Study Guide
Cholinoceptor Activating & Cholinesterase Inhibiting Drugs
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University:
Michigan State University -
Course:
PHM 450 | Introduction to Chemical Toxicology Academic year:
2024
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Views:
401
Pages:
52
Author:
omiliar74be
Cholinoceptor - Activating
&Cholinesterase-Inhibiting Drugs
1 2 Choline Ester ACE
Muscarinic Nicotinic
Acetylcholine
++++
+++
+++
Methacholine
+
++++
None
Carbachol
Negligible
++
+++
Bethanechol
Negligible
++
None
3 Mechanism of Action
Muscarinic transmission in the heart
Ach activates M2R linked via
Gi protein to a K+ channel
Causing hyperpolarization.
Voltage-dependent opening
of pacemaker Na+ channels
is shifted to more negative
Potentials
The phosphorylation of L-type Ca2+ channels is reduced.
M2R stimulates Gi protein↓→↓adenylyl cyclase→ ↓cAMP
formation→↓HR &↓ force of contraction.
4 Nicotinic transmission
at the neuromuscular
junction.
Ach interacts with subunits
of the nicotinic receptor to
open it, allowing Na+ to
produce an excitatory
postsynaptic potential
(EPSP).
The EPSP depolarizes the
muscle membrane,
generating an action
potential, and triggering contraction.
the extracellular Acetylcholinesterase(AChE) hydrolyzes Ach. 5 Effects of Direct-Acting Cholinoceptor
Stimulants
• Organ
Response
• Eye
• Sphincter muscle of iris
Contraction (miosis).
• Ciliary muscle
Contraction for near vision
facilitation of aqueous humor outflow
into the canal of Shlemm.
• Heart
• Sinoatrial node
• Atria
Atrioventricular node
Ventricles
Decrease in rate (negative chronotropy)
Decrease in contractile strength (negative
inotropy).
Decrease in conduction velocity (negative
dromotropy). Increase in refractory period.
Small decrease in contractile strength
6 Blood vessels
Arteries
Veins
Lung
Bronchial muscle
(bronchoconstriction)
Bronchial glands
Gastrointestinal tract
Motility
Sphincters
Secretion
Urinary bladder
Detrusor
Trigone and sphincter
Glands
Sweat, salivary, lacrimal
, nasopharyngeal
Dilation via . nitric oxide (NO)
Dilation via . nitric oxide (NO)
Contraction
Stimulation
Increase
Relaxation
Stimulation
Contraction
Relaxation voiding of urine
↑ Secretion
7 Organ System Effects
Cardiovascular System: M2
• IV infusions of low doses of Ach cause vasodilation,
reduction in blood pressure, and a reflex increase in
heart rate.
• Larger doses of a Ach produce bradycardia and
decrease a AV node conduction velocity and
hypotension.
• Decrease the contractility of atrial & ventricular cells.
• The direct slowing of sinoatrial rate & atrioventricular
conduction is often opposed by reflex sympathetic
discharge, elicited by the decrease in blood
pressure.
8 • IV injection of muscarinic agonists produces
marked vasodilation.
• Muscarinic agonists release nitric oxide (NO),
from the endothelial cells.
• The NO diffuses
to adjacent vascular
smooth muscle,
where it activates
guanylyl cyclase &
increases cGMP,
resulting in relaxation.
9 Pilocarpine
Natural alkaloid may produce
hypertension after a brief initial
hypotension.
The longer-lasting hypertensive
effect is due to sympathetic ganglionic activation caused
by activation of ganglionic M1 receptors, which elicit
slow excitatory postsynaptic potentials.
This effect, like the hypotensive effect, can be blocked
by atropine, an antimuscarinic drug.
10
Respiratory System:
Bronchoconstriction and increase bronchial secretion. Gastrointestinal Tract:
• increases the secretory and motor activity of the gut.
• The salivary and gastric glands are strongly
stimulated.
• Peristaltic activity is increased and most sphincters
are relaxed.
• The M3 receptor is
required for direct
activation of smooth
muscle contraction,
whereas the M2
receptor reduces cAMP
formation & relaxation
caused by
11
sympathomimetic drugs. Genitourinary Tract :
• Stimulate the detrusor muscle and relax the trigone
and sphincter muscles of the bladder, thus
promoting voiding.
• The function of M2 and M3 receptors in the urinary
bladder is the same as in intestinal smooth muscle.
• The human uterus is not sensitive to muscarinic
agonists.
Miscellaneous Secretory Glands
• Muscarinic agonists stimulate secretion of sweat,
lacrimal, and nasopharyngeal glands
12 Central Nervous System:
The CNS contains both muscarinic and nicotinic
receptors, the brain is richer in muscarinic sites
and the spinal cord contains more nicotinic sites.
Pilocarpine is used to induce chronic epilepsy in
rats, to examine different treatments (M1 effect).
oxotremorine produces tremor, hypothermia, and
antinociception (increased tolerance for pain ) M2.
Presynaptic nicotinic receptors regulate the release
of several neurotransmitters.
In high concentrations, nicotine induces tremor,
emesis, and stimulation of the respiratory center.
At still higher levels, nicotine causes convulsions
13
& fatal coma. Autonomic ganglia:
• In the CVS, the effects of nicotine are chiefly
sympathomimetic.
• Nicotine causes hypertension, tachycardia which
may alternate with a bradycardia mediated by
vagal discharge.
GIT and urinary tracts:
• The effects are parasympathomimetic:
nausea, vomiting, diarrhea, and voiding of urine
are commonly observed.
• Prolonged exposure may result in depolarizing
blockade of the ganglia.
14 Neuromuscular Junction:
• Nicotinic applied directly causes contractile
response varies from disorganized
fasciculations to a strong contraction of the
entire muscle.
• Nicotine also causes rapid development of
depolarization blockade; transmission
blockade persists even when the membrane
has repolarized.
• This latter phase of block is manifested as
flaccid paralysis of skeletal muscle.
15 Indirect-Acting Cholinomimetics
Reversible Cholinesterase
inhibitors.
Neostigmine
an ester composed of carbamic acid
([1]) and a phenol bearing
a quaternary ammonium group([2]).
Physostigmine
A naturally occurring carbamate,
is a tertiary amine.
Edrophonium is not an ester but binds
to the active site of the enzyme.
16 Metabolism of Acetylcholine
The positively charged nitrogen in the acetylcholine
molecule is attracted to the ionic site on
acetylcholinesterase, and hydrolysis is catalyzed at
the esteric site to form choline and acetic acid.
17 Neostigmine
Stabilized by an ionic bond at the anionic site and a
hydrolyzable covalent bond at the esteratic site, e.g.,
Stabilized by an ionic bond at the anionic
site and through weak hydrogen bonding
at the esteratic site.
18 Irreversible cholinesterase inhibitors.
organophosphate
Structures of some
organophosphate
cholinesterase
inhibitors.
The dashed lines
indicate the bond
that is hydrolyzed in
binding to the enzyme.
The shaded ester
bonds in malathion
represent the points
of detoxification of the
molecule in mammals
and birds.
19 a cholinesterase inhibitor attaches to
the serine hydroxyl group on ACh.E.
This prevents acetylcholine from
interacting with the cholinesterase
enzyme and being broken down.
20 21 22 Absorption, Distribution, and Metabolism
• Absorption of the quaternary carbamates from
the conjunctiva, skin, and lungs is poor, since
their permanent charge renders them relatively
insoluble in lipids.
• Thus, much larger doses are required for oral
administration than for parenteral injection.
• Distribution into the CNS is negligible.
Physostigmine, in contrast, is well absorbed
from all sites and can be used topically in the
eye.
• It is distributed into the CNS and is more toxic
than the more polar quaternary carbamates. 23 • The carbamates metabolized by nonspecific
esterases and by cholinesterase.
• The duration of their effect is determined
chiefly by the stability of the inhibitor-enzyme
complex , not by metabolism or excretion.
• The organophosphates (except for
echothiophate) are well absorbed from the skin,
lung, gut, and conjunctiva—thereby making them
dangerous to humans and highly effective as
insecticides.
• Parathion, malathion, must be activated in the
body by conversion to the oxygen analogs
24 Therapeutic Uses and Durations of
Action of Cholinesterase Inhibitors
Uses
Alcohols
• Edrophonium
Approximate Duration of Action
Myasthenia gravis, ileus,
5–15 minutes
Carbamates and related agents
• Neostigmine
Myasthenia gravis, ileus
• Pyridostigmine
Myasthenia gravis
• Physostigmine
Glaucoma
• Ambenonium
Myasthenia gravis
• Demecarium
Glaucoma
0.5–2 hours
3–6 hours
0.5–2 hours
4–8 hours
4–6 hours
Organophosphates
• Echothiophate
100 hours
Glaucoma
25 Mechanism of Action
• increase the concentration of endogenous
acetylcholine at cholinoceptors.
• Edrophonium is a quaternary alcohols, bind
electrostatically and by hydrogen bonds to
the active site, thus preventing access of
acetylcholine.
• The enzyme-inhibitor complex does not involve
a covalent bond and is short-lived (on the order
of 2–10 minutes).
26 • Carbamate esters, e.g., neostigmine and
physostigmine. undergo a two-step hydrolysis
sequence analogous to acetylcholine.
• However, the covalent bond of the
carbamoylated enzyme is more resistant to the
second (hydration) process, and this step is
correspondingly prolonged (30 minutes to 6
hours).
27 • The organophosphates. undergo initial
binding and hydrolysis by the enzyme,
resulting in a phosphorylated active site.
The covalent phosphorus-enzyme bond is
extremely stable and hydrolyzes in water at
a very slow rate (hundreds of hours).
After the initial binding-hydrolysis step, the
phosphorylated enzyme complex may
undergo a process called aging.
28 Aging involves the breaking of one of the
oxygen-phosphorus bonds of the inhibitor and
further strengthens the phosphorus-enzyme
bond.
Aging occurs within 10 minutes with the chemical
warfare agent, soman, and in 48 hours with the
agent, VX.
• Pralidoxime If given before aging has
occurred, is able to break the phosphorusenzyme bond and can be used as
"cholinesterase regenerator" drugs for
organophosphate insecticide poisoning.
29 Organ System Effects
Central Nervous System
• In low concentrations, the lipid-soluble
cholinesterase inhibitors cause a subjective
alerting response.
• In higher concentrations, they cause
generalized convulsions, which may be followed
by coma and respiratory arrest.
Eye, Respiratory Tract, GIT, Urinary Tract
The effects are qualitatively similar to the effects
of the direct-acting cholinomimetics.
30 Cardiovascular System
Mimic the effects of vagal nerve activation on
the heart.
Negative chronotropic, dromotropic, and
inotropic effects and cardiac output falls.
The fall in cardiac output is attributable to
bradycardia, decreased atrial contractility, and
some reduction in ventricular contractility.
The latter effect occurs as a result of prejunctional
inhibition of NE release.
31 Minimal effects by direct action on vascular
smooth muscle because most vascular beds
lack cholinergic innervation.
The net cardiovascular effects of moderate
doses of cholinesterase inhibitors consist of:
modest bradycardia
a fall in cardiac output
an increased vascular resistance
(sympathetic ganglion stimulation) that
result in a rise in blood pressure.
32 Neuromuscular Junction
• Low concentrations prolong and intensify the
actions of Ach.
This increases the strength of contraction,
especially in muscles weakened by curare-like
neuromuscular blockers or by myasthenia
gravis.
• At higher concentrations fibrillation of muscle
fibers. Antidromic firing (nerve impulses in a
direction opposite to normal) of the motor
neuron may also occur, resulting in
fasciculations that involve an entire motor unit.
33 • With marked inhibition of acetylcholinesterase,
depolarizing neuromuscular blockade occurs
followed by a phase of nondepolarizing
blockade as seen with succinylcholine.
• Some quaternary carbamate cholinesterase
inhibitors, e.g., neostigmine, have an additional
direct nicotinic agonist effect at the
neuromuscular junction.
• This may contribute to the effectiveness of these
agents as therapy for myasthenia.
34 Clinical Uses
The Eye
• Glaucoma was treated with pilocarpine,
methacholine, carbachol) or ChEIs
physostigmine, demecarium, echothiophate,
isoflurophate).
• These drugs have been replaced by topical -βblockers and prostaglandin derivatives.
• Acute angle-closure glaucoma is a medical
emergency that usually requires surgery.
• Initial therapy consists of a combination of a
direct muscarinic agonist and a cholinesterase
inhibitor (e.g., pilocarpine plus physostigmine).36 GI and Urinary Tracts
• Postoperative ileus (atony or paralysis of the
stomach or bowel following surgical manipulation)
and congenital megacolon.
• Urinary retention postoperatively or postpartum or
secondary to spinal cord injury or disease
(neurogenic bladder).
• Bethanechol and Neostigmine are the most
widely used, but it must be certain that there is no
mechanical obstruction to outflow before using the
cholinomimetic.
36 • Pilocarpine
has long been used to increase salivary
secretion.
• Cevimeline
A new direct-acting muscarinic agonist used
for the treatment of dry mouth associated with
Sjögren's syndrome.
(shoh-grinz, a systemic autoimmune disease in
which immune cells attack and destroy the
exocrine glands2 that produce tears and
saliva. ) and that caused by radiation damage
of the salivary glands.
37 Neuromuscular Junction
Myasthenia gravis is an autoimmune disease
affecting skeletal muscle neuromuscular
junctions. Antibodies are detected in 85% of
myasthenic patients.
The antibodies reduce nicotinic receptor
function.
Frequent findings are ptosis,
diplopia, difficulty in speaking &
swallowing, and extremity weakness.
Severe disease may affect all the muscles,
including those necessary for respiration.
38 • The disease resembles the neuromuscular
paralysis produced by d-tubocurarine.
• Patients with myasthenia are very sensitive to
the action of neuromuscular blockers and other
drugs that interfere with neuromuscular
transmission, eg, aminoglycoside antibiotics.
• Patients with ocular myasthenia may be treated
with cholinesterase inhibitors alone.
• Patients having more widespread muscle
weakness are also treated with
immunosuppressant drugs (steroids,
cyclosporine, and azathioprine).
• In some patients, the thymus gland is removed.
39 Edrophonium is used as a diagnostic test for
myasthenia.
• A 2 mg dose is injected IV. If the patient has
myasthenia gravis, an improvement in muscle
strength that lasts 5 minutes can be observed.
• Edrophonium is also used to assess the
adequacy of treatment with the longer-acting
cholinesterase inhibitors in patients with
myasthenia gravis.
• Clinical situations in which severe myasthenia
(myasthenic crisis) must be distinguished from
excessive drug therapy (cholinergic crisis). 40 • Long-term therapy is usually accomplished with
pyridostigmine; neostigmine or ambenonium.
• Muscarinic effects is controlled by atropine.
Tolerance to the muscarinic effects develops, so
atropine treatment is not required.
• Neuromuscular blockade is frequently produced
as an adjunct to surgical anesthesia. After
surgery, neostigmine and edrophonium are the
drugs of choice used to reverse this
pharmacologic paralysis promptly.
41 Central Nervous System
• Tacrine is an anticholinesterase used for the
treatment of mild to moderate Alzheimer's
disease.
Tacrine's efficacy is modest, and hepatic
toxicity is significant.
• Donepezil, is newer, more selective used in
treatment of cognitive dysfunction in
Alzheimer's patients.
• Given once daily because of its long half-life,
and it lacks the hepatotoxic effect of tacrine.
42 Toxicity
• Varies markedly depending on their absorption,
access to the CNS, and metabolism.
• Direct-Acting Muscarinic Stimulants
• Pilocarpine and the choline esters over
dosage cause:
nausea, vomiting, diarrhea, urinary urgency,
salivation, sweating, cutaneous vasodilation,
and bronchial constriction.
• The effects are all blocked competitively by
atropine
43 Certain mushrooms
contain muscarinic alkaloids.
(Amanita muscaria, the first source of
muscarine, contains very low
concentrations of the alkaloid.)
Ingestion of these mushrooms causes
typical signs of muscarinic excess
within 15–30 minutes.
Treatment is with atropine, 1–2 mg
parenterally.
44 Direct-Acting Nicotinic Stimulants
Acute Toxicity
• The fatal dose of nicotine is 40 mg, or 1 drop of the
pure liquid.
This is the amount of nicotine in two regular
cigarettes. Fortunately, most of the nicotine in
cigarettes is destroyed by burning or escapes via
the "side stream" smoke.
• Ingestion of nicotine insecticides or of tobacco by
infants and children is usually followed by vomiting,
limiting the amount of the alkaloid absorbed.
45 Toxic effects of a large dose of nicotine
are:
(1) central stimulant actions, which cause
convulsions and may progress to coma and
respiratory arrest;
(2) skeletal muscle end plate depolarization,
which may lead to depolarization blockade
and respiratory paralysis.
(3) hypertension and cardiac arrhythmias.
Treatment of acute poisoning is symptomdirected.
46 • Muscarinic excess resulting from
parasympathetic ganglion stimulation can be
controlled with atropine.
• Central stimulation is treated with
anticonvulsants such as diazepam.
Neuromuscular blockade is not responsive to
treatment and requires mechanical respiration.
• Fortunately, nicotine is metabolized and
excreted relatively rapidly. Patients who survive
the first 4 hours usually recover completely if
hypoxia and brain damage have not occurred. 47 Chronic Nicotine Toxicity
• Nicotine contributes to the increased risk of
vascular disease and sudden coronary death
associated with smoking.
• Also, the high incidence of ulcer recurrences in
smokers.
• Replacement therapy with nicotine in the
form of gum, transdermal patch, nasal spray, or
inhaler are used to help patients stop smoking.
Varenicline
• Has partial agonist action at central nicotinic
receptors.
• It also has antagonist properties that persist
48
because of its long half-life • It prevents the stimulant effect of nicotine at presynaptic
nicotinic receptors that cause release of dopamine.
• its use is limited by nausea and insomnia and also by
exacerbation of psychiatric illnesses, including anxiety and
49
depression. Cholinesterase Inhibitors
• The major source of intoxications is pesticide.
• pesticides can cause symptoms which persist
for days.
• chemical warfare agents (soman, sarin, VX)
induce effects rapidly.
. Miosis, salivation, sweating, bronchial
constriction, vomiting, and diarrhea.
CNS involvement (cognitive disturbances,
convulsions, and coma) usually follows rapidly,
accompanied by peripheral nicotinic effects,
especially depolarizing neuromuscular blockade.
50 Therapy always includes:
(1) maintenance of vital signs—respiration in
particular may be impaired.
(2) decontamination to prevent further absorption.
(3) atropine parenterally in large doses, given as
often as required to control muscarinic excess.
Therapy often also includes treatment with
pralidoxime, and benzodiazepines for seizures.
• Preventive therapy for cholinesterase
inhibitors warfare agents
• Personnel are given autoinjection syringes
containing pyridostigmine and atropine.
51 • Chronic exposure to certain organophosphate
compounds causes delayed neuropathy
associated with demyelination of axons.
• The effects are not caused by cholinesterase
inhibition but rather by neuropathy target
esterase (NTE) inhibition whose symptoms
(weakness of upper and lower extremities,
unsteady gait) appear 1–2 weeks after exposure.
• Another nerve toxicity called intermediate
syndrome occurs 1–4 days after exposure to
organophosphate insecticides. This syndrome is
also characterized by muscle weakness; its origin
is not known but it appears to be related to
52
cholinesterase inhibition.
Cholinoceptor Activating & Cholinesterase Inhibiting Drugs
of 52
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