The Parasympathetic Nervous System and Cholinergic Pharmacology
P
A
R
A
S
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M
P
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E
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Y
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T
E
M
Cholinerg
ic drugs elicit their effect
:
1)
via the parasympathetic synapses of effector organs
2)
via synapses of the autonomic nerve ganglia
3)
via synapses of neuromuscular junctions
4)
via
synapse
s in
CNS
-
influence synapses, where acetylcholine
(ACh)
acts
as their neurotransmitter
Cholinergic nervous system
- pharmacological interventions
parasympathomimetics
acetylcholine analog.
ACHE inhibitors
parasympat
h
olytics
ganglioplegics
muscle relaxants
N
M
gangliomimetics
Θ
Cholinomimeti
cs
- ↑ a
ctivity at cholinergic
synaps
es
–
direct
–
ACh and its analogues
they imitate
ACh
effects on
M
and
N receptor
s
–
indirect
-
ACHE inhibitors
always non-selective
»
short-term effect
- edro
ph
onium
»
intermediate and long-term effect
-
carbamates
(„stigmin
s
“)
»
very long effect
- organo
phosphates
Parasympat
homimetics
-
they imitate A
Ch
effect on
M
r
c.
–
direct
(
mostly non-selective effect
)
–
stimulatory agents selective to M
receptor
s for
ACh
Terminolog
y
:
-
agents blocking
acetylcholin
e receptors
Parasympat
holytics
-
M receptor blockers
-
without any effect on nicotinic receptors
Ganglioplegi
cs
- N
N
-recepto
r blockers
Peri
ph
er
al
m
uscle relaxants
(non-depolarizing
) –
-
N
M
-receptor
blockers
Terminolog
y:
Cholinolyti
cs
-
direct:
-
indirect:
e.g. presynaptic i
nhibi
tion of ACh release
Acetylcholine synthesis
choline in a lecithin form is a dietary supplement
lecithin acts as a precursor to ACh
Acetylcholine degradation
Cholinotrop
ic agents
-
according to the chemical structure
we distinguish
:
•
agents with quaternary ammonium cation
quaternary amines,
e.g. muscarine
with low GIT absorption (they do not cross BBB)
•
tertiary
amin
es
, e.g. natural alkaloids
(nicotine, physostigmine)
Cholinomimetics - cholinergic agonists
-
p
h
a
r
m
a
c
o
l
o
g
i
c
a
l
e
f
f
e
c
t
s
:
•
C
V
S
-
n
e
g
a
t
i
v
e
c
h
r
o
n
o
t
r
o
p
i
c
e
f
f
e
c
t
-
heart depression
-
generalized vasodilation
•
G
I
T
-
i
n
c
r
e
a
s
e
d
m
o
t
i
l
i
t
y
o
f
s
m
o
o
t
h
m
u
s
c
l
e
s
•
r
e
s
p
i
r
a
t
o
r
y
t
r
a
c
t
-
b
r
o
n
c
h
o
c
o
n
s
t
r
i
c
t
i
o
n
↑
b
r
o
n
c
h
i
a
l
s
e
c
r
e
t
i
o
n
•
e
y
e
-
m
i
o
s
i
s
,
↓
i
n
t
r
a
o
c
u
l
a
r
p
r
e
s
s
u
r
e
•
↑
l
a
c
r
i
m
a
t
i
o
n
•
↑
s
w
e
a
t
i
n
g
,
↑
s
a
l
i
v
a
t
i
o
n
•
C
N
S
-
t
r
e
m
o
r
,
i
n
c
r
e
a
s
e
d
l
o
c
o
m
o
t
i
o
n
acetylcholine
•
rapid biodegradation
by ACHE →
not used in
clinics
5-20 s effect after i.v.
administration
•
limited absorption after oral / s.c. administration
•
does not penetrate BBB
-
other choline esters:
carbachol
•
poor absorption from GIT
•
agonist of M and N Rc
•
n
ot hydrolyzed by cholinesterase
→
long duration of action
I:
ophthalmology - miosis
cevimeline
•
sele
c
tiv
e M agonist
- parasympat
h
omimet
ic
I: xerostomia (dry mouth)
, Sjögren
’s
syndrom
e
Acetylcholine and its analogues
•
↑ postganglionic neuronal activity
•
↑ neuromuscular signal transduction
•
↑ activity of parasympathetic effectors
•
↑ sympathetic
stimulation of sweat glands
- pharmacological effects:
BP,
brady
cardia, danger of heart arrest
nauzea,
cough,
dyspnoe
vascular dilation:
NO
release
salivation, lacrimation, ↑ mucosal gland secretion
excessive sweating
Acetylcholine and its analogues
pilocarpine
(Pilocarpus)
•
non-selective M receptor agonist
•
good
absorption from GIT
•
BBB
crossing
(→CNS
excitation
)
•
stimulates gland secretion
•
stimulates
m. sphincter pupilae
(eyedrops)
I: miotic agent used in
ophthalmology
2
-
4
%
, Sjögren's syndrome
muscarine
(I
nocybe, Clitocybe, Amanita
m
uscaria/phalloides
)
•
M
receptor
agonist, quater
nary amine
are
c
oline
(
Areca catechu
)
•
CNS stimulant, ter
tiary amine
•
M
and
N
receptor agonist
Cholinomimetics - natural alkaloids
ACHE inhibitors
s
h
o
r
t
-
t
e
r
m
(
R
E
V
E
R
S
I
B
L
E
)
l
o
n
g
-
t
e
r
m
(IRREVERSIBLE)
c
o
m
p
e
t
i
t
i
v
e
e
n
z
y
m
e
i
n
h
i
b
i
t
i
o
n
c
o
m
p
l
e
x
i
n
h
i
b
i
t
o
r
+
e
n
z
y
m
e
C
O
V
A
L
E
N
T
I
N
H
I
B
I
T
I
O
N
Indirect
cholinomimeti
cs
m
e
d
i
c
i
n
a
l
u
s
e
t
o
x
i
c
o
l
o
g
y
General indications:
•
glaucoma
•
GIT atony
•
urinary retention
•
antidotes of non-depolarizing muscle relaxants
•
myasthenia gravis (
use
quaternary amines)
•
Alzheimer‘s disease (
use
tertiary amines)
•
intoxication with organophosphates
•
poisoning associated with the central anticholinergic
syndrome (atropine)
Indirect c
holinomimeti
c agents
Reversible ACHE inhibitors
Side effects:
•
miosis
•
increased glandular secretion
•
nausea, diarrhea
•
heart
depressants (negative chronotropic effect)
•
CNS – stimulation followed by depression
•
neuromuscular junction -
f
asciculation and
twitching (overdose -
depolarization blockade)
•
overdosing =
cholinergic crisis
– depolarization
blockade
- muscle paralysis
Indirect c
holinomimeti
c agents
Reversible ACHE inhibitors
n
e
o
s
t
i
g
m
i
n
e
,
(
e
d
r
o
p
h
o
n
i
u
m
)
•
short-term effect
I:
diagnosis of myasthenia gravis
•
„decurarization“, antidotes of competitive
m
uscle relaxants
p
y
r
i
d
o
s
t
i
g
m
i
n
e
,
a
m
b
e
n
o
n
i
u
m
•
longer effect than neostigmine, slower onset of action
•
weaker muscarinic effect - less GIT side effects
I: m
yasthenia gravis
d
i
s
t
i
g
m
i
n
e
•
long-acting reversible ACHE inhibitor
I:
myasthenia gravis, atonic the urinary bladder, uterine atony,
postoperative GIT atony, paralytic ileus
Indirect cholinomimetics
Reversible
ACHE inhibitors
-
CNS
effects of drugs, that can cross the blood-brain barrier
p
h
y
s
o
s
t
i
g
m
i
n
e
I:
a
ntidote in acute intoxications with central anticholinergic
syndrome
g
a
l
a
n
t
a
m
i
n
e
,
r
i
v
a
s
t
i
g
m
i
n
e
,
d
o
n
e
p
e
z
i
l
I: dementias of the
Alzheimer´s type
•
galantamine has a positive allosteric effect
on ACh binding on N rec.
Indirect cholinomimetics
Reversible ACHE inhibitors
-
effects:
nausea, vomitus, sweating, CVS collapse,
breath depression,
f
asciculation and twitching
→
muscle paralysis, CNS
convulsions
- agents
: organophosphates
•
i
n
s
e
c
t
i
c
i
d
e
s
(
m
a
l
a
t
h
i
o
n
,
p
a
r
a
t
h
i
o
n
)
•
c
h
e
m
i
c
a
l
w
e
a
p
o
n
s
s
u
c
h
a
s
n
e
r
v
e
g
a
s
s
a
r
i
n
o
r
V
X
,
s
o
m
a
n
,
t
a
b
u
n
-
t
h
e
i
r
a
n
t
i
d
o
t
e
s
:
o
b
i
d
o
x
i
m
e
,
t
r
i
m
e
d
o
x
i
m
e
,
p
r
a
l
i
d
o
x
i
m
e
Indirect
cholinomimeti
cs
Ir
r
ever
sible
ACHE inhibitors
T
h
e
r
a
p
y
o
f
o
r
g
a
n
o
p
h
o
s
p
h
a
t
e
i
t
o
x
i
c
a
t
i
o
n
:
1.
reduce further neurotoxine absorption
2. m
echanical ventilation
3
.
a
t
r
o
p
i
n
e
i
.
v
.
i
n
h
i
g
h
d
o
s
e
s
2
m
g
e
v
e
r
y
5
m
i
n
u
n
t
i
l
a
s
l
i
g
h
t
o
v
e
r
d
o
s
e
(
i
n
m
a
s
s
-
c
a
s
u
a
l
t
y
s
e
t
t
i
n
g
s
s
.
c
.
)
4
.
A
C
H
E
r
e
a
c
t
i
v
a
t
o
r
s
:
o
b
i
d
o
x
i
m
e
,
(
p
r
a
l
i
d
o
x
i
m
e
)
5
.
t
h
e
r
a
p
y
o
f
m
u
s
c
l
e
c
o
n
v
u
l
s
i
o
n
s
i
.
v
.
b
e
n
z
o
d
i
a
z
e
p
i
n
e
s
6. high doses of reversible ACHE inhibitors
7.
bioscavengers
Irreversible
ACHE inhibitors
Indirect cholinomimetics
Parasympatholytics
t
e
r
t
i
a
r
y
a
m
i
n
e
s
q
u
a
t
e
r
n
a
r
y
a
m
i
n
e
s
b
l
o
c
k
a
d
e
o
f
M
r
e
c
e
p
t
o
r
s
b
l
o
c
k
a
d
e
o
f
M
>
N
r
e
c
e
p
t
o
r
s
atropine
scopolamine
tropi
c
amid
e
, cyklopentolate
oxybutynine
tolterodine
, fesoterodine
solifenacin, darifenacin
procyklidine, biperiden
(
pirenzepine, telenzepine
)
(homatropine)
butyls
c
opolamine
phenpiverine, propiverine
otilonium, glycopyrrolate
ipratropium, tiotropium
a
c
lidinium,
ume
c
lidinium
trospium
(oxyfenonium),(poldin)
General i
ndications:
•
spasmolytics
•
bronchodilating ag
ents
•
antiarrhythmics
•
mydriatics
•
premedication prior to GA
•
antiemetics
•
antiparkinson
agents
•
antidotes of pilocarpine, ACHEI poisoning
(physostigmine)
Parasympat
holytics
direct antimuscarinic agents
Side effects:
•
dry mouth
(xerostomia)
•
dry eyes (x
erophthalmia
)
•
loss of accommodation
(cycloplegia
)
•
heart
palpitations
•
constipation
•
urin
ary
retention
•
CNS: seizures, severe dyskinesias, hallucinations,
agitated delirium, respiratory depression, coma
Parasympat
holytics
direct antimuscarinic agents
PL with tertiary N
a
t
r
o
p
i
n
e
,
t
r
o
p
i
c
a
m
i
d
e
,
c
y
c
l
o
p
e
n
t
o
l
a
t
e
,
h
o
m
a
t
r
o
p
i
n
e
•
mydriasis (stimulation of m. sphincter pupilae)
•
cycloplegia (
paralysis of the ciliary muscle of the eye
)
I:
for diagnostic and therapeutic mydriasis
s
c
o
p
o
l
a
m
i
n
e
(
h
y
o
s
c
i
n
e
)
T
T
S
,
s
u
p
p
.
I: therapy of kinetosis, CNS depression
o
x
y
b
u
t
i
n
i
n
e
•
orally, TTS
•
pharmacokinetics: high 1
st
pass effect
I: antispasmodic agent used for overactive urine bladder
Selective parasympatholytics
:
d
a
r
i
n
e
f
a
c
i
n
,
s
o
l
i
f
e
n
a
c
i
n
•
M
3
uro
selective a
nta
gonists
I:
symptomatic therapy of overactive urinary bladder
(
p
i
r
e
n
z
e
p
i
n
e
)
•
gastric M1
receptor selective antagonist
•
former
indication: gastroduodenal ulcers
PL with tertiary N
-
do not cross
BBB (blood-brain barrier)
•
s
p
a
s
m
o
l
y
t
i
c
s
f
o
r
f
u
n
c
t
i
o
n
a
l
b
o
w
e
l
d
i
s
o
r
d
e
r
s
:
o
t
i
l
o
n
i
u
m
N
-
b
u
t
y
l
s
c
o
p
o
l
a
m
i
n
e
p
h
e
n
p
i
v
e
r
i
n
e
(
o
x
y
p
h
e
n
o
n
i
u
m
)
,
(
p
o
l
d
i
n
)
•
u
r
i
n
a
r
y
a
n
t
i
s
p
a
s
m
o
d
i
c
f
o
r
h
y
p
e
r
a
c
t
i
v
e
u
r
i
n
a
r
y
b
l
a
d
d
e
r
:
t
r
o
s
p
i
u
m
•
b
r
o
n
c
h
o
d
i
l
a
t
o
r
a
g
e
n
t
s
:
i
p
r
a
t
r
o
p
i
u
m
(
S
A
M
A
)
t
i
o
t
r
o
p
i
u
m
,
a
c
l
i
d
i
n
i
u
m
g
l
y
c
o
p
y
r
r
o
l
a
t
e
,
u
m
e
c
l
i
d
i
n
i
u
m
PL
with
quaternary
N
(LAMA)
* long acting
muscarinic antagonists
(LAMA)
short acting muscarinic antagonists (SAMA)
1
.
C
e
n
t
r
a
l
y
a
c
t
i
n
g
2
.
P
e
r
i
p
h
e
r
a
l
e
f
f
e
c
t
o
n
n
e
u
r
o
m
u
s
c
u
l
a
r
j
u
n
c
t
i
o
n
s
n
o
n
d
e
p
o
l
a
r
i
z
i
n
g
d
e
p
o
l
a
r
i
z
i
n
g
- N
M
antagonists
- N
M
agonists
- antag. by ACHEI
- decamethonium
- tubocurarin
e
- suxamethonium
- mivacurium
-
atracurium, cisatracurium
- rocuronium
, pipecuronium
-
(
pancuronium
,
vecuronium
)
i
n
d
i
r
e
c
t
m
u
s
c
l
e
r
e
l
a
x
a
n
t
s
:
d
a
n
t
r
o
l
e
n
e
,
b
o
t
u
l
i
n
u
m
t
o
x
i
n
Skeletal muscle relaxants
Dive into the world of the parasympathetic nervous system and cholinergic pharmacology, exploring concepts like cholinomimetics, parasympathomimetics, cholinolytics, and more. Discover how acetylcholine synthesis and degradation play crucial roles in these processes, and learn about different cholinotropic agents based on their chemical structures.
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Presentation Transcript
PARASYMPATHETIC NERVOUS SYSTEM
Cholinergic drugs elicit their effect: 1) via the parasympathetic synapses of effector organs 2) via synapses of the autonomic nerve ganglia 3) via synapses of neuromuscular junctions 4) via synapses in CNS - influence synapses, where acetylcholine (ACh) acts as their neurotransmitter
Cholinergic nervous system - pharmacological interventions acetylcholine analog. cholinotropics cholinomimetics cholinolytics ACHE inhibitors direct indirect indirect direct NN M NN M ganglioplegics parasympatholytics parasympathomimetics gangliomimetics NM muscle relaxants
Terminology: Cholinomimetics - activity at cholinergic synapses direct ACh and its analogues they imitate ACh effects on M and N receptors indirect - ACHE inhibitors always non-selective short-term effect - edrophonium intermediate and long-term effect - carbamates ( stigmins ) very long effect - organophosphates Parasympathomimetics - they imitate ACh effect on M rc. direct (mostly non-selective effect) stimulatory agents selective to M receptors for ACh
Terminology: Cholinolytics - direct: - agents blocking acetylcholine receptors Parasympatholytics - M receptor blockers - without any effect on nicotinic receptors Ganglioplegics - NN-receptor blockers Peripheral muscle relaxants (non-depolarizing) - NM-receptor blockers - indirect: e.g. presynaptic inhibition of ACh release
Acetylcholine synthesis choline in a lecithin form is a dietary supplement lecithin acts as a precursor to ACh + acetyl CoA choline choline acetyltransferase (CHAT) acetylcholine (ACh)
Acetylcholine degradation hydrolysis acetylcholinesterase (ACHE) acetylcholine + choline acetate
Cholinotropic agents - according to the chemical structure we distinguish: agents with quaternary ammonium cation quaternary amines, e.g. muscarine with low GIT absorption (they do not cross BBB) tertiary amines, e.g. natural alkaloids (nicotine, physostigmine)
Cholinomimetics - cholinergic agonists - pharmacological effects: CVS - negative chronotropic effect - heart depression - generalized vasodilation GIT - increased motility of smooth muscles respiratory tract - bronchoconstriction bronchial secretion eye - miosis, intraocular pressure lacrimation sweating, salivation CNS - tremor, increased locomotion
Acetylcholine and its analogues acetylcholine rapid biodegradation by ACHE not used in clinics 5-20 s effect after i.v. administration limited absorption after oral / s.c. administration does not penetrate BBB - other choline esters: carbachol poor absorption from GIT agonist of M and N Rc not hydrolyzed by cholinesterase long duration of action I: ophthalmology - miosis cevimeline selective M agonist - parasympathomimetic I: xerostomia (dry mouth), Sj gren s syndrome
Acetylcholine and its analogues postganglionic neuronal activity neuromuscular signal transduction activity of parasympathetic effectors sympathetic stimulation of sweat glands - pharmacological effects: BP, bradycardia, danger of heart arrest nauzea, cough, dyspnoe vascular dilation: NO release salivation, lacrimation, mucosal gland secretion excessive sweating
Cholinomimetics - natural alkaloids pilocarpine (Pilocarpus) non-selective M receptor agonist good absorption from GIT BBB crossing ( CNS excitation) stimulates gland secretion stimulates m. sphincter pupilae (eyedrops) I: miotic agent used in ophthalmology 2-4%, Sj gren's syndrome muscarine (Inocybe, Clitocybe, Amanita muscaria/phalloides) M receptor agonist, quaternary amine arecoline (Areca catechu) CNS stimulant, tertiary amine M and N receptor agonist
Indirect cholinomimetics ACHE inhibitors long-term (IRREVERSIBLE) short-term (REVERSIBLE) competitive enzyme inhibition complex inhibitor + enzyme COVALENT INHIBITION toxicology medicinal use
Indirect cholinomimetic agents Reversible ACHE inhibitors General indications: glaucoma GIT atony urinary retention antidotes of non-depolarizing muscle relaxants myasthenia gravis (use quaternary amines) Alzheimer s disease (use tertiary amines) intoxication with organophosphates poisoning associated with the central anticholinergic syndrome (atropine)
Indirect cholinomimetic agents Reversible ACHE inhibitors Side effects: miosis increased glandular secretion nausea, diarrhea heart depressants (negative chronotropic effect) CNS stimulation followed by depression neuromuscular junction - fasciculation and twitching (overdose - depolarization blockade) overdosing = cholinergic crisis depolarization blockade - muscle paralysis
Indirect cholinomimetics Reversible ACHE inhibitors neostigmine, (edrophonium) short-term effect I: diagnosis of myasthenia gravis decurarization , antidotes of competitive muscle relaxants pyridostigmine, ambenonium longer effect than neostigmine, slower onset of action weaker muscarinic effect - less GIT side effects I: myasthenia gravis distigmine long-acting reversible ACHE inhibitor I: myasthenia gravis, atonic the urinary bladder, uterine atony, postoperative GIT atony, paralytic ileus
Indirect cholinomimetics Reversible ACHE inhibitors - CNS effects of drugs, that can cross the blood-brain barrier physostigmine I: antidote in acute intoxications with central anticholinergic syndrome galantamine, rivastigmine, donepezil I: dementias of the Alzheimer s type galantamine has a positive allosteric effect on ACh binding on N rec.
Indirect cholinomimetics Irreversible ACHE inhibitors - effects: nausea, vomitus, sweating, CVS collapse, breath depression, fasciculation and twitching muscle paralysis, CNS convulsions - agents: organophosphates insecticides (malathion, parathion) chemical weapons such as nerve gas sarin or VX, soman, tabun - their antidotes: obidoxime, trimedoxime, pralidoxime
Indirect cholinomimetics Irreversible ACHE inhibitors Therapy of organophosphate itoxication: 1. reduce further neurotoxine absorption 2. mechanical ventilation 3. atropine i.v. in high doses 2 mg every 5 min until a slight overdose (in mass-casualty settings s.c.) 4. ACHE reactivators : obidoxime, (pralidoxime) 5. therapy of muscle convulsions i.v. benzodiazepines 6. high doses of reversible ACHE inhibitors 7. bioscavengers
Parasympatholytics tertiary amines blockade of M receptors quaternary amines blockade ofM >N receptors atropine scopolamine tropicamide, cyklopentolate oxybutynine tolterodine, fesoterodine solifenacin, darifenacin procyklidine, biperiden (pirenzepine, telenzepine) (homatropine) butylscopolamine phenpiverine, propiverine otilonium, glycopyrrolate ipratropium, tiotropium aclidinium, umeclidinium trospium (oxyfenonium),(poldin)
Parasympatholytics direct antimuscarinic agents General indications: spasmolytics bronchodilating agents antiarrhythmics mydriatics premedication prior to GA antiemetics antiparkinson agents antidotes of pilocarpine, ACHEI poisoning (physostigmine)
Parasympatholytics direct antimuscarinic agents Side effects: dry mouth (xerostomia) dry eyes (xerophthalmia) loss of accommodation (cycloplegia) heart palpitations constipation urinary retention CNS: seizures, severe dyskinesias, hallucinations, agitated delirium, respiratory depression, coma
PL with tertiary N atropine, tropicamide, cyclopentolate, homatropine mydriasis (stimulation of m. sphincter pupilae) cycloplegia (paralysis of the ciliary muscle of the eye) I: for diagnostic and therapeutic mydriasis scopolamine (hyoscine) TTS, supp. I: therapy of kinetosis, CNS depression oxybutinine orally, TTS pharmacokinetics: high 1stpass effect I: antispasmodic agent used for overactive urine bladder
PL with tertiary N Selective parasympatholytics: darinefacin, solifenacin M3uroselective antagonists I: symptomatic therapy of overactive urinary bladder (pirenzepine) gastric M1 receptor selective antagonist former indication: gastroduodenal ulcers
PL with quaternary N - do not cross BBB (blood-brain barrier) spasmolytics for functional bowel disorders: otilonium N-butylscopolamine phenpiverine (oxyphenonium),(poldin) urinary antispasmodic for hyperactive urinary bladder: trospium ipratropium (SAMA) tiotropium, aclidinium glycopyrrolate, umeclidinium bronchodilator agents: (LAMA) * long acting muscarinic antagonists (LAMA) short acting muscarinic antagonists (SAMA)
Skeletal muscle relaxants 1. Centraly acting 2. Peripheral effect on neuromuscular junctions nondepolarizing - NMantagonists - antag. by ACHEI - tubocurarine - mivacurium - atracurium, cisatracurium - rocuronium, pipecuronium - (pancuronium, vecuronium) depolarizing - NMagonists - decamethonium - suxamethonium indirect muscle relaxants: dantrolene, botulinum toxin
