direct cholinergic drugs profs. abdalqader alhaider & hanan hagar pharmacology unit
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DIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGS
Profs. Abdalqader Alhaider & Hanan HagarPharmacology 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 indirect-acting 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 Autonomic N.SControl skeletal muscles Control internal viscera
Voluntary Involuntary
Somatic nerve is one fiber autonomic nerve is two fibers )Preganglionic &
Postganglionic(
Pre-ganglionic fiber
Post-ganglionic fiber
ganglia
One fiber
Division of Autonomic Nervous System
• Sympathetic nervous system.
• Parasympathetic nervous system.
• Enteric nervous system.
ParasympatheticParasympathetic Nervous SystemNervous System
Is a craniosacral outflowIs 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
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(.
Nicotinic 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
ReceptorLocationsPharmacological actions
M1 Excitatory
CNS
gastric parietal cells
CNS excitation
Gastric acid secretion
M2 Inhibitory
Heart Cardiac inhibition
)Bradycardia(
M3
Excitatory
Exocrine glands
Smooth muscles )GIT, urinary tract, bronchial muscles(
Vascular endothelium
• Secretion of glands
• Smooth muscle contraction
• Vasodilatation )via nitric oxide(
M4 & M5CNSmemory, arousal, attention and analgesia
Muscarinic receptors
Nicotinic receptorsCentral cholinoceptors
Muscarinic receptorsPeripheral cholinoceptors
Almost excitatoryExcitatory or inhibitory
Autonomic ganglia Nn sympathetic & parasympathetic
stimulation
On all peripheral organs innervated by postganglionic parasympathetic fibers
Adrenal medulla Nn release of catecholamines
(adrenaline & noradrenaline)
Heart (bradycardia, M2) exocrine glands (secretion, M3)
Skeletal muscles Nmcontraction
Smooth muscles (contraction, M3))GIT, urinary tract, bronchial
muscles, uterus(
Cholinergic or parasympathetic receptors
Actions that are due to effects of Ach on nicotinic receptors and muscarinic receptors thus divided in two actions
1( Nicotinic actions2( Muscarinic Actions
Pharmacological actions of parasympathetic N.S.
Skeletal muscles: Low conc. of Ach muscle contractionHigh conc. of Ach persistent depolarization &
relaxation.
Stimulation of Autonomic ganglia
Stimulation of adrenal medulla: release of
catecholamines )Adrenaline & Noradrenaline(.
Nicotinic actions of Ach
Muscarinic actions of AchOrgansCholinergic actionsEyeContraction of circular muscle of iris
(miosis)(M3)Contraction of ciliary muscles for near
vision (M3)Decrease in intraocular pressure (IOP)
Heartendothelium
bradycardia ( decrease in heart rate ) (M2)
Release of NO (EDRF) LungConstriction of bronchial smooth muscles
Increase in bronchial secretion M3GITIncrease in motility (peristalsis)
Increase in secretionRelaxation of sphincter -defecation M3
Urinary bladder
Contraction of muscles Relaxation of sphincter M3 Urination
Exocrine glands
Increase of secretions of exocrine glandssweat, saliva, lacrimal, bronchial, intestinal secretions M3
Drugs that produce actions similar to
stimulation of parasympathetic system or
similar to Ach.
CholinomimeticsCholinomimeticsParasympathomimeticsParasympathomimetics
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
–Naturally occurring alkaloids e.g. Pilocarpine
–Synthetic choline esters
•Acetylcholine )M,N(
• Carbachol )M,N(
• Bethanechol )M(
• Cevimeline )M(
Direct CholinomimeticsDirect Cholinomimetics
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.
Carbacholo Has muscarinic actions similar to ACho Has nicotinic actions similar to Ach )side
effects(o Longer duration of actiono Used for treatment of glaucoma
Bethanechol o Has muscarinic actions similar to ACho Has no nicotinic actions o Longer duration of actiono 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 CarbacholBethanechol Pilocarpine
Chemistry Quaternary Polar
Quaternary Polar
Quaternary Polar
Tertiarynon polar
AbsorptionNOT better absorbed than
Ach
better absorbed than
Ach
Complete
Metabolismby
cholinesterase
metabolized by
cholinesterase
NOT metabolized by cholinesterase
DurationVery shortLonger )++(Longer )++(Longer )++(
administrationI.V.eye drops
Oral, eye drops
S.C.
Oral S.C.
oral, eye drops
AChM, N
CarbacholM,N
Bethanechol
M
Pilocarpine
Cevimeline M
ReceptorsMuscarinicNicotinic
MuscarinicNicotinic
MuscarinicMuscarinicMuscarinic
Muscarinic+++ +++ +++++++++
SelectivityNOTEye, GITUrinary bladder
GIT, Urinary
bladder
More on eye,
exocrine glands
Exocrine glands
Nicotinic+++ +++ NONONO
UsesNOGlaucomaParalytic ileus
Urinary retention
GlaucomaXerostomi
a
Sjogren's syndrome
direct Cholinomimetic
Contraindications of direct cholinomimetics
1. Bronchial asthma.
2. Peptic ulcer.
3. Angina pectoris
4. Incontinence
5. Intestinal obstruction
Thank you
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