Lecture - Pharmacology (NMJ blockers) Flashcards
General questions:
- What does “ergic” mean?
- So like, what would cholenergic mean?
- “Having to do with”
- “Having to do with choline”
- Describe, for the 100th time, how the synapse works? Include the note about the post-synaptic receptors
- What are the 10 sites of drug action in the synapse?
1.
AP go down the axon and the wave of depol causes the opening of Ca channels and then causes the conraction of pre-synpatic grid proteins (the green units) and they have contractile proteins attached and pull vesicles onto the gird and they fuse and rupture their contents in the cleft - this causes the conc of Ach in the cleft ot rise heaps bc small cleft
The Ach activates post-synap receptors. There are pre-synap receptors but not really in NMJ so dw but thye are in the brain etc bc they can be. activated by the released neurotransmitter - they detect when the conc too high (automatically detect the level of neurotransmitter thus autotransmitters) and downregulate the release. It’s a biofeedback loop.
- Look at the picture
This picture actually sums up the body nervous system - what’s all in red?
Yo
Synthesis, storage and release of Ach:
- Choline within the nerve terminal is acetylated by a cystolic enzyme - what is it called?
- Synthesis is capable of supporting what?
- What is Ach is packaged into what?
- When an action potential invades the terimal, what does the depolarisation trigger and what does this lead to? So tel me the actual process for how the Ach and co-transmitter molecules are expelled into the synaptic cleft
- Ach diffuses through the synaptic cleft to act at the post-synatic recepors only - true or false?
- Within the synaptic cleft, what breaks Ach down into choline and _____, terminating the action of the transmitter. The action of the transitter at the synapse is very rapid and very brief
* Choline within the nerve terminal is acetylated by a cytosolic enzyme - choline acetyl transferase (CAT).
* Synthesis is capable of supporting a very high rate of synaptic release.
* Most ACh is packaged into synaptic vesicles (10,000 - 50,000 molecules/vesicle)
* When an action potential invades the terminal, depolarization triggers Ca++ influx which leads to vesicle mobilization, fusion and exocytosis, ie. the vesicular membrane fuses with the terminal membrane and expels acetylcholine molecules and co-transmitter molecules into the synaptic cleft.
* ACh diffuses throughout the synaptic cleft to act at both presynaptic and postsynaptic receptors.
* Within the synaptic cleft acetylcholine is broken down by acetylcholinesterase (AChE) into choline and acetate, terminating the action of the transmitter. The action of the transmitter at the synapse is very rapid and very brief.
What is this and what are the red labels?
AchE inhibitors:
- What are they also known as? They are drugs which inhibit enzyme AchE therefore enchance what?
- Three major groups of them - what are they?
- What are the AchE inhitors used as treament in? Tell me about the condition (3)
- Anticholinesterases
- Short, medium and long
- short: 5mins roughly and reverible
- medium: maybe hours and reversible too
- long: they are real long and highly toxic probably because they are irreversible - Used in treatment of Myasthenia Gravis.
- Autoimmune disease causing a decreased number of functional postsynaptic nicotinic receptors on endplates
- Characterised by muscle weakness
- Generally only affects the small muscles of the head, neck and extremities, though severe cases can affect respiratory muscles
Ppl develop antibodies to their own nicotinic Ach receptors
Ach is already broken down and then there is too few nicotinic receptors for the remaining Ach (chronic muscle weakness)
If you can get more Ach getting across, that might improve the muscle function bc work at the few receptors - this is done by inhibiting AchE.
If docs suspect it, they’ll give the short duration AchE - you’ll see the difference and at that point, you have diagnosis. They will look more posture better, face lifts etc. But can’t keep taking short bc too much adherence
Why do we treat Alzheimer’s with AChE inhibitors?
can also be used in symptomatic treatment in Alzheimer’s - also used for glucoma etc (has to do with activaing para sym sytem)
In alheimer’s disease - loss of neurons in basal forebrain nucleus (they are cholenergic neurons and they are dying slowing) and little by little, Ach levels in brain going down so give AchE inhibitors so Ach can hang around in extracellular space and do shit
Ach nicotinic receptors
- How many subunits?
- How many sites for binding Ach molecules?
- How are muscuranic Ach receptors different?
- Five
- Two binding sites so need 2 Ach molecules
- They are G-proteins
What is agonist-induced receptor desensititsatio?
Not just at the NMJ, it’s in the brain and in peripheral system
If 2Ach binds to the redeptors, Na rushes in but dont want Na to keep rushing in. You want a burst of Na and then the whole systme to shut itself down bc excess Na will cause excess swelling and the water willl follow so get cell death after swelling etc. One way of shutting it down is ()
Three states of recepors:
- Most of the time is in resting state
- Voluntary motor activity - channels flip open but Ach broken down and the closed again
- But if Ach not quizkly removed by AchE and bound to the receptors (even if it’s at one receptor), if agonist binds too long then the receptor will snap shut - prevents excess Na coming into the musvle fibre or neuron in brain
So suxamethonium is a nicotinic agonist - it works by binding into the cleft and AchE doesnt break it down so it sorta hangs around. What does this mean in terms of muscle activation? Where would you use this?
IV drip line. Agonist that enters the cleft, activates the nicotinic receptors - cause AP. But it’s not broken down by AchE and you’re dripping it in IV! So the ligand gated ion channel says, “Okay, I’ll let you keep getting Na in” and muscle keeps twitching. You’ll see muscle fasiculation. So the () is activating the receptors - non volunatry. () holds the nicotinic receptor in open state for a few seconds and the muscle gets to 0mV and that means it’s paralysed (flaccid muscle paralysis) - even neurons, if you get over 0mV then they shut down (no more AP formed in both muscle or neurons if over 0mV) through agonist-induced receptor deactivation or whatever. Then after that paralysis, it will restore the mem potential but at that point, nic all desensitised so cant generate more AP. Even through RMP stored, the muscle stil remain unreponsive bc desensitised the receptors
Tranquiliser in dart guns. You can use this in surgery too, actually bc dont want the deep spinal reflex - dont want them twitching.
So agonist-induced receptor desensitization is one way to paralyse the muscle fibre (with, eg suxamethonium) but what’s another way?
Give example and explain why you’d use a synthetic version?
You block the Ach receptors at the NMJ
Curare is a competitive antagonist that binds reversibly to the Ach site.
Often the synthetic curare are cheaper and dont need to chop down vines etc
Also pharmocokinetics: you can inject the dimethyl…and will block the Ach from binding quick but if you turn off the IV drip, the person will recover slowly - you want them after surgery to be alert as soon as possible - dont want them paralysed for up to 80mins so you can give other drugs that give 100% paralysis but dont paralyse so long. So give synthetic versions bc have better pharmocokinetic profiles
