1. HuBio 543 September 19, 2007 Neil M. Nathanson K-536A, HSB 3-9457
Drugs acting at the neuromuscular junction

2. Autonomic Alternative
Katzung, “Basic and Clinical Pharmacology” 10th ed. , 2007 (accessmedicine.com)
Autonomic Amusements
Lewis & Elvin Lewis, “Medical Botany”
Davis, “The Serpent and the Rainbow”

3. Motor neurons cell bodies are in the ventral horn of the spinal cord

4. SynapticTransmission at Cholinergic Synapses
ACh
Choline
+ AcetylCoA
ACh + CoA
Acetyltransferase Ca ++
AChR
Na+
AChE
Ch +Ac

5. The Neuromuscular Junction

6. NMJ at the EM level
Nerve
Muscle
Basal Lamina

7. Choline + AcetylCoA ACh + CoA Ch +Ac AChE AChR Na+ Acetyltransferase++
AChR
Na+
AChE
Ch +Ac

8. Synaptic vesicles release ACh and then recycle and get refilled

9. Synaptic Vesicles Releasing ACh

10. Drugs that Act on Cholinergic Terminals
1. Hemicholinium-3: blocks choline uptake, depletes ACh
2. Vesamicol: inhibits ACh transport into synaptic vesicle
3. Black widow spider toxin: damages terminal; massive release and depletion of ACh
4. Botulinum toxins: taken up into terminal and blocks release of ACh

11. Bot Toxin A (Botox®):
Cleaves a protein on the nerve terminal
Bot Toxin B (Myobloc®): Cleaves a protein on the vesicle

12. Duration of Improvement After Botulinum Toxin
Hemifacial
Spasm
Blepharo-
spasm
Cervical
Dystonia
Spasmatic
Dysphonia
Hand 2 4 6 8 10 12 14 16
Duration of
Improvement
(Weeks)

13. Botulinum toxin relieves axillary hyperhidrosis
150
100
Sweat Production
(mg/min) 50 2 12 24
Weeks after injection into axilla

14. Uses of Botulinum Toxin
Persistent muscle spasms
Poststroke spasticity
Treatment of hyperhidrosis
Healing of anal fissure
May be useful in tension and migraine headaches
Elimination of facial wrinkles

15. Elimination of facial wrinkles by botulinum toxin
Before
After

16. What’s wrong with this picture?

18. ACh RECEPTORS
NICOTINIC
MUSCARINIC

19. Nicotinic ACh Receptor: A Ligand-Gated Ion Channel
Na+, Ca2+
ACh
ACh

20. ACh initiates a local depolarization at the synaptic region

21. Desensitization of nAChR
Muscle Depolarization
Squirt ACh
Bolus ACh

22. Rclosed + ACh
Ropen-ACh
Rdesen-ACh

23. Denervation Supersensitivity
Muscle Fiber R
Denervate
Re-innervate

24. Therapeutic Uses of Neuromuscular Blockers
Bind to nAChR and block neuromuscular transmission
Muscle relaxants during surgery
Facilitate manipulations during realignment of fractures
Decrease physical trauma during electroshock therapy

25. Competitive Neuromuscular Blockers
mivacurium
d-tubocurarine

26. California Addresses Death Penalty Concerns
May 16, 2007
California Addresses Death Penalty Concerns
By JENNIFER STEINHAUERS
State officials said Tuesday that they had addressed the plethora of serious concerns raised by a federal district judge last year over how California executed condemned inmates by lethal injections.
These were among the concerns that Judge Fogel raised:
-Not using consistent and reliable staff members for executions.
-A lack of training and supervision for those staff members.
-Poorly maintained records.
-Improperly mixed drugs.
-A poorly lighted execution area, a former gas chamber, preventing the proper monitoring of prisoners during executions.

27. Reversal of d-tubocurarine block of muscle contraction by neostigmine

28. Depolarizing Blockers
Partial agonists- first activate, then desensitize

29. Apnea After Cessation of Administration of SuCh40 80
120
160
100
200
Dose (mg)
Duration of Apnea
(min.)
Normals
Low pChE

30. ACh Interacts
With AChE
Acylated Enzyme
Intermediate
Active Enzyme

31. Edrophonium N CH2CH3 CH3 OH + Associates with anionic site of enzyme
Hydrogen
bonding
group

32. Carbamate Esters

33. Neostigmine Interacts
With AChE
Carbamylated Enzyme
Intermediate
Regenerated Enzyme

34. DFP Interacts
With AChE
Phosphorylated Enzyme

35. Regenerated
Enzyme
Phosphorylated
Enzyme
Pralidoxime
Regenerated
Enzyme

36. Aging of phosphorylated AChE
H C – O 7 3
P – O
ENZYME HO
Phosphorylated enzyme
Aged enzyme
The “aged” enzyme can no longer be reactivated by 2-PAM

37. Noncompetitive inhibitors of AChE
Bind to a site distinct from the catalytic site to inhibit enzyme activity
Used to improve/delay loss of cognition in patients with Alzheimer’s (to counteract the effects of the loss of cholinergic neurons)
Tacrine- first drug approved for treatment of Alzheimer’s; many actions in addition to AChE inhibition; high incidence of liver toxicity
Donepezil- more specific for inhibition of AChE; delays progression of symptoms; side effects- diarrhea, etc.- expected based on cholinergic stimulation-

38. Myasthenia Gravis
Scherer et al., JAMA 293, 1906 (2005)

39. Myasthenia Gravis Autoimmune Disease- Neuromuscular Weakness
Antibodies vs. nAChR- decrease nAChR # and Function
Treat with:
AChE Inhibitors- increase [ACh] at the NMJ- improves
efficiency of NM transmission (neostigmine, pyridostigmine)
Also: use a muscarinic receptor antagonist (e.g., atropine) to
counter effects of increased ACh at muscarinic synapses