Transcript 5-direct Cholinomimetics-1.ppt

DIRECT CHOLINERGIC DRUGS
Profs. Abdalqader Alhaider & Hanan Hagar
Pharmacology Unit
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
Division of Autonomic Nervous System
•
•
•
Sympathetic nervous system.
Parasympathetic nervous system.
Enteric nervous system.
Parasympathetic Nervous System
Is a craniosacral outflow
Neurotransmitter in parasympathetic nervous
system or cholinergic system is acetylcholine
and nerves are called cholinergic nerves
Cholinergic transmission
• The release of neurotransmitter Ach from
cholinergic nerves include the following steps:
1) Synthesis of Ach
2) Storage of Ach in storage vesicles
3) Release of Ach
4) Binding of Ach to postsynaptic receptors to
give actions
Cholinergic transmission
5) Metabolism by acetyl cholinesterase in
synaptic cleft to give choline and acetate.
acetyl cholinesterase
Acetylcholine
acetate + choline
6) Recycling of choline
Cholinergic transmission
Cholinergic transmission
Cholinergic or parasympathetic receptors


Nicotinic receptors (N) = central receptors.
Muscarinic receptors (M)= peripheral receptors
Central nicotinic
receptor
Peripheral muscarinic
receptor
Nicotinic receptors
Type I receptors : ion channel linked receptors
Located in:
Skeletal muscles (neuromuscular junction, Nm )
Autonomic ganglia (sympathetic and
parasympathetic ganglia, Nn).
Adrenal medulla (Nn).
CNS (Nn).
Muscarinic receptors
Type II receptors : G-protein linked receptors
• Five subclasses ; M1, M2, M3, M4 and M5
• M1, M3, M5 are excitatory or stimulatory in
function (stimulation)
• M2, M4 are inhibitory in function (inhibition).
• Located at all target organs that are innervated
by parasympathetic fibers (e.g, heart, CVS, eye,
bladder, etc).
Muscarinic receptors
Receptor
M1
Excitatory
M2
Inhibitory
Locations
CNS
gastric parietal
cells
Heart
Pharmacological actions
CNS excitation
Gastric acid secretion
Cardiac inhibition
(Bradycardia)
Exocrine glands
• Secretion of glands
Smooth muscles
(GIT, urinary tract, • Smooth muscle contraction
bronchial muscles)
Vascular endothelium • Vasodilatation (via nitric
oxide)
M4 & M5
CNS
memory, arousal, attention
and analgesia
M3
Excitatory
Cholinergic or parasympathetic receptors
Nicotinic receptors
Central cholinoceptors
Almost excitatory
Muscarinic receptors
Peripheral cholinoceptors
Excitatory or inhibitory
Autonomic ganglia Nn
sympathetic & parasympathetic
stimulation
Adrenal medulla Nn
release of catecholamines
(adrenaline & noradrenaline)
On all peripheral organs innervated
by postganglionic parasympathetic
fibers
Heart (bradycardia, M2)
exocrine glands (secretion, M3)
Skeletal muscles Nm
contraction
Smooth muscles (contraction, M3)
(GIT, urinary tract, bronchial
muscles, uterus)
Pharmacological actions of parasympathetic N.S.
Actions that are due to effects of Ach on
nicotinic receptors and muscarinic receptors
thus divided in two actions
1) Nicotinic actions
2) Muscarinic Actions
Nicotinic actions of Ach
 Skeletal muscles:
Low conc. of Ach  muscle contraction
High conc. of Ach persistent depolarization &
relaxation.
 Stimulation of Autonomic ganglia
 Stimulation of adrenal medulla: release of
catecholamines (Adrenaline & Noradrenaline).
Muscarinic actions of Ach
Organs
Cholinergic actions
Eye
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
Decrease in intraocular pressure (IOP)
bradycardia ( decrease in heart rate ) (M2)
Heart
endothelium
Release of NO (EDRF)
Lung
Constriction of bronchial smooth muscles
Increase in bronchial secretion M3
GIT
Increase in motility (peristalsis)
Increase in secretion
Relaxation of sphincter -defecation M3
Urinary
bladder
Contraction of muscles
Relaxation of sphincter M3
Urination
Increase of secretions of exocrine glands
sweat, saliva, lacrimal, bronchial, intestinal secretions
M3
Exocrine
glands
Cholinomimetics
Parasympathomimetics
Drugs that produce actions similar to
stimulation of parasympathetic system or
similar to Ach.
Types of cholinomimetics
Direct cholinomimetics
cause direct stimulation of cholinergic receptors.
Indirect cholinomimetics (anticholinesterases)
acts indirectly by inhibiting acetyl cholinesterase
thus prevent the hydrolysis of Ach.
Direct Cholinomimetics
Direct cholinomimetics
– Naturally occurring alkaloids e.g. Pilocarpine
– Synthetic choline esters
• Acetylcholine (M,N)
• Carbachol (M,N)
• Bethanechol (M)
• Cevimeline (M)
Acetylcholine (Ach)
Muscarinic and nicotinic agonist
Not used clinically because Ach
– Is not selective as it acts on both nicotinic and
muscarinic receptors
– Has short duration of action. Why?
– Due to rapid metabolism by
acetycholinesterase
Synthetic choline esters
include drugs as bethanechol, carbachol
 Quaternary ammonium compounds
contain N+ (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
o Has muscarinic actions similar to ACh
o Has nicotinic actions similar to Ach (side
effects)
o Longer duration of action
o Used for treatment of glaucoma
Bethanechol
o Has muscarinic actions similar to ACh
o Has no nicotinic actions
o Longer duration of action
o Used for treatment of paralytic ileus &
urinary retention.
Carbachol
1. Muscarinic actions on Eye, GIT, UT. (see the
previous table).
2. Has nicotinic actions (what are these actions?)
3. Used for

Mainly in glaucoma

Urinary retention & paralytic ileus (rarely
used due to its nicotinic actions)
Bethanechol
 Prominent muscarinic actions on GIT, UT.
 No nicotinic action
 Used for

Paralytic ileus

Urinary retention in cases of
post-operative atony & neurogenic bladder
Pilocarpine (natural alkaloids)
• Tertiary amine non polar = lipophilic
• well absorbed, good distribution
• Cross BBB (has central effects).
• Not metabolized by cholinesterase
• Long duration of action
• Direct muscarinic agonist
(mainly on eye & secretion).
Pilocarpine (continue…)
Uses:
• Xerostomia (dry mouth).
• Drug of choice in emergency glaucoma applied
as eye drops.
Adverse effects:
• Profuse sweating
• Salivation
• Bronchoconstriction
• Diarrhea
• CNS effects
Cevimeline
–Direct acting muscarinic agonist
–Used for treatment of dry mouth symptom
associated with Sjogren's syndrome
(autoimmune disease characterized by
decreased salivation).
ACh
Carbachol Bethanechol
Pilocarpine
Chemistry
Quaternary
Polar
Quaternary
Polar
Quaternary
Polar
Tertiary
non polar
Absorption
NOT
better
absorbed than
Ach
better
absorbed than
Ach
Complete
Metabolism
by
metabolized
cholinesterase
cholinesteras
e
Duration
Very short
Longer (++)
administration
I.V.
eye drops
Oral,
eye drops
S.C.
by
NOT metabolized by cholinesterase
Longer (++)
Oral
S.C.
Longer (++)
oral,
eye drops
direct Cholinomimetic
ACh
M, N
Carbachol
M,N
Bethanechol
Cevimeline
M
Pilocarpine
M
Receptors
Muscarinic
Nicotinic
Muscarinic
Nicotinic
Muscarinic Muscarinic
Muscarinic
+++
Selectivity
NOT
Nicotinic
+++
Uses
NO
+++
Eye, GIT
Urinary
bladder
+++
Glaucoma
+++
GIT,
Urinary
bladder
NO
Paralytic
ileus
Urinary
retention
Muscarinic
+++
+++
More on
eye,
exocrine
glands
Exocrine
glands
NO
NO
Glaucoma
Xerostomi
a
Sjogren's
syndrome
Contraindications of direct cholinomimetics
1.
2.
3.
4.
5.
Bronchial asthma.
Peptic ulcer.
Angina pectoris
Incontinence
Intestinal obstruction
Thank you