepinephrine or epinephrine

13. Cholinergic Receptors (Cholinoceptors)
• Cholinoceptor denotes receptors that respond to acetylcholine
• Two families/subtypes of cholinoceptors : muscarinic (M) and
nicotinic (N) receptors

14. Muscarinic (M) receptors
• Are G-protein coupled receptors (seven transmembrane domains)
• In addition to binding acetylcholine, also recognize muscarine, but
show a weak affinity for nicotine
• These receptors have been found in organs innervated by
parasympathetic nerves as well as on some tissues that are not
innervated by these nerves, eg, endothelial, and on those tissues
innervated by postganglionic sympathetic cholinergic nerves (sweat
gland)
• Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5 have been
identified

15. Nicotinic (N) receptors
• These receptors, in addition to binding ACh, also recognize nicotine, but
show a week affinity for muscarine
• N receptors are transmembrane polypeptide whose subunits form cation-
selective ion channels
• N receptors are located on plasma membranes of postganglionic cells in all
autonomic ganglia, of muscles innervated by somatic motor fibers (i.e.
Neuromuscular junction), and of some CNS neurons

16. Nicotinic (N) receptors
• When the nicotnic AchR is stimulated, the channel opens and
allows Na+
to rush into the cell
• This triggers depolarization of the cell and elicits a neruronal
action potential in postganglionic nerve or muscle
contraction (in skeletal muscles)
• N receptors located at the neuromuscular junction are
sometimes designated NM and the ganglionic (neuronal)
receptors are designated NN

17. Subtypes and Characteristics of Cholinoceptors
Receptor
type
Other Names Location Structural Features
Postreceptor
Mechanism
M1 Nerves Seven transmembrane
segments,
Gq/11 protein-linked
IP3, DAG cascade
M2 Cardiac M2 Heart, nerves,
smooth muscle
Seven transmembrane
segments, Gi/o protein-
linked
Inhibition of cAMP
production, activation
of K+
channels
M3 Glands, smooth
muscle,
endothelium
Seven transmembrane
segments,
Gq/11 protein-linked
IP3, DAG cascade
M4 CNS Seven transmembrane
segments, Gi/o protein-
linked
Inhibition of cAMP
production
M5 CNS Seven transmembrane
segments,
Gq/11 protein-linked
IP3, DAG cascade
NM Muscle type,
end plate
receptor
Skeletal muscle
neuromuscular
junction
Pentamer1
[(α1)2β1δγ)] Na+
, K+
depolarizing
ion channel
N Neuronal CNS, postganglionic Pentamer1
with α and Na+
, K+
depolarizing

18. The cholinergic drugs
Cholinoceptor-activating & Cholinesterase-
inhibiting drugs

19. Cholinomimetic agents
• Cholinomimetic drugs can elicit some or all of the effects that
acetylcholine (ACh) produces
• Include agents that act directly (cholinoceptor agonists/stimulants) or
indirectly acting mechanisms (cholinesterase inhibitors)

20. Action Potential
Na+
Ca 2+
Acetylcholinesterase
Presynaptic neuron
Postsynaptic target
Nicotinic
Receptor
α
α
β
Muscarinic
Receptor
Choline
Choline
Na+
Acetyl CoA
+ Acetylcholine
Choline
Acetyltransferase
H+
ACH
ACh
Choline Acetate
Neurotransmission at cholinergic neurons

21. Direct acting cholinergic stimulants

22. Cholinomimetic agents
• The directly acting cholinomimetics can be subdivided into:
• Agents that stimulate muscarinic receptors (Parasympathomimetic
drugs): stimulation of muscarinic receptors at parasympathetic
neuro-effector junctions
• Agents that stimulate nicotinic receptors in the CNS, autonomic
ganglia, and at the neuromuscular junction

23. Effector organ
M receptor
Sympathatic
Neuromuscular junction
NM receptor
Adrenal
medulla
Ganglionic
transmittion
Neuroeffector
transmittion
Parasympathatic
Sympathatic innervation of
adrenal medulla
Somatic
Effector organ
α or β Adrenergic receptor
NN receptor
NN receptor
NN receptor
Acetylcholine
Norepinephrine
Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems

24. Direct acting cholinergic stimulants
• These agents can be divided into two groups:
• Choline esters (acetylcholine, metacholine, carbachol, &
bethanechol)
• Naturally occurring cholinomimetic alkaloids (muscarine,
nicotine, pilocarpine, & lobeline)

25. Choline Ester
Susceptibility to
Cholinesterase
Muscarinic
Action
Nicotinic Action
Acetylcholine chloride ++++ +++ +++
Carbachol Negligible ++ +++
Methacholine + +++ None
Bethanechol Negligible +++ None
Muscarine Negligible +++ None
Pilocarpine Negligible +++ None
Pharmacology of acetylcholine-like agonists

26. Muscarinic agonists: Parasympathomimetics
• Cholinergic receptor agonists (also called acetylcholine-like
agonists) mimic the effects of ACh by binding directly to
cholinoceptors

27. Organ system effect of direct acting cholinomimetics

28. Organ Response
Eye
Sphincter muscle of iris Contraction (miosis)
Ciliary muscle Contraction for near vision (accommodation)
Heart
Sinoatrial node Decrease in rate (negative chronotropy)
Atria Decrease in contractile strength (negative inotropy). Decrease in
refractory period
Atrioventricular node Decrease in conduction velocity (negative dromotropy). Increase in
refractory period
Ventricles Small decrease in contractile strength
Blood vessels
Arteries, veins Dilation (via EDRF). Constriction (high-dose direct effect)
Lung
Bronchial muscle Contraction (bronchoconstriction)
Bronchial glands Secretion
Gastrointestinal tract
Motility Increase
Sphincters Relaxation
Secretion Stimulation
Urinary bladder
Detrusor Contraction
Trigone and sphincter Relaxation
Glands
Sweat, salivary, lacrimal, nasopharyngeal Secretion

29. Clinical uses of the direct acting cholinomimetics
• Glaucoma: cholinomimetics reduce intraocular pressure by causing
contraction of the ciliary body so as to facilitate outflow of aqueous humour
(e.g pilocarpine and carbachol).
• Bladder and bowel atony after surgery: Bethanechol
• Xerostomia associated with Sjögren's syndrome and that caused by
radiation damage of the salivary glands: pilocarpine
 The immune system attacks the tear and saliva glands, and other secretory glands throughout the body
 The symptoms of Sjögren's syndrome include: dry eyes. a dry mouth. dry skin.

30. Toxicity
Overdosage is characterized chiefly by exaggeration of the various
parasympathomimetic effects:
NVD (nausea, vomiting and diarrhea), urinary urgency, salivation, sweating,
hypotension with reflex tachycardia, cutaneous vasodilation, and bronchial
constriction
Treatment consists of the (1) parenteral administration of atropine in doses
sufficient to cross the BBB (blood brain barrier), (2) measures to support
the respiratory and CV (cardiovascular) systems

31. Nicotinic drugs
Drugs that modulate nicotinic receptors have very limited application because:
1. localization of these receptor subtypes
2. Pharmacological stimulation of ganglionic neuronal receptors (NN) has limited
utility because this receptor affect both branches of the ANS
Excessive stimulation of NM receptors can cause depolarization block: loss of
electrical excitability due to inactivation of voltage-gated sodium channels
3. If repeated doses of the agonist is used, the nicotinic cholinergic receptors
can quickly become desensitized leading to fasciulations and paralysis

32. Nicotinic drugs
In the brain, the α4β2 oligomer is the most abundant nicotinic receptor in the
brain
Activation of α4β2 nicotinic receptors is associated with greater release of
dopamine in the mesolimbic system: mild alerting action and the addictive
property of nicotine absorbed from tobacco
Chronic exposure to nicotine: activation (depolarization) followed by
desensitization
Sustained desensitization may contribute to the benefits of nicotine replacement
therapy in smoking cessation regimens

33. Nicotin replacement therapy
To help patients stop smoking
Available in the form of gum, transdermal patch, nasal spray, or
inhaler
Sustained desensitization of α4β2 receptors in the CNS and
reduces the desire to smoke and the pleasurable feelings of
smoking

34. Varenicline (Chantix®
)
Is a partial agonist at α4β2 nicotinic receptors
Varenicline prevents the stimulant effect of nicotine at presynaptic α4β2
receptors that causes release of dopamine
ADRs (Adverse drug reaction): nausea, insomnia, and exacerbation of
psychiatric illnesses, including anxiety and depression

35. Inhibitors of Acetylcholinesterase
Indirect acting cholinomimetics

36. Indirect acting cholinomimetics
• Acetylcholinesterase (AChE) is an enzyme that specifically cleaves
ACh to acetate and choline and, thus, terminates its action
• Inhibitors of AChE indirectly provide a cholinergic action by
prolonging the lifetime of acetylcholine in synapses where
acetylcholine is released physiologically (i.e. they have both
muscarinic and nicotinic effets)

37. Indirect acting cholinomimetics
There are three chemical groups of cholinesterase inhibitors:
1. Simple alcohols bearing a quaternary ammonium group, eg,
edrophonium
2. Carbamates (eg, neostigmine )
3. Organophosphates (eg, echothiophate)
2+3: pesticide use in agriculture and in the home

38. Indirect acting cholinomimetics
The anti-ChE agents potentially can produce all the following effects:
 Stimulation of muscarinic receptor responses at autonomic effector organs
 Stimulation, followed by depression or paralysis, of all autonomic ganglia
and skeletal muscle (nicotinic actions)
 Stimulation, with occasional subsequent depression, of cholinergic
receptor sites in the CNS

39. Organ system effect of indirect acting cholinomimetics
Central nervous system (CNS)
• In low concentrations, the lipid-soluble cholinesterase inhibitors cause
diffuse activation on the electroencephalogram and a subjective alerting
response
• In higher concentrations, they cause generalized convulsions, which may
be followed by coma and respiratory arrest

40. Organ system effect of indirect acting cholinomimetics
• Eye, Respiratory Tract, GIT, & Urinary Tract: similar to the effects of the
direct-acting cholinomimetics
• Neuromuscular junction
Low (therapeutic) concentrations moderately prolong and intensify
the actions of physiologically released acetylcholine. This increases
the strength of contraction
At higher concentration, with marked inhibition of acetylcholinesterase,
depolarizing neuromuscular blockade occurs and that may be
followed by a phase of nondepolarizing blockade (i.e. nicotinic
receptors can quickly become desensitized)

41. Clinical uses of the indirect acting cholinomimetics
• Glaucoma: physostigmine, demecarium, echothiophate, isoflurophate. For
chronic glaucoma
• Gastrointestinal and Urinary Tracts: Neostigmine is most commonly used
anticholinesterase agents in the treatment of adynamic ileus and atony of
the urinary bladder, both of which may result from surgery
• Antimuscarinic Drug Intoxication
To treat overdoses of drugs with antimuscarinic actions, such as atropine
Physostigmine (cholinesterase inhibitor) has been used for this application
because it enters the CNS and reverses the central as well as the
peripheral signs of muscarinic blockade

42. Clinical uses of the indirect acting cholinomimetics
Myasthenia gravis:
A chronic autoimmune neuromuscular disorder [acetylcholine receptor antibodies]
Symptoms: The main symptoms include severe muscle weakness, difficulty breathing (due to
weakness of the respiratory muscles), difficulty swallowing, slurred speech, and overall
worsening of muscle fatigue.
Long-term therapy for myasthenia gravis:
pyridostigmine (neostigmine is an alternative)
Anticholinesterase agents help to alleviate the weakness by elevating and prolonging the
concentration of ACh in the synaptic cleft, producing a greater activation of the remaining
nicotinic receptors

43. cholinergic crisis
:
an excessive accumulation of acetylcholine due to an overdose of cholinesterase
inhibitor medications
These medications prevent the breakdown of acetylcholine, leading to excessive
stimulation of acetylcholine receptors
.
Symptoms: The symptoms of cholinergic crisis may resemble those of
myasthenic crisis, but additional signs such as excessive salivation, sweating,
tearing, gastrointestinal disturbances (nausea, vomiting, diarrhea)
..…… ,
Distinguishing between myasthenic crisis and cholinergic crisis can
be challenging because their symptoms can overlap
.

44. Treatment for cholinergic crisis:
discontinuing the cholinesterase inhibitor medication.
Atropine, an anticholinergic medication, to counteract the excess acetylcholine effects.
Diagnosis and differentiating myasthenic crisis from cholinergic crises
A tensilon test, [edrophonium (IV) test], Administration of 2 mg of edrophonium will worsen
the clinical symptom in cholinergic crisis. The contrary is the case in myasthenic crisis.

45. Clinical uses of the indirect acting cholinomimetics
• Alzheimer’s Disease
• are approved for the palliative treatment of Alzheimer’s diseaseThey produce
modest but significant improvement in the cognitive function of patients
with mild to moderate Alzheimer’s disease, but they do not delay
progression of the disease
• These agents can cross the BBB to produce a reversible inhibition of
AChE in the CNS

46. Uses
Approximate Duration of Action
Edrophonium Myasthenia gravis, ileus,
arrhythmias
5
–
15
minutes
Neostigmine Myasthenia gravis, ileus 0.5
–
2
hours
Pyridostigmine Myasthenia gravis 3
–
6
hours
Physostigmine Glaucoma 0.5
–
2
hours
Ambenonium Myasthenia gravis 4
–
8
hours
Demecarium Glaucoma 4
–
6
hours
Echothiophate Glaucoma 100
hours
Therapeutic Uses and Durations of Action
of Cholinesterase Inhibitors

47. Toxicity
Major cause of toxicity is accidental intoxication from the use pesticide use in
agriculture and in the home
CNS symptoms include agitation, dizziness, and mental confusion (compounds
of extremely high lipid solubility)
 Excessive inhibition can ultimately lead to a cholinergic crisis that includes:
 GIT distress: NVD & excessive salivation
 Respiratory distress: bronchospasm & increased bronchial secretions
 CV distress: bradycardia
 Visual disturbance: miosis, blurred vision
 Sweating
 Loss of skeletal motor function: progressing through incoordination, muscle cramps,
weakness, fasciculation, and paralysis