CHOLINERGIC TRANSMISSIONCHOLINERGIC TRANSMISSIONMain NT is Acetylcholine (ACh). Main NT is Acetylcholine (ACh). A large number of peripheral ANS fibers synthesize & release Acetylcholine A large number of peripheral ANS fibers synthesize & release Acetylcholine

are called CHOLINERGIC fibers .They include:are called CHOLINERGIC fibers .They include: All pre-ganglionic efferent autonomic fibers.All pre-ganglionic efferent autonomic fibers. Somatic motor fibers to skeletal muscles.Somatic motor fibers to skeletal muscles. Most parasympathetic post ganglionic fibers.Most parasympathetic post ganglionic fibers. A few sympathetic post ganglionic fibers– to sweat glands.A few sympathetic post ganglionic fibers– to sweat glands.Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides

for transmission.for transmission.

Synthesis Storage & release and Synthesis Storage & release and DegradationDegradation

Synthesis:Synthesis:Choline actively transported into the nerve terminal.Choline actively transported into the nerve terminal.Acetyl CoA + CholineAcetyl CoA + Choline Choline Acetyl transferase Choline Acetyl transferase ACh + ACh +

CoACoAStorage:Storage: ACh. is transported into the vesicles ACh. is transported into the vesicles actively actively by vesicle associated by vesicle associated

transporter (transporter (VAT)VAT) & stored in it. Peptides, ATP &proteoglycans & stored in it. Peptides, ATP &proteoglycans are also stored in the vesicle .are also stored in the vesicle .

Acetylcholine is stored as quanta containing Acetylcholine is stored as quanta containing 1,000 - 50,0001,000 - 50,000 molecules in each.molecules in each.

One depolarization of autonomicpost ganglionic nerve may One depolarization of autonomicpost ganglionic nerve may release less & releases it over a larger area.release less & releases it over a larger area.

One depolarization of somatic nerve may release several hundred One depolarization of somatic nerve may release several hundred quanta.quanta.

Release: Release: Arrival of action potential.Arrival of action potential. Influx of calcium ions.Influx of calcium ions. Fusion of vesicleFusion of vesicle Formation of pore.Formation of pore. Exocytosis of several hundred quanta of Ach. into Exocytosis of several hundred quanta of Ach. into

the synapse.the synapse.

Termination of action: Termination of action: Ach binds to & Ach binds to & Activates the cholinoceptors. Activates the cholinoceptors.

The action is terminated The action is terminated within secondswithin seconds by by HydrolysisHydrolysis

AcetylcholineAcetylcholine Acetyl cholineterase Acetyl cholineterase Choline + Choline + Acetic AcidAcetic Acid

• Acetyl cholineteraseAcetyl cholineterase (true cholineterase) found in (true cholineterase) found in synapse & RBCs also.synapse & RBCs also.

• Butylyl cholineteraseButylyl cholineterase (pseudocholineterase) found in (pseudocholineterase) found in blood, plasma, liver, glia & many other tissues ---- has a blood, plasma, liver, glia & many other tissues ---- has a lower specificity for Ach. It metabolizes succinylcholine.lower specificity for Ach. It metabolizes succinylcholine.Genetically determined, some individuals in population Genetically determined, some individuals in population are deficient in this enzyme are deficient in this enzyme

SynthesisSynthesis blocked by hemicholinium —a research drugblocked by hemicholinium —a research drug

Storage Storage blocked by Vesamicol —a research drugblocked by Vesamicol —a research drug

Action potential generation & propagationAction potential generation & propagation blocked blocked by Local anesthetics, tetrodotoxin, sasitoxin.by Local anesthetics, tetrodotoxin, sasitoxin.

Entry of CaEntry of Ca++++ blocked by Aminoglycosides blocked by Aminoglycosides

Release:Release: Blocked by Botulinum toxin &Blocked by Botulinum toxin & Increased by Increased by αα- Latrotoxin (Spider venom)- Latrotoxin (Spider venom)

HydrolysisHydrolysis inhibited by Anticholinesterases inhibited by Anticholinesterases ReceptorsReceptors blocked by receptor antagonists.blocked by receptor antagonists.

Cholinergic receptors (Cholionoceptor): 2 main Cholinergic receptors (Cholionoceptor): 2 main typestypes

11. Muscarinic receptors (M) G-Protein coupled receptors.. Muscarinic receptors (M) G-Protein coupled receptors.2. Nicotinic receptors (N) Ligand gated Ion channel.2. Nicotinic receptors (N) Ligand gated Ion channel. Muscarinic receptors (M ): Muscarinic receptors (M ): They are activated by Ach & muscarine & other cholinergic They are activated by Ach & muscarine & other cholinergic

agonists.agonists. The actions produced by agonists are called muscarinic actions.The actions produced by agonists are called muscarinic actions. They are blocked by AtropineThey are blocked by Atropine LocationsLocations: Plasma membranes of the cells of tissues innervated : Plasma membranes of the cells of tissues innervated

by parasympathetic nerves in Heart, smooth muscles, exocrine by parasympathetic nerves in Heart, smooth muscles, exocrine glands & uninnervated Endothelial receptors, also CNS; brain is glands & uninnervated Endothelial receptors, also CNS; brain is richer in M receptors and spinal cord in N receptorsricher in M receptors and spinal cord in N receptors

Muscarinic receptors (M)Muscarinic receptors (M) 5 types : M5 types : M11,M,M22 , M , M33 ,M ,M44 ,M ,M5 5

Main locationsMain locations MM1--1-- presynaptic nerve terminals,CNS presynaptic nerve terminals,CNS MM22 -- heart -- heart MM3-3- smooth muscles, exocrine glands, smooth muscles, exocrine glands,

endothelium endothelium MM44 ,M ,M5--5-- Main location is CNS Main location is CNS G-Protein coupled receptors-G-Protein coupled receptors--- contain 7 -- contain 7

transmembrane domains , whose third loop is transmembrane domains , whose third loop is coupled to G-Protein that acts as a coupled to G-Protein that acts as a transducertransducer. .

Molecular Mechanism at Muscarinic receptorsMolecular Mechanism at Muscarinic receptors At MAt M11, M, M33 & M & M55:: Binding of ACh to receptor site.Binding of ACh to receptor site. Conformational change.Conformational change. Interaction with G protein--- GqInteraction with G protein--- Gq Coupling of Gq via Coupling of Gq via αα subunit to Phospholipasse subunit to Phospholipasse

C (effector enzyme).C (effector enzyme). Hydrolysis of phosphotidyl inositol(4, 5) Hydrolysis of phosphotidyl inositol(4, 5)

biphosphate-P2biphosphate-P2 Formation of second messengers-- ↑ IPFormation of second messengers-- ↑ IP33, DAG-- , DAG--

increased cytosolic Caincreased cytosolic Ca2+2+

↑ ↑ Cytosolic CaCytosolic Ca2+ 2+ , stimulates, stimulates or inhibits or inhibits enzymes---responseenzymes---response

PHOSPHO – INOSITOL SYSTEMBinding of drug with Muscarinic- cholinergic receptor (M1, M3, M5)

Activation of Phospholipase-C

Phosphatidyl Inositol 4-5 Biphosphate

Diacyl Glycerol (DAG) Inositol 1.4.5 Triphosphate (IP3)(Confined to Membrane) (Diffuses Into Cytosol)

Activation of protein kinase Release of Ca++ fromIntracellular SR & ER

Alteration in the activity of ca++ Dependent enzymes

Effect

MM22 Receptors: Receptors: a.a. Coupling of Coupling of GGi/oi/o via via βγβγ subunitsubunit with with adenylyl cyclaseadenylyl cyclase & ↓ & ↓ cAMPcAMP in the heart in the heartb.b. Coupling of Coupling of GiGi via via βγβγ subunit & opening of K+ subunit & opening of K+ channels channels in the heart.in the heart.

MM44 Receptors: Receptors: like M like M22

Moreover, muscarinic agonist attenuate Moreover, muscarinic agonist attenuate activation of Adenylyl cyclase. & modulate the activation of Adenylyl cyclase. & modulate the increase in cAMP by catecholaminesincrease in cAMP by catecholamines

Nicotinic ReceptorsNicotinic Receptors AGONISTS: Ach & Nicotine & other nicotinic agonists . andAGONISTS: Ach & Nicotine & other nicotinic agonists . andTwo subtypes:Two subtypes: N NN N and and NNM:M: a. a. NNNN : : ——Ion channel , pentamer Ion channel , pentamer composed ofcomposed of 2 2 αα , , ββ, , δδ , , γγ..Locations:Locations::Autonomic ganglia , adrenal medulla, Brain and spinal cord.:Autonomic ganglia , adrenal medulla, Brain and spinal cord.Antagonist: Antagonist: Ganglion blockers-Ganglion blockers-----TrimethaphanTrimethaphanNNM:M: Ion channel , pentamer , composed of Ion channel , pentamer , composed of 2 2 αα , 3 , 3ββ subunits subunitsLocation:Location: Skeletal Muscles motor end plate--Neuromuscular Skeletal Muscles motor end plate--Neuromuscular

Junction.Junction.Antagonist: Antagonist: Neuromuscular Junction blockersNeuromuscular Junction blockers----d-d-

tubocurarinetubocurarine

Molecular Mechanisms / Signal Molecular Mechanisms / Signal Transduction at Nicotinic ReceptorsTransduction at Nicotinic Receptors

a. a. NNMM : : Binding of AgonistBinding of Agonist, , Ach or Nicotine at binding sites on Ach or Nicotine at binding sites on

2 2 αα subunits. subunits. , there is conformational change – opening of the , there is conformational change – opening of the

channel.channel.Influx of Sodium ions----Depolarization– action potential Influx of Sodium ions----Depolarization– action potential

is generated.is generated.ResponseResponse: End-plate depolarization, skeletal muscle : End-plate depolarization, skeletal muscle

contractioncontraction

b.b. Neuronal (Peripheral& central) NNeuronal (Peripheral& central) NN N

Binding ofBinding of Ach , Nicotine at binding sites on 2 Ach , Nicotine at binding sites on 2 αα subunits.subunits.

Molecular Mechanisms: Molecular Mechanisms: Opening of sodium Opening of sodium channel.channel.

Influx of Sodium ions----Depolarization– action Influx of Sodium ions----Depolarization– action potential is generatedpotential is generated

Responses:Responses: In Automomic ganglia, adrenal medullaIn Automomic ganglia, adrenal medulla Depolarization and firing of post ganglionic neuron; Depolarization and firing of post ganglionic neuron;

depolarization of the medullary cell & secretion of depolarization of the medullary cell & secretion of catecholaminescatecholamines

In CNS:In CNS: Prejunctional control of neurotransmitter Prejunctional control of neurotransmitter releaserelease

subtypes/locations & characteristics of subtypes/locations & characteristics of cholinoceptorscholinoceptorsReceptReceptoror

LocationLocation MechanisMechanismm

Result of Result of ACh. ACh. bindingbinding

MM11 CNS Neurons, CNS Neurons, some some presynaptic presynaptic sites, sites, Sympathetic Sympathetic postganglionic postganglionic neuronsneurons

Gq-coupled Gq-coupled via via αα subunitsubunit

Stimulation Stimulation of of phospholipasphospholipase C ↑IPe C ↑IP33, , DAG , ↑ DAG , ↑ intracellular intracellular CaCa++++

MM22 Myocardium, Myocardium, smooth smooth muscles , some muscles , some presynaptic presynaptic sites, CNS sites, CNS NeuronsNeurons

Gi-coupled Gi-coupled via via βγβγ subunit subunit

Inhibition of Inhibition of Adenylyl Adenylyl cyclase cyclase ↓↓cAMP, cAMP, activates Kactivates K++ ChannelChannel

MM33 Smooth muscle, Smooth muscle, exocrine glands, exocrine glands, endothelium, endothelium, CNS NeuronsCNS Neurons

Gq-Gq-coupledcoupled

Like MLike M11

MM44 CNS Neurons; CNS Neurons; possibly vagal nerve possibly vagal nerve endingsendings

Gi-Gi-coupledcoupled

Like MLike M22

MM55 Vascular Vascular endothelium of endothelium of cerebral BV, CNS cerebral BV, CNS NeuronsNeurons

Gq-Gq-coupledcoupled

Like MLike M11

NNNN Post ganglionic Post ganglionic neurons of ANS neurons of ANS ganglia , Adrenal ganglia , Adrenal medulla ,CNS mainly medulla ,CNS mainly spinal cord. Some spinal cord. Some presynptic presynptic cholinergic cholinergic terminals.terminals.

Ion Ion channelchannel

Opening of channel, Na+. Influx, depolarization-- AP generation

NNMM Skeletal muscle Skeletal muscle neuromuscular end neuromuscular end plateplate

Ion Ion channelchannel

Opening of channels, Na+. Influx, depolarization--AP generation

PARASYMPATHOMIMETIC DRUGSPARASYMPATHOMIMETIC DRUGSOROR

CHOLINERGIC DRUGSCHOLINERGIC DRUGSOROR

CHOLINOMIMETIC DRUGSCHOLINOMIMETIC DRUGS

DEFINITION:DEFINITION:Parasympathomimetic / cholinergic drugs can be defined Parasympathomimetic / cholinergic drugs can be defined

as a group of drugsas a group of drugswhose effects resemble those of stimulating the whose effects resemble those of stimulating the

parasympathetic nerves/ Acetylcholine.parasympathetic nerves/ Acetylcholine.They include Direct Acting cholinergic receptor agonists & They include Direct Acting cholinergic receptor agonists &

Indirect Acting drugs Indirect Acting drugs which are anticholinesterases. which are anticholinesterases. Anticholinesterases inhibit the enzyme that terminates the Anticholinesterases inhibit the enzyme that terminates the

action of endogenously released Ach so concentration action of endogenously released Ach so concentration of Ach in the synapse is increased so the response is of Ach in the synapse is increased so the response is enhanced.enhanced.

. .

Classification of Cholinomimetic / Classification of Cholinomimetic / Cholinergic / Parasympathomimetic Cholinergic / Parasympathomimetic drugs:drugs:

A.A. Direct ActingDirect ActingB.B. Indirect Acting Indirect Acting A. Direct Acting Cholinergic Drugs:A. Direct Acting Cholinergic Drugs:I. Choline EstersI. Choline Esters

AcetylcholineAcetylcholine CarbacholCarbachol

MethacholineMethacholineBethanecholBethanechol

II. Cholinomimetic AlkaloidsII. Cholinomimetic Alkaloidsa. a. Mainly Muscarinic AgonistsMainly Muscarinic Agonists

Natural Alkaloids:Natural Alkaloids:Muscarine , Muscarine ,

Pilocarpine, ArecholinePilocarpine, ArecholineSynthetic Alkaloid:Synthetic Alkaloid: Cevimeline Cevimeline , ,

OxotramorineOxotramorineb. b. Mainly Nicotinic AgonistsMainly Nicotinic Agonists

Natural Alkaloids:Natural Alkaloids: Nicotine , Lobeline Nicotine , LobelineSynthetic: Synthetic: VareniclineVarenicline

Dimethylphenylpiperazinium Dimethylphenylpiperazinium (DMPP)(DMPP)

B. Indirect Acting Cholinergic DrugsB. Indirect Acting Cholinergic Drugs or or AnticholinesterasesAnticholinesterases

I- ReversibleI- Reversible II- Irreversible: Organophosphorus CompoundsII- Irreversible: Organophosphorus Compounds

I- ReversibleI- Reversiblea. Carbamatesa. Carbamates

i) i) Tertiary aminesTertiary amines : Physostigmine: Physostigmineii) ii) Quaternary Ammonium compoundsQuaternary Ammonium compounds

NeostigmineNeostigminePyridostigminePyridostigmineDistigmineDistigmineAmbenoniumAmbenoniumDemecarium Demecarium

b. Alcohols : b. Alcohols : EdrophoniumEdrophoniumc. Miscellaneous: c. Miscellaneous: Donepezil, Galantamine, Donepezil, Galantamine,

Rivastigmine ,Tacrine, Rivastigmine ,Tacrine, II. Irreversible Anticholinesterases / II. Irreversible Anticholinesterases / (Organophosphorous Compounds)(Organophosphorous Compounds)

1) 1) Therapeutically useful:Therapeutically useful: Ecothiophate Ecothiophate 2)2) War Gases:War Gases: Sarin , Tuban, Soman Sarin , Tuban, Soman 3)3) Insecticides:-Insecticides:- Parathion , MalathionParathion , Malathion

Di-isopropyl Fluorophosphate (DFP)Di-isopropyl Fluorophosphate (DFP)

AcetylcholineAcetylcholine It is the neurotransmitter of PSNS & somatic It is the neurotransmitter of PSNS & somatic

nerves to skeletal muscles.nerves to skeletal muscles. It is an ester of acetic acid & choline .It is an ester of acetic acid & choline . It is a quaternary ammonium compound, It is a quaternary ammonium compound,

permanently charged; can not penetrate permanently charged; can not penetrate membranes, so poorly absorbed & poorly membranes, so poorly absorbed & poorly distributed to CNS.distributed to CNS.

It is very rapidly hydrolyzed; large amounts must It is very rapidly hydrolyzed; large amounts must be infused I/V to produce detectable effects for 5-be infused I/V to produce detectable effects for 5-20 seconds.20 seconds.

I/M & S/C injection only produce local effectsI/M & S/C injection only produce local effects

Synthesis, Storage and Release. Synthesis, Storage and Release. Termination of Action:Termination of Action:Mechanism of action:Mechanism of action: Agonist at cholinergic receptorsAgonist at cholinergic receptors: :

Muscarinic receptorsMuscarinic receptors Nicotinic receptors Nicotinic receptors

Types & LocationTypes & LocationMolecular mechanismMolecular mechanism Already discussedAlready discussed

Pharmacological Actions/ Organ system Pharmacological Actions/ Organ system effects:effects:

Muscarinic Actions produced on:Muscarinic Actions produced on: EyeEye CVS (Heart, B.V) CVS (Heart, B.V) Respiratory system Respiratory system Gastro intestinal tractGastro intestinal tract Urinary bladder:Urinary bladder: Exocrine glands Exocrine glands Central Nervous SystemCentral Nervous System

Nicotinic ActionsNicotinic Actions Central Nervous System Central Nervous System Peripheral nervous system Peripheral nervous system N.M .Junction N.M .Junction

EYE: EYE: Stimulation of MStimulation of M33 receptors in circular muscle, receptors in circular muscle,

ciliary muscle, ciliary muscle, Lacrimal gland, endothelium of blood vessels.Lacrimal gland, endothelium of blood vessels.

MiosisMiosis (↓ size of pupil) due to contraction of (↓ size of pupil) due to contraction of circular/ sphincter muscle of iris. circular/ sphincter muscle of iris.

Cyclospasm / accommodation for near vision Cyclospasm / accommodation for near vision due to due to contraction of ciliary muscle contraction of ciliary muscle

Decrease in intraocular pressureDecrease in intraocular pressure. . ↑ ↑ Lacrimation Lacrimation due to stimulation of lacrimal due to stimulation of lacrimal

glands. glands. Conjunctival congestion Conjunctival congestion due to dilation of BV.due to dilation of BV.

SPASM OF ACCOMODATION SPASM OF ACCOMODATION (Cyclospasm): (Cyclospasm): Stimulation of M3 receptors in ciliary Stimulation of M3 receptors in ciliary muscle. muscle. Contraction of muscle pulls ciliary body Contraction of muscle pulls ciliary body forwards & inwards.forwards & inwards.Relaxation of suspensry ligament of the Relaxation of suspensry ligament of the lens.lens.The lens bulges more, & its focal length is The lens bulges more, & its focal length is decreased . decreased . Eye accommodated for near vision.Eye accommodated for near vision.

Decrease in intraocular pressure Decrease in intraocular pressure (IOP)(IOP)

Contraction of circular/ sphincter pupillae Contraction of circular/ sphincter pupillae muscle pulls the iris away from the angle of muscle pulls the iris away from the angle of anterior chamber. anterior chamber.

Contraction of ciliary muscle pulls the scleral Contraction of ciliary muscle pulls the scleral spur, opens up the trabecular mesh work at the spur, opens up the trabecular mesh work at the base of the muscle . base of the muscle .

Both these effects facilitate the out flow of Both these effects facilitate the out flow of aqueous humor in to the canal of Shlemm, which aqueous humor in to the canal of Shlemm, which drains the anterior chamber.drains the anterior chamber.

So there is decrease in the IOP in Glaucoma.So there is decrease in the IOP in Glaucoma.

CVS (Heart & B.V)CVS (Heart & B.V) ::Heart: Atria , SA node AV node are rich in cholinergic Heart: Atria , SA node AV node are rich in cholinergic

innervation, they have M2 receptorsinnervation, they have M2 receptorsSA node ----- SA node ----- ↓ in rate (negative chronotropic effect)↓ in rate (negative chronotropic effect)Atria ---- Atria ---- ↓ in contractile strength (negative inotropic ↓ in contractile strength (negative inotropic

effect)effect) ↓ ↓ in refractory period.in refractory period.

AV node ---- AV node ---- ↓ in conduction velocity (negative ↓ in conduction velocity (negative dromotropy)dromotropy)

↑ ↑ in refractory period.in refractory period.Ventricals -- small ↓ in contractile strength--poor cholinergic Ventricals -- small ↓ in contractile strength--poor cholinergic

innervation.innervation.

Reflex sympathetic responses affect Reflex sympathetic responses affect the heartthe heart

↓ ↓ blood pressure ---- reflex ↑ heart blood pressure ---- reflex ↑ heart rate.rate.

I/V infusion of 20-50mcg /min of AchI/V infusion of 20-50mcg /min of AchCauses vasodilation--- ↓ blood Causes vasodilation--- ↓ blood

pressure & reflex tachycardiapressure & reflex tachycardia

Direct cardiac actions mediated by MDirect cardiac actions mediated by M22 : :1.1. ↑ ↑ in Kin K++ Current --- Current --- IIK(AChK(ACh)) in SA & AV Node, purkinje in SA & AV Node, purkinje

cells , also in atrial & ventricular Muscle. , cells , also in atrial & ventricular Muscle. , 2.2. A ↓ in slow inward CaA ↓ in slow inward Ca++++ Current ---- Current ---- II(Ca) (Ca) in heart cells.in heart cells.3.3. ↓ ↓ in hyperpolarization activated current ---- in hyperpolarization activated current ---- IIf f --- --- that that

underlies diastolic depolarization underlies diastolic depolarization All 3 actions produces slowing of pacemaker rate--All 3 actions produces slowing of pacemaker rate--

bradycardiabradycardia1 & 2 cause hyper polarization ----1 & 2 cause hyper polarization ---- ↓ action potential ↓ action potential

duration & decease the contractility of atria & to duration & decease the contractility of atria & to some extent of ventricles.some extent of ventricles.

B.V: B.V: Arteries & veins Arteries & veins Vascular endothelium contains uninnervated --Vascular endothelium contains uninnervated --endothelial muscarinic ( Mendothelial muscarinic ( M33 ) receptors. ) receptors.

Injection of Ach causes dilation of all blood Injection of Ach causes dilation of all blood vessels by indirect mechanism.vessels by indirect mechanism.

It stimulates endothelium MIt stimulates endothelium M33 , generation of Endothelial , generation of Endothelial derived relaxing factor (EDRF) or Nitric oxide from derived relaxing factor (EDRF) or Nitric oxide from Arginine . Arginine .

EDRF diffuses to the vascular smooth muscle cells to EDRF diffuses to the vascular smooth muscle cells to stimulate protein kinase G production --- stimulate protein kinase G production --- hyperpolarization ---Relaxation of Smooth muscles.hyperpolarization ---Relaxation of Smooth muscles.

Dilation of BV.Dilation of BV.

Effect on Blood pressure:Effect on Blood pressure: Injection of Ach causes dilation of BV through Injection of Ach causes dilation of BV through

EDRF--- fall in Blood pressure.EDRF--- fall in Blood pressure. In the absence of circulating muscarinic In the absence of circulating muscarinic

agonists, the endothelial Magonists, the endothelial M3 3 have no known have no known function because Ach is never released into the function because Ach is never released into the circulation. circulation.

This effect can be blocked by Atropine.This effect can be blocked by Atropine.

Respiratory system:Respiratory system:Lungs:Lungs: Bronchial Smooth muscle MBronchial Smooth muscle M3 3 stimulation : contraction –stimulation : contraction –

bronchoconstriction.bronchoconstriction. Bronchial glands MBronchial glands M33 stimulation ----- ↑ Secretion stimulation ----- ↑ Secretion In bronchial asthma patients -- an attack may be In bronchial asthma patients -- an attack may be

precipitated.precipitated.

Gastro intestinal tract (MGastro intestinal tract (M3&3& M M2 2 ):):Motility ----- Increased throughout the gut due to Motility ----- Increased throughout the gut due to Smooth Smooth

muscle contraction which involves muscle contraction which involves depolarization of SM cells & depolarization of SM cells & calcium influx viacalcium influx via M M3.3.

Stimulation of smooth muscles of the gut.Stimulation of smooth muscles of the gut. Increased tone & motility, may cause colicky painIncreased tone & motility, may cause colicky pain Increased tone & motility of gall bladder & biliary ducts.Increased tone & motility of gall bladder & biliary ducts.Sphincters ---- RelaxedSphincters ---- RelaxedSecretion (MSecretion (M33) ---- stimulation) ---- stimulationSalivary & gastric secretions are markedly increased.Salivary & gastric secretions are markedly increased.Pancrease & small intestinal glands less stimulated.Pancrease & small intestinal glands less stimulated.MM2 2 reduces cAMP formation & relaxation by sympathetic reduces cAMP formation & relaxation by sympathetic

effect.effect.

Genitourinary tract Genitourinary tract (M(M3&3& M M2 2 ): Like ): Like GITGIT

Detrusor muscles ----- contractionDetrusor muscles ----- contractionTrigone & sphincter ----- relaxationTrigone & sphincter ----- relaxationSo voiding of urine.So voiding of urine.Human uterus insensitive to muscarinic agonistsHuman uterus insensitive to muscarinic agonists

Exocrine Glands Exocrine Glands (M(M33))::Stimulation of Thermoregulatory sweat, Stimulation of Thermoregulatory sweat,

salivary, lacrimal, nasopharyngeal gland ------ salivary, lacrimal, nasopharyngeal gland ------ ↑ Secretion↑ Secretion

Effects on Effects on CNS: CNS: Brain is rich in Muscarinic & Brain is rich in Muscarinic & Spinal cord in Nicotinic receptors.Spinal cord in Nicotinic receptors.

Effects on brainEffects on brain Activation of MActivation of M22 --- slow inhibition of neuron --- slow inhibition of neuron Activation of MActivation of M11 --- slow excitation of neuron --- slow excitation of neuron Important role in cognitive function specially Important role in cognitive function specially

memorymemory..Some agonists are useful in pre-senile dementia Some agonists are useful in pre-senile dementia of Alzheimer type ----loss of cholinergic neurons.of Alzheimer type ----loss of cholinergic neurons.

Nicotinic Effects:Nicotinic Effects: Central Nervous SystemCentral Nervous System Autonomic ganglia , Adrenal medulla , Autonomic ganglia , Adrenal medulla ,

Carotid & Aortic bodies. Carotid & Aortic bodies. N.M .JunctionN.M .Junction

Nicotinic action on CNS: brain stem & Nicotinic action on CNS: brain stem & cortexcortex

Low conc.----Mild alerting Low conc.----Mild alerting reaction.reaction.

High doses – Tremors , emesis , & High doses – Tremors , emesis , & stimulation stimulation of Respiratory center.of Respiratory center.

Toxic doses –-- ConvulsionsToxic doses –-- Convulsions

1. Peripheral nervous system.1. Peripheral nervous system.a)a) Autonomic ganglia:Autonomic ganglia: Both Both

parasympathetic & sympathetic ganglia parasympathetic & sympathetic ganglia are stimulated initially.are stimulated initially.

Prolonged exposureProlonged exposure may result in may result in depolarizing blockade of ganglia. depolarizing blockade of ganglia. The effects are according to the predominant The effects are according to the predominant system.system.BV BV mainly sympathetic ----- hypertension.mainly sympathetic ----- hypertension.GIT & UIT: GIT & UIT: Mainly Parasympathetic Mainly ParasympatheticNausea, vomiting, diarrhoea & voiding of Nausea, vomiting, diarrhoea & voiding of urine.urine.

b) Adrenal Medulla: b) Adrenal Medulla: Release of Release of Epinephrine & Nor-epinephrine.Epinephrine & Nor-epinephrine.

c) Stimulation of Nc) Stimulation of NNN on sensory nerve on sensory nerve endings on:endings on:

Afferent N in Coronary Art & carotid & aortic Afferent N in Coronary Art & carotid & aortic bodies.bodies.

Glomus cell in aortic bodies (also contain M Glomus cell in aortic bodies (also contain M receptors).receptors).

Complex medullary responses ---- respiratory Complex medullary responses ---- respiratory alteration & vagal discharge. alteration & vagal discharge.

3. Neuromuscular junction.3. Neuromuscular junction.Depolarization of MEP due to ↑ permeability Depolarization of MEP due to ↑ permeability

to Nato Na++ . . Contraction.Contraction. Flaccid paralysis due to persistent Flaccid paralysis due to persistent

depolarization.depolarization.

Therapeutic Uses: Therapeutic Uses: Acetylcholine is Acetylcholine is not used as a drugnot used as a drug due to: due to: Very short DOA due to rapid hydrolysis Very short DOA due to rapid hydrolysis

within seconds.within seconds. No selectivity of actionNo selectivity of action

Other Choline Esters:Other Choline Esters:Methacholine , Carbachol , BethanecholMethacholine , Carbachol , Bethanechol

All are permanently charged quaternary Ammonium All are permanently charged quaternary Ammonium compoundscompounds

Poorly absorbed, all hydrolyzed in GIT , less effective orally.Poorly absorbed, all hydrolyzed in GIT , less effective orally. Poorly distributed into CNS, not active in eye after topical Poorly distributed into CNS, not active in eye after topical

application.application. Resistant to hydrolysis by Acetylcholinesterase ---- longer Resistant to hydrolysis by Acetylcholinesterase ---- longer

DOA than Ach.DOA than Ach. More potent than ACh. More potent than ACh.

Methacholine:Methacholine: Differs from acetylcholine:Differs from acetylcholine: Acetate is replaced by carbamate & choline is methylated. ---It Acetate is replaced by carbamate & choline is methylated. ---It

is Acetyl, is Acetyl, ββ Methyl choline Methyl choline Negligible metabolism by cholinesterase Negligible metabolism by cholinesterase DOA longer than Ach. DOA longer than Ach. No Nicotinic effects.No Nicotinic effects. Muscarinic effects are more prominent on CVS. Muscarinic effects are more prominent on CVS.

Carbachol:Carbachol: Differs from acetylcholine:Differs from acetylcholine: It is carbamoylcholine ---- carbamic acid ester of choline.It is carbamoylcholine ---- carbamic acid ester of choline. Poor substrate for AChE .Slowly metabolized by other Poor substrate for AChE .Slowly metabolized by other

esterases esterases DOA longer than Ach.DOA longer than Ach. Has both muscarinic & Nicotinic effects.Has both muscarinic & Nicotinic effects. Muscarinic effects are more prominent on smooth muscles of Muscarinic effects are more prominent on smooth muscles of

GIT, UB & eye. GIT, UB & eye. Therapeutic uses: Therapeutic uses: Rarely used due to high Rarely used due to high

potency , receptor non- selectivity potency , receptor non- selectivity Glaucoma:Glaucoma: Used as Eye drops. Used as Eye drops.

Bethanechol:Bethanechol: A choline ester poor lipid solubilityA choline ester poor lipid solubilityDoes not enter CNS , not active in eye after topical application.Does not enter CNS , not active in eye after topical application.Differs from acetylcholine:Differs from acetylcholine: It is carbamoyl It is carbamoyl ββ Methyl choline ---- carbamic acid ester of cholineMethyl choline ---- carbamic acid ester of choline Negligible metabolism by cholinesteraseNegligible metabolism by cholinesterase DOA longer than Ach---0.3-2 hrsDOA longer than Ach---0.3-2 hrs No Nicotinic effects.No Nicotinic effects. Muscarinic effects are more prominent on smooth muscles of GIT, Muscarinic effects are more prominent on smooth muscles of GIT,

UB & eye. UB & eye.

Therapeutic Uses of BethanecholTherapeutic Uses of Bethanechol 1. 1. Depression of SM activity without Depression of SM activity without

obstructionobstruction Post operative Ileus---Abdominal distention.Post operative Ileus---Abdominal distention. Congenital MegacolonCongenital Megacolon Urinary retention Urinary retention Post operative , post partum , After SC Post operative , post partum , After SC

injury (Neurogenic bladder)injury (Neurogenic bladder)2. Reflux esophagitis.2. Reflux esophagitis.Dose--- Bethanechol 10-20 mg TDSDose--- Bethanechol 10-20 mg TDS

Properties of choline esters:Properties of choline esters:

Choline Choline EsterEster

SusceptibilitSusceptibility to y to cholinesteracholinesterasese

Muscarinic Muscarinic actionaction

Nicotinic Nicotinic action action

AcetylcholinAcetylcholine chloridee chloride

++++++++ ++++++ ++++++

MethacholinMethacholine chloridee chloride

++ ++++++++ NoneNone

Carbachol Carbachol chloridechloride

NegligibleNegligible ++++ ++++++

Bethanechol Bethanechol chloridechloride

NegligibleNegligible ++++ None None

Cholinomimetic AlkaloidsCholinomimetic Alkaloidsa. a. Mainly Muscarinic AgonistsMainly Muscarinic AgonistsNatural Alkaloids:Natural Alkaloids:Muscarine & Arecholine:Muscarine & Arecholine: Used as a Used as a research research

tooltool, Muscarine , Muscarine poisoningpoisoning may occur due to may occur due to certain mushroom (Inocybe) certain mushroom (Inocybe)

Pilocarpine:Pilocarpine: Used in Used in glaucomaglaucoma & as & as sialagougesialagouge SialagougeSialagouge – A drug which increases salivary – A drug which increases salivary

secretion.secretion.

Synthetic Alkaloids:Synthetic Alkaloids:Cevimeline:Cevimeline: Derivative of Ach., Used as Derivative of Ach., Used as

sialagougesialagouge Oxotramorine:Oxotramorine: Used as a Used as a research toolresearch tool, ,

Mostly affects M5 receptors in CNS.Mostly affects M5 receptors in CNS.

b. b. Mainly Nicotinic AgonistsMainly Nicotinic AgonistsNatural Alkaloids:Natural Alkaloids: Nicotine , Lobeline: Nicotine , Lobeline: ToxicityToxicitySynthetic: Synthetic: Varenicline– Varenicline– used to stop used to stop smoking.smoking.Dimethylphenylpiperazinium (DMPP)Dimethylphenylpiperazinium (DMPP)

Used as a research tool.Used as a research tool.VareniclineVarenicline–Partial agonist at N receptors–Partial agonist at N receptors Orally effective.Orally effective. High lipid solubilityHigh lipid solubility DOA: 12 hrsDOA: 12 hrs Used to stop smokingUsed to stop smoking..

Pilocarpine:Pilocarpine: A natural alkaloid.A natural alkaloid. Tertiary amine.Tertiary amine. Obtained from Pilocarpus jaborrandi leaves.Obtained from Pilocarpus jaborrandi leaves. Well absorbed from most sites of Well absorbed from most sites of

administration---- Topically in eye , orally & I/M. administration---- Topically in eye , orally & I/M. Stable to hydrolysis by AchE.Stable to hydrolysis by AchE.

MOA:MOA: It is a direct agonist at cholinergic It is a direct agonist at cholinergic receptors mainly muscarinic receptorsreceptors mainly muscarinic receptors

Effects:Effects: like Ach. , Nicotinic effects ---- mild. like Ach. , Nicotinic effects ---- mild. The most important effect is on Eye & exocrine The most important effect is on Eye & exocrine

glands.glands.

EYE: EYE: Activates M3 receptorsActivates M3 receptors Miosis /↓ size of pupil --contraction of sphincter Miosis /↓ size of pupil --contraction of sphincter

muscle of iris.muscle of iris. Cyclospasm / accommodation for near vision due to Cyclospasm / accommodation for near vision due to

contraction of ciliary muscle contraction of ciliary muscle Conjunctival hyperemia--- Dilatation of BV via Conjunctival hyperemia--- Dilatation of BV via

EDRFEDRF ↑ ↑ Lacrimation due to stimulation of lacrimal Lacrimation due to stimulation of lacrimal

glands. glands. Decrease in intraocular pressure.Decrease in intraocular pressure.

SPASM OF ACCOMODATION: SPASM OF ACCOMODATION: Lasts for 2 hours.Lasts for 2 hours. Stimulation of M3 receptors in ciliary muscle.Stimulation of M3 receptors in ciliary muscle. Contraction of muscle pulls ciliary body forwards & Contraction of muscle pulls ciliary body forwards &

inwards.inwards. Relaxation of suspensory ligament of the lens.Relaxation of suspensory ligament of the lens. The lens bulges more, & its focal length is The lens bulges more, & its focal length is

decreased . decreased . Eye accommodated for near vision.Eye accommodated for near vision.

I.O.P: I.O.P: Decreased in glaucoma,Decreased in glaucoma, In normal individual, little effect.In normal individual, little effect.

Contraction of sphincter pupillae pulls iris away form Contraction of sphincter pupillae pulls iris away form angle of ant. Chamber. Contraction of ciliary muscle angle of ant. Chamber. Contraction of ciliary muscle pulls the scleral spur, opens up the trabecular mesh pulls the scleral spur, opens up the trabecular mesh work at the base of the muscle.work at the base of the muscle.

Also restores alignment if distorted.Also restores alignment if distorted.Both these effects facilitate the out flow of aqueous Both these effects facilitate the out flow of aqueous humor in to the canal of schlemm, decreasing IOP.humor in to the canal of schlemm, decreasing IOP.

Effects of Pilocarpine on CVS:Effects of Pilocarpine on CVS: Given I/V, a brief initial hypotension , Given I/V, a brief initial hypotension , Then may produce longer-lasting Then may produce longer-lasting

hypertension .hypertension .Hypertension is due to vasoconstriction via Hypertension is due to vasoconstriction via

ganglionic effect.ganglionic effect.

Effects on Exocrine Glands:Effects on Exocrine Glands:Marked increase in salivary & other Marked increase in salivary & other

exocrine secretionsexocrine secretions

Therapeutic Uses: Therapeutic Uses: ROA: Pilocarpine is used --ROA: Pilocarpine is used --Topically in eye, orally or S/CTopically in eye, orally or S/C

Never I/V because pulmonary edema can occur.Never I/V because pulmonary edema can occur.1.1. Used in glaucoma (raised IOP):Used in glaucoma (raised IOP):As eye drops 0.5-4% or plastic film reservoir of drug.As eye drops 0.5-4% or plastic film reservoir of drug.Better tolerated than anti-cholinesterases.Better tolerated than anti-cholinesterases.OOA within a few minutes. & DOA 4-6 hours. OOA within a few minutes. & DOA 4-6 hours.

Open angle glaucoma: standard treatment-- life long. Open angle glaucoma: standard treatment-- life long. Secondary glaucoma- some cases for life long.Secondary glaucoma- some cases for life long. Angle-closure glaucoma prior to surgery.Angle-closure glaucoma prior to surgery.

2. To counteract the mydriasis produced by 2. To counteract the mydriasis produced by atropine.atropine.

3. To break up adhesions between iris & lens, 3. To break up adhesions between iris & lens, alternatively with Atropinealternatively with Atropine

4. Xerostomia: 5-10 mg orally or S/C as 4. Xerostomia: 5-10 mg orally or S/C as sialagoguesialagogue-- to increase salivary secretion in -- to increase salivary secretion in xerostomia due to xerostomia due to Sjogren syndrome.Sjogren syndrome. Head & neck radiation therapy.Head & neck radiation therapy. ParkinsonismParkinsonism

Glaucoma (raised IOP):Glaucoma (raised IOP): Aqueous humour is secreted slowly & Aqueous humour is secreted slowly &

continuously. continuously. Normal IOP is 10 to 15mmHg above Normal IOP is 10 to 15mmHg above

atmospheric pressure. When raised---Glaucoma. atmospheric pressure. When raised---Glaucoma. Glaucoma can damage the eye. Glaucoma can damage the eye. One of the preventable causes of blindness. One of the preventable causes of blindness.

Two types of glaucoma:Two types of glaucoma: Primary:Primary: Angle- closure & open-angle Angle- closure & open-angle Secondary:Secondary: Due to inflammation, Trauma, Due to inflammation, Trauma,

Surgical procedures. Surgical procedures. Angle closure glaucoma is a medical emergency, Angle closure glaucoma is a medical emergency,

initially treated with drugs but requires initially treated with drugs but requires surgery for permanent correction.surgery for permanent correction.

I.O.P:I.O.P: Decreased by following mechanism: Decreased by following mechanism: Contraction of sphincter pupillae pulls the iris away Contraction of sphincter pupillae pulls the iris away

from the angle of anterior chamber. from the angle of anterior chamber. Contraction of ciliary muscle pulls the scleral spur, Contraction of ciliary muscle pulls the scleral spur,

opens up the trabecular mesh work at the base of opens up the trabecular mesh work at the base of the muscle. the muscle.

Also causes realignment of trabeculae, if distroted.Also causes realignment of trabeculae, if distroted. Both these effects facilitate the out flow of aqueous Both these effects facilitate the out flow of aqueous

humor in to the canal of schlemm , which drains the humor in to the canal of schlemm , which drains the anterior chamberanterior chamber

So there is decrease in the IOP.So there is decrease in the IOP.

Pilocarpine is used in glaucoma.Pilocarpine is used in glaucoma.As eye drops 0.5-4% or plastic film reservoir of As eye drops 0.5-4% or plastic film reservoir of

drug.drug.Better tolerated than anti cholinesterases.Better tolerated than anti cholinesterases.OOA within a few minutes. & DOA 4-6 hours. OOA within a few minutes. & DOA 4-6 hours.

Open angle glaucoma: standard treatment-- Open angle glaucoma: standard treatment-- life long. life long.

Secondary glaucoma- some cases of - life long.Secondary glaucoma- some cases of - life long. Angle-closure glaucoma prior to surgery.Angle-closure glaucoma prior to surgery.Many other drugs are also used Many other drugs are also used in glaucomain glaucoma