Lecture 5- direct Cholinomimetics-1.ppt
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Transcript Lecture 5- direct Cholinomimetics-1.ppt
DIRECT CHOLINERGIC DRUGS
Prof. Hanan Hagar
Pharmacology Department
By the end of this lecture the student should know
• Classification of nervous system.
• Describe the various steps in cholinergic transmission.
• Mention the different types, locations and actions of
cholinergic receptors.
• Describe the effects of acetylcholine on major organs
• Classify cholinomimetic drugs.
• Describe the kinetics, actions and uses of direct and indirectacting cholinomimetic drugs.
Nervous system
Peripheral nervous
system
Central nervous
system
Efferent Division
(Motor)
Afferent Division
(Sensory)
Autonomic nervous
system
Somatic system
(skeletal muscles)
Enteric nervous system
Parasympathetic nervous system
Sympathetic nervous system
What are the differences between the somatic and the
autonomic nervous system?
Somatic N.S
•Control skeletal muscles
•Voluntary
•Somatic nerve is one fiber
Autonomic N.S
Control internal viscera
Involuntary
autonomic nerve is two
fibers (Preganglionic &
Postganglionic)
Post-ganglionic fiber
ganglia
Pre-ganglionic fiber
One fiber
Divisions of Autonomic Nervous System
•
•
•
Sympathetic nervous system.
Parasympathetic nervous system.
Enteric nervous system.
Parasympathetic Nervous System
(craniosacral outflow)
Neurotransmitter in parasympathetic or
cholinergic system is acetylcholine and nerves
are called cholinergic nerves
Cholinergic transmission
Cholinergic transmission
•
•
•
•
•
Synthesis
Storage
Release
Binding to receptors
Metabolism by acetylcholinesterase to give
choline and acetate
• Recycling of choline
Cholinergic transmission
Cholinergic or parasympathetic receptors
Nicotinic (N, central) receptors.
Muscarinic (M, peripheral) receptors.
Central nicotinic
receptor
Peripheral muscarinic
receptor
Nicotinic receptors
Type I receptors : ion channel linked receptors
Located in:
• Autonomic ganglia (Nn).
• Adrenal medulla (Nn)
• CNS (Nn)
• Neuromuscular junction (Nm)
Muscarinic receptors
Type II receptors : G-protein linked receptors
• Located at all target organs that are
innervated by parasympathetic fibers (e.g,
heart, CVS, eye, bladder, etc).
• Five subclasses exist (M1 - M5)
• M1, M3, M5 are excitatory in function
(stimulation).
• M2, M4 are inhibitory in function (inhibition).
Muscarinic receptors
Receptor
M1
Excitatory
Locations
Pharmacological actions
CNS
CNS excitation
gastric parietal cells Gastric acid secretion
M2
Inhibitory
Heart
M3
Excitatory
Exocrine glands
Smooth muscles
Vascular endothelium
M4 & M5
CNS
Cardiac inhibition
(Bradycardia)
• Secretion of glands
• Smooth muscle contraction
• Vasodilatation (via nitric oxide)
memory, arousal, attention and
Cholinergic or parasympathetic receptors
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
What are the actions of parasympathetic
nervous system?
1. Nicotinic actions
2. Muscarinic actions
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).
Muscarinic actions
Organs
Cholinergic actions
Eye
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)
Heart
endothelium
Lung
Constriction of bronchial smooth muscles
Increase bronchial secretion M3
GIT
Increase motility (peristalsis)
Increase secretion
Relaxation of sphincter M3
Urinary
bladder
Contraction of muscles
Relaxation of sphincter M3 - Urination
Exocrine
glands
Increase of all secretions
sweat, saliva, lacrimal, bronchial, intestinal secretions
M3
Cholinomimetics
Parasympathomimetics
Drugs that produce actions similar to
stimulation of parasympathetic system (or
similar to natural neurotransmitter, Ach).
Types of cholinomimetics
Direct cholinomimetics
cause direct stimulation of cholinergic receptors.
Indirect cholinomimetics (anticholinesterases)
increase action of Ach indirectly by inhibiting
acetylcholinesterase thus prevent the degradation
of Ach.
Direct Cholinomimetics
Direct cholinomimetics
• Acetylcholine (M,N)
• Carbachol (M,N)
• Bethanechol (M)
• Pilocarpine (M)
Acetylcholine (Ach)
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
Synthetic choline esters
include drugs as bethanechol, carbachol
Quaternary ammonium compounds (polar)
Poor distribution
can not cross BBB (No CNS effects)
Not metabolized by cholinesterase.
Have longer duration of action than Ach.
Never given I.V. or I.M BUT S.C.
Carbachol
1. Orally-S.C.
2. Not metabolized by cholinesterases.
3. Longer duration of action than Ach
4. Muscarinic actions on Eye, GIT, UT. (Table
5. Has nicotinic actions (what are these
actions?).
6. Used for
Mainly in glaucoma
Urinary retention & paralytic ileus (rarely
used due to its nicotinic actions)
Bethanechol
Orally-SC
Prominent muscarinic actions on GIT, UT.
No nicotinic action
Not metabolized by cholinesterases.
Longer duration of action than Ach
Used for
In paralytic ileus
In urinary retention (in cases of post-operative
atony, neurogenic bladder)
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).
Pilocarpine
Uses:
• Xerostomia (dry mouth).
• Drug of choice in emergency glaucoma applied as
eye drops.
Adverse effects:
• Profuse sweating
• Salivation
• Bronchoconstriction
• Diarrhea
• CNS effects
ACh
Chemistry
Quaternary
Polar
Absorption
NOT
Metabolism
by
metabolized
Carbachol Bethanechol
Quaternary
Polar
Quaternary
Polar
better
better
absorbed than absorbed than
Ach
Ach
NOT
NOT
Pilocarpine
Tertiary
non polar
Complete
NOT
by
cholinesterase cholinesterase
Duration
Very short
Longer (++)
Administ.
I.V.
eye drops
Oral,
eye drops
S.C.
Longer (++)
Oral
S.C.
Longer (++)
oral,
eye drops
ACh
Carbachol
Receptors
Muscarinic
Nicotinic
Muscarinic
Nicotinic
Muscarinic
+++
Selectivity
NOT
Nicotinic
+++
Uses
NO
+++
Eye, GIT
Urinary
bladder
+++
Bethanechol
Pilocarpine
Muscarinic
Muscarinic
+++
GIT,
Urinary
bladder
NO
Glaucoma
Paralytic ileus
Paralytic
ileus
Urinary
retention
Urinary
retention
+++
More on eye,
secretion
NO
Glaucoma
Xerostomia
Cevimeline
–Direct acting muscarinic agonist
–Used for treatment of dry mouth symptom
associated with Sjogren's syndrome.
Contraindications of cholinomimetics
1.
2.
3.
4.
5.
Bronchial asthma.
Peptic ulcer.
Angina pectoris
Incontinence
Intestinal obstruction
Thank you