DIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGSDIRECT CHOLINERGIC DRUGS

Prof. Hanan HagarPharmacology 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 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.S•Control 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

Divisions of Autonomic Nervous System

• Sympathetic nervous system.

• Parasympathetic nervous system.

• Enteric nervous system.

ParasympatheticParasympathetic Nervous SystemNervous System)craniosacral outflow()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

Type I receptors : ion channel linked receptors

Located in:

• Autonomic ganglia )Nn(.• Adrenal medulla )Nn(• CNS )Nn(• Neuromuscular junction )Nm(

Nicotinic 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

ReceptorLocationsPharmacological actionsM1

ExcitatoryCNS

gastric parietal cells

CNS excitation

Gastric acid secretion

M2 Inhibitory

Heart Cardiac inhibition

)Bradycardia(

M3

Excitatory

Exocrine glands

Smooth muscles

Vascular endothelium

• Secretion of glands

• Smooth muscle contraction

• Vasodilatation )via nitric oxide(

M4 & M5CNSmemory, arousal, attention and

Muscarinic receptors

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

Smooth muscles )GIT, urinary tract, bronchial muscles(

)M3( contraction

Almost excitatoryExcitatory or inhibitory

What are the actions of parasympathetic

nervous system?

1. Nicotinic actions

2. Muscarinic 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(.

Nicotinic actions

Muscarinic actionsOrgansCholinergic actionsEyeContraction of circular muscle of iris

(miosis)(M3)Contraction of ciliary muscles for near

vision (M3)Decrease in intraocular pressure

Heartendothelium

bradycardia ( heart rate ) (M2)Release of NO (EDRF)

LungConstriction of bronchial smooth musclesIncrease bronchial secretion M3

GITIncrease motility (peristalsis)Increase secretionRelaxation of sphincter M3

Urinary bladder

Contraction of muscles Relaxation of sphincter M3 - Urination

Exocrine glands

Increase of all secretionssweat, saliva, lacrimal, bronchial, intestinal secretions M3

Drugs that produce actions similar to stimulation of parasympathetic system )or similar to natural neurotransmitter, Ach(.

CholinomimeticsCholinomimeticsParasympathomimeticsParasympathomimetics

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• Acetylcholine )M,N(

• Carbachol )M,N(

• Bethanechol )M(

• Pilocarpine )M(

Direct CholinomimeticsDirect Cholinomimetics

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, carbacholQuaternary 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.

Carbachol1. Orally-S.C.2. Not metabolized by cholinesterases.3. Longer duration of action than Ach4. Muscarinic actions on Eye, GIT, UT. )Table5. 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 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 NOT NOT

DurationVery shortLonger )++(Longer )++(Longer )++(

Administ.I.V.eye drops

Oral, eye drops

S.C.

Oral S.C.

oral, eye drops

ACh Carbachol Bethanechol Pilocarpine

ReceptorsMuscarinicNicotinic

MuscarinicNicotinic

MuscarinicMuscarinic

Muscarinic+++ +++ ++++++

SelectivityNOTEye, GITUrinary bladder

GIT, Urinary

bladder

More on eye, secretion

Nicotinic+++ +++ NONO

UsesNOGlaucoma

Paralytic ileus

Urinary retention

Paralytic ileus

Urinary retention

GlaucomaXerostomia

Cevimeline –Direct acting muscarinic agonist

–Used for treatment of dry mouth symptom

associated with Sjogren's syndrome.

Contraindications of cholinomimetics

1. Bronchial asthma.2. Peptic ulcer.3. Angina pectoris4. Incontinence5. Intestinal obstruction

Thank you