Medicine

1. CHOLINERGIC TRANSMISSIONCHOLINERGIC TRANSMISSION
Main NT is Acetylcholine (ACh).Main NT is Acetylcholine (ACh).
A large number of peripheral ANS fibers synthesize & release AcetylcholineA 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 peptidesSome parasympathetic post ganglionic fibers utilize nitric oxide or peptides
for transmission.for transmission.

3. Synthesis Storage & release and DegradationSynthesis Storage & release and Degradation
Synthesis:Synthesis:
Choline actively transported into the nerve terminal.Choline actively transported into the nerve terminal.
Acetyl CoA + CholineAcetyl CoA + Choline Choline Acetyl transferaseCholine Acetyl transferase ACh + CoAACh + CoA
Storage:Storage:
 ACh. is transported into the vesiclesACh. is transported into the vesicles activelyactively by vesicle associated transporterby vesicle associated transporter
((VAT)VAT) & stored in it. Peptides, ATP &proteoglycans are also stored in the& stored in it. Peptides, ATP &proteoglycans are also stored in the
vesicle .vesicle .
 Acetylcholine is stored as quanta containingAcetylcholine 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 release less &One depolarization of autonomicpost ganglionic nerve may release less &
releases it over a larger area.releases it over a larger area.
 One depolarization of somatic nerve may release several hundred quanta.One depolarization of somatic nerve may release several hundred quanta.

4. 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 the synapse.Exocytosis of several hundred quanta of Ach. into the synapse.

5. Termination of action:Termination of action: Ach binds to & Activates theAch binds to & Activates the
cholinoceptors.cholinoceptors.
The action is terminatedThe action is terminated within secondswithin seconds by Hydrolysisby Hydrolysis
AcetylcholineAcetylcholine Acetyl cholineteraseAcetyl cholineterase Choline + Acetic AcidCholine + Acetic Acid
• Acetyl cholineteraseAcetyl cholineterase (true cholineterase) found in synapse &(true cholineterase) found in synapse &
RBCs also.RBCs also.
• Butylyl cholineteraseButylyl cholineterase (pseudocholineterase) found in blood,(pseudocholineterase) found in blood,
plasma, liver, glia & many other tissues ---- has a lower specificityplasma, liver, glia & many other tissues ---- has a lower specificity
for Ach. It metabolizes succinylcholine.for Ach. It metabolizes succinylcholine.
Genetically determined, some individuals in population areGenetically determined, some individuals in population are
deficient in this enzymedeficient in this enzyme

7. SynthesisSynthesis blocked by hemicholinium —a research drugblocked by hemicholinium —a research drug
StorageStorage blocked by Vesamicol —a research drugblocked by Vesamicol —a research drug
Action potential generation & propagationAction potential generation & propagation blocked by Localblocked by Local
anesthetics, tetrodotoxin, sasitoxin.anesthetics, tetrodotoxin, sasitoxin.
Entry of CaEntry of Ca++++
blocked by Aminoglycosidesblocked by Aminoglycosides
Release:Release: Blocked by Botulinum toxin &Blocked by Botulinum toxin &
Increased byIncreased by αα- Latrotoxin (Spider venom)- Latrotoxin (Spider venom)
HydrolysisHydrolysis inhibited by Anticholinesterasesinhibited by Anticholinesterases
ReceptorsReceptors blocked by receptor antagonists.blocked by receptor antagonists.

8. Cholinergic receptors (Cholionoceptor): 2 main typesCholinergic receptors (Cholionoceptor): 2 main types
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 agonists.They are activated by Ach & muscarine & other cholinergic 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 by: Plasma membranes of the cells of tissues innervated by
parasympathetic nerves in Heart, smooth muscles, exocrine glands &parasympathetic nerves in Heart, smooth muscles, exocrine glands &
uninnervated Endothelial receptors, also CNS; brain is richer in M receptorsuninnervated Endothelial receptors, also CNS; brain is richer in M receptors
and spinal cord in N receptorsand spinal cord in N receptors

9. Muscarinic receptors (M)Muscarinic receptors (M)
 5 types : M5 types : M11,M,M22 , M, M33 ,M,M44 ,M,M55
Main locationsMain locations
 MM1--1-- presynaptic nerve terminals,CNSpresynaptic nerve terminals,CNS
 MM22 -- heart-- heart
 MM3-3- smooth muscles, exocrine glands, endotheliumsmooth muscles, exocrine glands, endothelium
 MM44 ,M,M5--5-- Main location is CNSMain location is CNS
 G-Protein coupled receptors-G-Protein coupled receptors--- contain 7 transmembrane-- contain 7 transmembrane
domains , whose third loop is coupled to G-Protein that acts as adomains , whose third loop is coupled to G-Protein that acts as a
transducertransducer..

10. 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 viaCoupling of Gq via αα subunit to Phospholipasse C (effectorsubunit to Phospholipasse C (effector
enzyme).enzyme).
 Hydrolysis of phosphotidyl inositol(4, 5) biphosphate-P2Hydrolysis of phosphotidyl inositol(4, 5) biphosphate-P2
 Formation of second messengers-- ↑ IPFormation of second messengers-- ↑ IP33, DAG-- increased, DAG-- increased
cytosolic Cacytosolic Ca2+2+

↑↑ Cytosolic CaCytosolic Ca2+2+
, stimulates, stimulates or inhibits enzymes---responseor inhibits enzymes---response

11. PHOSPHO – INOSITOL SYSTEM
Binding 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++
from
Intracellular SR & ER
Alteration in the activity of ca++
Dependent enzymes
Effect

12.  MM22 Receptors:Receptors:
a.a. Coupling ofCoupling of GGi/oi/o viavia βγβγ subunitsubunit withwith adenylyl cyclaseadenylyl cyclase & ↓& ↓
cAMPcAMP in the heartin the heart
b.b. Coupling ofCoupling of GiGi viavia βγβγ subunit & opening of K+ channelssubunit & opening of K+ channels
in the heart.in the heart.
 MM44 Receptors:Receptors: like Mlike M22
 Moreover, muscarinic agonist attenuate activation of AdenylylMoreover, muscarinic agonist attenuate activation of Adenylyl
cyclase. & modulate the increase in cAMP by catecholaminescyclase. & modulate the increase in cAMP by catecholamines

14. Nicotinic ReceptorsNicotinic Receptors
 AGONISTS: Ach & Nicotine & other nicotinic agonists . andAGONISTS: Ach & Nicotine & other nicotinic agonists . and
Two subtypes:Two subtypes: NNNN andand NNM:M:
a.a. NNNN :: ——Ion channel , pentamerIon channel , pentamer composed ofcomposed of 22 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-----TrimethaphanTrimethaphan
NNM:M: Ion channel , pentamer , composed ofIon channel , pentamer , composed of 22 αα , 3, 3ββ subunitssubunits
Location:Location: Skeletal Muscles motor end plate--NeuromuscularSkeletal Muscles motor end plate--Neuromuscular
Junction.Junction.
Antagonist:Antagonist: Neuromuscular Junction blockersNeuromuscular Junction blockers----d-tubocurarined-tubocurarine

16. Molecular Mechanisms / Signal Transduction atMolecular Mechanisms / Signal Transduction at
Nicotinic ReceptorsNicotinic Receptors
a.a. NNMM ::
Binding of AgonistBinding of Agonist,, Ach or Nicotine at binding sites on 2Ach or Nicotine at binding sites on 2 αα subunits.subunits.
, there is conformational change – opening of the channel., there is conformational change – opening of the channel.
Influx of Sodium ions----Depolarization– action potential is generated.Influx of Sodium ions----Depolarization– action potential is generated.
ResponseResponse: End-plate depolarization, skeletal muscle contraction: End-plate depolarization, skeletal muscle contraction

17. b.b. Neuronal (Peripheral& central) NNeuronal (Peripheral& central) NNN
Binding ofBinding of Ach , Nicotine at binding sites on 2Ach , Nicotine at binding sites on 2 αα subunits.subunits.
Molecular Mechanisms:Molecular Mechanisms: Opening of sodium channel.Opening of sodium channel.
Influx of Sodium ions----Depolarization– action potential is generatedInflux of Sodium ions----Depolarization– action potential is generated
Responses:Responses:
In Automomic ganglia, adrenal medullaIn Automomic ganglia, adrenal medulla
Depolarization and firing of post ganglionic neuron; depolarization ofDepolarization and firing of post ganglionic neuron; depolarization of
the medullary cell & secretion of catecholaminesthe medullary cell & secretion of catecholamines
In CNS:In CNS: Prejunctional control of neurotransmitter releasePrejunctional control of neurotransmitter release

19. subtypes/locations & characteristics of cholinoceptorssubtypes/locations & characteristics of cholinoceptors
ReceptorReceptor LocationLocation MechanismMechanism Result of ACh.Result of ACh.
bindingbinding
MM11
CNS Neurons, someCNS Neurons, some
presynaptic sites,presynaptic sites,
SympatheticSympathetic
postganglionicpostganglionic
neuronsneurons
Gq-coupledGq-coupled viavia
αα subunitsubunit
Stimulation ofStimulation of
phospholipase Cphospholipase C
↑IP↑IP33, DAG , ↑, DAG , ↑
intracellular Caintracellular Ca++++
MM22
Myocardium, smoothMyocardium, smooth
muscles , somemuscles , some
presynaptic sites,presynaptic sites,
CNS NeuronsCNS Neurons
Gi-coupled viaGi-coupled via
βγβγ subunitsubunit
Inhibition ofInhibition of
Adenylyl cyclaseAdenylyl cyclase
↓↓cAMP, activatescAMP, activates
KK++
ChannelChannel

20. MM33
Smooth muscle, exocrineSmooth muscle, exocrine
glands, endothelium,glands, endothelium,
CNS NeuronsCNS Neurons
Gq-coupledGq-coupled Like MLike M11
MM44 CNS Neurons; possiblyCNS Neurons; possibly
vagal nerve endingsvagal nerve endings
Gi-coupledGi-coupled Like MLike M22
MM55 Vascular endothelium ofVascular endothelium of
cerebral BV, CNS Neuronscerebral BV, CNS Neurons
Gq-coupledGq-coupled Like MLike M11
NNNN Post ganglionic neurons ofPost ganglionic neurons of
ANS ganglia , AdrenalANS ganglia , Adrenal
medulla ,CNS mainly spinalmedulla ,CNS mainly spinal
cord. Some presynpticcord. Some presynptic
cholinergic terminals.cholinergic terminals.
Ion channelIon channel Opening of
channel, Na+
.
Influx,
depolarization-- AP
generation
NNMM Skeletal muscleSkeletal muscle
neuromuscular end plateneuromuscular end plate
Ion channelIon channel Opening of
channels, Na+
.
Influx,
depolarization--AP
generation

22. PARASYMPATHOMIMETIC DRUGSPARASYMPATHOMIMETIC DRUGS
OROR
CHOLINERGIC DRUGSCHOLINERGIC DRUGS
OROR
CHOLINOMIMETIC DRUGSCHOLINOMIMETIC DRUGS

23. DEFINITION:DEFINITION:
Parasympathomimetic / cholinergic drugs can be defined as a group of drugsParasympathomimetic / cholinergic drugs can be defined as a group of drugs
whose effects resemble those of stimulating the parasympathetic nerves/whose effects resemble those of stimulating the parasympathetic nerves/
Acetylcholine.Acetylcholine.
They include Direct Acting cholinergic receptor agonists &They include Direct Acting cholinergic receptor agonists & Indirect ActingIndirect Acting
drugsdrugs which are anticholinesterases.which are anticholinesterases.
Anticholinesterases inhibit the enzyme that terminates the action ofAnticholinesterases inhibit the enzyme that terminates the action of
endogenously released Ach so concentration of Ach in the synapse isendogenously released Ach so concentration of Ach in the synapse is
increased so the response is enhanced.increased so the response is enhanced.
..

24. Classification of Cholinomimetic / Cholinergic /Classification of Cholinomimetic / Cholinergic /
Parasympathomimetic drugs:Parasympathomimetic drugs:
A.A. Direct ActingDirect Acting
B.B. Indirect ActingIndirect Acting
A. Direct Acting Cholinergic Drugs:A. Direct Acting Cholinergic Drugs:
I. Choline EstersI. Choline Esters
AcetylcholineAcetylcholine
CarbacholCarbachol
MethacholineMethacholine
BethanecholBethanechol

25. II. Cholinomimetic AlkaloidsII. Cholinomimetic Alkaloids
a.a. Mainly Muscarinic AgonistsMainly Muscarinic Agonists
Natural Alkaloids:Natural Alkaloids:
Muscarine , Pilocarpine, ArecholineMuscarine , Pilocarpine, Arecholine
Synthetic Alkaloid:Synthetic Alkaloid: CevimelineCevimeline ,, OxotramorineOxotramorine
b.b. Mainly Nicotinic AgonistsMainly Nicotinic Agonists
Natural Alkaloids:Natural Alkaloids: Nicotine , LobelineNicotine , Lobeline
Synthetic:Synthetic: VareniclineVarenicline
Dimethylphenylpiperazinium (DMPP)Dimethylphenylpiperazinium (DMPP)

26. B. Indirect Acting Cholinergic DrugsB. Indirect Acting Cholinergic Drugs or Anticholinesterasesor Anticholinesterases
I- ReversibleI- Reversible
II- Irreversible: Organophosphorus CompoundsII- Irreversible: Organophosphorus Compounds
I- ReversibleI- Reversible
a. Carbamatesa. Carbamates
i)i) Tertiary aminesTertiary amines : Physostigmine: Physostigmine
ii)ii) Quaternary Ammonium compoundsQuaternary Ammonium compounds
NeostigmineNeostigmine
PyridostigminePyridostigmine
DistigmineDistigmine
AmbenoniumAmbenonium
DemecariumDemecarium

27. b. Alcohols :b. Alcohols : EdrophoniumEdrophonium
c. Miscellaneous:c. Miscellaneous: Donepezil, Galantamine, Rivastigmine ,Tacrine,Donepezil, Galantamine, Rivastigmine ,Tacrine,
II. Irreversible Anticholinesterases /II. Irreversible Anticholinesterases /
(Organophosphorous Compounds)(Organophosphorous Compounds)
1)1) Therapeutically useful:Therapeutically useful: EcothiophateEcothiophate
2)2) War Gases:War Gases: Sarin , Tuban, SomanSarin , Tuban, Soman
3)3) Insecticides:-Insecticides:- Parathion , MalathionParathion , Malathion
Di-isopropyl Fluorophosphate (DFP)Di-isopropyl Fluorophosphate (DFP)

28. AcetylcholineAcetylcholine
 It is the neurotransmitter of PSNS & somatic nerves to skeletalIt is the neurotransmitter of PSNS & somatic nerves to skeletal
muscles.muscles.
 It is an ester of acetic acid & choline .It is an ester of acetic acid & choline .
 It is a quaternary ammonium compound, permanently charged;It is a quaternary ammonium compound, permanently charged;
can not penetrate membranes, so poorly absorbed & poorlycan not penetrate membranes, so poorly absorbed & poorly
distributed to CNS.distributed to CNS.
 It is very rapidly hydrolyzed; large amounts must be infused I/VIt is very rapidly hydrolyzed; large amounts must be infused I/V
to produce detectable effects for 5-20 seconds.to produce detectable effects for 5-20 seconds.
 I/M & S/C injection only produce local effectsI/M & S/C injection only produce local effects

30. 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 receptorsNicotinic receptors
Types & LocationTypes & Location
Molecular mechanismMolecular mechanism
Already discussedAlready discussed

31. Pharmacological Actions/ Organ system effects:Pharmacological Actions/ Organ system effects:
Muscarinic Actions produced on:Muscarinic Actions produced on:
 EyeEye
 CVS (Heart, B.V)CVS (Heart, B.V)
 Respiratory systemRespiratory system
 Gastro intestinal tractGastro intestinal tract
 Urinary bladder:Urinary bladder:
 Exocrine glandsExocrine glands
 Central Nervous SystemCentral Nervous System

32. Nicotinic ActionsNicotinic Actions
 Central Nervous SystemCentral Nervous System
 Peripheral nervous systemPeripheral nervous system
 N.M .JunctionN.M .Junction

33. EYE:EYE:
Stimulation of MStimulation of M33 receptors in circular muscle, ciliary muscle,receptors in circular muscle, ciliary muscle,
Lacrimal gland, endothelium of blood vessels.Lacrimal gland, endothelium of blood vessels.
 MiosisMiosis (↓ size of pupil) due to contraction of circular/ sphincter(↓ size of pupil) due to contraction of circular/ sphincter
muscle of iris.muscle of iris.
 Cyclospasm / accommodation for near visionCyclospasm / accommodation for near vision due todue to
contraction of ciliary musclecontraction of ciliary muscle
 Decrease in intraocular pressureDecrease in intraocular pressure..
 ↑↑ LacrimationLacrimation due to stimulation of lacrimal glands.due to stimulation of lacrimal glands.
 Conjunctival congestionConjunctival congestion due to dilation of BV.due to dilation of BV.

34. SPASM OF ACCOMODATION (Cyclospasm):SPASM OF ACCOMODATION (Cyclospasm):
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 suspensry ligament of the lens.Relaxation of suspensry ligament of the lens.
The lens bulges more, & its focal length is decreased .The lens bulges more, & its focal length is decreased .
Eye accommodated for near vision.Eye accommodated for near vision.

35. Decrease in intraocular pressure (IOP)Decrease in intraocular pressure (IOP)
 Contraction of circular/ sphincter pupillae muscle pulls the irisContraction of circular/ sphincter pupillae muscle pulls the iris
away from the angle of anterior chamber.away from the angle of anterior chamber.
 Contraction of ciliary muscle pulls the scleral spur, opens up theContraction of ciliary muscle pulls the scleral spur, opens up the
trabecular mesh work at the base of the muscle .trabecular mesh work at the base of the muscle .
 Both these effects facilitate the out flow of aqueous humor in toBoth these effects facilitate the out flow of aqueous humor in to
the canal of Shlemm, which drains the anterior chamber.the canal of Shlemm, which drains the anterior chamber.
 So there is decrease in the IOP in Glaucoma.So there is decrease in the IOP in Glaucoma.

36. CVS (Heart & B.V)CVS (Heart & B.V) ::
Heart: Atria , SA node AV node are rich in cholinergic innervation, theyHeart: Atria , SA node AV node are rich in cholinergic innervation, they
have M2 receptorshave M2 receptors
SA node -----SA node ----- ↓ in rate (negative chronotropic effect)↓ in rate (negative chronotropic effect)
Atria ----Atria ---- ↓ in contractile strength (negative inotropic effect)↓ in contractile strength (negative inotropic effect)
↓↓ in refractory period.in refractory period.
AV node ----AV node ---- ↓ in conduction velocity (negative dromotropy)↓ in conduction velocity (negative dromotropy)
↑↑ in refractory period.in refractory period.
Ventricals -- small ↓ in contractile strength--poor cholinergic innervation.Ventricals -- small ↓ in contractile strength--poor cholinergic innervation.

37.  Reflex sympathetic responses affect the heartReflex sympathetic responses affect the heart
 ↓↓ blood pressure ---- reflex ↑ heart rate.blood pressure ---- reflex ↑ heart rate.
I/V infusion of 20-50mcg /min of AchI/V infusion of 20-50mcg /min of Ach
Causes vasodilation--- ↓ blood pressure & reflexCauses vasodilation--- ↓ blood pressure & reflex
tachycardiatachycardia

38. 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 cells , also inin SA & AV Node, purkinje cells , also in
atrial & ventricular Muscle. ,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 ---- IIff ------ that underliesthat underlies
diastolic depolarizationdiastolic depolarization
All 3 actions produces slowing of pacemaker rate--All 3 actions produces slowing of pacemaker rate-- bradycardiabradycardia
1 & 2 cause hyper polarization ----1 & 2 cause hyper polarization ---- ↓ action potential duration &↓ action potential duration &
decease the contractility of atria & to some extent of ventricles.decease the contractility of atria & to some extent of ventricles.

40. B.V:B.V: Arteries & veinsArteries & veins
Vascular endothelium contains uninnervated --endothelialVascular endothelium contains uninnervated --endothelial
muscarinic ( Mmuscarinic ( M33 ) receptors.) receptors.
 Injection of Ach causes dilation of all blood vessels by indirectInjection of Ach causes dilation of all blood vessels by indirect
mechanism.mechanism.
It stimulates endothelium MIt stimulates endothelium M33 , generation of Endothelial derived, generation of Endothelial derived
relaxing factor (EDRF) or Nitric oxide from Arginine .relaxing factor (EDRF) or Nitric oxide from Arginine .
 EDRF diffuses to the vascular smooth muscle cells to stimulateEDRF diffuses to the vascular smooth muscle cells to stimulate
protein kinase G production --- hyperpolarization ---Relaxation ofprotein kinase G production --- hyperpolarization ---Relaxation of
Smooth muscles.Smooth muscles.
 Dilation of BV.Dilation of BV.

42. Effect on Blood pressure:Effect on Blood pressure:
 Injection of Ach causes dilation of BV through EDRF--- fall inInjection of Ach causes dilation of BV through EDRF--- fall in
Blood pressure.Blood pressure.
 In the absence of circulating muscarinic agonists, the endothelialIn the absence of circulating muscarinic agonists, the endothelial
MM33 have no known function because Ach is never released intohave no known function because Ach is never released into
the circulation.the circulation.
 This effect can be blocked by Atropine.This effect can be blocked by Atropine.

43. Respiratory system:Respiratory system:
Lungs:Lungs:
 Bronchial Smooth muscle MBronchial Smooth muscle M33 stimulation : contraction –stimulation : contraction –
bronchoconstriction.bronchoconstriction.
 Bronchial glands MBronchial glands M33 stimulation ----- ↑ Secretionstimulation ----- ↑ Secretion
 In bronchial asthma patients -- an attack may be precipitated.In bronchial asthma patients -- an attack may be precipitated.

44. Gastro intestinal tract (MGastro intestinal tract (M3&3& MM22 ):):
Motility ----- Increased throughout the gut due toMotility ----- Increased throughout the gut due to Smooth muscle contraction whichSmooth muscle contraction which
involvesinvolves depolarization of SM cells & calcium influx viadepolarization of SM cells & calcium influx via MM3.3.
 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 ---- Relaxed
Secretion (MSecretion (M33) ---- stimulation) ---- stimulation
Salivary & gastric secretions are markedly increased.Salivary & gastric secretions are markedly increased.
Pancrease & small intestinal glands less stimulated.Pancrease & small intestinal glands less stimulated.
MM22 reduces cAMP formation & relaxation by sympathetic effect.reduces cAMP formation & relaxation by sympathetic effect.

45. Genitourinary tractGenitourinary tract (M(M3&3& MM22 ): Like GIT): Like GIT
Detrusor muscles ----- contractionDetrusor muscles ----- contraction
Trigone & sphincter ----- relaxationTrigone & sphincter ----- relaxation
So voiding of urine.So voiding of urine.
Human uterus insensitive to muscarinic agonistsHuman uterus insensitive to muscarinic agonists
Exocrine GlandsExocrine Glands (M(M33))::
Stimulation of Thermoregulatory sweat, salivary, lacrimal,Stimulation of Thermoregulatory sweat, salivary, lacrimal,
nasopharyngeal gland ------ ↑ Secretionnasopharyngeal gland ------ ↑ Secretion

46. Effects onEffects on CNS:CNS: Brain is rich in Muscarinic & Spinal cord inBrain is rich in Muscarinic & Spinal cord in
Nicotinic receptors.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 speciallyImportant role in cognitive function specially memorymemory..
Some agonists are useful in pre-senile dementia of AlzheimerSome agonists are useful in pre-senile dementia of Alzheimer
type ----loss of cholinergic neurons.type ----loss of cholinergic neurons.

47. Nicotinic Effects:Nicotinic Effects:
 Central Nervous SystemCentral Nervous System
 Autonomic ganglia , Adrenal medulla , Carotid & AorticAutonomic ganglia , Adrenal medulla , Carotid & Aortic
bodies.bodies.
 N.M .JunctionN.M .Junction

48. Nicotinic action on CNS: brain stem & cortexNicotinic action on CNS: brain stem & cortex
Low conc.----Mild alerting reaction.Low conc.----Mild alerting reaction.
High doses – Tremors , emesis , & stimulationHigh doses – Tremors , emesis , & stimulation
of Respiratory center.of Respiratory center.
Toxic doses –-- ConvulsionsToxic doses –-- Convulsions

49. 1. Peripheral nervous system.1. Peripheral nervous system.
a)a) Autonomic ganglia:Autonomic ganglia: Both parasympathetic &Both parasympathetic &
sympathetic ganglia are stimulated initially.sympathetic ganglia are stimulated initially.
Prolonged exposureProlonged exposure may result in depolarizing blockademay result in depolarizing blockade
of ganglia.of ganglia.
The effects are according to the predominant system.The effects are according to the predominant system.
BVBV mainly sympathetic ----- hypertension.mainly sympathetic ----- hypertension.
GIT & UIT:GIT & UIT: Mainly ParasympatheticMainly Parasympathetic
Nausea, vomiting, diarrhoea & voiding of urine.Nausea, vomiting, diarrhoea & voiding of urine.

50. b) Adrenal Medulla:b) Adrenal Medulla: Release of Epinephrine &Release of Epinephrine &
Nor-epinephrine.Nor-epinephrine.
c) Stimulation of Nc) Stimulation of NNN on sensory nerve endingson sensory nerve endings
on:on:
 Afferent N in Coronary Art & carotid & aortic bodies.Afferent N in Coronary Art & carotid & aortic bodies.
 Glomus cell in aortic bodies (also contain M receptors).Glomus cell in aortic bodies (also contain M receptors).
Complex medullary responses ---- respiratory alteration &Complex medullary responses ---- respiratory alteration &
vagal discharge.vagal discharge.

51. 3. Neuromuscular junction.3. Neuromuscular junction.
Depolarization of MEP due to ↑ permeability to NaDepolarization of MEP due to ↑ permeability to Na++
..
 Contraction.Contraction.
 Flaccid paralysis due to persistent depolarization.Flaccid paralysis due to persistent depolarization.

52. Therapeutic Uses:Therapeutic Uses:
Acetylcholine isAcetylcholine is not used as a drugnot used as a drug due to:due to:
 Very short DOA due to rapid hydrolysis withinVery short DOA due to rapid hydrolysis within
seconds.seconds.
 No selectivity of actionNo selectivity of action

53. Other Choline Esters:Other Choline Esters:
Methacholine , Carbachol , BethanecholMethacholine , Carbachol , Bethanechol
 All are permanently charged quaternary AmmoniumAll 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 topicalPoorly distributed into CNS, not active in eye after topical
application.application.
 Resistant to hydrolysis by Acetylcholinesterase ---- longerResistant to hydrolysis by Acetylcholinesterase ---- longer
DOA than Ach.DOA than Ach.
 More potent than ACh.More potent than ACh.

55. Methacholine:Methacholine: Differs from acetylcholine:Differs from acetylcholine:
 Acetate is replaced by carbamate & choline is methylated. ---ItAcetate is replaced by carbamate & choline is methylated. ---It
is Acetyl,is Acetyl, ββ Methyl cholineMethyl choline
 Negligible metabolism by cholinesteraseNegligible 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.

56. 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 otherPoor substrate for AChE .Slowly metabolized by other
esterasesesterases
 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 ofMuscarinic effects are more prominent on smooth muscles of
GIT, UB & eye.GIT, UB & eye.
Therapeutic uses:Therapeutic uses: Rarely used due to high potency , receptor non-Rarely used due to high potency , receptor non-
selectivityselectivity
Glaucoma:Glaucoma: Used as Eye drops.Used as Eye drops.

57. Bethanechol:Bethanechol: A choline ester poor lipid solubilityA choline ester poor lipid solubility
Does 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 carbamoylIt is carbamoyl ββ Methyl choline ---- carbamic acid ester ofMethyl choline ---- carbamic acid ester of
cholinecholine
 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 ofMuscarinic effects are more prominent on smooth muscles of
GIT, UB & eye.GIT, UB & eye.

58. Therapeutic Uses of BethanecholTherapeutic Uses of Bethanechol
1.1. Depression of SM activity without obstructionDepression of SM activity without obstruction
 Post operative Ileus---Abdominal distention.Post operative Ileus---Abdominal distention.
 Congenital MegacolonCongenital Megacolon
 Urinary retentionUrinary retention
Post operative , post partum , After SC injuryPost operative , post partum , After SC injury
(Neurogenic bladder)(Neurogenic bladder)
2. Reflux esophagitis.2. Reflux esophagitis.
Dose--- Bethanechol 10-20 mg TDSDose--- Bethanechol 10-20 mg TDS

59. Properties of choline esters:Properties of choline esters:
Choline EsterCholine Ester Susceptibility toSusceptibility to
cholinesterasecholinesterase
MuscarinicMuscarinic
actionaction
Nicotinic actionNicotinic action
AcetylcholineAcetylcholine
chloridechloride
++++++++ ++++++ ++++++
MethacholineMethacholine
chloridechloride
++ ++++++++ NoneNone
CarbacholCarbachol
chloridechloride
NegligibleNegligible ++++ ++++++
BethanecholBethanechol
chloridechloride
NegligibleNegligible ++++ NoneNone

60. Cholinomimetic AlkaloidsCholinomimetic Alkaloids
a.a. Mainly Muscarinic AgonistsMainly Muscarinic Agonists
Natural Alkaloids:Natural Alkaloids:
Muscarine & Arecholine:Muscarine & Arecholine: Used as aUsed as a research toolresearch tool, Muscarine, Muscarine
poisoningpoisoning may occur due to certain mushroom (Inocybe)may occur due to certain mushroom (Inocybe)
Pilocarpine:Pilocarpine: Used inUsed in glaucomaglaucoma & as& as sialagougesialagouge
SialagougeSialagouge – A drug which increases salivary secretion.– A drug which increases salivary secretion.

62. Synthetic Alkaloids:Synthetic Alkaloids:
Cevimeline:Cevimeline: Derivative of Ach., Used asDerivative of Ach., Used as sialagougesialagouge
Oxotramorine:Oxotramorine: Used as aUsed as a research toolresearch tool, Mostly, Mostly
affects M5 receptors in CNS.affects M5 receptors in CNS.

63. b.b. Mainly Nicotinic AgonistsMainly Nicotinic Agonists
Natural Alkaloids:Natural Alkaloids: Nicotine , Lobeline:Nicotine , Lobeline: ToxicityToxicity
Synthetic:Synthetic: Varenicline–Varenicline– used to stop smoking.used to stop 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..

64. 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 administration---- Topically inWell absorbed from most sites of administration---- Topically in
eye , orally & I/M.eye , orally & I/M.
 Stable to hydrolysis by AchE.Stable to hydrolysis by AchE.

65. MOA:MOA: It is a direct agonist at cholinergic receptors mainlyIt is a direct agonist at cholinergic receptors mainly
muscarinic receptorsmuscarinic receptors
Effects:Effects: like Ach. , Nicotinic effects ---- mild.like Ach. , Nicotinic effects ---- mild.
 The most important effect is on Eye & exocrine glands.The most important effect is on Eye & exocrine glands.

66. EYE:EYE: Activates M3 receptorsActivates M3 receptors
 Miosis /↓ size of pupil --contraction of sphincter muscle of iris.Miosis /↓ size of pupil --contraction of sphincter muscle of iris.
 Cyclospasm / accommodation for near vision due toCyclospasm / accommodation for near vision due to
contraction of ciliary musclecontraction of ciliary muscle
 Conjunctival hyperemia--- Dilatation of BV via EDRFConjunctival hyperemia--- Dilatation of BV via EDRF
 ↑↑ Lacrimation due to stimulation of lacrimal glands.Lacrimation due to stimulation of lacrimal glands.
 Decrease in intraocular pressure.Decrease in intraocular pressure.

67. 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 & inwards.Contraction of muscle pulls ciliary body forwards & inwards.
 Relaxation of suspensory ligament of the lens.Relaxation of suspensory ligament of the lens.
 The lens bulges more, & its focal length is decreased .The lens bulges more, & its focal length is decreased .
 Eye accommodated for near vision.Eye accommodated for near vision.

68. 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 angle of ant.Contraction of sphincter pupillae pulls iris away form angle of ant.
Chamber. Contraction of ciliary muscle pulls the scleral spur, opens upChamber. Contraction of ciliary muscle pulls the scleral spur, opens up
the trabecular mesh work at the base of the muscle.the trabecular mesh 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 humor in to theBoth these effects facilitate the out flow of aqueous humor in to the
canal of schlemm, decreasing IOP.canal of schlemm, decreasing IOP.

69. 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 hypertension .Then may produce longer-lasting hypertension .
Hypertension is due to vasoconstriction via ganglionic effect.Hypertension is due to vasoconstriction via ganglionic effect.

70.  Effects on Exocrine Glands:Effects on Exocrine Glands:
Marked increase in salivary & other exocrineMarked increase in salivary & other exocrine
secretionssecretions

71. 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.

72. 2. To counteract the mydriasis produced by atropine.2. To counteract the mydriasis produced by atropine.
3. To break up adhesions between iris & lens, alternatively with3. To break up adhesions between iris & lens, alternatively with
AtropineAtropine
4. Xerostomia: 5-10 mg orally or S/C as4. Xerostomia: 5-10 mg orally or S/C as sialagoguesialagogue-- to increase-- to increase
salivary secretion in xerostomia due tosalivary secretion in xerostomia due to
 Sjogren syndrome.Sjogren syndrome.
 Head & neck radiation therapy.Head & neck radiation therapy.
 ParkinsonismParkinsonism

73. Glaucoma (raised IOP):Glaucoma (raised IOP):
 Aqueous humour is secreted slowly & continuously.Aqueous humour is secreted slowly & continuously.
 Normal IOP is 10 to 15mmHg above atmospheric pressure.Normal IOP is 10 to 15mmHg above atmospheric pressure.
When raised---Glaucoma.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.

74. Two types of glaucoma:Two types of glaucoma:
 Primary:Primary: Angle- closure & open-angleAngle- closure & open-angle
 Secondary:Secondary: Due to inflammation, Trauma, SurgicalDue to inflammation, Trauma, Surgical
procedures.procedures.
Angle closure glaucoma is a medical emergency, initially treatedAngle closure glaucoma is a medical emergency, initially treated
with drugs but requires surgery for permanent correction.with drugs but requires surgery for permanent correction.

75. I.O.P:I.O.P: Decreased by following mechanism:Decreased by following mechanism:
 Contraction of sphincter pupillae pulls the iris away from the angle ofContraction of sphincter pupillae pulls the iris away from the angle of
anterior chamber.anterior chamber.
 Contraction of ciliary muscle pulls the scleral spur, opens up theContraction of ciliary muscle pulls the scleral spur, opens up the
trabecular mesh work at the base of the muscle.trabecular mesh work at the base of 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 humor in to theBoth these effects facilitate the out flow of aqueous humor in to the
canal of schlemm , which drains the anterior chambercanal of schlemm , which drains the anterior chamber
 So there is decrease in the IOP.So there is decrease in the IOP.

76.  Pilocarpine is used in glaucoma.Pilocarpine is used in glaucoma.
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 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 usedMany other drugs are also used in glaucomain glaucoma