Pharmacology parasympathetic nervous system- in brief

1. the parasympathetic
nervous system
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2. The Parasympathetic Nervous System
•All information should be reviewed by reading
–Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, 10th edition
–Basic and Clinical Pharmacology, 9th edition
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3. Functions of the Parasympathetic Nervous System
•Protects the retina from excess light
•Decreases heart rate
•Promotes glandular secretions
•Promotes the emptying of hollow organs
•Promotes the conservation of energy
•Promotes rest and repair
•Physiologically antagonizes the sympathetic nervous
system
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4. Dual Innervation at Most Sites
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5. Concept of Dominance in the Autonomic Nervous System
•The sympathetic nervous system dominates at some
sites
•The parasympathetic nervous system dominates at
other sites
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6. Parasympathetic Innervation From Brain
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7. Parasympathetic Innervation From the Sacral Cord
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8. Synthesis of Acetylcholine
Acetylcholine
Choline
Acetyl CoA
+
Choline acetylase
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9. Cholinergic Fiber
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10. Acetylcholine and Its Metabolites
Acetylcholine
Choline Acetate
hydrolysis
+
AChE
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11. Agents Affecting Cholinergic Transmission
•Hemicholinium
•Latrotoxin
•Vesamicol
•Calcium
•Physostigmine
•Atropine
•d-Tubocurarine
•Botulinus Toxin
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12. Uses of Botulinum Toxin Type A
Therapeutic Uses
–Blepharospasm
–Strabismus
–Cervical dystonia (spasmodic torticollis)
–Spasm of vocal cords
–Achalasia
•Cosmetic Uses
–Eyebrow furrows
–Frontalis muscle hyperactivity
–Lateral canthal wrinkles
–Axillary and palmar hyperhydrosis
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13. General Actions of Acetylcholine
•Promotes transmission in postganglionic autonomic fibers
•Promotes release of epinephrine and norepinephrine from
the adrenal medulla
•Promotes transmission in skeletal muscle fibers
•Promotes the functions of the parasympathetic nervous
system at cardiac muscle, smooth muscles and glands
•Promotes sympathetic thermoregulatory sweating
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14. Neuronal Innervation to Organs
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15. •Autonomic ganglia
–Nicotinic sites
–Muscarinic sites
•Adrenal medulla
–Nicotinic sites: Release of epinephrine (90%) and norepinephrine
(10%) into the circulation.
Reproduced from Basic and Clinical Pharmacology
Actions Mediated by NN Nicotinic Receptor
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16. Activities Within Cell Bodies of
Autonomic Ganglia
Postganglionic neuron,
sympathetic or
parasympathetic
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17. •End plate of skeletal muscle
fiber - generation of the EPP
Actions Mediated by NM Nicotinic Receptor
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18. Nature of Nicotinic Receptors
•Nicotinic receptors are pentameric and ionotropic - the
receptor proteins themselves form ion channels
•The ion channels are ligand-gated
•Two subtypes
–NN

subtype is present on cell body of postganglionic
autonomic neuron

–NM

subtype is present at the endplate of the
neuromuscular junction
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19. Agonists and Antagonists at Nicotinic Receptor Subtypes
RECEPTOR
TYPE/LOCATION
TISSUE
RESPONSE
SPECIFIC AGONISTS SPECIFIC
ANTAGONISTS
NN
Autonomic ganglia
Adrenal medulla
Generation
of the fEPSP
1,1-Dimethyl-4-
phenylpiperazinium
Tetramethylammonium
Cytisine
Epibatidine
Hexamethonium
Trimethaphan
NM
End plate of the
neuromuscular
junction
Generation
of the end
plate
potential
Phenyltrimethylammonium

a-Bungarotoxin
d-Tubocurarine

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20. Response to Doses of Nicotine
•Low Dose
–Autonomic ganglia
–Adrenal medullary cell
–End plate of skeletal muscle
•High Dose
–Autonomic ganglia
–Adrenal medullary cell
–End plate of skeletal muscle
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21. Muscarinic Receptors
•Muscarinic receptors
–The alkaloid muscarine mimics the actions of
acetylcholine at these receptor sites
–Metabotropic
•Associated with guanine nucleotide binding proteins (G-
proteins)
•Span the cell membrane seven times
–Several subtypes: M1,

M2,

M3,

M4,

M5

–Associated with various biochemical and
electrophysiological responses
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22. Biochemical Actions Associated With Muscarinic Receptors
M1, M3, and M5 muscarinic receptors
associate with Gq-protein; result:
activation of phospholipase Cb
M2, and M4 muscarinic receptors
associate with Gi-protein; result:
inhibition of adenyl cyclase
X
phosphatidylinositolbiphosphate (PIP)
2

inositoltriphosphate
(IP)
3 diacylglycerol (DAG)
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23. G-Protein Coupled Receptors
Review biochemistry, physiology, and pharmacology
textbooks for the interaction of G-proteins and receptors.
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24. Activation of Phospholipase Cb by Muscarinic Receptor Subtypes
•M1, M3, M5 muscarinic receptors
•Gq-GTP binding protein involved
•Agonist binds to the receptor
•The receptor associates with Gq-protein
•Gq-protein exchanges GDP for GTP
•The a subunit of Gq-protein dissociates from the bg dimer
and activates the effector molecule phospholipase Cb
•Phospholipase Cb hydrolyzes
phosphatidylinositolbiphosphate (PIP
2
) to
inositoltriphosphate (IP
3
) and diacylglycerol (DAG)
•IP3 releases Ca
2++
from the endoplasmic reticulum and
with DAG, activates protein kinase C
•The reaction is terminated by hydrolysis of GTP by the aq
monomer; reassociation of aq with the bg dimer
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25. Specific Antagonists for Muscarinic Receptor Subtypes
Darifenacin Smooth
muscles and
glands
M3
Tripitamine
Gallamine*
Cardiac
muscle fiber
M2
Pirenzepine
Telenzepine
Autonomic
ganglia,
gastric tissue
M1
SELECTIVE
ANTAGONIST(S)
TISSUE RECEPTOR
*Also blocks the nicotinic receptor
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26. ACTIONS OF ACETYLCHOLINE
AT ORGAN SITES
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27. Parasympathetic Innervation to the Eye
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28. Parasympathetic Control of Accomodation
From The Nurse, Pharmacology, and Drug Therapy
Parasympathetic
stimulation allows
contraction of the ciliary
muscle.
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29. Flow of Aqueous From the Eye
From Basic and Clinical Pharmacology
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30. Parasympathetic Function at Organs Sites (1)
•Gastrointestinal tract
–Longitudinal muscles
–Circular muscles
–Sphincter muscles
•Bile duct
•Gall bladder
•Urinary tract
–Ureters
–Detrusor muscle of the bladder
–Trigone
–Sphincter muscle of the bladder
•Bronchial smooth muscles
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31. Parasympathetic Function at Organs Sites (2)
•Lacrimal glands
•Pharyngeal glands
•Salivary glands
•Mucus glands
–Respiratory tract
–Esophagus
•Intestinal glands
•Gastric glands
•Pancreas
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32. Parasympathetic Control of the Cardiovascular System
•SA Node
•Atrial muscle
•AV node
•Purkinje fibers
•Ventricles
•Blood vessels
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33. Nitric Oxide Mediated Vasodilation
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34. Neuronal and Hormonal Control of Blood Pressure
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35. Cardiovascular Responses to Low and High Doses of ACh
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36. Sites of Dominance in the ANS
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics
1
The vast majority of blood vessels do not receive parasympathetic innervation
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37. Cholinergic Agents
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38. Cholinergic Agents
Alkaloids
Nicotine
Lobeline
Arecoline
Muscarine
Pilocarpine
Synthetic Agents
Dimethylphenylpiperazinium-
(DMPP)
Oxotremorine
Methacholine
Bethanechol
Carbachol
Cevimeline
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39. Nicotine
•Nicotine mimics the actions of acetylcholine at nicotinic
sites
–Cell body of the postsynaptic neurons
•sympathetic and parasympathetic divisions
–Chromaffin cells of the adrenal medulla
–End plate of skeletal muscle fiber
•Affinity for NN sites versus NM sites
•Used as an insecticide
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40. Muscarine
•Muscarine mimics the actions of acetylcholine at
smooth muscles, cardiac muscles, and glands
•Poisoning by muscarine produces intense effects
qualitative to those produced by cholinergic
stimulation of smooth muscles, cardiac muscle, and
glands
•Muscarine is found in various mushrooms
–Amanita muscaria: content of muscarine is very
low
–Inocybe sp: content of muscarine is high
–Clitocybe sp: content of muscarine is high
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41. Pilocarpine
•Has muscarinic actions
•Used for xerostomia
•Used for glaucoma
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42. Structure of Acetylcholine and its Derivatives
Acetylcholine Methacholine
Bethanechol Carbachol
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43. Therapeutic Uses of Cholinergic Agonists
•Dentistry
–Pilocarpine
–Cevimeline
•Ophthalmology
–Pilocarpine
–Carbachol
•Gastrointestinal tract
–Bethanechol
•Urinary bladder
–Bethanechol
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44. Contraindications to the Use of Choline Esters
•Hyperthyroidism
•Asthma
•Coronary insufficiency
•Peptic ulcer
•Organic obstruction in bladder or gastrointestinal tract
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45. Toxicity of Choline Esters
•Flushing
•SWEATING (diaphoresis)
•Abdominal cramps
•Spasm of the urinary bladder
•Spasm of accomodation
•Miosis
•Headache
•Salivation
•Bronchospasm
•Lacrimation
•Hypotension
•Bradycardia
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46. Agents That Inhibit Acetylcholinesterase
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47. Acetylcholinesterase
(True Cholinesterase)
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48. Acetylcholinesterase (1)
•Sites of location
–Cholinergic neurons
–Cholinergic synapses
–Neuromuscular junction
–Red blood cells
•Substrates
–Acetylcholine is the best substrate
–Methacholine is a substrate
–Hydrolyzes ACh at greater velocity than choline esters with
acyl groups larger than acetate or proprionate
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49. Acetylcholinesterase (2)
•Esters that are not substrates
–Bethanechol
–Carbachol
–Succinylcholine
•Its inhibition produces synergistic interaction with
methacholine and additive actions with bethanechol
and carbachol
•Drugs that block its hydrolysis of esters are called
cholinesterase inhibitors
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50. Drug Interactions of Choline Esters and Inhibitors of
Acetylcholinesterase - Synergism versus Additivity
•Methacholine
•Carbachol
•Bethanechol
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51. Butyrylcholinesterase
(Plasma esterase, pseudocholinesterase,
serum esterase, BuChE, PseudoChE)
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52. Butyrylcholinesterase (1)
•Sites of location
–Plasma, liver, glial cells, other tissues
•Substrates
–Butyrylcholine is the best
–Acetylcholine
–Succinylcholine
–Procaine
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53. Butyrylcholinesterase (2)
•Esters that are not substrates
–Methacholine, bethanechol, and carbachol
•Is inhibited by carbamyl and organophosphate
inhibitors of acetylcholinesterase
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54. Active Site of Acetylcholinesterase
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55. Interaction of AChE and Acetylcholine
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56. Acetylation of AChE and Release of Choline
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57. Hydroxyl Group of Water Attacks the Carbonyl Group of
Acetylated-AChE to Liberate AChE
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58. Carbamyl Inhibitors of AChE
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59. •Their action promoting accumulation of ACh at
muscarinic or nicotinic receptors is the basis of their
pharmacological, therapeutic, and toxic actions
•Are derivatives of carbamic acid
•Bind covalently to the esteratic site of AChE, resulting
in carbamylation of the enzyme
Carbamyl Inhibitors of AChE (1)
Carbamic acid Carbamic acid ester
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60. •Quaternary compounds bind to the ionic binding site
of AChE
•Their induce accumulation of AChE at nicotinic and
muscarinic sites, producing pharmacological
responses qualitative to cholinergic stimulation
•Inhibition of AChE is reversible, in the order of hours
•Are metabolized in the plasma by plasma esterases
Carbamyl Inhibitors of AChE (2)
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61. •High doses produce skeletal muscle weakness due to
depolarizing blockade at the end plate of the
neuromuscular junction
•High doses produce a profound fall in cardiac output
and blood pressure
•Their inhibition of AChE is not reversed by
pralidoxime
Carbamyl Inhibitors of AChE (3)
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62. •Quaternary ammonium compounds do not cross the
blood-brain barrier
•For oral administration, high doses must be given
Carbamyl Inhibitors of AChE (4)
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63. Neostigmine Carbamylates Acetylcholinesterase
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64. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
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65. Organophosphate Inhibitors of
Acetylcholinesterase
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66. •Chemical characteristics
•Promote accumulation of ACh at
–NM nicotinic receptor
–NN nicotinic receptor
–Muscarinic receptor
Organophosphate Inhibitors of Acetylcholinesterase (1)
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67. •Their action promoting accumulation of ACh at the
muscarinic receptor of the ciliary muscle is the basis
of their therapeutic effectiveness in open angle
glaucoma
•Only two of these agents are used for therapeutics
–Echothiophate for glaucoma
–Diisopropylflurophosphate (DFP) for glaucoma (?)
Organophosphate Inhibitors of AChE (2)
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68. •Inhibition of AChE by these agents is irreversible
–New enzyme synthesis is required for recovery of
enzyme function
•They also inhibit pseudocholinesterase
•Metabolized by A-esterases (paroxonases) present in
plasma and microsomes. They are metabolized by
CYP450.
Organophosphate Inhibitors of AChE (3)
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69. •Enzyme inhibition by these agents can be reversed
by cholinesterase reactivators such as pralidoxime if
administered before “aging” of AChE has occurred.
Inhibition by agents that undergo rapid “aging” is not
reversed.
•Except for echothiophate, these agents are extremely
lipid soluble, and some are very volatile.
Organophosphate Inhibitors of AChE (4)
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70. Diisopropylflurophosphate (DFP) is a Substrate for AChE
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71. The Extremely Slow Hydrolysis of Phosphorylated-AChE
New enzyme synthesis
is required for recovery
of enzyme function
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72. Various “States” of Acetylcholinesterase
Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE
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73. Acetylated-AChE Is Very Rapdily Hydrolyzed
AChE + Acetylcholine  AChE-acetylated + choline
AChE-acetylated + H
2
O  AChE + acetate
Hydrolysis of AChE-acetylated is rapid, in the order of
microseconds
P
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74. Carbamylated-AChE Is Hydrolyzed Slowly
AChE + Carbamyl inhibitor  AChE-carbamylated +
noncarbamylated metabolite
AChE-carbamylated + H
2
O  AChE + carbamic acid
derivative
Hydrolysis of the AChE-carbamylated is slow, in the order of
hours. The carbamylated enzyme is reversibly inhibited, and
recovery of function is in the order of hours
Enzyme after phosphorylation by neostigmine
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75. Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly
AChE + organophosphate inhibitor 
AChE-phosphorylated + nonphosphorylated metabolite
AChE-phosphorylated + H
2
O  AChE + phosphorylated
derivative
Hydrolysis of the AChE-phosphorylated is extremely slow,
in the order of days. The phosphorylated enzyme is
considered to be irreversibly inhibited, and recovery of
function is in the order of days. Pralidoxime, a reactivating
agent, may be adminstered to a subject before the enzyme
has “aged.”
Enzyme after phosphorylation by DFP
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76. AGING OF ACETYLCHOLINESTERASE
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77. Loss of An Alkyl Group From Phosphorylated
AChE “Ages” the Enzyme
AChE, phosphorylated
and inhibited by DFP
“Aged” AChE
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78. “Aging” of Phosphorylated- AChE
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79. Cholinesterase Reactivation
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80. Reactivation of Phosphorylated Acetylcholinesterase
•Oximes are used to reactivate phosphorylated AChE
•The group (=NOH) has a high affinity for the phosphorus
atom
•Pralidoxime has a nucleophilic site that interacts with the
phosphorylated site on phosphorylated-AChE
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81. Pralidoxime Reacts Chemically with Phosphorylated-AChE
The oxime group makes a nucleophilic attack upon the phosphorus atom
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82. Oxime Phosphonate and Regenerated AChE
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83. Limitations of Pralidoxime
•Pralidoxime does not interact with carbamylated-AChE
•Pralidoxime in high doses can inhibit AChE
•Its quaternary ammonium group does not allow it to
cross the blood brain barrier
•“Aging” of phosphorylated-AChE reduces the
effectiveness of pralidoxime and other oxime
reactivators
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84. Other Cholinesterase Reactivators
•Diacetylmonoxime
–Crosses the blood brain barrier and in
experimental animals, regenerates some of the
CNS cholinesterase
•HI-6 is used in Europe
–Has two oxime centers in its structure
–More potent than pralidoxime
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85. Edrophonium
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86. Edrophonium is a Short Acting Inhibitor that Binds
to the Ionic Site but Not to the Esteratic Site of AChE
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87. Pharmacology of Acetylcholinesterase Inhibition
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88. Inhibition of Acetylcholinesterase Produces
Stimulation of All Cholinergic Sites
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89. Carbamyl Inhibitors of AChE
•Physostigmine
•Neostigmine (N
+
)
•Pyridostigmine (N
+
)
•Ambenonium (N
+
)
•Demecarium (N
+
)
•Carbaryl
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90. Pharmacology of Carbamyl Inhibitors of
Acetylcholinesterase
•Eye
•Exocrine glands
•Cardiac muscle
•Smooth muscles
•Skeletal muscle
•Toxicity
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91. Therapeutic Uses of Inhibitors of Acetylcholinesterase
•Glaucoma (wide angle)
•Atony of the bladder
•Atony of the gastrointestinal tract
•Intoxication by antimuscarinic agents (use
physostigmine)
•Intoxication by tricyclic antidepressants (TCA’s) or
phenothiazines (use physostigmine)
•Recovery of neuromuscular function after competitive
blockade of NN receptor of skeletal muscle fibers
•Myasthenia gravis
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92. Therapeutic Uses of Edrophonium
•Diagnosis of myasthenia gravis
•In conjunction with chosen therapeutic agent to
determine proper dose of agent
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93. Determining Proper Dose of AChE Inhibitor
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94. Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease
•Tacrine
•Donepezil
•Rivastigmine
•Galantamine
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95. Organophosphate Inhibitors
of AChE
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96. Some Organophosphate Inhibitors of
Acetylcholinesterase
•Tetraethylpyrophosphate
•Echothiophate (N
+
)
•Diisopropylflurophosphate (DFP)
•Sarin
•Soman
•Tabun
•Malathion
•Parathion
•Diazinon
•Chlorpyrifos
•Many others
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97. Organophosphate Inhibitors - 2
Diisopropylfluorophosphate
(DFP)
Soman
Sarin
Tabun
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98. Echothiophate
Therapeutic use - local application to the eye for wide
angle glaucoma
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99. Conversion of Parathion to Paraoxon
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100. Conversion of Malathion to Malaoxon
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101. Malathion Is Hydrolyzed by Plasma Carboxylases in Birds
and Mammals but Not Insects
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102. Carboxyl Esterases
•Preferentially hydrolyzes aliphatic esters
•Malathion is a substrate
•Are inhibited by organophosphates
•May also be called aliesterases
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103. Uses of Malathion
•Insecticide
•Therapeutics
–Used as a lotion for Pediculus humanus capitis
associated with pediculosis
–0.5% solution in 78% isopropranolol is
pediculicidal and ovicidal
–Ovide is the brand name
–Primoderm was the former brand name
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104. Malathion Metabolism
•Rapidly metabolized by birds and mammals
•Plasma carboxylases are involved
•Insects do not possess the enzyme
•Organophosphates inhibit malathion metabolism
•Malathion is toxic to fish
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105. Aryl Esterases
•Are found in the plasma and liver
•Hydrolyzes organophosphates at the
– P-F bond
– P-CN bond
– Phosphoester bond
– Anhydride bond
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106. EPA And Organophosphates
•Diazinon
–No longer allowed to be manufactured for indoor
use in as of March 1, 2001 or for garden use as of
June 3, 2001
–Found in Real Kill
®
, Ortho
®
, Spectracide
®
–Limited agricultural use is allowed
•Chlorpyrifos (Dursban) has been phased out
•Parathion has been phased out for agricultural use in
the United States
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107. NERVE AGENT VX
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-
PHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
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108. NERVE AGENT VX
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-
PHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
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109. Organophosphates as Nerve Gas Agents
in Chemical Warfare (1)
•Extremely volatile agents such as sarin, tabun, soman,
and agent VX may be used as nerve agents in chemical
warfare.
•Accumulation of ACh at cholinergic receptors produces
effects reflecting stimulation of cardiac muscle, smooth
muscles and glands. Such effects would be identical to
those caused by muscarine poisoning.
•Bradycardia and hypotension occur. However, in some
cases, tachycardia may be observed, due to intense
sympathetic discharge in response severe hypoxemia.
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110. Organophosphates as Nerve Gas Agents
in Chemical Warfare (2)
•Irreversible inhibition of acetylcholinesterase by these
agents produces accumulation of ACh at the end
plate of skeletal muscle fibers. This in turn leads to
depolarizing blockade of the N
M
nicotinic receptor.
Skeletal muscle paralysis occurs. Movement is
impossible. The diaphragm is also paralyzed. The
individual eventually dies due to respiratory paralysis.
•Pralidoxime, atropine, and removal of the person
from the source of exposure are all to be employed in
cases of posioning.
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111. Use of Pyridostigmine During the Gulf War
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112. Pharmacology of Muscarinic Receptor
Blockade
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113. Acetylcholine is an agonist at
both muscarinic and nicotinic
receptors
The nicotinic actions of
acetylcholine remain when
muscarinic receptors are
blocked
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114. Muscarinic Receptor Blockade Does Not Affect
Ganglionic Transmission
X
Muscarinic receptor blockade prevents generation of the IPSP and the
sEPSP but not the fEPSP
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115. Muscarinic receptor blockade does not interfere with transmission at
autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers.
Sympathetic adrenergic functions are not affected.
XX
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116. In Dual Innervated Organs, Muscarinic Receptor
Blockade Allows Sympathetic Dominance
X
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117. Atropine
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118. Characteristics of Atropine
•Source
–Atropa belladonna
–Datura stramonium
•Known as Jamestown weed or jimsonweed
•Chemical nature
–An alkaloid
•Alternate name is d,l-hyoscyamine
•Nature of blockade
–Competitive
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119. Response to ACh in the Presence of Atropine
Log dose of acetylcholine
Response
control
atropine
Atropine competitively inhibits muscarinic reponses to ACh
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120. Actions of Atropine at Tissue Sites
•Eye
–Sphincter muscle of the iris: mydriasis
–Ciliary muscle: cycloplegia
Atropine limits
focusing to
distant objects
Accomodation
is blocked by
atropine
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121. Changes in Accomodation and Pupillary Diameter after
Administration of an Antimuscarinic Agent
Changes in Accomodation and Pupillary
Diameter after Administration of a Drug
0 15 30 45 60 75 90
0
2
4
6
8
10
pupil diameter
accomodation
Time (minutes)
Accomodation (diopters)
Pupil diameter (mm)
Reproduced from Basic and Clinical Pharmacologywww.freelivedoctor.com

122. Actions of Atropine At Smooth Muscles And Glands
•Eye
•Lacrimal glands
•Mucus glands of the pharynx and nasal cavity
•Bronchial smooth muscle
•Gastric glands
•Intestinal glands
•Pancreas
•Mucus glands of the respiratory tract
•Lacrimal glands
•Eccrine sweat glands
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123. Cardiovascular Actions of Atropine
•Heart rate
–Low dose
–High dose
•Systemic blood vessels
•Peripheral resistance
•Cutaneous blood vessels
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124. Response to Doses of Atropine
Reproduced from Basic and Clinical Pharmacology
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125. M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A
Small Negative Feedback Effect Upon ACh Release in Response to
Nerve Impulse Flow
postsynaptic
fiber
cardiac
muscle fiber
ACh
ACh
ACh
(----)
M1
M2
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126. M1Receptor Blockade Eliminates the Negative Feedback Effect and
Increases ACh Release in Response to Nerve Impulse Flow
postsynaptic
fiber
cardiac
muscle fiber
Pirenzepine is an
M1 antagonist
x
ACh
ACh
ACh
ACh
M1
M2
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127. Intravenous infusion of acetylcholine in high doses produces actions at numerous
sites. Bradycardia and hypotension are among the results. Such actions are
accentuated in the presence of inhibitors of AChE (they also block plasma
pseudocholinesterase).
i.v. infusion
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128. Prior blockade of muscarinic receptors followed by intravenous infusion of a high
dose of ACh converts the bradycardiac and hypotensive responses to tachycardia
and hypertension, mediated through the nicotinic receptors.
x
x
x
i.v. infusion
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129. Effect Of Atropine in Relation
to Dosage ...
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130. Dose of Atropine
DOSE EFFECT
0.5 mg Slight decline in heart rate
Some dryness of mouth
Inhibition of sweating
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131. Dose of Atropine
DOSE EFFECT
1.0 mg Definited dryness of mouth
Thirst
Inreased heart rate, sometimes
preceded by slowing
Mild dilatation of pupil
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132. Dose of Atropine
DOSE EFFECT
2.0 mg Rapid heart rate
Palpitation
Marked dryness of mouth
Dilated pupils
Some blurring of near vision
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133. Dose of Atropine
DOSE EFFECT
5.0 mg All the previous symptoms are
marked
Difficulty in speaking and swallowing
Restlessness and fatigue
Headache
Dry hot skin
Difficulty in micturition
Reduced intestinal peristalsis
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134. Dose of Atropine
DOSE EFFECT
10 mg Previous symtoms are more marked
and more Pulse, rapid and weak
Iris practically obliterated
Vision very blurred
Skin flushed, hot, dry, and scarlet
Ataxia
Restlessness and excitement
Hallucinations and delirium
Coma
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135. The previous five slides are reproduced from
Goodman and Gilman’s
The Pharmacological Basis of Therapeutics
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136. Scopolamine (1)
•Source - Hyoscyamus niger (henbane)
•Chemical nature of the molecule
•Nature of blockade
•Changes in the dose response curve of muscarinic
agonists in the presence of scopolamine
•Lower doses of scopolamine (0.1 - 0.2 mg) produce
greater cardiac slowing than an equivalent dose of
atropine. Higher doses produce tachycardia
•Low doses of scopolamine produce CNS effects that
are not seen with equivalent doses of atropine
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137. Scopolamine (2)
•Therapeutic doses of scopolamine normally produce
CNS depression, manifested as drowsiness,
amnesia, fatigue, dreamless sleep, reduction in REM,
euphoria
•In the presence of pain, the same therapeutic dose
occasionally cause excitement, restlessness,
hallucinations, or delirium. Such excitement is always
seen with large doses, as is also seen with large
doses of atropine
•Therapeutic use - prophylaxis of motion sickness; an
adhesive preparation, the Transderm scop is used
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138. Therapeutic Uses of Antimuscarinic Agents
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139. Therapeutic Uses of Muscarinic Antagonists (1)
•Cardiovascular System - atropine is generally used
for the following cases
–Improper use of choline esters
–Sinus or nodal bradycardia in cases of excessive
vagal tone associated with myocardial infarct
–Hyperactive carotid sinus (syncope and severe
bradycardia)
–Second degree heart block
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140. Therapeutic Uses of Muscarinic Antagonists (2)
•Gastrointestinal Tract
–Peptic ulcers
•In Europe, Japan, and Canada, M
1
muscarinic
receptor antagonists such as pirenzepine and
telenzepine are used
•In the U.S. H
2
histamine antagonists such as
cimetidine are used
–Spasticity of the g.i. tract
•M
3
muscarinic antagonists are being investigated
–Excessive salivation associated with heavy metal
poisoning and parkinsonism
–Production of partial blockade of salivation in patients
unable to swallow
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141. Therapeutic Uses of Muscarinic Antagonists (3)
•Urinary Bladder
–Reverse spasm of the ureteral smooth muscle
(renal colic)
–Increase bladder capacity in cases of enuresis
–Reduce urinary frequency in cases of hypertonic
bladder
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142. Therapeutic Uses of Muscarinic Antagonists (4)
•Central Nervous System
–Parkinson’s disease
–Motion sickness
–Produce tranquilization and amnesia prior to
surgery and in certain cases such as labor (not a
prominent use anymore)
–Anesthesia, to inhibit salivation (not a prominent
use anymore)
–Prevent vagal reflexes induced by surgical
manipulation of organs
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143. Therapeutic Uses of Muscarinic Antagonists (5)
•Posioning by inhibitors of acetylcholinesterase
•Mushroom poisoning due to muscarine
•In conjunction with inhibitors of acetylcholinesterase
when they are used to promote recovery from
neuromuscular blockade after surgery
•Injudicious use of choline esters
•Prevent vagal reflexes induced by surgical
manipulation of visceral organs
Atropine is used for the above
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144. Toxicity of Atropine
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145. Contraindications to the Use Of Antimuscarinic Agents
•Narrow Angle Glaucoma
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146. Flow of Aqueous and Its Escape From the Eye
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147. Contraindications to the Use of Antimuscarinic Agents
•Narrow angle glaucoma
•Hypertrophy of the prostate gland
•Atony of the bladder
•Atony of the G.I. Tract
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148. Tertiary Muscarinic Antagonists and Their Uses
•Ophthalmic applications
–Cyclopentolate
–Tropicamide
–Homatropine
•Parkinson’s disease
–Benztropine
–Trihexphenidyl
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149. Tertiary Muscarinic Antagonists and Their Uses
•Used for antispasmodic purposes
–Flavoxate - urinary bladder
–Oxybutynin - urinary bladder
–Tolterodine - urinary bladder
–Dicyclomine
–Oxyphencyclimine
In general, they are useful for spasms of the g.t. tract,
bile duct, ureters,
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150. Tolterodine
•Therapeutic use - reduce urinary urgency
•Metabolism
–Cytochrome P450
–Active metabolite is DD-01
•Drug interactions
–Ketoconazole
–Erythromycin
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151. Quaternary Ammonium Antagonists (1)
•General characteristics
•Pharmacology and therapeutic uses
•Distinct side effects with high and sometimes
therapeutic doses
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152. Quaternary Ammonium Antagonists (2)
•Methantheline (N
+
)
•Propantheline (N
+
)
•Methscopolamine (N
+
)
•Homatropine methylbromide (N
+
)
•Oxyphenonium (N
+
)
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153. Quaternary Ammonium Antagonists (3)
•Anisotropine (N
+
)
•Glycopyrrolate (N
+
)
•Isopropamide (N
+
)
•Mepenzolate (N
+
)
•Ipratropium (N
+
)
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154. Ipratropium
•Uses
•Distinctiveness from atropine
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155. M1 Muscarinic Receptor Antagonists
•Pirenzepine
– Blocks the M1 and the M4 receptor
– Its usefulness for peptic ulcer
•Telenzepine
–Blocks the M1 receptor
–Its usefulness for peptic ulcer
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156. M2 Muscarinic Receptor Antagonists
•Tripitamine
– Blocks the M2 receptor
– Blocks the action of acetylcholine at cardiac
muscle fibers
•Gallamine
–Blocks M2

muscarinic and the NN nicotinic sites
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157. M3 Muscarinic Receptor Antagonist
•Darifenacin
– Blocks the M
3
receptor
– Blocks the actions of acetylcholine at smooth
muscles and glands
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158. Drugs of Other Classes With Antimuscarinic Activity (1)
•Tricyclic antidepressants
–Imipramine
–Amitriptyline
–Protriptyline
–Others
.:
DEMONSTRATION
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159. Drugs of Other Classes With Antimuscarinic Activity (2)
•Phenothiazine Antipsychotic Agents
–Chlorpromazine
–Thioridazine
–Perphenazine
–Others
.:
DEMONSTRATION
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160. Drugs of Other Classes With Antimuscarinic Activity (3)
•Dibenzodiazepine antipsychotic agents
–Clozapine
–Olanzepine
•Dibenzoxazepine antipsychotic agents
–Loxapine
.:
DEMONSTRATION
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161. Drugs of Other Classes With Antimuscarinic Activity (4)
•H
1
Histamine receptor blocking agents
–Diphenhydramine
–Dimenhydrinate
–Promethazine
–Carbinoxamine
–Dimenhydrinate
–Pyrlamine
–Tripelennamine
–Brompheniramine
–Chlorpheniramine
–Cyproheptadine
.:
DEMONSTRATION
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