Block 1 Lecture 7 -- Muscarinics Flashcards
HACU
hi-affinity choline transporter
ChAT
choline acetyltransferase
VAChT
vesicular ACh Transporter
Postsynaptic cholinergic receptors:
M1 or N
Presynaptic cholinergic receptors:
M2 or N (+ HACU)
Function of presynaptic M2
mitigate action potential-mediated release
Function of presynaptic N
potentiate action-potential-mediated ACh release
Where is AChE located?
pre and postsynaptic membranes
Describe the structure of the Nicotinic receptor.
pentamer
- (a1)2b1dg or (a1)2b1de
- g is fetal, e is adult
- 2x ACh bind at a or d/e
What nicotinic isoform is present in the somatic nervous system?
a1
What nicotinic isoform is present in the autonomic ganglia and adrenal medulla?
a3
Describe the variability of Nicotinic isoforms? Give an ex.
Many CNS isoforms (alpha or beta unit variations only)
– a7 likes Ca much more than Na
What is the MoA of Onobotulinum Toxin A?
indirect mAChR and nAChR for skeletal + smooth muscle relaxation
– prevents SNARE protein complexation to prevent exocytosis membrane fusion
How often is Botox administered?
q2-3 months
SNARE:
soluble N-ethylmalemide sensitive-factor attachment receptors
What are SNARE proteins?
PM and vesicle-associated isoforms required to complex for NT-vesicle fusion to plasma membrane for exocytosis
What kinds of tolerances can develop to Botox?
- Abs (PK)
- upregulation of postsynaptic nAChRs (rebound hypersensitivity)
also diffusion to other areas
What are uses of Botox?
1) focal dystonias
2) abnormal muscle contractions
3) migraine and tension headache
What are examples of focal dystonias?
1) blepharospasm
2) writer’s cramp
3) carpal tunnel
4) vocal cord spasm
5) oral dysphagias/achalasia
What are examples of abnormal muscle contractions?
1) strabismus
2) MS, cerebral palsy
3) spastic bladder
4) tics (tourette’s)
5) hyperhidrosis
What is Sjorgren’s syndrome?
A condition that results in the destruction of exocrine glands (mainly salivary + lacrimal) and dry mouth
What are complications of Sjorgrens?
dry mouth, difficulty speaking, infection, eye damage, tooth decay
What can cause Sjorgren’s dz?
primary = autoimmune Abs-mediated secondary = radiation, other
What is muscarine?
an alkaloid from the North American Fly Agaric mushroom
What potentially-lethal compounds are found in muscarine?
ibotenic acid (excitatory AA) muscimol (GABAa agonist)
What is mycetism?
mushroom poisoning producing strong SLUDGE effects from mAChR stimulation
How is mycetism treated?
Atropine (for inocybe or clitocybe-induced)
What mushroom genera contain the most muscarine?
Inocybe and clitocybe
What are uses of muscarinic agonists?
1) non-obstructive GI disorders with immobility
2) non-obstructive bladder disorders with immobility
3) xerostomia
4) ophth exams (miosis) and glaucoma
What are uses for Bethanechol?
Spinal Cord Injury (GI tract and bladder emptying)
What is the MoA for bethanechol?
M3-selective mAChR agonist that is poorly absorbed from GI and does not cross the BBB
What are C/I’s for mAChR agonism?
1) PUD
2) asthma
3) MI recovery
4) BPH
5) Parkinsons
What is the MoA of atropine?
non-selective, competitive mAChR antagonist
What are other mAChR antagonists?
atropine
scopolamine
hyoscyamine
What are uses of mAChR antagonists?
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
How is hyperhidrosis treated?
local botox
How are mAChR antagonists used for motion sickness and vestibular disturbances?
- Vertigo is often associated with other ANS effects (sweating/n/v)
- ACh is NT at vestibular sensory afferents (reduce)
What is a cycloplegic?
a drug that blocks ciliary muscle activity (block accommodation for measuring refractory errors)
How is scopolamine different from atropine?
more lipophilic
What type of GPCR are M1 receptors?
Gq
What type of GPCR are M2 receptors?
Gi
What type of GPCR are M3 receptors?
Gq
Where are M1’s located?
CNS (CX, HP, STR)
Enteric NS
Parietal stomach cells
Where are M2’s located?
atria
presynaptic CNS
Where are M3’s located?
exocrine glands
smooth muscle
endothelium
Fx of M1 agonism
CNS excitation
GI motility
acid secretion
Fx of M2 agonism
decreased HR
inhibit presynaptic CNS neurons
Fx of M3 agonism
exocrine secretions
smooth muscle contraction; vasodilation via NO
endothelium: NO production
