Transcript No Slide Title

The parasympathetic
nervous system
The Parasympathetic Nervous System
• All information should be reviewed by reading
– Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, 12th edition
– Basic and Clinical Pharmacology, 12th edition
Functions of the Parasympathetic Nervous System
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Protects the retina from excess light (miosis)
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
Dual Innervation at Most Sites
Concept of Dominance in the Autonomic Nervous System
• The sympathetic nervous system dominates at some
sites
• The parasympathetic nervous system dominates at
other sites
Parasympathetic Innervation From Brain
Parasympathetic Innervation From the Sacral Cord
Synthesis of Acetylcholine
+
Acetyl CoA
Choline
Choline acetylase
Acetylcholine
Cholinergic Fiber
Acetylcholine and Its Metabolites
hydrolysis
AChE
Acetylcholine
+
Choline
Acetate
Agents Affecting Cholinergic Transmission
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Hemicholinium
Latrotoxin
Vesamicol
Calcium
Physostigmine
Atropine
d-Tubocurarine
Botulinus Toxin
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
Neuronal Innervation to Organs
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
Actions Mediated by NN Nicotinic Receptor
• Autonomic ganglia
– Nicotinic sites
– Muscarinic sites
Reproduced from Basic and Clinical Pharmacology
• Adrenal medulla
– Nicotinic sites: Release of epinephrine (90%) and norepinephrine
(10%) into the circulation.
Activities Within Cell Bodies of
Autonomic Ganglia
ACh
Postganglionic neuron,
sympathetic or
parasympathetic
Actions Mediated by NM Nicotinic Receptor
• End plate of skeletal muscle
fiber - generation of the EPP
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
Agonists and Antagonists at Nicotinic Receptor Subtypes
RECEPTOR
TISSUE
SPECIFIC AGONISTS
TYPE/LOCATION RESPONSE
SPECIFIC
ANTAGONISTS
NN
Autonomic ganglia
Adrenal medulla
Generation
of the fEPSP
1,1-Dimethyl-4phenylpiperazinium
Tetramethylammonium
Cytisine
Epibatidine
Hexamethonium
Trimethaphan
NM
End plate of the
neuromuscular
junction
Generation
of the end
plate
potential
Phenyltrimethylammonium
-Bungarotoxin
d-Tubocurarine
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
Muscarinic Receptors
• Muscarinic receptors
– The alkaloid muscarine mimics the actions of
acetylcholine at these receptor sites
– Metabotropic
• Associated with guanine nucleotide binding proteins (Gproteins)
• Span the cell membrane seven times
– Several subtypes: M1, M2, M3, M4, M5
– Associated with various biochemical and
electrophysiological responses
Biochemical Actions Associated With Muscarinic Receptors
M2, and M4 muscarinic receptors
associate with Gi-protein; result:
inhibition of adenyl cyclase
X
M1, M3, and M5 muscarinic receptors
associate with Gq-protein; result:
activation of phospholipase Cb
phosphatidylinositolbiphosphate (PIP)2
inositoltriphosphate (IP)3
diacylglycerol (DAG)
G-Protein Coupled Receptors
Review biochemistry, physiology, and pharmacology
textbooks for the interaction of G-proteins and receptors.
Activation of Phospholipase Cb by Muscarinic Receptor Subtypes
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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  subunit of Gq-protein dissociates from the bgdimer
and activates the effector molecule phospholipase Cb
• Phospholipase Cbhydrolyzes
phosphatidylinositolbiphosphate (PIP2) to
inositoltriphosphate (IP3) and diacylglycerol (DAG)
• IP3 releases Ca2++ from the endoplasmic reticulum and
with DAG, activates protein kinase C
• The reaction is terminated by hydrolysis of GTP by the q
monomer; reassociation of q with the bgdimer
Specific Antagonists for Muscarinic Receptor Subtypes
SELECTIVE
RECEPTOR
TISSUE
M1
Autonomic
ganglia,
gastric tissue
Cardiac
muscle fiber
Pirenzepine
Telenzepine
Smooth
muscles and
glands
Darifenacin
M2
M3
*Also blocks the nicotinic receptor
ANTAGONIST(S)
Tripitamine
Gallamine*
ACTIONS OF ACETYLCHOLINE
AT ORGAN SITES
Parasympathetic Innervation to the Eye
ccomodations 1 & 2
Parasympathetic Control of Accomodation
Parasympathetic
stimulation allows
contraction of the ciliary
muscle.
From The Nurse, Pharmacology, and Drug Therapy
Flow of Aqueous From the Eye
From Basic and Clinical Pharmacology
Parasympathetic Function at Organs Sites (1)
• Gastrointestinal tract
– Longitudinal muscles
– Circular muscles
– Sphincter muscles
• Bile duct
• Gall bladder
• Urinary tract
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Ureters
Detrusor muscle of the bladder
Trigone
Sphincter muscle of the bladder
• Bronchial smooth muscles
Parasympathetic Function at Organs Sites (2)
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Lacrimal glands
Pharyngeal glands
Salivary glands
Mucus glands
– Respiratory tract
– Esophagus
• Intestinal glands
• Gastric glands
• Pancreas
Parasympathetic Control of the Cardiovascular System
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SA Node
Atrial muscle
AV node
Purkinje fibers
Ventricles
Blood vessels
Nitric Oxide Mediated Vasodilation
Neuronal and Hormonal Control of Blood Pressure
Cardiovascular Responses to Low and High Doses of ACh
Sites of Dominance in the ANS
SITE
PREDOMINANT TONE
Arterioles1
Veins1
Heart
Radial muscle of the iris
Sphincter muscle of the iris
Ciliary muscle of the eye
Müller’s muscle
Bronchial smooth muscle
Gastrointestinal tract
Urinary tract
Salivary glands
Eccrine sweat glands
Apocrine sweat glands
Pilomotor muscles
Sympathetic (adrenergic)
Sympathetic (adrenergic)
Parasympathetic
Sympathetic ( adrenergic)
Parasympathetic
Parasympathetic
Sympathetic ( adrenergic)
Parasympathetic
Parasympathetic
Parasympathetic
Parasympathetic
Sympathetic (cholinergic)
Sympathetic ( adrenergic)
Sympathetic ( adrenergic)
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics
1The
vast majority of blood vessels do not receive parasympathetic innervation
Cholinergic Agents
Cholinergic Agents
Alkaloids
Nicotine (N)
Lobeline
Arecoline
Muscarine(M)
Pilocarpine(M)
Synthetic Agents (MN)
Dimethylphenylpiperazinium(DMPP)
Oxotremorine
Methacholine
Bethanechol
Carbachol
Cevimeline
Nicotine
• Nicotine mimics the actions of acetylcholine at nicotinic
sites
– Cell body of the postsynaptic neurons (NN)
• sympathetic and parasympathetic divisions
– Chromaffin cells of the adrenal medulla
– End plate of skeletal muscle fiber (NM)
• Affinity for NN sites versus NM sites
• Used as an insecticide
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
Pilocarpine
• Has muscarinic actions
• Used for xerostomia
• Used for glaucoma
Structure of Acetylcholine and its Derivatives
Acetylcholine
Bethanechol
Methacholine
Carbachol
Therapeutic Uses of Cholinergic Agonists
• Dentistry
– Pilocarpine
– Cevimeline
• Ophthalmology
– Pilocarpine
– Carbachol
• Gastrointestinal tract
– Bethanechol
• Urinary bladder
– Bethanechol
Contraindications to the Use of Choline Esters
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Hyperthyroidism
Asthma
Coronary insufficiency
Peptic ulcer
Organic obstruction in bladder or gastrointestinal tract
Toxicity of Choline Esters
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Flushing
SWEATING (diaphoresis)
Abdominal cramps
Spasm of the urinary bladder
Spasm of accomodation
Miosis
Headache
Salivation
Bronchospasm
Lacrimation
Hypotension
Bradycardia
Agents That Inhibit Acetylcholinesterase
Acetylcholinesterase
(True Cholinesterase)
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
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
Drug Interactions of Choline Esters and Inhibitors of
Acetylcholinesterase - Synergism versus Additivity
• Methacholine
• Carbachol
• Bethanechol
Butyrylcholinesterase
(Plasma esterase, pseudocholinesterase,
serum esterase, BuChE, PseudoChE)
Butyrylcholinesterase (1)
• Sites of location
– Plasma, liver, glial cells, other tissues
• Substrates
– Butyrylcholine is the best
– Acetylcholine
– Succinylcholine
– Procaine
Butyrylcholinesterase (2)
• Esters that are not substrates
– Methacholine, bethanechol, and carbachol
• Is inhibited by carbamyl and organophosphate
inhibitors of acetylcholinesterase
Active Site of Acetylcholinesterase
Interaction of AChE and Acetylcholine
Acetylation of AChE and Release of Choline
Hydroxyl Group of Water Attacks the Carbonyl Group of
Acetylated-AChE to Liberate AChE
Carbamyl Inhibitors of AChE
Carbamyl Inhibitors of AChE (1)
• 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
Carbamic acid
Carbamic acid ester
Carbamyl Inhibitors of AChE (2)
• 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 (3)
• 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 (4)
• Quaternary ammonium compounds do not cross the
blood-brain barrier
• For oral administration, high doses must be given
Neostigmine Carbamylates Acetylcholinesterase
Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
Organophosphate Inhibitors of
Acetylcholinesterase
(indirect action, irreversible)
Organophosphate Inhibitors of Acetylcholinesterase (1)
• Chemical characteristics
• Promote accumulation of ACh at
– NM nicotinic receptor
– NN nicotinic receptor
– Muscarinic receptor
Organophosphate Inhibitors of AChE (2)
• 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 (3)
• 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 (4)
• 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.
Diisopropylflurophosphate (DFP) is a Substrate for AChE
The Extremely Slow Hydrolysis of Phosphorylated-AChE
New enzyme synthesis
is required for recovery
of enzyme function
Various “States” of Acetylcholinesterase
Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE
Acetylated-AChE Is Very Rapdily Hydrolyzed
AChE + Acetylcholine  AChE-acetylated + choline
AChE-acetylated + H2O  AChE + acetate
Hydrolysis of AChE-acetylated is rapid, in the order of
microseconds
P
Carbamylated-AChE Is Hydrolyzed Slowly
AChE + Carbamyl inhibitor  AChE-carbamylated +
noncarbamylated metabolite
AChE-carbamylated + H2O  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
Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly
AChE + organophosphate inhibitor 
AChE-phosphorylated + nonphosphorylated metabolite
AChE-phosphorylated + H2O  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
AGING OF ACETYLCHOLINESTERASE
Loss of An Alkyl Group From Phosphorylated
AChE “Ages” the Enzyme
AChE, phosphorylated
and inhibited by DFP
“Aged” AChE
“Aging” of Phosphorylated- AChE
Cholinesterase Reactivation
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
Pralidoxime Reacts Chemically with Phosphorylated-AChE
The oxime group makes a nucleophilic attack upon the phosphorus atom
Oxime Phosphonate and Regenerated AChE
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
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
Edrophonium
Edrophonium is a Short Acting Inhibitor that Binds
to the Ionic Site but Not to the Esteratic Site of AChE
Pharmacology of Acetylcholinesterase Inhibition
Inhibition of Acetylcholinesterase Produces
Stimulation of All Cholinergic Sites
Carbamyl Inhibitors of AChE
(indirect, reversible action)
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Physostigmine
Neostigmine (N+)
Pyridostigmine (N+)
Ambenonium (N+)
Demecarium (N+)
Carbaryl
Pharmacology of Carbamyl Inhibitors of
Acetylcholinesterase
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Eye
Exocrine glands
Cardiac muscle
Smooth muscles
Skeletal muscle
Toxicity
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
Therapeutic Uses of Edrophonium
• Diagnosis of myasthenia gravis
• In conjunction with chosen therapeutic agent to
determine proper dose of agent
Determining Proper Dose of AChE Inhibitor
Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease
• Tacrine
• Donepezil
• Rivastigmine
• Galantamine
Organophosphate Inhibitors
of AChE
Some Organophosphate Inhibitors of
Acetylcholinesterase
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Tetraethylpyrophosphate
Echothiophate (N+)
Diisopropylflurophosphate (DFP)
Sarin
Soman
Tabun
Malathion
Parathion
Diazinon
Chlorpyrifos
Many others
Organophosphate Inhibitors - 2
Diisopropylfluorophosphate
(DFP)
Sarin
Soman
Tabun
Echothiophate
Therapeutic use - local application to the eye for wide
angle glaucoma
Conversion of Parathion to Paraoxon
Conversion of Malathion to Malaoxon
Malathion Is Hydrolyzed by Plasma Carboxylases in Birds
and Mammals but Not Insects
Carboxyl Esterases
• Preferentially hydrolyzes aliphatic esters
• Malathion is a substrate
• Are inhibited by organophosphates
• May also be called aliesterases
R(CH2)CO-OR'
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
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
Aryl Esterases
• Are found in the plasma and liver
• Hydrolyzes organophosphates at the
– P-F bond
– P-CN bond
– Phosphoester bond
– Anhydride bond
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
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYLPHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
NERVE AGENT VX
NERVE AGENT VX
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYLPHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
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.
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 NM 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.
Use of Pyridostigmine During the Gulf War
Pharmacology of Muscarinic Receptor
Blockade
Acetylcholine is an agonist at
both muscarinic and nicotinic
receptors
The nicotinic actions of
acetylcholine remain when
muscarinic receptors are
blocked
Muscarinic Receptor Blockade Does Not Affect
Ganglionic Transmission
X
Muscarinic receptor blockade prevents generation of the IPSP and the
sEPSP but not the fEPSP
X
X
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.
In Dual Innervated Organs, Muscarinic Receptor
Blockade Allows Sympathetic Dominance
X
Atropine
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
Response
Response to ACh in the Presence of Atropine
Log dose of acetylcholine
Atropine competitively inhibits muscarinic reponses to ACh
Actions of Atropine at Tissue Sites
• Eye
Accomodations 1 & 2
– Sphincter muscle of the iris: mydriasis
– Ciliary muscle: cycloplegia
Atropine limits
focusing to
distant objects
Accomodation
is blocked by
atropine
Ac c omoda tion (diopter s)
Pupil diameter (mm)
Changes in Accomodation and Pupillary Diameter after
Changes in Accomodation and Pupillary
Administration
of an Antimuscarinic Agent
Diameter after Administration of a Drug
10
pup il diameter
8
6
4
a cco modation
2
0
0
15
30
45
60
75
90
Time (minutes)
Reproduced from Basic and Clinical Pharmacology
Actions of Atropine At Smooth Muscles And Glands
•
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•
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•
•
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
Cardiovascular Actions of Atropine
• Heart rate
– Low dose
– High dose
• Systemic blood vessels
• Peripheral resistance
• Cutaneous blood vessels
Response to Doses of Atropine
Reproduced from Basic and Clinical Pharmacology
M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A
Small Negative Feedback Effect Upon ACh Release in Response to
Nerve Impulse Flow
postsynaptic
fiber
M1 ACh
ACh
ACh
M2
cardiac
muscle fiber
M1Receptor Blockade Eliminates the Negative Feedback Effect and
Increases ACh Release in Response to Nerve Impulse Flow
postsynaptic
fiber
x
M1 ACh
ACh
ACh
M2
Pirenzepine is an
M1 antagonist
ACh
cardiac
muscle fiber
i.v. infusion
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).
x
x
x
i.v. infusion
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.
Effect Of Atropine in Relation
to Dosage ...
Dose of Atropine
DOSE
0.5 mg
EFFECT
Slight decline in heart rate
Some dryness of mouth
Inhibition of sweating
Dose of Atropine
DOSE
1.0 mg
EFFECT
Definited dryness of mouth
Thirst
Inreased heart rate, sometimes
preceded by slowing
Mild dilatation of pupil
Dose of Atropine
DOSE
2.0 mg
EFFECT
Rapid heart rate
Palpitation
Marked dryness of mouth
Dilated pupils
Some blurring of near vision
Dose of Atropine
DOSE
5.0 mg
EFFECT
All the previous symptoms are
marked
Difficulty in speaking and swallowing
Restlessness and fatigue
Headache
Dry hot skin
Difficulty in micturition
Reduced intestinal peristalsis
Dose of Atropine
DOSE
10 mg
and more
EFFECT
Previous symtoms are more marked
Pulse, rapid and weak
Iris practically obliterated
Vision very blurred
Skin flushed, hot, dry, and scarlet
Ataxia
Restlessness and excitement
Hallucinations and delirium
Coma
The previous five slides are reproduced from
Goodman and Gilman’s
The Pharmacological Basis of Therapeutics
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
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
Therapeutic Uses of Antimuscarinic Agents
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
Therapeutic Uses of Muscarinic Antagonists (2)
• Gastrointestinal Tract
– Peptic ulcers
• In Europe, Japan, and Canada, M1 muscarinic
receptor antagonists such as pirenzepine and
telenzepine are used
• In the U.S. H2 histamine antagonists such as
cimetidine are used
– Spasticity of the g.i. tract
• M3 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
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
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
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
Toxicity of Atropine
Contraindications to the Use Of Antimuscarinic Agents
• Narrow Angle Glaucoma
Flow of Aqueous and Its Escape From the Eye
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
Tertiary Muscarinic Antagonists and Their Uses
• Ophthalmic applications
– Cyclopentolate
– Tropicamide
– Homatropine
• Parkinson’s disease
– Benztropine
– Trihexphenidyl
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,
Tolterodine
• Therapeutic use - reduce urinary urgency
• Metabolism
– Cytochrome P450
– Active metabolite is DD-01
• Drug interactions
– Ketoconazole
– Erythromycin
Quaternary Ammonium Antagonists (1)
• General characteristics
• Pharmacology and therapeutic uses
• Distinct side effects with high and sometimes
therapeutic doses
Quaternary Ammonium Antagonists (2)
•
•
•
•
•
Methantheline (N+)
Propantheline (N +)
Methscopolamine (N +)
Homatropine methylbromide (N +)
Oxyphenonium (N +)
Quaternary Ammonium Antagonists (3)
•
•
•
•
•
Anisotropine (N+)
Glycopyrrolate (N+)
Isopropamide (N+)
Mepenzolate (N+)
Ipratropium (N+)
Ipratropium
• Uses
• Distinctiveness from atropine
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
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
M3 Muscarinic Receptor Antagonist
• Darifenacin
– Blocks the M3 receptor
– Blocks the actions of acetylcholine at smooth
muscles and glands
Drugs of Other Classes With Antimuscarinic Activity (1)
• Tricyclic antidepressants
– Imipramine
– Amitriptyline
– Protriptyline
– Others
.:
DEMONSTRATION
Drugs of Other Classes With Antimuscarinic Activity (2)
• Phenothiazine Antipsychotic Agents
– Chlorpromazine
– Thioridazine
– Perphenazine
– Others
.:
DEMONSTRATION
Drugs of Other Classes With Antimuscarinic Activity (3)
• Dibenzodiazepine antipsychotic agents
– Clozapine
– Olanzepine
• Dibenzoxazepine antipsychotic agents
– Loxapine
.:
DEMONSTRATION
Drugs of Other Classes With Antimuscarinic Activity (4)
• H1 Histamine receptor blocking agents
– Diphenhydramine
–
–
–
–
–
–
–
–
–
Dimenhydrinate
Promethazine
Carbinoxamine
Dimenhydrinate
Pyrlamine
Tripelennamine
Brompheniramine
Chlorpheniramine
Cyproheptadine
.:
DEMONSTRATION