Pharm-NMB Drugs Flashcards
(33 cards)
What is the other name for neuromuscular blocking drugs (NMBs)?
paralytics
Describe the development of paralytic agents?
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)
What is tubocurare?
Alkaloid from Curare Vine (Chondendron tomentosum) carried in hollow bamboo tubes, called Tube Curare or Tubocurare. It is no longer used in the US.
What are the non-depolarizing NMB agents? (3)
There are two structural classes of non-depolarizing agents:
a. Isoquinolone Derivatives: Atracurium
b. Steroid Derivatives: Pancuronium, Vecuronium
What are the depolarizing NMB agents?
There is only one: Succinlycholine
What are the Reversal agents? (2)
Pyridostigmine, Neostigmine
What is the purpose of reversal agents?
These are given post-procedurally to reverse the residual effects of the paralytic agent and restore normal neuromuscular activity and tone.
What is unique about Sugammedex compared to the other reversal agents?
It is ONLY used after the use of STEROIDAL NMB agents.
How do isoquinolone and steroidal non-depolarizing MB agents compare structurally?
They are entirely different structurally in their 3-dimensionality. Even between steroidal agents, there are two sites where individual drugs vary in substituents.
Pharmacologically, how can we activate cholinergic receptors?
We can activate them via both directly (alkaloids and choline esters) and indirectly acting (increase Ach via AchE inhibitors) cholinomimetics.
What are the cholinergic receptors?
They are divided into Nicotinic (N) and Muscarinic (M) Receptors.
What are the subdivisions of Nicotinic Receptors, and where are they located? Which Nicotinic receptor do paralytic agents act on?
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.
Describe the physiology of Nicotinic Ach Receptors. What type of drug affects these channels?
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.
How is Ach ligand activity terminated? What types of drugs affect this?
It is very short-lived and terminated by the enzyme Acetylcholinesterase (AchE). This can be inhibited by AchE-Inhibitors
What is the fundamental difference b/t non-depolarizing NMB agents (ie Rocuronium) and the depolarizing agent, succinylcholine?
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).
Describe the effects of succinylcholine on the muscle in more detail.
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.
How can the magnitude of paralysis and durability of drug action be monitored?
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)
What are the two phases of depalrizing agent effects?
- Phase 1: depolarizing block
2. Phase 2: desensitized block
Describe Phase 1 Depolarization block.
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
Describe Phase II Desensitization block.
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
ADME of Non-Depolarizing NMBs?
- Rapid initial distribution; slower elimination
- Highly ionized, poorly protein bound
- 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)
- Elim: both hepatic and renal (hepatic much more rapid)
How are steroidal agents metabolized/eliminated?
They are metabolized to much less potent 3-OH metabolites. Eliminated hepatically (faster) and renally.
What is different about the inactivation of the 2 main isoquinolone NMBs?
Hepatic Metabolism+ Hofmann Elimination
Metabolism of atracurium involves a non-enzymatic and enzymatic ester hydrolysis
How does the metabolism of Atracurium (immediate acting) differ from Cisatracurium?
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.
