HL PDA III Exam I - Pharmacology of Neuromuscular Blocking Agents LOs

True or False: nicotinic receptors are ionotropic

True

Where are nicotinic receptors located?

autonomic ganglia and skeletal muscles

Explanation: autonomic ganglia → postsynaptic → PNS and SNS pre-ganglionic nerves

What is the function of nicotinic receptors?

They mediate excitatory effect ACh has on skeletal muscles and ligand-gated ion channels are opened by ACh to allow Na+ to flow through

What is the location of excitation contraction coupling?

neuromuscular junction

True or False: excitation contraction coupling has 2 types of Na channels

True

What are the types of Na channels within excitation contraction coupling?

ligand gated and voltage gated Na channels

True or False: voltage gated Na channels are also calling nicotinic receptors

False

Explanation: LIGAND gated Na channels are nicotinic

True or False: voltage gated Na channels are fast

True

Explanation: they propagate an AP along the t-tubule

True or False: muscle AP is similar to neuronal AP

True

Explanation: the end results differ though!

What is the end result of a muscle AP?

contraction

What is the end result of a neuronal AP?

NT release

Where do the somatic motor neurons release ACh at in excitation contraction coupling?

NMJ when the nerve AP arrives at the axon terminal

True or False: net entry of Na+ through ACh receptor channel initiates muscle AP

True

Explanation: ACh diffuses across NMJ → binds nicotinic receptors → opens channels → Na+ influx into the muscle cell ('depolarization') when the voltage gated Na+ channels are open

What does an AP in t-tubules do to the DHP receptor?

It alters the conformation → opens the channel

Explanation: AP propagates down the t-tubule when Na+ channels ope

True or False: DHP receptor closes RyR Ca2+ release channels in the SR and Ca2+ leaves the cytoplasm

False

Explanation: it OPENS RyR and Ca2+ ENTERS the cytoplasm

Why does the DHP receptor open RyR Ca2+ release channels?

When AP reaches bottom of t-tubule, a conformation change of DHP receptors (that's coupled to RyR channels) occurs → opens and Ca2+ is released

Explanation: the remaining steps are Ca2+ dependent in excitation contraction coupling

True or False: Ca2+ binds to troponin

True

Explanation: this allows actin-myosin binding

What happens once Ca2+ is released during excitation contraction coupling?

It does not stay within the cytoplasm and SERCA (Ca2+ pump) pulls the ions back into the SR

True or False: a volley between ACh release and Ca2+ leaving SR cancels out a muscle contraction

False

Explanation: this is needed to sustain a contraction!

What speed at the voltage gated Na+ channels at the top of an AP in excitation contraction coupling?

Fast

Explanation: at this point they cannot be opened

True or False: K+ efflux, muscle repolarization, and fast Na+ channels reset for the next depolarization

True

Explanation: these channels CAN be opened again when the next AP occurs

What do myosin heads and actin filaments do during a contraction?

Myosin Heads: execute power stroke

Actin Filaments: slide towards the center of a sarcomere

True or False: AChE is a speedy enzyme

True

Explanation: ACh is broken down very quickly by AChE

What channels are located in the t-tubule membrane?

Voltage gated Na+ channels (AP propagation) and voltage gated K+ channels (repolarization)

Where is DHP located?

bottom of the t-tubule

Explanation: it is voltage sensitive, so it will change shape and activate RyR

What type of antagonist is a non-depolarizing agent?

Competitive

What is the MOA of competitive antagonists?

compete with ACh for binding sites of nicotinic receptors on skeletal muscles

Explanation: this action can be overcome by increasing ACh concentration with a cholinesterase inhibitor

What is an example of a cholinesterase inhibitor?

Neostigmine

True or False: non-depolarizing agents have a simple MOA

True

What is the duration of action for non-depolarizing agents?

they can be long, intermediate, and short

What are the 2 types of non-depolarizing agents?

benzylsioquinolones and amino steroids

What is the ending of benzylsioquinolones?

-curiums

What is the ending of amino steroids

-curoniums

What is the structure of non-depolarizing agents?

steroid derivative,

ACh hidden within,

1-2 quaternary amine groups

True or False: non-depolarizing agents can only be administered orally

False

Explanation: they can only be administered parenterally

Which non-depolarizing agent is metabolized independently of kidney/liver?

Benzylsioquinolones

Explanation: they are metabolized via esterases from the plasma and hoffman elimination → eliminated unchanged in the urine, feces, or bile

What does it mean if a benzylsioquinolone is excreted changed in the urine, feces, or bile?

That a plasma metabolic reaction occurred

What is ester hydrolysis?

esterases within the plasma are hydrolyzed → OH + ester

What is another name for plasma esterases?

pseudocholinesterase OR butyrylcholinesterase

What is hoffman elimination?

elimination of an amine and production of an alkaline

True or False: amino steroids are metabolized by the liver/kidney

True

Explanation: de-acetylation via CYP450 in the liver and clearance is affected by the function of kidney/liver

What is the MOA of a depolarizing agent?

nicotinic receptor agonists that mimic ACh to allow entry of receptors

True or False: paralysis differs depending on the dose of neuromuscular blockers

True

explanation: low, moderate, or high doses

What paralysis occurs with low doses of neuromuscular blockers?

effects the small muscles of the fingers and eyes

What paralysis occurs with moderate doses of neuromuscular blockers?

effects arms, legs, neck, and trunk

What paralysis occurs with high doses of neuromuscular blockers?

effects intercostal muscles and diaphragm

What order would paralysis recover occur?

intercostal muscles and diaphragm → arms, legs, neck, and trunk → muscles of fingers and eyes

What is the MOA of succinylcholine?

binds and stimulates nicotinic receptors at NMJ similarly to ACh, BUT is resistant to AChE

True or False: longer lasting depolarization with succinylcholine use can lead to flaccid paralysis

True

Explanation: flaccid paralysis is loss of muscle tone/contraction during paralysis #stuck and there are TWO phases

What occurs in the 1st phase of flaccid paralysis?

prolong depolarization means the nicotinic receptor is held open, Na+ continuously flows into the cell, repolarization cannot occur; therefore, AP not produced, Ca2+ is stuck in SR, and the muscle is flaccid

What occurs in the 2nd phase of flaccid paralysis?

desensitization (not fully understood MOA)

True or False: succinylcholine is hydrolyzed to succinic acid and choline through plasma butyrylcholinesterase

True

What is the onset time of succinylcholine?

30-60 seconds (rapid)

What is the duration time of succinylcholine?

5-10 minutes (ultra short acting)

Would succinylcholine be used for short or long procedures?

Both!

Explanation: Succinylcholine is the only NMJ blocker used clinically. The use for long-term procedures is less common, but is used for a fast onset and must be followed by a longer-acting agent. The use for short-term procedures include intubation, endoscopy, and ECT

True or False: succinylcholine causes muscle fasciculation and soreness for 1-2 days

True

Is succinylcholine reversible?

No

Explanation: giving an AChE inhibitor would enhance the effects

When would long duration of action occur with succinylcholine use?

If a patient has defective plasma cholinesterase

True or False: prolonged use of succinylcholine causes Ca+ release from muscles

False

explanation: it causes K+ release which increases risk for burn patients and hyperkalemia → arrhythmias

What does malignant hyperthermia cause in regards to succinylcholine use?

rigidity and increased body temp from burning so much ATP,

Ca2+ release goes cray,

RyR genetic defect most likely (not closing as fast as it should)

True or False: NMJ blockers are highly polar with 1-2 quaternary amines

True

Are NMJ blockers orally bioavailable?

Nah, usually IV

True or False: NMJ blockers are very water soluble, do not penetrate the BBB, and are uncharged at physiological pH

False

explanation: they are CHARGED at physiological pH

What are the adverse effects of non-depolarizing agents?

Histamine release, ganglionic block, and vagolytic effects

Describe histamine release

causes bronchospasm, hypotension, and secretions (bronchial, salivary, GI)

Describe ganglionic block

causes decreased BP (reflex tachycardia) because of decreased SNS

Explanation: nicotinic receptors are not specific to JUST skeletal muscles, they can be found in the autonomic ganglia where they can act as competitive antagonists which blocks ANS communication

Describe vagolytic effects

increased HR due to loss of vagal input into the heart

Explanation: vagus nerve releases ACh to slow the HR and non-depolarizing agents block muscarinic receptors too

When would we prefer benzylisoquinolones?

In patients who have impairments in liver or kidney function because they metabolize independently

When would we avoid aminosteroids?

Patients who have impairments in liver or kidney function because they are mostly excreted unchanged in the urine, bile, or feces; however, some metabolism occurs via deacetylation (i.e., CYP3A4) which is dependent on liver and kidney function

When would we avoid non-depolarizing agents?

They release histamine, cause hypotension, and release secretions so we should avoid use in asthma patients. Also, they lower BP, so we should avoid in patients with bradycardia

What are the drug interactions of NMJ blockers?

AChE inhibitors,

inhalation anesthetics,

aminoglycosides/tetracyclines

How do AChE inhibitors interact with NMJ blockers?

they can increase ACh concentration

Explanation: Can be used to treat overdose with non-depolarizing blocks or to reverse the effects after surgery. Also, Muscarinic Antagonists (i.e., scopolamine, atropine) are necessary because inhibiting AChE → increases ACh → acts on muscarinic receptors throughout the body which is NOT ideal (especially in the heart b/c slows down HR)

How do inhalation anesthetics interact with NMJ blockers?

they produce muscle relaxation and decreases dose of NMJ blockers

How do aminoglycosides interact with NMJ blockers?

produce neuromuscular blockade by inhibiting release of ACh

How to tetracyclines interact with NMJ blockers?

produce neuromuscular blockade by chelating Ca2+

What is botox?

Botulinum toxin

What is the MOA of botox?

acts to inhibit vesicular release of ACh

Explanation: the heavy chain mediates binding to the presynaptic nerve terminal of cholinergic neurons which allows it to then be internalized into the cholinergic nerve. the light chain of the toxin is a protease that cleaves a protein associated with vesicular release of ACh

True or False: intra-dermal and IM injections of very small amounts will paralyze muscles

True

What can you use botox for cosmetically?

decreases wrinkles,

decreases spasticity or abnormal muscle tone (multiple sclerosis, cerebral palsy, stroke),

treats hyperhydrosis,

and helps migraines

What is the duration of action of botox?

single series of injections lasts for months

Explanation: new axon terminals must grow from the axon and inervate the muscles

What are muscle relaxants?

relieve muscle spasms (spinal injury, cerebral palsy, multiple sclerosis, stroke)

True or False: diazepam can be used as a muscle relaxant, but causes sedation

True

What is baclofen?

Muscle Relaxer

What is the MOA of baclofen?

Reduces the release of excitatory neurotransmitters by binding to the GABA-B presynaptic receptors within the brain stem, dorsal horn of the spinal cord, and other CNS sites

True or False: baclofen is a Gi coupled receptor, Ca channel entry, and K efflux

True

Explanation: lowkey idrk but it's in the slides

True or False: tizanidine is a muscle relaxer that produces 1/10th to 1/15th the effect of clonidine on BP

True

Explanation: selective alpha 2