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38 Cards in this Set
- Front
- Back
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Contractions of the skeletal muscles are controlled by... |
The somatic nervous system - voluntarily controlled - signals originate from the brain and travel to motor neurons to innervate skeletal muscle fibres |
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What is the neuromuscular junction (NMJ)? |
Intermediary between motor neurons and the skeletal muscle |
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What does the NMJ consist of? |
- Prejunctional motor nerve ending (axonal terminal) - Highly folded postjunctional skeletal muscle membrane aka the sarcolemma (motor end-plate) - Synaptic cleft
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The neurotransmitter at the NMJ is... |
Acetylcholine! |
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Steps of synaptic transmission at the NMJ |
AP is conducted down the axon of motor neuron to the prejunctional motor nerve ending |
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When AP reaches axon terminal... |
Voltage-gated Ca++ channels opens |
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Opening of voltage-gated Ca++ channels... |
Influx of Ca++ causes exocytosis of ACh containing vesicles into the synaptic cleft |
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Release of Ach into the synaptic cleft... |
Binds to nicotinic cholinergic receptors on the motor end plate -> increase channel permeability to Na+ & K+ |
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Net influx of Na+ does what? |
Increases the resting membrane potential (-90mV) and creates a local depolarization at the motor end plate aka END-PLATE POTENTIAL |
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If the end-plate potential reaches threshold... |
An AP is generated and propagated across surface of skeletal muscle fibres via opening of voltage-gated Na+ channels outside motor end plate --> resulting in muscle contraction! |
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What happens to the leftover ACh in the synaptic cleft? |
It gets rapidly hydrolyzed by acetylcholinesterase allowing the membrane to repolarize to resting membrane potential |
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In summary... |
AP is conducted down motor neuron to prejunctional motor nerve ending -> opens VG-Ca++ channels -> exocytosis of ACh to synaptic cleft -> ACh diffuses across cleft to bind nicotinic cholinergic receptors -> increases channel Na+ and K+ permeability -> net influx of Na+ causes depolarization and end-plate potential -> if threshold is reached, AP is generated and propagated across surface of skeletal muscle fibres -> muscle contraction |
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How are end-plate potentials generated? |
Opening of nicotinic cholinergic receptors |
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How are APs generated? |
Opening of VG-Na+ channels |
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Action of neuromuscular blockers |
- Bind to nicotinic cholinergic receptors (which are ligand-gated cation channels) at the NMJ - They only block synaptic transmission at skeletal muscles - They do not block nerve transmission and AP generation |
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Overall effect of neuromuscular blockers |
Temporary paralysis of skeletal muscles and muscle relaxation |
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Structure of neuromuscular blockers |
- Similar to Ach - Contains 1-2 quaternary nitrogens which lowers lipid solubility and limits CNS penetration
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How are neuromuscular blockers administered? |
- All administered parentally - Typically IV
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Two groups of neuromuscular blockers are... |
1) Depolarizing neuromuscular blockers 2) Non-depolarizing neuromuscular blockers |
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Example of depolarizing neuromuscular blocker |
Succinylcholine (SCh) |
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Examples of non-depolarizing neuromuscular blocker |
Isoquinoline derivative - d-tubocurarine Steroid derivative - pancuronium |
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Characteristics of succinylcholine |
- Rapid onset of action (<1 min) - Short duration of action (5-10 min) - Acts as an agonist at the nicotinic cholinergic receptor |
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What is the difference between SCh and ACh? |
SCh is longer acting |
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How is SCh hydrolyzed? |
Butyrylcholinesterase or pseudocholinesterase - These enzymes are not found in the synaptic cleft - Therefore, hydrolysis of SCh is slower than ACh
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Cholinesterase inhibitors can... |
Enhance the action of SCh by preventing its degradation |
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Common side effects of SCh are: |
Bradycardia, hyperkalemia, muscle pain |
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What is the first phase in the mechanism of action for SCh? |
Depolarizing Block |
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What happens in the first phase? |
- Muscle twitches (fasiculation) - Blocks synaptic transmission by causing a long-term persistent depolarization as nicotinic cholinergic receptors do not close immediately (membrane cannot repolarize) - Depolarized membrane is unresponsive because VG-Na+ channels remain inactive
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VG-Na+ channels consist of two gates, which are: |
Upper gate (voltage dependent) - this gate closes at resting membrane potential Lower gate (time dependent) - this gate closes after a certain amount of time
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How does SCh inactivate the VG-Na+ channels? |
The lower gate only opens when the membrane repolarizes Since SCh causes a long-lasting depolarization, the membrane does not repolarize
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What is the second phase in the mechanism of SCh? |
Desensitizing block |
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What happens during the desensitizing block? |
- Prolonged exposure to SCh - Repolarization occurs, but continuous activation of SCh can desensitize receptors - Receptors will become less sensitive to ACh even in the absence of SCh |
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Characteristics of non-depolarizing blockers |
- Slow onset of action (2-3 min) - Longer duration of action (20-120 min) - Acts as competitive antagonist to block the nicotinic cholinergic receptors |
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Cholinesterase inhibitors can... |
Decrease action of non-depolarizing blockers because there will be more ACh to outcompete the blockers |
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What is the effect of non-depolarizing blockers on end-plate potentials? |
They prevent the end-plate potential from reaching threshold -> NO AP can be generated! |
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Characteristics of isoquinoline derivatives (d-tubocurarine) |
- High potency - No vagolytic effect (does not affect vagus nerve) - Releases histamines -> tachycardia, bronchospasm, hypotension - Excreted by the kidney
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Steroid derivatives (pancuronium) |
- High potency - Exhibits vagolytic effects -> tachycardia - No histamine release - Excreted by kidney and metabolized by liver
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Clinical uses of non-depolarizing blockers? |
- Facilitate tracheal intubation - Improve intraoperative surgical conditions via muscle relaxation |
