CIS - Pharm. of Neuromuscular Junctions Flashcards
Antibodies to which of the following would most likely cause this patients presenting sx? (ptosis)
a. ACH
b. Choline acetyltransferase
c. myosin light chain kinase
d. Na/K ATPase
e. nicotinic acetylcholine receptors
E.
Give two examples of intracellular molecules?
Choline acetyltransferase
myosin light chain kinase
Describe myasthenia gravis
immune disorder characterized by progressive weakness and fatigue throughout the day
Worsens with activity and is improved with rest
circulating antibodies against nAChR are common in diagnosis
Why would ptosis be common with patients with myasthenia gravis?
Because there is a HIGH regional distribution of muscle weakness of muscles surrounding the eyes and mouth
patients might get tired eating
An inhibitor of which of the following is most appropriate to treat this patients symptoms? (patient has myasthenia gravis)
a. Acetylcholinesterase
b. Choline acetyltransferase
c. Choline transporter
d. Muscarinic acetylcholine receptor
e. SNARE complex
a. Acetylcholinesterase
Because we have a reduction of the ACH receptors, there is a more difficult time inducing a muscle contraction
So you want an increase in ACH in the synapse, so you do not want the acetylcholinesterase breaking ish down, because you want ACH to make the contraction via post-synaptic receptors
If you are wanting to treat the patient that has myasthenia gravis, what charge would you want the drug to have? (acetylcholinesterase inhibitor)
a. charged
b. uncharged
a. charged
Want to keep the drug out of the brain and out of the CNS, so you want it to be charged in order to stay in the periphery
Uncharged drugs will cross the BBB and into the CNS
What are two fast tests for myasthenia gravis prior to Ab testing?
- Tension (edrophonium testing) Achetylcholinesterase inhibitor to see if the symptoms disappeared
- Ice pack to see if the sx disappear
Anesthesia is induced with propofol and a neuromuscular blocking agent that produces muscle fasciculations (twitches) upon administration. Which of the following fits this description?
a. acetylcholinesterase inhibitor
b. Botulinum
c. d-turbocurarine
d. succinylcholine
e. Tetanus toxin
d. succinylcholine
drug that causes paralysis by acting as an agonist (compound that elicits a natural pharmacological response)
Contacts the receptor over and over and over again, and there is paralysis of the muscle because there is not an action potential that is able to get past since the receptors are being constantly annoyed by the succinylcholine. It results in a flaccid paralysis
What is an antagonist in pharmacology?
Inhibits a natural physiological response
What is an agonist that causes paralysis?
Succinylcholine
Describe d-turbocarine- what does she do?
Causes paralysis by acting as an antagonist and blocking the muscle receptors (stops a physiological process from occurring)
True/False: Tetanus toxin is not used in any clinical setting.
TRUE
Describe a non depolarizing blockade
Prevents access of ACH to its receptor and block depolarization
Describe a depolarizing blockade
Keeps the ACH open, either the receptor is weakened or the drug gets stuck in the channel, and nothing can get through and cause a response
AT 4.5 hours after incision, the patients body temperature is 40.9 C. At this time, a rise of more than 0.5 C is observed in less than 15 minutes. What is most likely the diagnosis? (The patient has an increased CO2)
a. Lung carcinoma
b. Malignant hyperthermia
c. Myosarcoma
d. Rhabdomyolysis
e. Succinylcholine overdose
b. malignant hyperthermia
Describe malignant hyperthermia
hypermetabolic response to volatile anesthesia
What are the molecular mechanisms of MH?
RYR1 mutations: the muscles are unable to sequester calcium and there is a constant contraction
If this patients (MH patient in surgery) is left untreated and uncontrolled what is the most likely consequence?
a. Brain damage
b. Heart failure
c. Kidney failure
d. liver failure
e. permanent paralysis
c. kidney failure- rhabdomyolysis
Describe rhabdomyolysis
final common pathway for injury is an increase in intracellular free ionized cytoplasmic and mitochondrial Ca2+
Increased CA2+ leads to increase ROS and leads to muscle cell death
Lysis of the muscle cells leads to acute renal failure
Which of the following agents is most appropriate to treat this patient? (MH)
a. Acetylcholinesterase
b. Dantrolene
c. Tetrodotoxin
d. Succinylcholine
e. Tetanus toxin
b. Dantrolene- drug that blocks the ryanodine receptor (RYR1) and will keep the CA2+ in the SR and is necessary in order to stop the sustained contraction
What happens after it is recognized that the patient has malignant hyperthermia?
Anesthesia is stopped
Ventilation is increased with 100% oxygen to combat systemic acidosis
Cooling blankets; ice to surfaces
Dantrolene is administered
Skeletal muscle synapses with one long motor neuron from the spinal cord. What is the signal that is used at the synapse between the neuron and muscle fibers?
Acetylcholine (ACh)
What type of receptors are used at the synapse of a motor neuron and skeletal muscle?
Nicotinic ACh receptors
What are the steps involved in neuromuscular junction transmission?
1) Axonal conduction
2) Junctional transmission (cholinergic)
3) ACh signaling
4) Muscle contraction
Nicotinic (and muscarinic) are types of __________ receptors, meaning they bind to ACh.
Cholinergic
Junctional transmission has 4 steps that occur with the ACh itself. What are these steps?
1) ACh synthesis
2) ACh storage
3) ACh release
4) ACh destruction
In ACh synthesis, a cholinergic neuron first absorbs _______ from outside the cell via a ________ transporter.
Choline
Choline
In ACh synthesis, once choline is inside the cell then _______ _______ will combine Acetyl CoA and Choline to form _________.
Choline acetyltransferase (ChAT) Acetylcholine (ACh)
Immediately after ACh is synthesized, it is shuttled into storage vesicles via an ACh vesicular transporter. This transporter is (ATP/GTP) dependent.
ATP
Patients with Alzheimers disease have reduced cerebral production of what enzyme?
ChAT (Choline acetyltransferase)
***This is what combines Acetyl CoA and Choline to make ACh
How many molecules of ACh are within each vesicle?
1 K - 50 K
A motor nerve terminal may contain over ______ vesicles.
300 K
When the action potential has reached the end of the motor neuron (pre-synapse) then ________ _______ channels open due to the depolarization. This allows ________ to enter the cell and promote the vesicles holding ACh to fuse with the membrane.
Voltage-gated Calcium
Calcium
Once the vesicles holding ACh are close to the membrane, these vesicular and plasma membrane proteins will initiate vesicle-plasma membrane fusion and release of ACh.
VAMPs (on vesicle)
SNAPs (on membrane)
How many ACh vesicles will rupture per action potential?
About 125 vesicles
Once fusion of the vesicle to the membrane occurs, ACh will be released into the synapse via exocytosis. This ACh will go on to activate post-synaptic receptors which are…
Nicotinic ACh receptors (nAChR)
To stop post-synaptic signaling by ACh, the enzyme ___________ will cleave ACh into choline and acetate.
Acetylcholinesterase (AChE)
What happens to choline produced by AChE from cleaning ACh?
It is recycled back into the pre-synaptic motor neuron via the choline transporter.
This occurs at the nerve terminal to replenish the number of available vesicles when post-synaptic signaling has stopped.
Endocytosis
ACh can activate two subsets of receptors, which are…
Nicotinic (nAChR)
Muscarinic (mAChR)
nAChRs are activated by ACh and ________.
Nicotine
mAChRs are activated by ACh and _________.
Muscarine
This type of ACh receptor is a ligand-gated ion channel (Na+).
nAChR
This type of ACh reception is a G-protein coupled receptor.
mAChR
T/F. mAChR and nAChR are both present at pre- and post-junctional membranes.
True
Only this type of ACh receptor is present at skeletal neuromuscular junctions, because the Na+ increase causes muscle action potentials (muscle contraction).
nAChR
This type of ACh receptor is not located at skeletal neuromuscular junctions but is present in other end organs. Also causes contraction.
mAChR
What type ACh receptor would be found on smooth muscle and cardiac muscle?
mAChR
mAChR induces what response in smooth muscle?
Contraction
mAChR induces what response in cardiac muscle?
Decreased HR
Decreased conduction velocity
Decreased contraction
Slight decreased contraction in atrium and ventricle
mAChRs are GPCRs and activation leads to a series on intracellular events triggered by second messengers (occurs in seconds). The term for this is ________.
Metabotropic
nAChRs are ligand-gated ion channels that allow ions to pass through the channel pore when activated (fastest synaptic events in nervous system, milliseconds). The term for this is ________.
Ionotropic
T/F. In ion channels, ions are selected based on the charge of the amino acids lining the pore of the channel. Negatively charged amino acids line the pore of channels that pass positively charged ions and vice versa.
True
In nAChRs, ________ and ________ line the pores (negative charge) making the channel selective for positives charges which are Na+, Ca2+, and K+. In the case of skeletal muscle, it’s ______.
Aspartic acid
Glutamic acid
Na+
What are agonists of skeletal muscle nAChRs?
ACh
Nicotine
Succinylcholine
What are antagonists of skeletal muscle nAChRs?
d-tubocurarine
Atracurium
Vecuronium
Pancuronium
These subtypes of nAChRs are also excitatory and induce contractions. Their agonists are ACh and Nicotine but their antagonists are Mecamylamine.
Peripheral Neuronal nAChRs
Central Neuronal nAChRs
Put the following events at the NMJ in order, from start to finish:
A. Influx of Na+ initiates an AP, which propagates throughout the muscle fiber.
B. nAChRs open leading to a relatively large influx of Na+ compared to a smaller efflux of K+
C. An AP in the motor neuron is propagated to the terminal button.
D. Local current flows between the depolarized end plate and adjacent membrane.
E. ACh is destroyed by AChE, terminating the muscle cell’s response.
F. The presence of an AP triggers the opening of voltage-gated Ca2+ channels.
G. ACh diffuses across the synaptic cleft and activates nAChRs.
H. Local flow opens voltage-gated Na+ channels.
I. Ca2+ triggers the release of ACh from vesicles.
1) C
2) F
3) I
4) G
5) B
6) D
7) H
8) A
9) E
This agent can affect the nerve action potential and is not used clinically. It works by inhibiting voltage-gated Na+ channels, which blocks axonal conduction. This inhibits the nerve fiber from activating skeletal muscle, causing paralysis.
Tetrodotoxin
Tetrodotoxin is considered poison from what?
Puffer fish
If Tetrodotoxin is given at high doses, death can occur due to what?
Respiratory failure
Hypotension
Local anesthetics also inhibit voltage-gated Na+ channels, thus blocking axonal conduction. They are utilized for pain control during a variety of clinical procedures. What are local anesthetics often used?
Lidocaine
Bupivacaine
Procaine
Botulism is caused by ________ ________, a hetogenous group of gram-positive, rod-shaped, spore-forming, obligate anaerobic bacteria that is often found on vegetables, fruits, and seafood. It exists in soil and marine sediment worldwide.
Clostridium botulinum
This toxin works by cleaving the components of the core SNARE complex involved in exocytosis, preventing the release of ACh. Essentially, it won’t allow the vesicle to fuse.
Botulinum toxin
________ is classically described as the acute onset of bilateral cranial neuropathies associated with symmetric descending weakness. There are no sensory deficits except blurred vision.
Botulism
_________ botulism symptoms often include nausea, vomiting, abdominal pain, diarrhea, and dry mouth.
Food borne
What are clinical uses of Botulinum toxin?
Temporary improvement of lines/wrinkles of face
Prophylaxis of chronic migraine headaches
________ is a nervous system disorder characterized by muscle spasms that is caused by the the toxin-producing anaerobe Clostridium ________, which is found in the soil (ingested).
Tetanus
Tetani
This toxin works by blocking the fusion of the synaptic vesicles by targeting synaptobrevin. After binding to the presynaptic membrane of the NMJ, the toxin is internalized and transported retroaxonally to the spinal cord.
Tetanus toxin
This toxin causes spastic paralysis due to its actions on the spinal inhibitory interneurons, blocking release of inhibitory neurotransmitters that normally serve to relax contracted muscle by inhibiting excitatory motor neurons.
Tetanus toxin
Generalized ________ typically presents as spastic paralysis with symptoms that include lockjaw, autonomic overactivity (restlessness, sweating, tachycardia), stiff neck, board-like rigid abdomen, etc.
Tetanus
Botulinum toxin and Tetanus toxin both affect vesicular ACh release, but work differently. How do they differ?
Botulinum toxin – Stays in NMJ
Tetanus toxin – Moves to spinal cord
Neuromuscular blocking drugs consist of both agonists and antagonists of the ________ that can prevent synaptic transmission.
nAChR
(ANTAGONISTS/AGONISTS) activate the receptor to signal as a direct result of binding to it.
Agonists
(ANTAGONISTS/AGONISTS) bind to receptors but do not activate generation of a signal.
Antagonists
This is a type of Curare alkaloid that competes with ACh for the nAChR on the motor end plate, decreasing the size of the action potential.
d-tubocurarine
What occurs due to Curare alkaloids inhibiting ACh from binding to the nAChR?
Flaccid paralysis of skeletal muscle
Are Curare alkaloids considered depolarizing or nondepolarizing?
Nondepolarizing – because it inhibits ACh from binding, not allowing depolarization to occur
Are Curare alkaloids considered an agonist or antagonist?
Antagonist – because it blocks binding of ACh, not allowing generation of signal
Curare alkaloids are used clinically for what?
Anesthesia to relax skeletal muscle (longer lasting)
How can paralysis due to Curare alkaloids be reversed?
By using an AChE inhibitor to increase ACh in the NMJ
This neuromuscular blocker binds to skeletal muscle nAChRs and initially causes depolarization. It does not release and causes continued depolarization, which leads to receptor blockade and paralysis.
Succinylcholine
Is Succinylcholine considered depolarizing or nondepolarizing?
Depolarizing – binds and causes continued depolarization
Is Succinylcholine considered an agonist or antagonist?
Agonist – binds and induces a signal (depolarization)
What is Succinylcholine used for?
Anesthesia (short-term; 3-5 minutes)
How is paralysis caused by Succinylcholine reversed?
Time (wait for effects to wear off because it’s short lasting)
These inhibitors bind to AChE and block its enzymatic activity. They work to increase the concentration of ACh at the NMJ.
Cholinesterase inhibitors
Why are Cholinesterase inhibitors used for dementia in Alzheimer’s patients?
Alzheimer’s patients have less ChAT (remember this enzyme combines Acetyl CoA and Choline to make ACh). By decreasing the amounts of the AChE, then what little ACh they do have will be saved.
What clinical uses can Cholinesterase inhibitors be used for?
- Dementia (Alzheimer’s or Parkinson’s)
- Myasthenia Gravis
- Nerve gas and organophosphate pesticide exposure
- Reversal of neuromuscular blockade during anesthesia
This inhibits ryanodine receptors in the sarcoplasmic reticulum and blocks release of Ca2+. Affects muscle contraction.
Dantrolene
***When NMJ activates skeletal muscle there is a huge influx of Ca2+ at the sarcoplasmic reticulum, and this Ca2+ is responsible for contraction of myofibers.
What are clinical uses for Dantrolene?
Malignant hyperthermia (fast rise in body temp and severe muscle contractions when someone is given anesthesia – ***after exposure to Succinylcholine or inhalation anesthetic)
Spasticity associated with upper motor neuron disorders
These are a superfamily of proteins with the primary role of mediating vesicle fusion and can be divided into two categories: vesicle and target.
SNAREs (v-SNAREs and t-SNAREs)
The v-SNARE protein called _________, is also known as VAMP (vesicle associated membrane protein).
Synaptobrevin
The t-SNARE proteins are called…
Syntaxin
SNAP-25
When the v-SNARE and t-SNARE proteins form the core SNARE complex, they bring the vesicle and presynaptic membranes into close contact. Upon arrival of the action potential in the axon terminal, calcium rushes in and interacts with the calcium sensor protein ________ on the vesicle membrane, which triggers vesicle fusion and exocytosis.
Synaptotagmin
This is an autoimmune disease where antibodies to muscle subtype of nAChRs decrease receptor concentration on muscle membrane, resulting in progressive muscle weakness and muscle fatigue.
Myasthenia Gravis
Malignant Hyperthermia can cause renal failure due to…
Rhabdomyolysis
***Lysis of muscle cells leading to renal failure
If there is a CNS disorder, what charge would we want on the medication used?
Negative charge – so it can pass Blood Brain Barrier
***Positively charged drugs are used for the periphery, because they can’t pass the BBB
