Block 1 Lecture 7 -- Muscarinics

Question 1

HACU

Answer 1

hi-affinity choline transporter

Question 2

ChAT

Answer 2

choline acetyltransferase

Question 3

VAChT

Answer 3

vesicular ACh Transporter

Question 4

Postsynaptic cholinergic receptors:

Answer 4

M1 or N

Question 5

Presynaptic cholinergic receptors:

Answer 5

M2 or N (+ HACU)

Question 6

Function of presynaptic M2

Answer 6

mitigate action potential-mediated release

Question 7

Function of presynaptic N

Answer 7

potentiate action-potential-mediated ACh release

Question 8

Where is AChE located?

Answer 8

pre and postsynaptic membranes

Question 9

Describe the structure of the Nicotinic receptor.

Answer 9

pentamer

• • (a1)2b1dg or (a1)2b1de
• • g is fetal, e is adult
• • 2x ACh bind at a or d/e

Question 10

What nicotinic isoform is present in the somatic nervous system?

Answer 10

a1

Question 11

What nicotinic isoform is present in the autonomic ganglia and adrenal medulla?

Answer 11

a3

Question 12

Describe the variability of Nicotinic isoforms? Give an ex.

Answer 12

Many CNS isoforms (alpha or beta unit variations only)

– a7 likes Ca much more than Na

Question 13

What is the MoA of Onobotulinum Toxin A?

Answer 13

indirect mAChR and nAChR for skeletal + smooth muscle relaxation
– prevents SNARE protein complexation to prevent exocytosis membrane fusion

Question 14

How often is Botox administered?

Answer 14

q2-3 months

Question 15

SNARE:

Answer 15

soluble N-ethylmalemide sensitive-factor attachment receptors

Question 16

What are SNARE proteins?

Answer 16

PM and vesicle-associated isoforms required to complex for NT-vesicle fusion to plasma membrane for exocytosis

Question 17

What kinds of tolerances can develop to Botox?

Answer 17

• • Abs (PK)
• • upregulation of postsynaptic nAChRs (rebound hypersensitivity)

also diffusion to other areas

Question 18

What are uses of Botox?

Answer 18

1) focal dystonias
2) abnormal muscle contractions
3) migraine and tension headache

Question 19

What are examples of focal dystonias?

Answer 19

1) blepharospasm
2) writer’s cramp
3) carpal tunnel
4) vocal cord spasm
5) oral dysphagias/achalasia

Question 20

What are examples of abnormal muscle contractions?

Answer 20

1) strabismus
2) MS, cerebral palsy
3) spastic bladder
4) tics (tourette’s)
5) hyperhidrosis

Question 21

What is Sjorgren’s syndrome?

Answer 21

A condition that results in the destruction of exocrine glands (mainly salivary + lacrimal) and dry mouth

Question 22

What are complications of Sjorgrens?

Answer 22

dry mouth, difficulty speaking, infection, eye damage, tooth decay

Question 23

What can cause Sjorgren’s dz?

Answer 23

primary = autoimmune Abs-mediated
secondary = radiation, other

Question 24

What is muscarine?

Answer 24

an alkaloid from the North American Fly Agaric mushroom

Question 25

What potentially-lethal compounds are found in muscarine?

Answer 25

``` ibotenic acid (excitatory AA) muscimol (GABAa agonist) ```

Question 26

What is mycetism?

Answer 26

mushroom poisoning producing strong SLUDGE effects from mAChR stimulation

Question 27

How is mycetism treated?

Answer 27

Atropine (for inocybe or clitocybe-induced)

Question 28

What mushroom genera contain the most muscarine?

Answer 28

Inocybe and clitocybe

Question 29

What are uses of muscarinic agonists?

Answer 29

1) non-obstructive GI disorders with immobility 2) non-obstructive bladder disorders with immobility 3) xerostomia 4) ophth exams (miosis) and glaucoma

Question 30

What are uses for Bethanechol?

Answer 30

Spinal Cord Injury (GI tract and bladder emptying)

Question 31

What is the MoA for bethanechol?

Answer 31

M3-selective mAChR agonist that is poorly absorbed from GI and does not cross the BBB

Question 32

What are C/I's for mAChR agonism?

Answer 32

1) PUD 2) asthma 3) MI recovery 4) BPH 5) Parkinsons

Question 33

What is the MoA of atropine?

Answer 33

non-selective, competitive mAChR antagonist

Question 34

What are other mAChR antagonists?

Answer 34

atropine scopolamine hyoscyamine

Question 35

What are uses of mAChR antagonists?

Answer 35

1) GI disorders (spastic colon, endoscopy, PUD) 2) OAB, neurogenic bladd, nocturnal enuresis 3) ophthalmology (midriasis) 4) asthma, COPD, emphysema (b2 adjunct) 5) surgery (intubation, PONV, amnestic) 6) mycetism and AChE-I poisoning 7) diaphoresis/hyperhidrosis 8) motion sickness/vestibular 9) PD

Question 36

How is hyperhidrosis treated?

Answer 36

local botox

Question 37

How are mAChR antagonists used for motion sickness and vestibular disturbances?

Answer 37

- - Vertigo is often associated with other ANS effects (sweating/n/v) - - ACh is NT at vestibular sensory afferents (reduce)

Question 38

What is a cycloplegic?

Answer 38

a drug that blocks ciliary muscle activity (block accommodation for measuring refractory errors)

Question 39

How is scopolamine different from atropine?

Answer 39

more lipophilic

Question 40

What type of GPCR are M1 receptors?

Answer 40

Gq

Question 41

What type of GPCR are M2 receptors?

Answer 41

Gi

Question 42

What type of GPCR are M3 receptors?

Answer 42

Gq

Question 43

Where are M1's located?

Answer 43

CNS (CX, HP, STR) Enteric NS Parietal stomach cells

Question 44

Where are M2's located?

Answer 44

atria | presynaptic CNS

Question 45

Where are M3's located?

Answer 45

exocrine glands smooth muscle endothelium

Question 46

Fx of M1 agonism

Answer 46

CNS excitation GI motility acid secretion

Question 47

Fx of M2 agonism

Answer 47

decreased HR | inhibit presynaptic CNS neurons

Question 48

Fx of M3 agonism

Answer 48

exocrine secretions smooth muscle contraction; vasodilation via NO endothelium: NO production