Unit 5 Pharmacology: Neuromuscular Blocker Reversal Agents Flashcards
What type of bond is formed when edrophonium binds to the anionic site on acetylcholine?
Electrostatic
Acetylcholinesterase hydrolyzes Ach into what 2 things?
Choline and acetate
How to drugs such as edrophonium, neostigmine, and pyridostigmine work?
They reversibly inhibit acetylcholinesterase which indirectly increases the concentration of acetylcholine at the neuromuscular junction, since more Ach is present it is better able to compete for alpha binding sites on the nicotinic receptor and antagonize the block. The NMB must still be eliminated from the body!
Pseudocholinesterase is inhibited by what NMB reversal agents? What does this mean?
neostigmine and pyridostigmine.
If sux is given after one of these reversal agents, duration of sux will be prolonged
What are the 2 ways AchE inhibitors increase the concentration of Ach at the nicotinic receptor?
Enzyme inhibition
Presynaptic effects
What are the 3 ways to inhibit AchE? What type of inhibition is each one? What drug(s) do this?
- Electrostatic attachment
Competitive inhibition
Edrophonium - Formation of carbamyl esters
Competitive inhibition
Neostigmine, pyridostigmine, physostigmine - Phosphorylation
Non-competitive inhibition
Organophosphates and echothiophate
What are the 2 possible mechanisms that AchE inhibitors have presynaptic site of action?
- Similar to sux, AchE inhibitors stimulate the presynaptic receptor and cause it to release additional Ach
- Inhibition of AchE near the presynaptic receptor increases the concentration of Ach in this region, so it is actually Ach that stimulates this receptor
What is the primary mechanism of edrophonium most likely?
Presynaptic
Edrophonium: Dose Onset Duration Metabolism & Elimination Best pairing
Dose: 0.5 - 1.0 mg/kg Onset: 1 -2 min Duration: 30 - 60 min Metabolism & Elimination: Renal 75%, liver 25% Best pairing: atropine
Neostigmine: Dose Onset Duration Metabolism & Elimination Best pairing
Dose: 0.02 - 0.07 mg/kg Onset: 5 - 15 min Duration: 45 - 90 min Metabolism & Elimination: Renal 50%, liver 50% Best pairing: Glycopyrrolate
Pyridostigmine: Dose Onset Duration Metabolism & Elimination Best pairing
Dose: 0.1 - 0.3 mg/kg Onset: 10 - 20 min Duration: 60 - 120 min Metabolism & Elimination: Renal 75%, liver 25% Best pairing: Glycopyrrolate
What is the significance of renal failure with reversing NMBs?
Renal failure prolongs both duration of action for both AchE inhibitors and NMBs, so there is no need to adjust dose or re-dose.
AchE inhibitors have a ceiling effect? T/F
True
The onset of action of AchE inhibitors is directly related to what?
Depth of block
Mixing AchE inhibitors yields what type of effect?
Additive
1 + 1 = 2
When compared to adults, antagonism with neostigmine is (faster or slower) in infants and children
Faster
Which AchE inhibitors do not cross the BBB? Why?
Edrophonium, neostigmine, and pyridostigmine
They are quaternary amines
What AchE inhibitor does cross the BBB? Why?
Physostigmine
It is a tertiary amine
Besides reversal of NMB, what other use does neostigmine have in the OR? How about physostigmine?
Neostigmine: intrathecal (50- 100mcg) produces analgesia. Side effects include N/V, pruritus, and prolongation of sensory and motor block
Physostigmine: 40mcg/kg reduces the incidence of post op shivering. Its efficacy matches meperidine and clonidine.
By increasing the concentration of Ach at the muscarinic receptor, AchE inhibitors cause a predictable set of ________
Parasympathetic side effects
Cholinergic side effects
Mnemonic for cholinergic side effects:
Diarrhea Urination Miosis Bradycardia Bronchoconstriction Emesis Lacrimation Laxation Salivation
What muscarinic antagonist (anticholinergic) increases HR the most?
Atropine
What muscarinic antagonist (anticholinergic) produces the most sedation?
Scopolamine
What muscarinic antagonist (anticholinergic) does not cause sedation?
Glycopyrrolate
What muscarinic antagonist (anticholinergic) is the best antisialagogue?
Scopolamine
What muscarinic antagonist (anticholinergic) produces the most mydriasis?
Scopolamine
What muscarinic antagonist (anticholinergic) prevents motion induced nausea the best?
Scopolamine
What muscarinic antagonist (anticholinergic) decreases gastric H+ secretion the most?
All about equal
What muscarinic antagonist (anticholinergic) produces no mydriasis?
Glycopyrrolate
What muscarinic antagonist (anticholinergic) does not prevent motion induced nausea?
Glycopyrrolate
What muscarinic antagonist (anticholinergic) produces the best smooth muscle relaxation?
Equal between atropine and Glycopyrrolate
Atropine and scopolamine are naturally occurring ______, what does this mean?
Tertiary amines.
They are lipophilic and cross the BBB, GI tract, and placenta
Why can’t Glycopyrrolate cross lipid barriers?
It is a quaternary ammonium derivative, it is ionized. So it does not possess CNS activity or cross the placenta
Small does of atropine have what paradoxical effect? Why?
Paradoxical bradycardia.
Probably due to inhibition of the presynaptic M1 receptor on vagal nerve endings whose job is to reduce Ach release via a negative feedback loop, if it’s blocked this turn off the loop and allows for continued Ach release and bradycardia
Do muscarinic antagonist (anticholinergic) affect HR in transplant patients?
No. But they will experience the other cholinergic effects from AchE inhibitors and should still be given a muscarinic antagonist.
What NMB does Sugammadex reverse?
The aminosteroids:
Roc > VEC > pancuronium
What is the MOA of sugammadex?
A gamma-cyclodextrin made of 8 sugars assembled in a ring, the ring encapsulates the NMB rendering it inactive.
What are the side effects of sugammadex?
Because it does not interact with neuromuscular receptors and neurotransmitters, it has no major systemic side effects
How is the dose of sugammadex calculated? Why?
On the degree of block present, because there is a need for a 1:1 molar ratio between sugammadex and NMB
Sugammadex dosing for Rocuronium:
TOF 2/4 or better 2 mg/kg
TOF 0/4 + 2 PTC or better 4 mg/kg
3 minutes after Roc 1.2 mg/kg or less - 16 mg/kg
Sugammadex dosing with Vecuronium
TOF 2/4 or better 2 mg/kg
TOF 0/4 + 2 PTC or better 4 mg/kg
How is sugammadex metabolized?
Sugammadex and the sugammadex-rocuronium complex are excreted unchanged by the kidneys
What can you do if a patient needs to be paralyzed after receiving Sugammadex?
Use a benzylisoquinolinium or Succinylcholine - If 16 mg/kg of sugammadex was used, only option.
If 4 mg/kg or less was used you can redoes roc or vec:
If between 5 min to 4 hours - roc 1/2 mg/kg
If more than 4 hours roc 0.6 mg/kg or vec 0.1 mg/kg
How common is anaphylaxis with sugammadex?
0.3% of patients
What complications have been reported with sugammadex?
Bradycardia
Cardiac arrest
What may be of particular concern with sugammadex use in adult females?
It binds oral contraceptives
