Lecture 3 - M-Cholinomimetics. Anticholinesterase Drugs.ppt

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1. Slide-lectureN3
М-cholinomimetics.
Anticholinesterase drugs

2. NERVOUS SYSTEM
•CENTRAL
•Brain
•Spinal cord
•PERIPHERAL
•Somatic (voluntary)
•Autonomic (vegetative):
-Afferent;
-Efferent:
1) sympathetic
2) parasympathetic

3. NEUROTRANSMITTERS
•are chemical substances which transmit nerve
impulses across the synapses (that is from one
neuron and from neuron to effector cells).
FATE OF NEUROTRANSMITTERS:
1. Some portion diffuse out into the surrounding
tissue
2. Some portion destroyed by the enzymes
3. Some portion re-uptaken by the nerve
endings

4. TYPES OF NEUROTRANSMITTERS
•EXCITATORY:acetylcholine, NA, 5-HT,
histamine, prostaglandin, glutamic acid, aspartic acid.
•INHIBITORY:GABA, glycine, alanine, dopamine,
substance P, endorphines, enkephalines

5. Autonomic innervation
•Cholinergic
(mediator -acetylcholine)
•Adrenergic(mediator –noradrenaline)

6. Organs that receive only sympathetic innervation:
Blood vessels, ventricles, pilomotor muscles, kidney
and liver
Organs that receive only parasympathetic
innervation:Ciliary muscle of the eye, lacrimal
glands, gastric and bronchial glands
Organs that receive both sympathetic and
parasympathetic innervation:SA and AV nodes, iris,
gastrointestinal smooth muscle

7. Centers: Midbrain, Medulla oblongata. In spinal cord-Craniosacral part.

8. Parasympathetic system
•Cranialnerve nuclei
Preganglionic cholinergic nuclei:
•III -n. oculomotorius
•VII -n. facialis
•IX -n. glossopharyngeus
•X -n. vagus
•Sacral origin

9. Cholinoceptors
•Nicotinic (N-cholinoceptors)
•All the ganglia including the supra-renal medulla
•At the neuromuscular junction of skeletal muscles
•Muscarinic (M-cholinoceptors)
•М1-stomach
•М2 -heart
•М3-smooth muscle and glands

10. Acetylcholine
•it is the mediator that released in nerve endings
of:
•Allpre-ganglionic fibres(sympathetic and
parasympathetic);
•Allpost-ganglionicparasympatheticfibres
•Somepostganglionicsympathetic fibres
(thermoregulation; sweat glands secretion
anddilation of skeletal muscle vessels);
•Adrenal medulla;
•Somatic fibres supplying skeletal muscles;
•Some neurons of CNS

11. Sites of acetylcholine’s action
•Acetylcholine synthesis
•Release of acetylcholine
•Interaction with cholinoreceptors
•Enzymatic hydrolysis of acetylcholine into
choline and acetate
•Choline is recaptured into presynaptic endings

12. 2 types of cholinesterase participate in the
hydrolysis of acetylcholine
•1) True cholinesterase (acetylcholinesterase) which occurs in
the CNS, red blood cells and in cholinergicstructures.True
cholinesterase is responsible for the hydrolysis of acetylcholine released
in the process of cholinergic transmission.
•2) Pseudocholinesterase (Butyrylcholinesterase) which
occurs in the liver and plasma.
The duration of action of ACh is very short because of its rapid hydrolysis
by both enzymes.

13. Combination of acetylcholine with
cholinergic receptor
CH3 O
-
+
H3C–N –CH2–CH2–O –C –CH3
CH3
_____________ cholinergic receptor ________________
anionic site esteratic site
( -) (+)

14. Molecular (post-receptor) mechanism of
acetylcholine action
Smooth muscle
cell
M1receptor
Heart
pacemaker cell
M2 receptor
Secretory cell
M3receptor
Phospholipase
C inc.
K
+
-channel
activation
Phospholipase
C inc.
Ca
2+
in
cytosol inc.
Slowing of
diastolic
depolarization
Ca
2+
in
cytosol inc.
Tone increaseRate decr. Secretion inc.

15. Drugsaffecting onM -cholinoceptors
(classification)
•М-cholinomimetics(cholinergic agonists)
•М-cholinoblockers(anticholinergic drugs,
аtropine-like drugs)

16. Cholinomimetics
Direct-acting Indirect-acting
(anticholinesterase agents)
Muscarinic Nicotinic
Choline esters Alkaloids
Irreversible
Organophosphates
(very long-acting)
Reversible , carbamates
(intermediate, long-acting)
Edrophonium (short-acting)

17. Cholinomimetics
•are drugs which mimic the effects produced by
stimulation of parasympathetic nervous
system.
They can be divided into 2 groups:
•1) drugs that act directly on receptors (muscarinic
and nicotinic agonists)
•2) anticholinesterases (indirect-acting), which inhibit
acetylcholinesterase, and so allow ACh to
accumulate in the synapse and produce its effects

18. Effects of stimulation of parasympathetic nervous
system:
HEART
•Decrease cardiac output
•Decrease heart rate, bradycardia (“-ve”
chronotropic action)
•Decrease force of atrial contraction (“-ve” inotropic)
•Decrease conduction velocity(“-ve” bathmotropic)
•Decrease automaticity (“-ve” dromotropic)

19. Effects of stimulation of parasympathetic nervous
system:
SMOOTH MUSCLES
•Stimulate motility
(increase in tone) :
•Bronchi
(bronchoconstriction)
•Stomach
•Intestine
•Gall bladder
•Urinary bladder
(contraction of detrusor
muscle)
• Sphincters
relaxation:
•Stomach
•Intestine
•Urinary
bladder
(relaxation of trigone
and sphincter, leading
to urination)

20. Effects of stimulation of parasympathetic nervous
system:
BLOOD VESSELS
•vasodilatation:
•Skeletal muscles
•Corpus cavernosus
•Blood vessels: ACh give I.V. causes fall of BP. On the
endothelial cells of the blood vessels there are M-receptors.
Combination of these receptors and ACh leads to release of a
substance called EDRF (NO, powerful vasodilator). However,
most blood vessels have no parasympathetic innervation and
so the physiological function of vascular M-receptors is
uncertain.

21. Effects of stimulation of parasympathetic nervous
system:
GLANDS
•Increase in secretion:
•bronchial
•gastric
•intestinal
•salivary
•lacrimal
•pharyngeal glands

22. Effects of stimulation of parasympathetic nervous system:
EYE
•contraction of the pupillae sphincter
muscle and miosis
•decrease intraocular pressure through action
of sphincter pupillae and ciliary muscle
•spasm of accommodation
(stimulation of ciliary muscle contraction, for
near vision)

23. Therapeutic uses (indications) of
cholinergic drugs
•Myasthenia gravis, both for diagnosis (edrophonium)
and treatment (neostigmine, pyridostigmine)
•To stimulate the bladder and bowel after surgery
(bethanechol, carbachol): postoperative abdominal
distension, gastric atony, congenital megacolon, oesophageal
reflux, urinary retention (postoperative, postpartum, myogenic
or neurogenic bladder)
•To lower intraocular pressure in chronic simple
glaucoma (pilocarpine)
•As antidote in atropine intoxication (physostigmine)

24. Side effects of cholinergic drugs
•D –diarrhea
•U –urination
•M –miosis
•B –bronchoconstriction
•E –excitation of skeletal muscles
•L –lacrimation
•S –salivation and sweating
Note: These adverse effects are typical for all direct and indirect cholinergic
agonists, not just ACh.

25. Anticholinesterases
•OPC combine only with esteratic site and
phosphorylate it. The covalent phosphorous-enzyme
bond is very stable and the enzyme is inactivated for
hundreds of hours. For this reason, the OPC are
referred to as irreversible (long-acting)
anticholinesterases. They are extremely toxic and
used as insecticides (parathion, malathion) and
chemical warfare agents (“nerve gases” such as
tabun, sarin, soman). 1 week is required for synthesis
of new enzyme molecule.

26. Signs and symptoms of
organophosphate poisoning
Muscarinic
manifectations
Nicotinic
manifestations
CNS
manifestations
Bronchoconstriction
Increased bronchial
secretion
Sweating
Salivation
Lacrimation
Bradycardia
Hypotension
Miosis
Blurring of vision
Urinary incontinence
Muscular
fasciculation
Tachycardia
Restlessness
Insomnia
Tremors
Confusion
Ataxia
Convulsions
Respiratory
depression
Circulatory
collapse

27. Treatment of OPC poisoning
•Atropine is the mainstay of treatment;
2 mg are given I.V. as soon as possible and
repeated every 5-10 min until dryness of the
mouth and HR in excess of 70 beats per
minute indicate that its effect is adequate

28. Treatment of OPC poisoning
Enzyme reactivation
•Pralidoxime, that is cholinesterase reactivator, 1.0 g
should be given 4 hourly I.M.. Efficacy is best if it’s
administered within 12 hours of poisoning.
•It lessens the effects of the accumulated ACh, and,
unlike atropine, it has both antinicotinic and
antimuscarinic effects.

29. Treatment of OPC poisoning
•Strong nucleophiles (e.g. pralidoxime) can split
the phosphorus -enzyme bond initially
formed by OPC and “regenerate” the enzyme.
Later this becomes impossible because a
process of “ageing” strengthens the
phosphorus-enzyme bond.

30. Contraindications to cholinergic agonists
•Bronchial asthma, because they may precipitate severe bronchospasm
•Hyperthyroidism because of the danger of inducing cardiac arrhythmias
•Peptic ulcer because they increase gastric acid secretion
•Coronary insufficiency because hypotension produced by these
drugs further reduces coronary flow
•Mechanical obstruction of GIT and urinary tract
•Parkinsonism

31. Pilocarpine
•Good lipid solubility, natural alkaloid, duration of action 30 min -2
hrs.
•Used in ophthalmology to contract pupil, to reduce high intraocular
pressure, atrophy of ophthalmic nerve.
BETHANECHOL(Urecholine)
•Durationofaction30min-2hrs,isactiveorally.
GI smooth muscle stimulant: postoperative abdominal distention,
paralytic ileus;
Urinary bladder stimulant;
For post-operative; post-partum urinary retention ;
To treat diminished salivation secondary to radiation
Muscarine is of no therapeutic use. It is present in small amounts in
the fungus Amanita muscara.

32. CARBACHOL
•May be used as a miotic in surgery.
•May be used also in treatment of glaucoma.
•Rarely used in practice because of nicotinic stimulation activity.
•Duration of action 30 min-2 hours
METHACHOLINE
•is used for diagnostic purposes: testing for bronchial hyperreactivity and
asthma.
PHYSOSTIGMINE
•enterstoCNS,lipophilic.Duration30min-2hours
•Therapeuticuses:Primaryinophthalmologytoproducemiosisand
decreaseIOP(glaucoma),incaseofkeratitis.
•Increasesintestinalandbladdermotility
•Alsousedinthetreatmentofmyastheniaandoverdosesofatropine
(cholinoblocker)

33. NEOSTIGMINE
•Can’tentertoCNS,morepolar
•Longdurationofaction,usually2-4hours
•Used to stimulate urinary bladder and GIT
•Antidote for tubocurarine and other competitive
neuromuscular blocking agents
•Symptomatic treatment of myasthenia gravis
•Glaucoma
•Stimulation of labor

34. Edrophonium
•Similar to neostigmine, except that is more rapidly absorbed and has a
shorter duration of action (5-15 min)
•Used in the diagnosis of myasthenia gravis
improvement -----mysthenia gravis
(due to insufficient
anticholinesterase agent)
Edrophonium
2 mg I.V.
worsening ------cholinergic crisis
(due to excessive
anticholinesterase agent)

35. Pyridostigmine, ambenonium
•are used orally in the treatment of myasthenia gravis, good
absorption, longer duration of action than neostigmine (4-8
hrs)
Demecarium
-Used for glaucoma
Echothiophate
-Prolonged action (2-7 days), may cause systemic effects, used
as eye drops in glaucoma