Clearly explanation on cholinergic system receptors and its Pharmacological actions with animations...

1. CHOLINERGIC DRUGS
MR
Cell membrane
Ach
Ravi Indla
Department of Pharmacology
Karuna Medical College
Palakkad, Kerala..

2. Ach is the major neuro humoral
transmitter
Synthesized locally in the
Cholinergic nerve endings

3. Ach
Ach
MR
Ca+
Ca+
Ca+
Ca+
Ca+
Ca+
Ca+
Intracellular Response
Na+
Cell membrane
Nerve ending
M2 Auto receptor
Cho
line
Ace
tate
Cho
line
Cho
line
AcoE-A

4. Synthesis Storage and destruction
of Ach
Synthesis
 Choline is actively taken up by the axonal
membrane by Na+:choline transporter.
 This Choline Acelyted with the help of
ATP and Coenzyme-A by the enzyme
ACYLCHOLINETRANFERASE .

5. Storage
 Ach stored in ionic solution with in synaptic
vesicles
 Some free Ach is also present in the cytoplasm of
cholinergic terminals
Release:
 Release of Ach is by Exocytosis response to AP
 Release is inhibited by Botulinum Toxins &
Black widow Spider toxin.

6. Degradation:
 Ach Is degraded by an Enzyme
 Immediately after release, the Ach is Degraded
by the enzyme called CHOLINESTRASE.
Choline + CoE-A  Ach
Cholinesterase
Choline Acetate

7. Ach
Ach
MR
Ca+
Ca+
Ca+
Ca+
Ca+
Ca+
Ca+
Intracellular Response
Na+
Cell membrane
Nerve ending
M2 Auto receptor
Cho
line
Ace
tate
Cho
line
Cho
line
AcoE-A

8. Ach
C
C
Transport of Ach into Vesicle is
Inhibited by
HEMICHOLINIUM
Release of Ach from
Vesicle is Blocked by
BOTULINUM
TOXIN
CHOLINESTRASE
ANTICHOLINESTRASES
Acetate
Ach
Ach

10. Cholinoceptors
 Two classes of receptors
MUSCARINIC & NICOTINIC
 Muscarinic receptors are GPCR
 NICOTINIC receptors belongs to Ligand
gated receptors

11.  SUBTYPES of MUSCARINIC RECEPTORS:
M1,M2,M3,M4,M5
 SUBTYPES of NICOTINIC RECEPTORS:
Nm,Nn

12. MASCARINIC RECEPTORS
 Receptors are selectively stimulated by
MASCARINE
 Blocked by ATROPINE
 Located primarily on Autonomic effector
cells in HEART, BLOOD VESSELS, EYE,
SMOOTH MUSCLES, URINARY TRACT,
SWEAT GLANDS

13. Muscarinic Auto-receptors (M2 )
 Present pre-junctionally on
Post-ganglionic Cholinergic nerve endings
 Activation of these Auto-Receptors
Inhibits the further release of Ach

14. In Blood Vessels:
 Most of blood vessels contains
MASCARINIC receptors in the
Endothelium
 Response shows by the release of EDRF
from the endothelium-diffuses into the
Smooth muscles-induces Relaxation.

15. Sub types of Muscarinic receptors
M1: (Neuronal receptor)
 Located in Ganglion cells and central
neurons, Especially Cortex, Hippocampus
and Corpus striatum
Role: Mediating gastric Secretion, Relaxation
of LES/ By Vagal stimulation
 Learning & Memory, Motor fn.

16. M2 : (CARDIAC) Cardiac Muscarinic
receptors are Predominantly M2 Subtype
 Atria, Conductive tissue of heart.
 Auto-receptors on presynaptic nerve
terminals are M2 Subtype.
Effects:
 Decrease HR
 Cardiac arrest (due increase refractory
period)
 Atrial contraction reduced, no change in
Ventricular contraction.

17. M3: (SMOOTH MUSCLE, GLANDS)
BLOOD VESSELS
 Vasodilatation through EDRF release
 M2 & M3 Receptors mediates most of the
Muscarinic actions

18.  M4– Mediates facilitation and inhibition
of neurotransmitter in Certain areas of
the Brain
 M5–Found to facilitate Dopamine release

19. NICOTINIC RECEPTORS(LGCC)
 Selectively active by NICOTINE.
 Blocked by d-TC(d-Tubacurarine ) or
Hexamethonium
Activation:
 Nicotinic receptor activation
 Opening of channels
 Results rapid inflow of cations into the cell
DEPOLARISATION, Increase ACTION POTENTIAL

20. SUBTYPES of NICOTINIC receprors
 Nm , Nn
Nm: (Skeletal muscle end plate)
 Mediates skeletal muscle contraction
 Selectively Stimulated by PHENYL
TRIMETHYL AMMONIUM
 Blocked by Tubocurarine

21. Nn:
 Autonomic Ganglia
 Adrenal medullary cells
 Spinal cord
 Certain Areas of the Brain
 Selectively stimulated by Dimethyl
phenyl piperazinium
 Blocked by Hexamethonium

22. Cholinergic drugs
These are the Drugs which produce
the actions similar to that of Ach.
 Action due to the stimulation of
Cholinergic receptors
(Or)
 By increasing the availability of Ach at the
sites

23. Classification of Cholinomimitics
Alkaloids
 Acetylcholine
 Methacholine
 Carbachol
 Bethanecol
New: Cevimeline
 Muscarine
 Pilocarpine
 Arecoline
Choline Esters

24. Pharmacological action of
Acetylcholine
MUSCARINIC-Heart:M2 sub type
 Decreases the diastolic depolarization
 Decreases the Rate of Impulse generation
 Ventricular contraction also decreased
 Force of atrial contraction is markedly
reduced
 Bradycardia

25. BLOOD VESSELS (M3 Receptors)
 All Blood vessels DILATED
 Fall in BP
 Vasodilatation is primarily due to the
Stimulation of EDRF-Nitric Oxide
 Response is minimal with injected
Cholinomimitics

26. SMOOTH MUSCLES (M3 receptors)
 Smooth muscles in most Organs is
Contracted
 Tone and Peristalsis is Increased in GIT
 Peristalsis of URATER is increased-
Voiding of urine
 Bronchial smooth muscle is
CONSTRICTED
 Asthmatics are highly sensitive

27. GLANDS (M3 receptors)
 Secretion from all para-sympathitically
innervated GLANDS is INCREASED
 SWEATING
 SALIVATION
 Lacrimation
 Tracheobronchial secretions increased
 Gastric secretion also increased
 Secretion of MILK & BILE is not
affected

28. EYE (M3)
 Pupil Constricted
 Due to the contraction of Circular
muscles of IRIS MIOSIS
 Used in Glaucoma

29. NICOTINIC(GANGLIA & SKELETAL
MUSCLE)
 Both Sympathetic and Para sympathetic
ganglia are stimulated(Higher doses)
 Higher doses of Ach After ATROPINE causes
Tachycardia.
 Rise in BP due to the stimulation of
Sympathetic ganglia
 Skeletal muscle is CONTRACTED(Intra
arterial inj-Twitchings and Faciculations)
 IV inj—NO effect(Hydrolysis)

30. CNS
 No central effects are seen
 Does not penetrate BBB
 Intra cerebral inj Causes STIMULATION
followed by DEPRESSION

31. Acetylcholine(M & N)
 Natural substance & NT at Aut-Ganglia.
 Rapidly destroyed by both
Acetylcholinestrase , Butyrylcholinestrase /
Pseudocholinestrase.
 Not used therapeutically
 Has both Muscarinic and Nicotinic effects.

32. Methacholine(M)
 Mainly Muscarinic action.
 Hydrolyzed by AchE but not with BchE.
 METHACHOLINE was occasionally used to
terminate PSVT.

33. Bethanecol (M)
 Only Muscarinic action.
 Not destroyed by either of AchE & BchE.
 Prominent action on GIT, Bladder.
 Useful for Neurogenic bladder, Post
operative paralytic Ileus, Retention of
Urine.

34. Carbachol(M & N)
 Not destroyed either of Cholinestrases
 Uses are same like Bethanecol.

35. Drug Interactions
 Anti-ChE like Physostigmine Potentiate the
Action of Ach.
 Methacholine- Less marked
 Carbachol & Bethanecol – Additive
 Atropine Blocks all Muscarinic action of all
cholinergic drugs.
 Adrenaline is the Physiological antagonist of
Ach.

36. Cholinomimitic Alkaloids
PILOCARPINE: 5-10mg TDS
 Pilocarpus microphyllus
 Has Prominent MUSCARINIC action
 Also stimulates Ganglia (Ganglionic Muscarinic
receptors)
 It increases all secretions
Cardiovascular effects is Complex
 Small doses-Fall in BP
 High doses-Rise in BP (Ganglionic stimulation)
 Used in Glaucoma
Dose should lower in hepatic impairment.

37. MUSCARINE
 Occurs in poisonous mushroom AMANITA
MUSCARIA
 Selective Muscarinic receptor Agonist
 No Therapeutic use
ARECHOLINE: Found in Betel nut
Areca catechu
 No theraputic use.

38. Cevimeline: 30mg TDS
 Derivative of Ach
 Muscarinic Agonist
 High affinity for M3 on lacrimal and
Salivary glands
 Fewer side effects compare with
Pilocarpine.

39. CI Precautions & ADRS
Contraindications of Muscarinic Agonists:
 Asthma, COPD
 Urinary and GI Obstruction, Acid peptic
disease
 Cardiovascular: Hypotension, Bradycardia
Hyperthyroidism

40. ADRS
 Diarrhea.
 Abdominal Cramps.
 Nausea & Vomiting.
 Tightness in the urinary bladder.
 Difficulty in visual accommodation.
 Hypotension.
These effects are less with Topical
application.

41. Thank You