PRINCEEEEEY Flashcards
what does cholinergic mean?
via Ach
structure of Ach?
Ch3-C=O-O-CH2-N+ x3 CH3
draw out
permanent positive charge on N
ester link where Ach is cleaved to activate it.
general cholinergic transmission?
voltage sensitive calcium channels
Ca enters
Ach vesicles fuse
bind to ACh receptors on target organ
ACh esterase break down into acetate and choline
how is choline recycled?
choline acetyl transferase
choline - ACh
AcetylCoA - CoA
nicotinic/muscarinic receptors?
Muscarinic - GPCR, slow monomeric M1-5 subtypes 1ACh site agonists: muscarine, pilocarpine antagonists: atropine, hyoscine
Nicotinic - ligand gated, fast pentameric 18 subunits 2ACh sites agonists: nicotine, suxamethonium antagonists: atracurium, tubocurarine, bungarotoxin
antagonists of NMJ?
conotoxin M1
cobratoxin
bind to same site as ACh extremely tightly.
not really competitive antagonist.
describe competitive antagonists at nAChRs
flacid paralysis.
block site of ACh, no Ca influx
can reverse by increasing conc of ACh
describe agonists at nAChR
depolarising blocker.
muscle twitching followed by flacid paralysis.
sustained depolarisation followed by decreased electrical sensitivity/desensitization.
can bind but won’t open channels.
can’t be reversed with AChE inhibitors.
applications of NMJ blockers?
muscle relaxation during surgery.
name drugs which block NMJ
non depolarizing competitive blockers:
atracurium
pancuronium
tubocurarine - african hunting, bad effects on autonomic system
dopolarising blockers:
suxamethonium
pharmacokinetics of blockers on NMJ?
Intravenous - rapid (30 sec onset)
Suxamethonium - hydrolysed by serum Cholinesterase (fast recovery - 3 min). dangerous if low s ChE
Atracurium - breaks down spontaneously, very safe.
Pancuronium – much longer duration of action (100 -200 minutes). Used in euthanasia, executions.
what receptors are responsible for nicotine addiction?
receptor containing 2 x a4 and 3 x B2 in a pentomer.
present in CNS.
treatment for nicotine addiction?
varenicline (champix) = partial agonist at a4B2 receptor.
describe botulinum toxin
Active principle in botulism food poisoning, lethal dose in mice = 1 trillionth of a gram!
Blocks release of ACh by breaking down SNARE proteins
effects of botulinum toxin?
Paralysis of skeletal muscle, autonomic block,
systemic effects = death
Can be used to paralyze muscles on local/small basis,
can treat muscle spasms, wrinkle removal
describe inhibitors of Acetylcholinesterase.
stop breakdown on ACh.
prevents termination of signalling.
name irreversible inhibitors of AChE
Nerve gases and insecticides e.g. sarin, VX covalently modify AChE
Causes muscle paralysis and over activation of autonomic nervous system (esp parasympathetic)
Atropine counters some symptoms on heart rate/bp (via mAChR). doesn’t help muscle paralysis
Pralidoxime regenerates enzyme if administered within five hours.
reversible inhibitors of Acetylcholinesterase
Competitive (edrophonium, physostigmine, neostigmine, rivastigmine)
Non-competitive (tacrine, donepezil)
Used in situations where there is a need to “Boost” cholinergic transmission.
Uses of reversible Acetylcholinesterase inhibitors
Reversal of non-depolarizing NMJ blocker e.g. pancuronium
Autoimmune myasthenia gravis:
immune attack on nAChR in NMJ. Increasing ACh boosts transmission via remaining receptors.
increases muscle strength.
edrophonium (test); pyridostigmine, neostigmine, physostigmine
Alzheimer’s disease:
loss of cholinergic neurons.
tacrine, donepezil
what is the safety margin of end plate potential?
high SM of EPP means large safety net, ie too many receptors/ACh to ensure all goes to plan
what is myasthenia?
muscle weakness, comes about when safety margin is compromised.
describe myasthenia gravis
“Severe Muscle Weakness” Drooping eyelids, double vision Impaired speech Limb, trunk muscles Respiration Incidence: 1:10000
can’t fire AP as easily, less muscle contraction thus weakness.
breathing problems since diaphragm is skeletal muscle.
why does myasthenia gravis occur?
autoimmune disorder, attack on nAChR on muscle membrane
Internalisation - antibodies bind to nAChR, less AChR present
Immune attack - end plate damage
Denatured a subunit is antigenic
Most antibodies compete with one another
Main Antigenic Region (MIR) -amino acids 67-76
67-76 on extracellular loop of a subunit, exposed.
describe the membrane with myasthenia gravis
fewer nAChRs.
changed shaped of membrane,??
