Cholinergic agonists

(Cholinomimetics)

Study Unit 3.2

Compiled by Prof Daan Venter /
1
Adatpted by Dr M Viljoen

Study sections 3.2 3.3

reversible
inhibitors

indirectly acting
drugs
(Cholinesterase inhibitors)

irreversible
inhibitors

cholinergic
agonists

direct
acting nicotine
agonists
directly acting
muscarinic
agonists

drugs influencing the

parasympathetic nervous system

Ganglionblockers
Competitive antagonists
on nicotinic receptors
in the ganglia

Antimuscarinic drugs
Competitive antagonists
on muscarinic receptors
2

Parasympathetic Nervous System

second messengers and G-proteins

Smooth muscle cell

Facilitate
relaxation

Facilitate
contraction

NA

A Ch

M 3 Gq PLC-
PIP2

Inhibit
relaxation

Gs

(+)

AC

DAG
IP3

( -)
Gi

M23

sAMP PDE
cAMP

ATP
ATP
Ca2+

ACh

(- )

5-AMP
Contraction

G: G-protein; PLC: phospholipase C;

PIP2: fosfatidielinositol-bifosfaat; DAG: diacylglycerol;
AC: adenylyl cyclase; cAMP: cyclic 3,5-adenosine monophosphate;
PDE: phosphodiesterase; 5-AMP: inactive AMP

Blood vessel
Smooth muscle
Endothelium
Lumen
ACh

M3
relaxation

NO
NO

NO: nitrogen oxide = direct vasodilator

Gastro-intestinal sphincter
ganglion
Preganglionic
parasympathetic
neuron

Ach

Postganglionic
parasympathetic
neuron

M1

Lumen

relaxation

IN

Smooth muscle
IN

inhibiting neurotransmitter

Drugs that mimic or increase

cholinergic action
Senu-einde
DrugsAsetylcholine
that influence
electric
properties
muscarinic
agonists:
nicotinic
agonists:
esterase
blockers: of
muscarine,
bethanechol
nicotine,
lobeline
presynaptic
nerveedrophonium
terminals:
physostigmine,
(Competitive
synergism)
(reversible)
4-aminopyridine

+
mitochondria

nicotinic agonist

Ca2+

Nik N
ACh

Ca2+

ACh

ACh

ACh

ACh M
Mus

4-Aminopyridine

cell

Ch

ctor
Effe

Muscarinic
agonist

ACh AChE
AChER
acetate

Acetylcholine esterase blocker

Directly Acting Cholinergic

Agonists

Cholinergic Agonists
Acetic acid- and carbamic acid esters of choline
N(CH3)3

N(CH3)3

N(CH3)3

N(CH3)3

CH2

CH2

CH2

CH2

CH2

CH CH3

CH2

CH CH3

C O

C O

C O

C O

CH3

CH3

NH2

NH2

Acetylcholine

methacholine

carbachol

Nicotine / Varenicline = Nicotine agonists

bethanechol

directly acting muscarinic agonists

agonists

Receptor selectivity

methacholine
carbachol
bethanechol
Pilocarpine
muscarine

muscarinic
muscarinic and nicotinic
muscarinic
muscarinic
muscarinic

Substrate for
AChE
yes
no*
no
no
no

* Low affinity for AChE

the effects of all these agonists are exclusively muskarinic
the adverse effects of the muscarinic drugs are directly coupled to their
Interaction with muscarinic receptors (DUMB2ELS).
10

Effects of Muscarinic Agonists

Bradycardia and endothelium dependant vasodilatation
(reduced blood pressure due to NO)
contraction of visceral smooth muscles
(intestine, bladder, trachea, etc.)
Constriction of pupil (miosis) and contraction of ciliary
muscles
(reduce intra-ocular pressure)

11

Treatment??

Poisoning by Toadstool
Cholinergic agonist - Muscarinic effects
eye: miosis (constriction of pupil)
cardiovascular: reduction in heart rate and
contraction
Respiratory system: brongoconstriction and
increased secretions
Gastrointestinal tract: increased motility, relaxation of
the sphincters
Urinary tract: sphincters relax and bladder contacts
Glands: increased secretions
Nicotine
12
poisoning??

Clinical Indications M / N Agonists:

Betanechol: Rx Urin retention, Atony
Post operative (ileus/stomach)
Pilocarpine : Rx Glaucoma
Cevimeline : Rx Sjgren Syndrome ?
Nicotine / Varenicline: Rx Smoking cessation

13

Cholinergic Agonists
Degradation by cholinesterase (hydrolysis)
N(CH3)3

N(CH3)3

N(CH3)3

N(CH3)3

CH2

CH2

CH2

CH2

CH2

CH CH3

CH2

CH CH3

C O

C O

C O

C O

CH3

CH3

NH2

NH2

Acetylcholine
AChE
BuChE

methacholine
AChE
BuChE

carbachol

bethanechol

AChE
BuChE

Not
degraded

AChE, BuChE:: mainly responsible for degradation

AChE, BuChE: To a lesser degree responsible for degradation

14

Cholinesterase Inhibitors
(indirectly acting mimetics)

reversible- and irreversible

enzyme inhibitors
15

Cholinesterase Inhibitors
REVERSIBLE

IRREVERSIBLE***

edrophonium* K

Dyflos

neostigmine* M

Ecotiofate

pyridostigmine* M

parathion

physostigmine** M

malathion

* Quaternary amine
(hydrophilic)

** tertiary amine
(lipophilic)

*** highly lipophilic

K: short acting; M: medium acting; L: long acting

16

Clinical uses: Reversible

Cholinesterase Inhibitors
Narcosis reversing of non-depolarizing neuromuscular
blockers (tubocurarine) after a surgical procedure
operation

neostigmine: intra-venous, no influence on CNS

Myasthenia gravis (Not direct acting M-agonist)

edrophonium: diagnose
neostigmine: time of action, 2-4 h
pyridostigmine: time of action, 3-6 h

Poisoning with muscarinic antagonist (atropine)

physostigmine: increases acetylcholine concentration - muscarinic

antagonism is surmountable
17

Clinical uses Reversible

Cholinesterase Inhibitors (cont.)
Glaucoma reduce intra-ocular pressure
physostigmine

Urine retention
neostigmine

Supraventricular arrhythmia
edrophonium

Myasthenia gravis
vs Cholinergic
crisis???

Alzheimers disease
Tacrine

Strabismus : Cholinomimetics
TCA overdose

Physostigmine
18

Biotransformation of parathion

Organophosphate
NO2

NO2

Cytochrome P450

S
P

CH3 CH3
parathion

Insects, birds
mammals

O
P

CH3 CH3
paroxon
19

Interaction of Organophosphate with

AChE
O CH2CH3
P
O CH2CH3

O2N

Phosphorylation AChE

HO

Trp Glu

Ser

Trp: tryptophan
Glu: glutamate
Ser: serine

AChE

pralidoxime

O2N

Trp Glu

OH

O CH2CH3
P
O CH2CH3

Ser

AChE

pralidoxime only works if it is administered shortly after poisoning

20

Symptoms of
Organophosphate Poisoning
Interaction with M-receptors
all muscarinic effects (DUMB2ELS)

Interaction with N-receptors

effects of NM- and NN-receptors
NM-

CNS (Lipophilic)
Hallucinations, Respiratory suppression
21

Treatment of
Organophosphate poisoning
Respiration
Assist breathing

Remove contaminated clothing

Halts further poisoning

Reduce action of acetylcholine

atropine

Reactivation of ACh-esterase
Pralidoxime / obidoxime
22

Glaucoma

23

Glaucoma
Angle-closure glaucoma

Acute
Accompanied by pain and sudden increase in pressure
Notable haziness

Open-angle glaucoma

Chronic
Pressure increases steadily without accompanying pain

Loss of eyesight almost unnoticeable

24

Radial muscle ()
Trabecular meshwork
Schlems canal
Longitudinal ciliary
smooth muscle
(M)

a
Korne

Iris

Sphfincter (M)

Lens

Ciliary sphincter Epithelium () Zonules

muscle
(M)

After treatment of angle-closure glaucoma with cholinomimetics

Longitudinal ciliary
smooth muscle is
contracted and stretch
the trabecular meshwork

Iris

Sphincter contracted,
cause miosis

Lens
Ciliary sphincter muscle is contracted,
relaxing the zonoles

Zonules
relaxed

Lens more convex

(near vision)

25

Glaucoma treatment (autonomic)

Pilocarpine (muscarinic agonist)
Generally employed as eye drops

Ecotiophate (anticholinesterase) / Physiotigmine

Eye drops.

Timolol (-adrenoceptorantagonist)

5 Betablockers???

Eye drops.

Acetazolamide (carbonic acid anhydrase inhibitor)

Diuretic

Apraclonidine (2-adrenoceptoragonist) / Brimonidine

Eye

drops
Adrenalien/Dipivefrin

26

Clinical problems
Cholinomimetics
Effects:

Marked PSN activity: reduction of blood pressure,

brongoconstriction, salivation, miosis, sweat, gastrointestinal
discomfort (DUMB2ELS)

Contraindicated for patients with:

asthma
chronic obstructive pulmonary disease
peptic ulcers
obstruction of the urinary tract or gastrointestinal tract

WHY ???
27

Cholinergic Antagonists
(Anticholinergic drugs)

Study section 3.3

28

Drugs Inhibiting Cholinergic Action

Muscarinic antagonists
Ganglion blockers
Neuromuscular blockers
Other drugs that reduce of inhibit acetylcholine

29

Drugs that inhibit cholinergic

Ganglionblocker:
action
hexamethonium,
trimethaphanrelease:
Inhibitors
of Acetylcholine

Inhibitors of Muscarinic
high affinityantagonists
(Competitive
antagonists)
Nerve ending
botulinus
toxine
(antimuscarinic drugs:inhibitors of vesikular
uptake:
Ganglionblocker
choline transport:
atropine, dicyclomine, scopolamine
hemicholine
ChAT
(competitive
antagonists)
+
ACh
Ch
AcCoA
Vesamicol

Bromo
pyruvate

PDH

Pir
AcCoA
mitochondria

ACh

vesamicol
Ca2+

ACh
GB N

Ca2+
ACh

ACh

ACh
AM M
Antimuscarine

inhibitors of pyrovate dehydrogenize:

Ch

bromo pyruvate

cell

Hemicholine

ctor
Effe

botulinus toxine

30

Muscarinic Antagonists

31

Main effects of muscarine

antagonists

Reduce secretions (dry mouth)

Tachycardia
Pupil dilatation and reduced accommodation
Relaxation of smooth muscles
(intestine, bladder, trachea, etc.)
Reduce secretion of gastric juice
Central nervous system (CNS) effects; antiemetics, anti-parkinson

32

Clinical uses
Muscarinic antagonists
Cardiovascular
atropine: treatment of sinus-bradycardia after myocardial infarct

Ophtalmic
atropine, scopolamine, tropicamide: eye examination, dilate pupil

Neurological
scopolamine: prevent motion sickness
benztropine, trihexyphenidyl: Parkinsons disease

Respiratory
ipratropium: no thickening of mucus

Urinary tract
okxybutynin, flavoxate: nocturia (urinary incontinence), spasm of urinary
tract
33

Clinical uses (cont.)

Muscarinic antagonists
Pre-medication for operations not generally in use

atropine, scopolamine: to dry up secretions

Gastrointestinal tract - relaxation of GI smooth muscles

(antispasmodic) and diminishing gastric juice secretion
Scopolamine buthylbromide: facilitate endoscope and GI radiology

dicyclomine: irritable bowl syndrome

dicyclomine, oxybutynin, methylatropine: antispasmodic
Pirenzipine (M1-selective) mainly replaced by H2-antagonists and proton
pump inhibitors: peptic ulcers

Poisoning with toadstool or organophosphate

Atropine

Hyperhydrosis: Glycopyrrolate; Botox ONLY under arms, AlCl2

34

Clinical problems
Muscarinic Antagonists
Effects:

urine retention, constipation, tachycardia, dry mouth,

mydriasis, reduce sweet
toxic psychosis

Contraindicated by patients with:

with atony (relaxation) of the intestine

urinary retention
prostate hypertrophy
elderly persons
patients with angle-closure (glaucoma)
35

Atropine (Atropa Belladona) Poisoning

NB!NB! children NB!NB!
Simptome:
urine retention, constipation, tachycardia, dry mouth, mydriasis,
reduce sweet
CNS: psychosis/ irritability / convulsions
Respiratory suppression

Treatment:

Symptomatic Rx
Physostigmine (lipophilic) small doses/slow IV (Dangerous)
Physostigmine for TCA overdose can potentiate cardiotoxicity
Neostigmine for peripheral effects
36

Ganglion Blocking Agents

37

Ganglion blockers

hexamethonium
trimethaphan
Mecamylamine
block NN-receptors on ion channels

38

Clinical uses
Ganglion blocking agents

Hypertensive crisis
trimethaphan: reduces blood pressure in an emergency
Dissecting aorta aneurysm
Because of adverse effects these drugs, with exception of
trimethaphan, are not in use anymore

39

Drugs reducing action of

acetylcholine on N-receptors

40

Drugs that reduce the action of Ach

Inhibition is caused by various mechanisms
Reduction of Ach release
these drugs cause simultaneously muscle relaxation and ganglionblockade

botulinus toxin: continuous muscle spasms/wrinkles/hyperhydrosis under

arms / cerebral palsy

Continual Depolarization
in these cases the ganglia is blocked after initial receptor stimulation

nicotine: no clinical use as ganglion blocker

Acetylcholine (continual inhibition of Ach esterase)

41

Drugs acting on Neuromuscular

junctions
(Muscle relaxants)
Study section 3.4

42

Study section 3.4

Centrally acting
drugs

Katzung
Chapter 27

Muscle relaxants

Depolarizing drugs

Non-depolarizing drugs

agonists

Competitive antagonists

Direct involvement
with calcium
mechanism

43

Non-depolarizing
Muscle Relaxants
Nm
Competitive
Antagonists
44

Non-depolarizing Muscle Relaxants

d-Tubocurarine

Gallamine

hypotension (ganglion block plus

histamine release vasodilatation)
Brongo constiction (histamine release)

Alcuronium

effects as for tubocurarine

releases less histaminen
shorter acting than tubocurarine

tachycardia (potent muscarinic

antagonist)
does not release histamine

Pancuronium

Almost no tachycardia, no
hypotension (weak muscarinic
antagonist)
does not release histamine
Rokuronium/ Vecuronium
Atracurium / Mivacurium

Al these drugs possess a bi-quaternary structure: hydrophilic

Skeletal relaxation is reversed with: neostigmine + ??atropine??45

Interaction of non-depolarizers with NMreceptors

Tubocurarine (non-depolarizing drug)

Tub

Na+

Na+

Tub
ACh

Tub
ACh

ACh
Tub

ACh
Tub

Membrane

K+

Inside of membrane

K+
46

Drugs with additive action

on the blocking effect of muscle
relaxants

Aminoglycoside-antibiotics
Local anesthetics
Quinidine
Inhalation anesthetics

47

Clinical problems
non-depolarizing agents
Older products
Blood pressure and change in heart rate
Release of histamine
Ganglionic effects
Muscarinic effects
Controlled reversion is difficult (some drugs)
Newer products
Minimal or no cardiac effects
Minimal or no release of histamine
effect easily reversed
48

Depolarizing
Muscle Relaxants
Nm
Agonist
49

Depolarizing Muscle Relaxant

Ach

CH3

CH3

H3C NCH2CH2OCCH2CH2COCH2CH2N CH3

CH3

CH3

Succinylcholine / Suxamethonium
O

HO CCH2CH2C OH
Suksinile acid
50

Depolarizing Muscle Relaxants

Succinylcholine Clinical use

duration: 6-8 min

Scoline-apnee increase in duration to 2-3 hours
Genetic defect on pseudo-cholinesterase / exposure to
organophosphate poisoning / neonates or patients with liver diseases.
Treatment artificial ventilation

Bradycardia direct muskarine action

Increase intra-ocular pressure - muscarinic effect
Maligne hyperthermia - very rare / inheritable / intense muscle cramps /
increased temp Treated with Dantrolene)

Dexamethonium not used clinically, No esther groups and thus not

easily degraded

Long acting
51

Skeletal Muscle
Neuromuscular junction
Normal conditions: Nerve impulse release adequate ACh
to revoke depolarization / action potential in a muscle
ACh is quickly degraded (200 s)
Longer recovery process on end template / refractory
period
If ACh degradation by ChE-inhibitors is reduced then
more ACh will bind to different receptors
It leads to initial contraction then relaxation due to cont.
stimulation
This will result in unsynchronized movements and
eventually to muscle relaxation / apnea
52

Interaction of depolarizers with

NM-receptors
Suk Succinylcholine (depolarizer)

Na+

Na+

Suk

Suk

K+

n
it o
a
z
i
Membraan
r
a
l
o
ep
D

Intracellular

Suk

Suk

K+
53

Clinical problems
Succinylcholine
Hyperkalemia (severe burns)
Increased intra-ocular and intragastric pressure
Additional vagal stimulation: salivation;
hypotension; bradicardia
Malignant hyperthermia
Post operative myalgia
Atropine administered for repeated succinylcholine
doses to vagus effects

54

Centrally acting
muscle relaxants (Spasmolytics)
Diazepam: benzodiazepine
Baclofen : GABA agonist: As effective as
diazepam causes less sedation
Tizanidine: 2-agonist like clonidine, much less
hypotensive effects. Rx Spastic conditions +
Chronic migraine

55

Other centrally acting

muscle relaxants (Spasmolytics)
Dantrolene hidantoen derivative (like phenytoin) with central
acting effects but muscle relaxation is peripheral action
Causes direct blockade of muscle contractions via
interference on Ca2+
release in SR
Rx malignant hyperthermia due to general anesthetics;
succinylcholine
Botulinum Toxin - Ach release also in skeletal muscles. Rx
Cerebral palsy

56