Transcript Smooth muscles

Autonomic nervous system
Cholinergic agonists
(CHOLINOMIMETICS)
PhD. A.V. Aleksandrova
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Functional divisions within the
nervous system
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What are the differences between the somatic and the
autonomic nervous system?
• Somatic N.S
Autonomic N.S
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Control internal viscera
Involuntary
autonomic nerve is
two fibers
(Preganglionic &
Postganglionic)
Control skeletal muscles
Voluntary
Somatic nerve is one
fiber
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Efferent neurons of the
autonomic nervous system
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Sympathetic ANS
•
The 1st neuron of sympathetic division is
located in the thoracolumbar region of the spinal
cord (T1-L3) and the 2nd is disposed either in
the paravertebral, or in the prevertebral ganglia.
Postganglionic non-myelinated nerve fibres
arising from neurones in the ganglia, innervate
most organs of the body
• The neurotransmitter released by sympathetic
nerve endings is noradrenaline.
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Parasympathetic system
•
The 1st neuron of parasympathetic system is
located in the brain stem and in the sacral region
of the spinal cord. The preganglionic fibres leave
the central nervous system in the III, VII, IX and
X pairs of cranial nerves and the third and fourth
sacral spinal roots.
• Ganglia are located either in the tissue of
effector organ or near it. The nerve endings of
the postganglionic parasympathetic fibres
release neurotransmitter acetylcholine. All the
preganglionic nerve fibres (sympathetic and
parasympathetic;) are myelinated and release
acetylcholine from the nerve terminals which
depolarizes the ganglionic neurones by
activating nicotinic receptors.
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Parasympathetic Nervous System
(craniosacral outflow)
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Cholinergic nervous fibres are:
1) preganglionic (sympathetic and parasympathetic);
2) all postganglionic parasympathetic;
3) postganglionic sympathetic which supply sweat
glands and vessels of skeletal muscles;
4) somatic nerves;
5) nerves which supply adrenal medulla and carotic
sinuses;
6) neurons of CNS
Adrenergic nervous fibres are:
1) postganglionic sympathetic, except those which
supply sweat glands and vessels of skeletal muscles;
2) neurons of CNS
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Cholinergic transmission
Main NT is Acetylcholine (Ach).
A large number of peripheral ANS fibers which
synthesize & release Acetylcholine are called
CHOLINERGIC fibers. They include:
• All pre-ganglionic efferent autonomic fibers.
• Somatic motor fibers to skeletal muscles.
• Most parasympathetic post ganglionic fibers.
• A few sympathetic post ganglionic fibers– to
sweat glands.
Some parasympathetic post ganglionic fibers utilize
nitric oxide or peptides for transmission.
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Fate of acetylcholine released
by cholinergic fiber
• ACh is released from the nerve into the synaptic
cleft and binds to ACh receptors on the postsynaptic membrane, relaying the signal from the
nerve.
• Ach-esterase, located on the post-synaptic
membrane, terminates the signal transmission
by hydrolyzing ACh.
• The liberated choline is reuptaken by the presynaptic membrane and used for resynthesis of
ACh.
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Cholinergic synapse
• Nerve terminal of
cholinergic fibre contains
numerous vesicles with
neurotransmitter
acetylcholine (ACh) that is
released from presynaptic
membrane.
• Release of acetylcholine
depends on sufficient
influx of Ca 2+, which
occurs under the influence
of action potential.
ATP
negative
feedback
ATP
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Cholinergic receptor types
• Two cholinergic
receptor subtypes
have been identified
by selective
agonists: muscarinic
(M-cholinoceptors)
and nicotinic (Ncholinoceptors). At
least 5 subtypes of
muscarinic receptors
(M1 – M5) have
been distinguished.
• There are 3 main
classes of Ncholinoceptors: the
muscle, ganglionic,
and CNS classes.
MUSCARINIC
M1
M2
M3
M4
Eye
Heart
Smooth muscles
Exocrine glands
CNS
NICOTINIC
M5
NM
NN
Ganglions
Carotid sinus
Skeletal muscles
Adrenal glands
CNS
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Muscarinic receptors
• High affinity to muscarine
• M1 – gastric parietal cells, saliva, CNS
• M2 - cardiac cells, smooth muscle,
CNS
Amanita muscaria
• M3 - bladder, exocrine glands, smooth muscle, eye, CNS
• M1&M3 – Gq
• M2 - Gi
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Nicotinic receptors
• High affinity to nicotine
• NM- neuro-muscular junction
• NN – ganglion, adrenal gland
CNS, carotid sinus
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Mechanisms of impulse
transmission
• Muscarinic receptors belong to G-protein
coupled receptors. Transmission of impulses
through M1, M3, M5 cholinoceptors is realized
by phospholipase C, inositol triphosphate and
diacylglycerol
• Stimulation of M2 and M4 cholinoceptors results
in inhibition of adenylate cyclase and decrease in
intracellular cAMP.
• N- cholinoceptors are ion channel coupled. Their
stimulation results in opening of Na+ channels
that causes depolarization.
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Muscarinic receptors
M1
M3
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M-cholinoceptors
Receptor
M1
Excitatory
Locations
CNS
gastric parietal cells
M2
Inhibitory
Heart
M3
Excitatory
Exocrine glands
Smooth muscles
Vascular endothelium
M4 & M5
CNS
Pharmacological actions
CNS excitation
Gastric acid secretion
Cardiac inhibition
(Bradycardia)
• Secretion of glands
• Smooth muscle contraction
• Vasodilatation (via nitric oxide)
memory, arousal, attention and
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N-cholinoceptors
Cholinoc Localization
eptors
Effects of stimulation
NN
Autonomic
Increase in parasympathetic and
ganglia
sympathetic reactions
(parasympatheti
c and
sympathetic)
NN
Adrenal medulla Increase in adrenaline release, increase in
BP
NM
Skeletal muscle
Increase in tone, contraction
Carotid sinus
Reflex respiratory centre stimulation
CNS
Stimulation
NN
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Nicotinic receptors
Central cholinoceptor
Muscarinic receptors
Peripheral cholinoceptor
Ion channel linked receptors
G protein linked receptors
Autonomic ganglia (sympathetic &
parasympathetic) stimulation ( Nn
)
On all peripheral organs that
receive postganglionic
parasympathetic fibers
Adrenal medulla (Nn)
release of catecholamines
(Adrenaline & Noradrenaline)
Heart (M2) inhibition
exocrine glands (M3) contraction
Skeletal muscle
(Neuromuscular junction)
(Nm) Contraction
Almost excitatory
Smooth muscles (GIT, urinary
tract, bronchial muscles)
(M3) contraction
Excitatory or inhibitory
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Nicotinic actions
Skeletal muscles:
• Low conc. of nicotine  muscle contraction
• High conc. of nicotine persistent depolarization
& relaxation.
Ganglia:
stimulation of sympathetic& parasympathetic
ganglia.
Adrenal medulla
release of catecholamines (A & NA).
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Muscarinic actions
Organs
Eye
Heart
endothelium
Lung
GIT
Urinary
bladder
Exocrine
glands
Cholinergic actions
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
Decrease in intraocular pressure
bradycardia ( heart rate ) (M2)
Release of NO (EDRF)
Constriction of bronchial smooth muscles
Increase bronchial secretion M3
Increase motility (peristalsis)
Increase secretion
Relaxation of sphincter M3
Contraction of muscles
Relaxation of sphincter M3 - Urination
Increase of all secretions
sweat, saliva, lacrimal, bronchial, intestinal secretions
M3
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Cholinomimetics
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I. Direct acting
1. Muscarinic agonists (Mcholinomimetics)
Pilocarpine
Oxothermorine
Aceclidine
2. Nicotinic agonists
Lobeline
Dimethylphenylpiperazinum
(DMPP)
3. Muscarinic and nicotinic
agonists
Acethylcholine
Carbachol
II. Indirect acting (muscarinic
and nicotinic agonists –
anticholinesterase agents)
1. Reversible
Neostigmine (Proserinum)
Physostigmine
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Pyridostigmine
Edrophonium
Ambenonium chloride
(Oxazylum)
Galanthamine
2. Irreversible
(Organophosphates)
Echotiophate
Isoflurophate
Arminum
Drugs used in poisoning with
organophosphates
1. Reactivators of
acetylcholine esterase
Pralidoxime
Dipiridoxinum
Izonitrozinum
Obidoxime
2. M-cholinoblockers
Atropine
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Pharmacological effects
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Bradycardia, decrease in blood pressure
Raising the tone of smooth muscles of internal organs
Stimulation of intestinal motility
Reducing sphincter of alimentary canal and bladder
Increased secretory activity of the exocrine glands
Constriction of the pupil of the eye (miosis)
spasm of accommodation
Reducing intra ocular pressure
Relief of pulses in mionevralnomu skeletal muscle
synapse, strengthening their contractility (anticholinergic
drugs)
• Stimulation of the central nervous system (means of
penetrating the blood-brain barrier)
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Main clinical usage
• 1. Glaucoma (Pilocarpine, Physostigmine,
Armine)
• 2. Infants (Neostigmine)
• 3. Postoperative atony of the intestines and
bladder (Neostigmine)
• 4. Paralysis, paresis, neuritis, polyneuritis
(Neostigmine)
• 5. Dusturbances of skeletal muscle contractile
function after cranial trauma, polio and stroke
(Galanthamine hydrobromide)
• 6. Belladonna poisoning (Neostigmine,
Physostigmine, Galanthamine)
• 7. Overdose nondepolarizing muscle relaxants
(Neostigmine)
• 8. Xerostomia (Pilocarpine)
• 9. Respiratory depression (Cititon, Lobeline)
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Side effects of cholinomimetics
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1. Bradycardia
2. Bronchospasm
3. Intestinal cramps, colic, diarrhea
4. Hypersalivation
5. Blurred vision
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Contraindications
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1. Bradycardia, A-V block
2. Asthma
3. Gastric ulcer and 12 duodenal ulcer
4. Epilepsy (Neostigmine)
5.Pregnancy (Neostigmine)
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Direct acting cholinergic agonists
ACETYLCHOLINE
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Direct acting cholinergic agonists
ACETYLCHOLINE
1. Decrease in heart rate and cardiac output
2. Decrease in blood pressure
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Direct acting cholinergic agonists
ACETYLCHOLINE
3. Other actions
4. Clinical use very rare: eye drops to obtain miosis
Muscarinic and nicotinic agonist not used
clinically because Ach is not selective (N, M)
Has short duration of action. Why?
Due to rapid metabolism by
acetycholinesterase
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Direct acting cholinergic agonists
1.
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3.
4.
Stimulation of atonic bladder
Nonobstructive urinary retention
Neurogenic atony
Megacolon
Ophthalmology
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Direct acting cholinergic agonists
PILOCARPINE
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
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Direct acting cholinergic agonists
PILOCARPINE
Natural alkaloids
Tertiary amine lipophilic
Pharmacokinetics
It is well absorbed
Good distribution
Cross BBB (has central effects).
Long duration of action
Direct muscarinic agonist
(mainly on eye & secretion).
Jaborandi (Pilocarpus pennatifolius)
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Direct acting cholinergic agonists
PILOCARPINE
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Pilocarpine
• Uses:
• Xerostomia (dry mouth).
• Drug of choice in emergency glaucoma applied as eye drops.
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Adverse effects:
Profuse sweating
Salivation
Bronchoconstriction
Diarrhea
CNS effects
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Aceclidinum
• a synthetic preparation;
• administered SC, IM, or topically (eye drops); not
toxic;
• does not penetrate CNS;
• M-cholinomimetic;
• used for the treatment of atonia of the intestine
and urinary bladder, as well as for glaucoma.
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Mushroom poisoning
 Miosis
 Hyper salivation
 Excessive sweating, lacrimation
 Cold, wet skin
 Bradycardia
 Polyuria
 Diarrhea
 Convulsions
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N-CHOLINOMIMETICS
• They stimulate N-cholinoreceptors in zona
carotis and initiate a reflexive increase
• in the activity of the respiratory and vasomotor
centers resulting in the short stimulation of
breathing and elevation of BP.
• They also stimulate N-cholinoreceptors in the
adrenal medulla, increase the secretion of
epinephrine, which causes vasoconstriction and
the elevation of BP
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NICOTINE
• It is a tobacco alkaloid with a dose-dependent
action on N-cholinoreceptors.
• Effects of nicotine are manifested in tobacco
smoking.
• Nicotine causes dependence that leads to abuse
of tobacco and results in the development of
cardiovascular and lungs pathology.
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Physiological effects of nicotine at
CNS NN receptors
• • ↑Emesis (vomiting) due to actions on
chemoreceptor trigger zone of medulla
oblongata
• • Dependence (i.e. makes it hard to quit
smoking)
• • Respiratory depression (only at very high
doses) due to actions on medulla oblongata also contribution from blockade of diaphragm
and intercostal muscles
• • Tremors + convulsion (only at very high doses)
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Physiological effects of nicotine at
peripheral NN receptors
• Many Effects of Nicotine Involve Ganglia
• • ↑GI motility (nausea, diarrhea, vomiting) –
Stimulation of parasympathetic ganglia
• • ↑Heart rate, ↑blood pressure – Stimulation of
sympathetic ganglia innervating heart and blood
vessels – Release of EPI from adrenal medulla –
Stimulation of chemoreceptors → reflex ↑heart
rate, vasoconstriction
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Lobeline
• is an alkaloid; is administered IV and acts during 3-5
min;
• stimulates N-cholinoreceptors;
• is used for emergency help in the respiratory arrest,
asphyxia, asphyxia of newborns; is used to treat
tobacco abuse in the form of combined tablets
• is not used for collapse due to its ability to provoke
transitory a decrease in BP resulting from the
stimulation of n.vagus center.
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Cytitonum
• the name of a cytizine solution;
• administered IV, acts 3-5 min;
• stimulates N-cholinoreceptors; reflexly stimulates
respiration and increases BP;
• used for emergency help in respiratory arrest
and collapse;
• an ingredient of combined tablets against
tobacco abuse.
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Indirect acting cholinergic agonists
Reversible
Irreversible
Edrophonium
Neostigmine
Physostigmine
Rivastigmine
Galantamine
Echothiophate
Organophosphates
Arminum
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Mechanism of action
Mechanism of action:
Anticholinesterases prevent
hydrolysis of Ach by antagonizing
cholinesterase thus increase Ach
concentrations and actions at the
cholinergic receptors (both nicotinic
and muscarinic).
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Pharmacological effects of anticholinesterases
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Muscarinic actions
Nicotinic actions
CNS actions:
Excitation, convulsion, respiratory failure, coma
only for lipid soluble anticholinesterases
physostigmine & phosphate ester except
Ecothiophate.
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Reversible
Physostigmine
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Reversible anticholinesterase
Tertiary ammonium compound
Non polar (lipid soluble)
Good lipid solubility
Good oral absorption
Has muscarinic & nicotinic
actions
• cross BBB (has CNS effects)
Calabar Bean
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Reversible
Physostigmine
Indications
1. Atony of intestine
2. Atony of bladder
3. Glaucoma
4. Overdose of
ATROPINE,
ANTIPSYCOTICS,
ANTIDEPRESSANTS
Side effects
1. Convulsions
2. Bradycardia
3. Paralysis of skeletal muscle
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Reversible
Neostigmine
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3.
4.
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB
Reversible
anticholinesteras
5. Has muscarinic &
nicotinic actions
(prominent on GIT &
urinary tract).
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Reversible
Neostigmine
Indications
Side effects
1. Paralyzes
2. Myastenia gravis
3. Antidote of neuromuscular blocker
TUBOCURARINE
1. Salivation
2. Flushing
3. Decreased BP
4. Abdominal pain
5. Diarrhea
6. Bronchospasm
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Contraindications
Neostigmine
1. Bronchial asthma
2. Intestinal inflammation,
obstruction
3. Bladder obstruction
4. Peritonitis
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Galantamine
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an alkaloid from Galanthus Woronowi;
administered SC, IM;
penetrates into CNS;
has a reversible anticholinesterase action;
used for the treatment of paralysis, neuritis,
early stages of Alzheimer’s disease and other
neurological diseases;
• is not used in glaucoma due to its irritative
action.
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Reversible
Edrophonium
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4.
5.
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB
Fast elimination
Duration 10-20 min
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Reversible
Edrophonium
1. Diagnosis of myasthenia gravis
2. Antidote of neuro-muscular
blocker
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Reversible
Rivastigmine
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
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Reversible
Rivastigmine
Alzheimer disease
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Irreversible
Echothiophate
Mechanism
-Irreversible anticholinesterase
-Binds to cholinesterase by strong
covalent bond.
-Have very long duration of action
-Aging make bond extremely stable
-Used for glaucoma.
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Toxicology
Organophosphates
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Toxicology
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal motility
Emesis
Miosis
Death is caused by breath insufficiency, bronchospasm and lungs edema
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Toxicology
1. Reactivation of acetylcholinesterase
• PRALIDOXIME
Not enter BBB
2. M-cholinoblocker
• ATROPINE
 Antimuscarinic only
3. Anticonvulsant
• DIAZEPAM
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Pralidoxime (PAM)
cholinesterase reactivator
• Acts by regeneration of cholinesterase enzyme.
• reactivates recently inhibited enzymes before
aging.
Uses
I.V.  over 15-30 min for organophosphate
intoxication.
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Summary for cholinomimetics & their uses
Eye : treatment of glaucoma
Pilocarpine (direct muscarinic agonist)
Physostigmine -Ecothiophate (indirect cholinomimetics)
Urinary retention and paralytic ileus
Bethanechol (direct)
Neostigmine (indirect)
Myasthenia gravis (only indirect cholinomimetics)
Pyridostigmine, Neostigmine, Ambenonium
Xerostomia
Pilocarpine –Cevimeline (Sjogren’s syndrome)
Alzheimer’s disease: Rivastigmine, Donepezil
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