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