Pharm-NMB Drugs

Question 1

What is the other name for neuromuscular blocking drugs (NMBs)?

Answer 1

paralytics

Question 2

Describe the development of paralytic agents?

Answer 2

The development of paralytic agents evolved out the discovery of paralyzing plant extracts in South America (Peru). This included a series of alkaloids from the Curare Vine (Chondrodendon Tomentosum/ampihuasca). The final product was stored in various forms, including in hollow bamboo (Tube curare), in small gourds (Calabash curare), in small clay pots (Pot curare)

Question 3

What is tubocurare?

Answer 3

Alkaloid from Curare Vine (Chondendron tomentosum) carried in hollow bamboo tubes, called Tube Curare or Tubocurare. It is no longer used in the US.

Question 4

What are the non-depolarizing NMB agents? (3)

Answer 4

There are two structural classes of non-depolarizing agents:

a. Isoquinolone Derivatives: Atracurium
b. Steroid Derivatives: Pancuronium, Vecuronium

Question 5

What are the depolarizing NMB agents?

Answer 5

There is only one: Succinlycholine

Question 6

What are the Reversal agents? (2)

Answer 6

Pyridostigmine, Neostigmine

Question 7

What is the purpose of reversal agents?

Answer 7

These are given post-procedurally to reverse the residual effects of the paralytic agent and restore normal neuromuscular activity and tone.

Question 8

What is unique about Sugammedex compared to the other reversal agents?

Answer 8

It is ONLY used after the use of STEROIDAL NMB agents.

Question 9

How do isoquinolone and steroidal non-depolarizing MB agents compare structurally?

Answer 9

They are entirely different structurally in their 3-dimensionality. Even between steroidal agents, there are two sites where individual drugs vary in substituents.

Question 10

Pharmacologically, how can we activate cholinergic receptors?

Answer 10

We can activate them via both directly (alkaloids and choline esters) and indirectly acting (increase Ach via AchE inhibitors) cholinomimetics.

Question 11

What are the cholinergic receptors?

Answer 11

They are divided into Nicotinic (N) and Muscarinic (M) Receptors.

Question 12

What are the subdivisions of Nicotinic Receptors, and where are they located? Which Nicotinic receptor do paralytic agents act on?

Answer 12

a. Nicotinic n Receptors found on Autonomic Ganglia.
b. Nicotinic m Receptors found on Skeletal muscle and motor end plates.
Paralytic agents act on Nm Receptors on skeletal muscle.

Question 13

Describe the physiology of Nicotinic Ach Receptors. What type of drug affects these channels?

Answer 13

a. The N-Ach-Rec is a multimeric ligand-gated ion channel that gates sodium influx into the cell, leading to depolarization.
b. In order for the channel to be activated, it is necessary for 2 molecules of Ach, one binds to each binding site on the two alpha subunits.
c. This Ach binding is very short-lived
d. These receptors are altered by NMB agents.

Question 14

How is Ach ligand activity terminated? What types of drugs affect this?

Answer 14

It is very short-lived and terminated by the enzyme Acetylcholinesterase (AchE). This can be inhibited by AchE-Inhibitors

Question 15

What is the fundamental difference b/t non-depolarizing NMB agents (ie Rocuronium) and the depolarizing agent, succinylcholine?

Answer 15

a. The non-depolarizing agents prevents opening of the channel when it binds, preventing any activation of muscle contraction.
b. The depolarizing agent, succinylcholine, occupies the receptor and blocks the channel. It actually gates for initial muscle contraction, but the drug persists on the receptor binding site and also physically blocks closure of the opened Na channel. Thus initial muscle contraction is replaced by flaccid paralysis (depolarizing agent may also cause desensitization of end plate by occupying the receptor and causing persistent depolarization).

Question 16

Describe the effects of succinylcholine on the muscle in more detail.

Answer 16

After drug application, there is a rapid muscle contraction (instant increase in muscle tone). The muscle cells depolarize, and the membrane remains in this depolarized state while sodium channels remain open, bc their closure is a prerequisite for repolarization to begin. Ultimately, Na channels do close, and the normal process of repolarization occurs.

Question 17

How can the magnitude of paralysis and durability of drug action be monitored?

Answer 17

Using devices like the Peripheral Nerve Stimulator shown in the picture. This device sends a current b/t electrodes placed on the skin along the course of a peripheral nerve, most commonly the ulnar nerve. W/ this setup, the twitches of the adductor pollicus muscle are evaluated to asses the depth of the neuromuscular blockade. (more on handout)

Question 18

What are the two phases of depalrizing agent effects?

Answer 18

1. Phase 1: depolarizing block

2. Phase 2: desensitized block

Question 19

Describe Phase 1 Depolarization block.

Answer 19

a. Endplate potential (EPP) is depolarized to -55mV
b. Immediate onset
c. Lower dose-dependence
d. Rapid recovery
e. No fade
f. Initial muscle contraction increased by AchE inhibition
g. Muscle: FASCICULATIONS (brief muscle twitching), then flaccid paralysis

Question 20

Describe Phase II Desensitization block.

Answer 20

a. EPP transitions towards -80mV (even though it repolarizes, the receptor is desensitized)
b. Slower transition of onset
c. Higher dose-dependence or follows prolonged infusion
d. More prolonged recovery
e. Fade (followed by post-tetanic potentiation)
f. Reversed of antagonized by AchE inhibition
g. Muscle responds with flaccid paralysis

Question 21

ADME of Non-Depolarizing NMBs?

Answer 21

1. Rapid initial distribution; slower elimination
2. Highly ionized, poorly protein bound
3. Duration of action closely correlates with t1/2 (indicating that binding kinetics to N-R are short-lived and effects are dependent on local tissue concentration)
4. Elim: both hepatic and renal (hepatic much more rapid)

Question 22

How are steroidal agents metabolized/eliminated?

Answer 22

They are metabolized to much less potent 3-OH metabolites. Eliminated hepatically (faster) and renally.

Question 23

What is different about the inactivation of the 2 main isoquinolone NMBs?

Answer 23

Hepatic Metabolism+ Hofmann Elimination

Metabolism of atracurium involves a non-enzymatic and enzymatic ester hydrolysis

Question 24

How does the metabolism of Atracurium (immediate acting) differ from Cisatracurium?

Answer 24

a. Atracurium has a main toxic metabolite, LAUDANOSINE , which causes SEIZURES.
b. Cisatricurium has less dependence on hepatic inactivation, producing less Laudanosine, and releasing LESS HISTAMINE. It has largely replaced atracurium bc it has all the advantages with fewer side effects.

Question 25

Metabolism of Succinylcholine

Answer 25

a. Extremely short duration of action (5-10 min)
b. Rapid hydrolysis by butryylcholinesterase (liver) and high capacity PSEUDOCHOLINESTERASE (PLASMA). Therefore, NMJ sees only a small percentage of IV dose, and action is terminated by diffusion from the cleft.

Question 26

Is there genetic variation of plasma/pseudocholinesterase?

Answer 26

Yes, there is much genetic variation of pseudocholinesterase expression/activity. Some pt’s are at increased risk of abnormally long duration of succinylcholine effect. Dibucaine Test is used to identify (dibucaine is an enzyme inhibitor); can also use Acholest Test Paper.

Question 27

Which NMB agent has the longest duration of action?

Answer 27

Pancuronium most likely

Question 28

Which has shortest duration of action?

Answer 28

Succinylcholine

Question 29

What is the elimination route of the isoquinolones?

Answer 29

a. Atracurium: Spontaneous (enzymatic and nonenzymatic hydrolysis)
b. Cisatracurium: Mostly spontaneous

Question 30

What is the metab/elim of steroidals?

Answer 30

1. Pancuronium: 80% Renal+ some Hepatic

2. Rocuronium/Vecuronium: 75-90% Hep+ Renal

Question 31

What are the most potent and least potent of the non-depolarizing agents?

Answer 31

Most potent: Pancuronium/Vecuronium (6)

Least Potent: Atracurium (1.5)

Question 32

What other tissues are N-Receptors located in and what are some of the possible off-target drug actions of NMBs?

Answer 32

a. Nn-R’s are found in autonomic ganglia, so stimulation can produce dsyregulation of ANS activity and balance
b. Muscarinic-R’s can also be affected, in particular, M2-R’s in cardiac tissue, where it closes calcium channels to reduce the rate and force of contraction. Activation can lead to diminished CV capability
c. Histamine Release

Question 33

Which have off-target effects? What are they?

Answer 33

Atracurium→slight histamine release
Pancuronium→Moderate block of Cardiac M2 Receptors→increased rate and force of contraction bc M2 cant close Ca2+ channels
Succinlycholne→Ganglia stimulation (of Nn); Cardiac M2 stimulation→reduced CV capability; slight histamine release