MSK pharma Flashcards
Skeletal muscle innervation?
Motorneurones with myelinated axons
- the motor neurone axon divides into unmyelinated branches which innervate an individual skeletal muscle cell (muscle fibre)
- branches further divide into multiple fine branches, each ending in a terminal bouton that forms a synapse with the muscle membrane at the neuromuscular junction
Motor unit?
The neurone and the number of fibres that it innervates
What is the neurotransmitter for skeletal muscle?
Acetylcholine
* APs are conducted via axon to the boutons causing release of transmitter
End plate neuron?
Post-synaptic terminal after terminal bouton in neuromuscular junction
What surrounds the terminal bouton? Where are nicotinic ACh receptors found?
- Schwann cell surrounds terminal bouton
* Nicotinic ACh receptors found in junctional folds
Pre-synaptic processes at neuromuscular junction?
- Choline transported into terminal by choline transporter (symport with Na+)
- ACh synthesised from choline + acetyl CoA by choline acetyltranferase
- ACh stored in vesicles by vesicular ACh transporter
- AP causes depolarisation and opens voltage-gated Ca++ channels
- Ca++ allows ACh to exit vesicles via exocytosis
Post-synaptic processes at neuromuscular junction?
- ACh activates nicotinic receptors
- Nicotinic receptor is Na+ and K+ channel
- When channel is open, influx of Na+ is greater than K+ so depolarisation known as END PLATE POTENTIAL is generated
What are nicotinic ACh receptors?
Pentamer of glycoprotein subunits [(α1)2β1δε) surrounding a central cation selective pore
Electrical responses to synaptically released ACh at end plate?
- The electrical response to one quantum of transmitter is a miniature endplate potential (m.e.p.p)
- Many m.e.p.ps summate to produce the end-plate potential (e.p.p)
- An e.p.p that exceeds threshold triggers contraction
What is muscle action potential generated by?
- Voltage-activated Na+ channels in end plate
* NOT nicotinic receptors (they generate e.p.p which trigger sopening of Na+ channels)
How do some drugs or toxins cause muscle paralysis?
reduce amplitude of e.p.p., does not reach threshold for opening voltage-activated Na+ channels, no muscle action potential is generated
How muscle action potential causes contraction?
- AP spreads over sarcolemma of skeletal muscle and enters T tubules
- Triggers release of Ca+ from SR which causes contraction (via troponin interaction)
What causes rapid termination of neuromuscular transmission?
acetylcholinesterase (AChE) - hydrolyses ACh to choline (taken up by choline transporter) and acetate (diffuses from synaptic cleft)
Insectacides and nerve agents?
Block the action of AChE
Neuromyotonia (Isaac’s syndrome) s/s? (4)
Ax?
Tx?
- Muscle cramps, stiffness, slow relaxation (myotonia), and muscle twitches (fasiculations)
- Ax: AUTOIMMUNE antibodies against voltage-activated K+ channels resulting in hyperexcitability (repetitive firing)
- Tx: anti-convulsants (e.g. carbamazepine, phenytoin) which block voltage-activated Na+ channels
Lambert-Eaton Myasthenic Syndrome (LEMS) s/s? Associated with?
Ax?
Tx?
- muscle weakness in the limbs
- associated with small cell carcinoma of the lung
- AUTOIMMUNE antibodies against Ca2+ channels causing reduced Ca2+ following depolarization and so reduced vesicular release of ACh
- Tx: anticholinesterases (e.g. pyridostigmine) and potassium channel blockers (e.g. 3,4-diaminopyridine) which increase the concentration of ACh in the synaptic cleft
Myasthenia gravis?
Ax?
Tx?
- progressively increasing muscle weakness during periods of activity - weakness of the eye and eyelid muscles is a presenting feature
- Ax: AUTOIMMUNE antibodies against nicotinic ACh receptors reduce amplitude of the e.p.p.
- Tx: anticholinesterases (e.g. pyridostigmine) and immunosuppressants (e.g. azathioprine)
Botulinum toxin?
Comps?
Tx?
Uses of botulinum toxin? (2)
- Extremely potent exotoxin (related to tetanus and diptheria toxins) that irreversibly inhibits ACh release (prevent exocytosis)
- Comps = death
- Tx = anti-cholinesterases
Uses
- Low dose can treat overactive muscles (dystonias)
- Smooth out wrinkles
Curare-like compounds? Effect? Clinical use?
competitive antagonists of the nicotinic ACh receptor (e.g. vecuronium, atracurium)
- Reduce amplitude of e.p.p to below threshold for muscle action potential generation
- used clinically to induce reversible muscle paralysis i.e. during surgery
