Neuromuscular Physiology and Pharmacology

Question 1

Synchronous contraction of the cells in a motor unit is called … and is often vigorous enough to be observed through the skin

Answer 1

fasciculation

Question 2

Most adult human muscles have only one neuromuscular junction per cell. An important exception is some of the cells in …

They are tonic muscles, and, unlike other mammalian striated muscles, they are multiply innervated with several neuromuscular junctions strung along the surface of each muscle fiber

Answer 2

extraocular muscles

Question 3

Succinylcholine effects on the extraocular muscle

Answer 3

Ocular muscles are important to an anesthesiologist because depolarizing muscle relaxants (e.g., succinylcholine) affect them
differently than they do on most skeletal muscles. Instead of causing a brief contraction, followed by paralysis, the depolarizing drug causes a long-lasting contracture response
that pulls the eye against the orbit and could contribute to an increase in intraocular fluid pressure.The clinical significance of the succinylcholine-induced increase in intraocular pressure has been questioned.

Although many textbooks invoke the reported extrusion of intraocular contents with succinylcholine, the basis for this effect seems to
be anecdotal.

Clinical studies, however, have indicated that succinylcholine-induced contractions of the extraocular muscles can last as long as 1 to 2 minutes and isometric tensions larger than 12 g can develop for each extraocular muscle.Thus, succinylcholine probably should not be given to patients with open eye injuries

Question 4

Alignment of the presynaptic receptor site is achieved by adhesion molecules or specific cell-surface proteins located on both sides of the synapse that grip each other across the synaptic cleft and hold together the prejunctional and postjunctional synaptic apparatuses. One such protein implicated in synapse adhesion is …, which binds to … on the postsynaptic membrane

Answer 4

neurexin

neuroligins

Question 5

Quanta of ACh, together with adenosine
triphosphate (ATP), are stored in the vesicle and covered by vesicle membrane proteins.

Synaptophysin is a glycoprotein component of the vesicle membrane.

Synaptotagmin is …

Phosphorylation of another membrane protein, synapsin, facilitates vesicular trafficking to the release site.

Synaptobrevin (vesicle-associated membrane protein [VAMP]) is a SNARE protein involved in …

Answer 5

the vesicle’s calcium sensor

attaching the vesicle to the release-site
proteins at the nerve terminal

Question 6

What are the mechanism of the posttetanic potentiation observed after NDMRs use?

Answer 6

During a nerve action potential, sodium from outside flows across the membrane, and the resulting depolarizing voltage opens the calcium channels, which allows entry of calcium ions into the nerve and causes acetylcholine to be released.

An effect of increasing calcium in the nerve ending is also clinically observed as the so-called posttetanic potentiation (PTP), which occurs after a nerve of a patient paralyzed with an NDMR is
stimulated at high, tetanic frequencies. Calcium enters the nerve with every stimulus, but it accumulates during the tetanic period because it cannot be excreted as quickly as the nerve is stimulated.

Because the nerve ending contains more than the normal amount of calcium for some time after the tetanus, a stimulus applied to the nerve during this time causes the release of more than the normal amount of acetylcholine. The abnormally large amount of acetylcholine
antagonizes the relaxant (temporarily) and causes the characteristic increase in the size of the twitch (i.e., post tetanic facilitation)

Question 7

Which calcium channels are associated with the acetilcholine release?

Answer 7

Calcium enters the nerve through specialized proteins called calcium channels.

Of the several types of calcium channels, two seem to be important for the release of transmitter: P channels and the slower L channels.

P channels, probably the type responsible for the normal release of transmitter, are found only in nerve terminals.

Question 8

What mechanism limits the effects of calcium influx in the nerve terminal?

Answer 8

In addition to calcium channels, several forms
of potassium channels are present in the nerve terminal, including voltage-gated and calcium-activated potassium channels. Potassium channels limit the duration of nerve terminal depolarization and hence the entry of calcium
and the release of transmitter

Question 9

Describe the pathophysilogy of the Eaton-Lambert (or Lambert-Eaton) myasthenic syndrome and how this disease affects the neuromuscular blocking agents

Answer 9

The Eaton-Lambert myasthenic syndrome,
which should not be confused with myasthenia gravis, is an acquired autoimmune disease in which antibodies are directed against voltage-gated calcium channels at nerve endings. In this syndrome, decreased function of the calcium channel causes decreased release of transmitter,
which results in inadequate depolarization and muscle weakness. Patients with Eaton-Lambert myasthenic syndrome exhibit increased sensitivity to depolarizing and nondepolarizing relaxants

Question 10

Conseqeunces of higher-than-normal concentrations of bivalent inorganic cations in the neuromuscular system

Answer 10

Higher-than-normal concentrations of bivalent inorganic cations (e.g., magnesium, cadmium, manganese) can also block the entry of calcium through P channels and profoundly impair neuromuscular transmission. This mechanism is behind the typical muscle weakness and
potentiation of the effect of muscle relaxants in a mother and fetus when magnesium sulfate is administered to treat preeclampsia

Question 11

Why don’t calcium channels blockers cause muscle weakness?

Answer 11

P calcium channels, are not affected by calcium entry-blocking drugs such as verapamil, diltiazem, and nifedipine. These drugs have profound effects on the slower L channels present in the cardiovascular system. As a result, the L-type calcium channel blockers have no significant effect at therapeutic doses on the normal release of acetylcholine or on the strength of normal neuromuscular
transmission.

Question 12

Are neuromuscular blocking agents affected by CCBs?

Answer 12

Calcium entry-blocking drugs may increase the block in neuromuscular transmission induced by NDMRs. The effect is small, and not all investigators have been able to observe it. The explanation may lie in the fact that nerve endings also contain L-type calcium channels.

The effects of calcium channels on depolarizing relaxants, if any, are unknown

Question 13

The SNARE proteins include …

Answer 13

the synaptic-vesicle protein, synaptobrevin;

the plasmalemma-associated protein, syntaxin;

and the synaptosomeassociated protein of 25-kd (SNAP-25)

Question 14

The current model of protein-mediated membrane fusion in exocytosis is as follows. When there is an action potential and calcium
ions enter, 1… becomes phosphorylated, which frees the vesicle from its attachment to the cytoskeleton.

2… and … SNAP-25 are complexes attached to the plasma membrane.

After the initial contact, the 3… on the vesicle forms a ternary complex with 4…

5… is the protein on the vesicular membrane that acts as a calcium sensor, localizes the synaptic vesicles to synaptic zones rich in calcium channels, and stabilizes the vesicles in the docked state

Answer 14

1 - synapsin

2 - Syntaxin and SNAP-25

3 - synaptobrevin

4 - syntaxin and SNAP-25

5 - Synaptotagmin

Question 15

Botulinum neurotoxin mechanism of action

Answer 15

Botulinum neurotoxin selectively digests one or all SNARE proteins and blocks exocytosis of the vesicles, which ultimately results in muscle weakness or more profound muscle paralysis. This toxin may produce a partial or complete chemical denervation

Question 16

Denervation decreases acetylcholinesterase at
the junctional and extrajunctional areas. Other acquire diseases involving cholinesterases are related to chronic inhibition of acetylcholinesterase by … pesticides or … [gas] or to chronic … therapy given as prophylaxis against nerve gas poisoning.

Answer 16

organophosphate

nerve gas (e.g., sarin)

pyridostigmine

Question 17

Three isoforms of postjunctional nicotinic AChRs exist, describe’

Answer 17

• A junctional or mature receptor
• An extrajunctional or immature (fetal) receptor
• And the more recently described neuronal α7 nicotinic receptor

Question 18

AChRs are synthesized in muscle cells and are anchored to the end-plate membrane by a special 43-kd protein known as …

Answer 18

rapsyn

Question 19

Describe the subunist tha form the AChRs

Answer 19

• The mature receptor consists of 2 α1-, β1-, δ-, and ε-subunits
• The fetal (immature, extrajunctional) receptor consists of 2 α1-, β1-, δ-, and γ-subunits;
• The neuronal α7 AChR consists of five α7-subunits

Question 20

In which AChR’s subunit the acetylcholine binds?

Answer 20

α1 or α7

Question 21

How can depolarizing muscle relaxantas shift from excitation of muscle contraction
to block of transmission?

Answer 21

Depolarization of the end plate by the depolarizing relaxant initially causes the voltage gate in adjacent sodium channels to open, thereby producing a wave of depolarization that sweeps along the muscle and generates
a muscle contraction.
Shortly after the voltage-dependent gate opens, the time-dependent inactivation gate closes.
Because the relaxant is not removed from the cleft, the end plate continues to be depolarized. Because the sodium channels immediately adjacent to the end plate are influenced by depolarization of the end plate, their voltage-dependent gates stay open and their inactivation gates stay closed.
Since sodium cannot flow through a channel that has a closed inactivation gate, the perijunctional muscle membrane does not depolarize

Consequently, the muscle membrane is separated into three zones:
(1) the end plate, which is depolarized by succinylcholine;
(2) the perijunctional muscle membrane, in which the sodium channels are frozen in an inactivated
state; and
(3) the rest of the muscle membrane, in which the sodium channels are in the resting state

This phenomenon is also called accommodation

Question 22

During the accomodation cause by depolarizing muscle relaxants, ca a diret eletrical stimulus to the muscle cause contraction?

Answer 22

Yes

During accommodation, when the synapse is inexcitable through the nerve (transmitter),
direct electrical stimulation of muscle causes muscle contraction because the sodium channels beyond the junctional area are in the resting excitable state

Question 23

Drugs That Can Cause or Promote Desensitization of Muscle Nicotinic
Receptors

Answer 23

1) Volatile anesthetics
Halothane
Sevoflurane
Isoflurane

2) Antibiotics
Polymyxin B

3) Cocaine

4) Alcohols
Ethanol
Butanol
Propanol
Octanol

5) Barbiturates
Thiopental
Pentobarbital

6) Agonists
Acetylcholine
Decamethonium
Carbachol
Succinylcholine

7) Acetylcholinesterase inhibitors
Neostigmine
Pyridostigmine
Di-isopropyl-fluorophosphate
Edrophonium

8) Local anesthetics
Dibucaine
Lidocaine
Prilocaine
Etidocaine

9) Phenothiazines
Chlorpromazine
Trifluoperazine
Prochlorperazine

10) Phencyclidine

11) Calcium channel blockers
Verapamil

Question 24

Which drugs may cause AChR Channel block and potentiate neuromuscular blockade?

Answer 24

• Neostigmine and related cholinesterase inhibitors
• Antibiotic
• Cocaine
• Quinidine
• Piperocaine
• Tricyclic antidepressant
• Naltrexone
• Naloxone
• Histrionicotoxin

Question 25

Describe de phase II block

Answer 25

A phase II block is a complex phenomenon associated with a typical fade in muscle during continuous exposure to depolarizing drugs.

This fade phenomenon is likely due to the interaction of depolarizing action of succinylcholine on distinct neuronal (prejunctional) AChRs; these prejunctional
receptors are blocked by higher-than-usual concentrations of succinylcholine. This fade after succinylcholine is at least partly dependent on a presynaptic interaction with cholinergic transmission of importance for neurotransmitter mobilization and release. However, fade in muscle during repetitive nerve stimulation can also be attributable to postjunctional AChR block

Other factors may also be involved.
1) The repeated opening of channels allows a continuous efflux of potassium and influx of sodium, and the resulting abnormal electrolyte
balance distorts the function of the junctional membrane.
2) Calcium entering the muscle through the opened channels can cause disruption of receptors and the sub-end-plate elements themselves.
3) The activity of the sodium-potassium
adenosine triphosphatase pump in the membrane increases with increasing intracellular sodium and, by pumping sodium out of the cell and potassium into it, works to restore
the ionic balance and membrane potential toward normal.
As long as the depolarizing drug is present, the receptor channels remain open and ion flux through them remains frequent

Question 26

alfa 7 AChR particularities

Answer 26

Choline, a precursor and metabolite of acetylcholine (and succinylcholine), is a weak agonist of conventional muscle AChRs but is a full agonist of muscle α7 AChRs; that is, concentrations of choline that do not open conventional AChR channels will open α7
AChR channels.

Furthermore, no desensitization of the
α7 AChRs occurs even during the continued presence of choline, thus allowing a greater chance for potassium to efflux (approximately 145 mEq/L) from within the cell to
the extracellular space, including plasma (approximately 4.5 mEq/L), down its concentration gradient.

The α7 AChRs expressed in neuronal tissue are also readily desensitized with choline, a feature that contrasts with muscle α7 AChRs, which do not desensitize with choline

Question 27

The potency of NDMRs is … in patients with up regulation of immature AChRs, as demonstrated by the resistance to their neuromuscular effects documented in patients with burns, denervation, sepsis, and immobilization

Answer 27

reduced

Question 28

In light of recent research, it seems that, in some pathologic states (like denervation, immobilization, sepsis…), the resistance to nondepolarizers is more likely due to the junctional area expression of the … AChRs, which has a decreased affinity
to NDMRs.

Some NDMRs may also cause a partial agonist response in … receptors, thus explaining the decreased potency in conditions in which upregulation of AChRs occurs

Answer 28

α7

immature

Question 29

Sensitivity to muscle relaxants can begin to change beyond …hours after an injury or hospitalization

Answer 29

72

Question 30

To emphasize the distinction between neural and muscle nicotinic receptors, the former are sometimes designated … and the latter …

Answer 30

Nn

Nm

Question 31

Why does succinylcholine don’t cause fade in the tetanic stimulation?

Answer 31

in the clinically relevant concentration range, succinylcholine neither activates nor
inhibits the presynaptic α3β2 autoreceptor (responsible for the positive feedback of ACh inte the synaptic cleft).

This observation may be the reason for the typical lack of fade during succinylcholine-induced neuromuscular block.