Name the 3 ways to modulate Pre-synaptic transmission at the Neuromuscular junction?
1) Anti-biotics like Aminoglycosides (bind free Calcium) and Tetracycline (Chelate free calcium) and Volatile Anasthetics (Halothane/Isoflorane) bloc calcium so less available for vesicles to fuse with membrane and release NT
2) Botulinum Toxin enzymatically cleaves Snare Proteins (SNAP-25, Syntaxin, Synaptobrevin/Vamp) required for vesicular docking and release of synaptic vesicles so blocks Ach quantal secretion
3) Hemocholinium blocks the Choline transporter for reuptake into nerve terminal
Structure of the Embryonic vs Adult Nicotinic Ach Receptor?
5 subunits together with 4 different gene products:
-1 Beta and 1 Delta
- Gamma for Embryonic OR Epsilon for Adult Ach binding on Alpha subunits
and need 2 mlcls of Ach to activate but only 1 mlcl of drug to block activation
What are the Non-depolarizing NMBA?
D-tubocurarine (curare dTC) Pancuronium Vecuronium Cisatracurium Rocuronium
What is the main depolarizing NMBA?
Mechanism of Action of Non-Depolarizing NM Blockers?
Competitive Antagonists with Ach for nicotinic receptors
Mechanism of Action of Depolarizing NM Blockers?
Causes slow, small depolarization of RMP from -90 to around -60 leading to increased Threshold for AP and inactivation of Na Channels ....so can not respond to voltage changes Depolarizes cell and CAN NOT REPOLARIZE bc inactivated channels and ....soooo cannot get AP
Prolonged stimulation can lead to DUAL BLOCK which is also desensitization of Ach receptors
How are NMBA administered and why?
ALL are charged!!! do not cross BBB All given IV or IM and not absorbed orally
two NMBA that incrase Histamine release?
Curare and Succinyl choline
What is special about Cisatracurium
Undergoes Hoffmann Elimination - spontaneous elimination and cleavage so good to use in trauma pts where enzymes important for degradation might be low
Effect of Age on treatment with NMBA?
Infants are more sensitive to Non-depolarizing blockers and less sensitive to Depolarizing blockers
They have less nAchReceptors so need less non-depol for block and more depol to stimulate AP
Effect of Temperature on NMBA?
Low Temperature (Hypothermia) and need MORE non-depolarizing blocker bc less sensitive to it bc reduced enzymatic activity of Na/K/ATPase in plasma membrane so RMP is less
Need LESS Depolarizing blocker bc MORE sensitive to it bc RMP is increased
Genetic effect on NMBA?
Butyril Cholinesterase made by liver and degrades Succinyl Choline and so without it or with genetically ineffective isozymes then given succinyl choline and maintain paralysis for LONG period of time
Effects of Electrolyte Balance on NMBA?
Calcium concentration - used in conjunction with volatile anasthetic or aminoglycoside Antibiotic, then need LESS Non-depolarizing blocker for relaxation
POtassium concentration - Hypokalemia hyperpolarizes membrane and so need LESS non-depolarizing for blockade and Hyperkalemia depolarizes membrane so need MORE non-depolarizing for blockade (opposite is true for depolarizing)
Trauma with hypovolemia and ruptured cells spilling K+ into extracellular space - need less depolarizing - CONTRAINDICATED FOR SUCCINYL CHOLINE - can cause heart failure
What happens in Myasthenia Gravis patients with NMBA?
MG patients have reduced Ach Receptors available in muscles, so they are VERY sensitive to non-depolarizing blockers (like infants)
What happens with use NMBA in Bronchiogenic Carcinoma patients? Small cell carcinoma
Like Lamburg - Eaton with block of L-type receptors to Calcium channels and so fewer vesicles of Ach released. Becuase of the reduced pre-synaptic release of Ach, pts are sensitive to both types of blockers
What happens to NMBA use in liver disease patients?
The liver produces Butyrlcholinesterase and so SuCh metabolism is decreased as well as metabolism to Vecuronium and Rocuronium
What happens in Malignant Hyperthermia?!?!?!
Mutation in the Ryanidine Receptor so once it's open it doesn't close (Calcium release receptor in SR of muscle) Contracture and build up of heat with release of Calcium stores in muscles INDUCED BY SuCh!!!!
What are the Ganglionic Blocking Agents?
Mecamylamine, Pentolinium, Trimethaphan, Hexamethonium