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,??
treatment of myasthenia gravis?
Thymectomy, taking thymus out. remission in 70%, we dunno y lol.
Immunosuppression, open to immune attacks
Plasma exchange with donor, contains antibodies, only temporary??
Cholinesterase inhibitors, increases conc of ACh in synaptic cleft. good stuff.
Anti-idiotype antibodies
antibodies to the antibodies, future therapy.
describe Lambert Eaton Myasthenic Syndrome.
why is it’s diagnosis good?
auto immune attack on voltage sensitive calcium channels on pre synaptic membrane.
paraneoplastic disorder - 60% of people with LEMS have lung cancer.
can see LEMS symptoms before cancer symptoms.
compare LEMS to MG.
MG:
eyes first, neck/swallowing
arms and legs later on
LEMS:
legs –> arms –> eyes
what happens to babies born to mothers with MG?
have a form of MG, not auto immune only temporary.
mothers antibodies passed through placenta.
once those antibodies passed through the body the baby will recover.
describe Congenital Myasthenic Syndromes
Diverse inherited disorders Autosomal dominant, recessive
Synaptic, pre- or post-synaptic mechanisms
Pre-synaptic:
Decrease in synaptic vesicles
Decrease in ACh synthesis/packaging
(decreased release of ACh)
Synaptic:
Decrease acetylcholine esterase
(cation overload, depolarising block)
Post-synaptic:
Mutations in AChR subunit genes
what are Slow Channel Myasthenic Syndromes?
simplified end plate.
decreased AChR.
widened synapse/ as in bigger gap between pre/post.
open/closed states or summin
wut
how many ACh receptors does a nAChR have?
2, on each a subunit.
dem graph things rates idk wut
butt
Values of rate constants determines distribution openings and closings
slow channel syndrome alpha G153S?
glycine to syrine
opens too frequently
dissociation rate constant for ACh decreased from 17000 to 1000.
rate at which channel closes (a) decreases from 2300 to 900.
slowing of channel closing and slowing of ACh dissociation over stimulates the receptor.
slow channel syndrome alpha V249F?
valine to phenylalamine.
249 just below the channel gate, in the M2 (2nd TMD)
opening time increases
closing time decreases
dissociation rates decrease
rate constants n that?
B
a
k-1 k-2
B opening time of channel
a closing time of channel
k-1 dissociation rate of first ACh
describe all slow channel MS
SCMS
aN217K, eT264P, b266M + others
Dominant - cation overload (depol. block)
Variable clinically, M2 > M1 > EC domain
Treatment???
reduce receptor function
what happens if you give somebody with SCMS AChE inhibitors?
even more channel activation, nonono.
describe P121L fast channel MS
prolene to lucine
Severe myasthenic symptoms
Normal endplate structure
Normal number AChR
B decreases, opening rate decreases and rarely opens.
Autosomal recessive.
Patients have two e subunit mutations
eG-8R signal peptide
eS143L deletion of glycosylation site
Respond to AChE inhibitors (incompletely)
what is a mode switch mutation?
(only seen in lab)
Insertion in cytoplasmic loop of epsilon
Reduced expression of epsilon
Compensatory expression of foetal gamma subunit instead, which doesn’t work as well.
Entire kinetic scheme disrupted in lab, not in patient since expression levels are too low.
startle syndrome?
ligand gated ion channel channelopathy.
mutation in glycine receptor, inhibitory NTR in spinal cord.
epilepsies?
mutation in GABA A or neuronal nicotinic receptors.
