2. Pharmacology of Neuromuscular Blocking Drugs History And Clinical
Dr: mehdi Ebtehaj
Department of Anesthesia Qazvin medicine University (December Azar 1395)

3. Histort
In1942Griffith and Johnson described d-tubocurarine (dtc) as a safe drng to provide SmR
One year later in 1943 Cullen described the use of this drug in 131 patients

4. In1954 Beecher and Todd reported a six fold increase in mortality in patients receiving dtc com paired with patient who had no received a MR

5. Succinylcholine introduced by thesleff and foldes and associates in 1952 chaned anesthesia practice
Because the drug rapid onset of effect and ultra short duration (rapid endotracheal intubation and recovery )

6. In1964 Baird and Reid first reported an the clinical administration of the first synthetic aminno steroid Pancuronium
The development of the intermediate acting resulted acting resulted in the introduction of vecuronium an aminosteroid .and atra curume a benzylisoquinolinium clinical practicin 1989

7. Vecuronium was the first muscle relaxand to have an intermediate duration and minimal cardiovascula action
Mivacurium- the first short acting no depolarizing MR was in traduced into clinical practica in the 1990

8. Rocuronium an intermediate acting nondepolariziny blocker with a very rapid unset
Other neuromuscular blockers includ pipecuronium , doxacurium
Cisatracurium and rapacuronium Altho all do not remanin in use
Gant a curium and CW002 are undergning invesyig ation

9. NMBD should be administered in Anesthetic patient's
Not be used tor prevent patient movement
Awareness during surgery and in the ICU has been described inmultipte publications

10. Ec muscle relaxant given inappropriately may provide the surgeon with optimal condions but is paralyzed but not anesthetized99 Cullen and larson

11. Post junction effect
In adult mamma lain skeletal muscle the nicotinic acetylcholine receptor (nAChR )is a pent metric couple of tow α (Alfa) subunits in associated with single ß (beta) ð(Delta) and E (epsilon)
They formed trans membrane pore or channel as well as extracellular binding pockets for acetyl choline or other agonist and antagonist

12. Each of the two Alfa subunits has an acetylcholine –binding site
These sites are located in Pockets within the receptor protein approximately 3nm abe Alfa – Delta and Alfa – epsilon

13. The fetal (nAchR) contains a y (gawa )subunit instead epsilon submit
Once activated by acetyl choline the mature n AchR has a shorter opening time and a higher conductance to sodium potassium and calcium than dose the fetal nAchR which has a considerably opening time

14. Functionally the ion channel of the acetylcholine receptor is cased in the resting state
Binding of two A molecules to the Alfa submits initiates conformational changes that open the channel
If one molecule of no depolarizer compete tine An tag onsite AchR two agonist can not bind and neuromuscular transmission in inhibited

15. Succ a depolarizing produces prolonged depolarization of the end plate region which results in the
1- desensitization of the AchR
2inactivation of voltage gated sodium channels at the neuromuscular junction
3-increase in potassium permeability in the surrounding membranes
The end results are failure of action potential generation and neuromuscular block ad

16. The fetal n AchR is a low conductance channel in contrast to the high conductance channel of the adult n AchR
Thus acetyl choline release causes brief activation and a reduce probability of the channels opening
These respotor are resistant to no depolarizing and more sensitive to Succyl choline

17. Pre junc tional Effects
Pre junctional receptors are involvey in the modulation of acetyl choline release in the neuromuscular junction
Both nicotinic muscarinic receptors on the motor nerre ending has been described

18. Pre junctional nicotinic reseptors are activated by acetyl choline and function in a positive feed back control system that serve to mention arailabity of Ach when decanal for it is high
The G protein – Coupled muscarinic receptors are also involved in the feed back modulation of Ach release
The pre junctional M and M2 receptors are involved in facilitation and in habitation of acetyl choline release respectively by modulation of a calcium influx

19. The pre junction nicotinic receptors are involved with mobilization of acetyl choline but not directly with the release process
Heace blocked of the pre junction nicotinic receptors by non depolarizing prevents acetyl choline from being mad available fast enough.to support tetanic or train of foure stimulation
In contrast the pre junctional muscarinic receptors are involved with up modulation or down modulation of the release mechanism