1. Cholinergic Receptors

2. Cholinergic Receptors: Types
Muscarinic receptors
Nicotinic receptors
Based on selective activation and antagonism.

3. Subtypes and characteristic of cholinoceptors
Receptor
Type
Other
Names
Location
Structual
Features
Postreceptor
Mechanism M1
M 1a
Nerves
Seven transmembrane segments,
G protein-linked
IP3,DAG cascade M2
M 2a,
Cardiac M2
Heart,nerves,
smooth muscle
Seven transmembrane segments,G protein-linked
Inhibition of cAMP production,
activation of K+ channels

4. Seven transmembrane segments,
Receptor
Type
Other
Names
Location
Structual
Features
Postreceptor
Mechanism M3
M2b,
glandular M2
Glands,
smooth muscle,
endothelium
Seven transmembrane segments,
G protein-linked
IP3 , DAG cascade
m41
?CNS
Inhibition of cAMP production

5. Seven transmembrane segments,
Receptor
Type
Other
Names
Location
Structual
Features
Postreceptor
Mechanism
m51
?CNS
Seven transmembrane segments,
G protein-linked
IP3 , DAG cascade NM
Muscle type, end plate receptor
Skeletal muscle neuromuscular junction
Pentamer ( α2βδγ)2
NA+, K+ depolarizing ion channel

6. α and β subunits only as α2β2 or α3β3
Receptor
Type
Other
Names
Location
Structual
Features
Postreceptor
Mechanism NN
Neuronal type,
ganglion receptor
Postganglionic cell body, dendrite
α and β subunits only as α2β2 or α3β3
NA+, K+ depolarizing
ion channel

7. Receptors and signal transduction in the ANS: Nicotinic Receptorsb g d

8. Receptors and signal transduction in the ANS
Cholinergic Receptors
Nicotinic
Muscarinic M1 M3 M5 M2 M4

9. Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors

10. Receptors and signal transduction in the ANS: Muscarinic receptors (M1, M3, M5)NH 3
(+)
Phospho - G
lipase C q
PIP 2
COOH IP
Diacylglycerol 3
Increase Ca 2+
Activate Protein
Kinase C
Response

12. Receptors and signal transduction in the ANS: Muscarinic Receptors
(M2 and M4)

13. The major groups of cholinoceptor-activating drugs

14. Cholinergic agonists Two (2) types Direct – Indirect
occupy and activate receptors
Indirect
inhibit acetylcholinesterase
levels of Ach increase
Ach stimulates receptors

15. Esters of Choline

16. Esters of Choline hydrophilic differ in breakdown by Ach’esterase
acetylcholine - very susceptable
methacholine - 3X less susceptible
bethanechol - not susceptible
methacholine & bethanechol
longer duration of action than Ach
mostly activate muscarinic receptors

17. Direct Esters of choline – mostly activate muscarinic receptors
methacholine
bethanechol
Alkaloids – activate both muscarinic and nicotinic receptors
pilocarpine
nicotine

18. Properties of choline esters
Susceptibility to Cholinesterase
Muscarinic Action
Nicotinic Action
Acetylcholine chloride
++++
+++
Methacholine chloride +
None
Carbachol chloride
Negligible ++
Bethanechol chloride

19. Alkaloids (pilocarpine and nicotine)
Highly lipid soluble
well absorbed from GI tract
get into brain
Capable of both muscarinic and nicotinic receptor activation

21. Effect of direct-acting cholinoceptor stimulants
Organ
Response
Eye
Sphincter muscle of iris
Ciliary muscle
Contraction (miosis)
Contraction for near vision
Lung
Bronchial muscle
Bronchial glands
Contraction (bronchoconstriction)
Stimulation

22. Organ Response Heart Sinoatrial node Atria Atrioventricular node
Ventricles
Decrease in rate (negative chronotropy)
Decrease in contractile strength (negative ionotropy),Decrease in refractory period
Decrease in conduction velocity, Increase in refractory period
Small decrease in contractile strength

23. Organ Response Blood vessels Arteries Veins Dilation (via EDRF),
Constriction (high-dose effect)
Urinary bladder
Detrusor
Trigone and sphincter
Contraction
Relaxation

24. Organ Response Gastrointestinal tract Motility Sphincters Secretion
Increase
Relaxation
Stimulation
Glands
Sweat, salivary, lacrimal,
nasopharyngeal

25. Eye pupillary sphincter muscle contraction (miosis)
ciliary muscle contraction
opens drainage canals in anterior chamber
lowers intraocular pressure
lens thickens for near vision

26. CV Effects Direct effects on heart Reduced vascular resistance –
decreased SA and AV conduction velocity
decreased force of atrial contraction
Reduced vascular resistance –
activation of receptors on endothelium
generation of nitric oxide (NO)
NO causes vascular muscle relaxation
Effects on BP modified by reflexes

27. Cardiac Conduction - Ach
Increased K+ conduction – slows conduction
SA node
AV node
Decreased inward Ca++ current – reduces force of contraction
Slowed pacemaker rate opposed by reflexes
Ventricles are less directly affected (parasympathetic innervation of ventricles much less than atria)

28. Respiratory Effects bronchial smooth muscle contraction
respiratory gland secretion
asthmatics highly sensitive

29. GI Effects Increased secretion Increased motility - diarrhea
gastric glands
salivary glands
Increased motility - diarrhea

30. Cholinergic receptors in the brain
Brain has muscarinic receptors
Esters don’t penetrate
Alkaloids penetrate well
Brainstem and spinal cord contain nicotinic receptors
Mild alerting from smoking
Seizures in overdose

31. Clinical Uses of Cholinergic Agonists
Glaucoma – physostigmine once used
GI and urinary stimulation - bethanechol
myasthenia gravis
edrophonium for diagnosis or testing
pyridostigmine for treatment

32. SLUDGE: Toxicity Salivation Lacrimation Urination Defecation
Gastric Emptying

33. Cholinergic Blockers
More selective than agonists; may block muscarinic or nicotinic receptors selectively

34. Cholinergic Blockers muscarinic blockers - very useful in medicine
ganglionic blockers - not used much
neuromuscular blockers - used for skeletal muscle relaxation in surgery

35. Antimuscarinic Drugs alkaloids – naturally occurring tertiary amines
atropine
scopolamine
tertiary amines
dicyclomine
benztropine
quaternary amines - ipratropium

36. Antimuscarinic Drugs tertiary amines & alkaloids
lipid soluble
good absorption from mucous membranes and skin
penetration into brain
wide distribution e.g. brain & periphery
highly selective for muscarinic receptor
quaternary amines - opposite of above

37. Antimuscarinic Drugs alkaloids – naturally occurring tertiary amines
atropine
scopolamine
tertiary amines
dicyclomine
benztropine
quaternary amines - ipratropium

38. Atropine & Scopolamine
plant origin
atropine - Atropa belladonna
scopolamine - Hyoscyamus niger
well absorbed from mucous membranes or skin
competes with Ach for muscarinic receptors
organs differ in sensitivity to these drugs

39. Atropine most sensitive intermediate sensitivity - heart tissues
salivary glands
bronchial glands
sweat glands
intermediate sensitivity - heart tissues
least sensitive - parietal cells
highly selective for muscarinic receptors

40. Atropine - CNS sedation in therapeutic doses
hallucinations in toxic doses
bradycardia when given parenterally
antimotion sickness effects
antiparkinsonism effects

41. Atropine - Eye relaxes pupillary sphincter muscle
unopposed sympathetic effects
mydriasis or dilation
paralysis of the ciliary muscle - cycloplegia
reduction in lacrimal secretion - dry eye

42. Atropine Heart & Cardiovascular System
initial bradycardia - central effect (?)
tachycardia due to blockade of vagal slowing
Opposes ach effects on SA depolarization
Opposes ach effects on AV conduction
ventricles are less affected
overall - little affect on BP

43. Atropine respiratory tract
some bronchodilation
reduction of respiratory secretions
a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma
genitourinary tract - ureter and bladder relaxation
sweat glands - suppressed by atropine

44. Atropine dry mouth slight, if any, decrease in gastric secretion
GI motility decreased
decreased gastric emptying
constipation

45. Atropine Poisoning dry as a bone blind as a bat red as a beet
very dangerous in children - hyperpyrexia

46. Therapeutic Uses antiparkinsonism effects
motion sickness - scopolamine given via transdermal patch
eye examinations - usually something short-acting (e.g. phenylephrine) is used rather than atropine
asthma - ipatropium aerosol
insecticide poisoning