NMBDs: Non-depolarizing (Exam III) Flashcards
What are the 4 main differences between all of the non-depolarizing muscle blockers?
- Onset;
- Duration of action;
- Rate of recovery;
- Metabolism
What is the MoA of non-depolarizing blockers?
- Pre-junctional sites → block ACh release;
- Post junctional → Compete with ACh at nACh-R for alpha subunits → no conformational change
Which type of neuromuscular blocking drug will cause a conformational change of the nicotinic ACh receptor?
Succinylcholine
What are the characteristics of a non-depolarizing block?
- ↓ twitch response to a single stimulus;
- Unsustained response (fade) to continuous stimulus;
- TOF ratio < 0.7;
- Post-tetanic potentiation;
- Potentiation of other non-depolarizing drugs;
- Antagonism by anticholinesterase drugs;
- No fasciculations during onset
- Phase II drug
Why would you not give an intubating dose of rocuronium and then give vecuronium as the rocuronium starts to offset?
Non-depolarizing neuromuscular blockers will potentiate each others effects.
When would you use a priming dose of a non-depolarizing paralytic?
* What non-depolarizing NMBD would you give and how much?
ONLY with succinylcholine to avoid its side effects (fasciculations, eye weakness, etc.)
* 5mg of Rocuronium as a defasiculating dose for SUX
What is fade?
- Fade suggestssomefibers are contracting while some are blocked (Some of the fibers are more susceptible to NMBDs)
- Skeletal muscle contraction is either all or nothing.
What are the 3 major adverse side effects of non-depolarizing NMBD?.
- Cardiovascular effects
- Criticall illness mypopathy
- Altered responses
What causes the adverse CV effects of non-depolarizing blockers?
- Release of histamine;
- Effects at cardiac muscarinic receptors;
- Effects on nACh-R at autonomic ganglia
Why do the adverse CV effects of non-depolarizing blockers vary between patients?
- Underlying diseases
- Pre-op meds
True/False
The cardiovascular adverse effects of non-depolarizing NMBDs are rarely clinically significant?
True
What is the “Autonomic Margin of Safety”?
- Essentially Therapeutic Index
Difference between dose thatproducesblockade (ED95) and dose thatcreatescirculatory effects.
* The autonomic margin of safety is the same for pancuronium (has essentially no therapeutic index) but very different doses for vec, roc, and cis.
Which non-depolarizing blocker has a required dose that both causes blockade and adverse CV effects?
Pancuronium
Essentially no therapeutic index
What adverse event have non-depolarizing blockers been shown to have in critically ill patients?
When does this occur?
- Critical Illness Myopathy (skeletal muscle weakness)
- Weeks to months after NMBD discontinuation
Who is most often affected by critical illness myopathy?
- Had MODS for > 6 days;
- Usually had an aminosteroid NMBD;
- Administered Glucocorticoids prior to NMBD
Why is critical illness myopathy thought to occur?
Possible ↓ clearance or active metabolites
Which volatile gasses exhibit a dose-dependent enhancement of NMBDs?
When is the onset?
Why is this?
- Desflurane > Sevoflurane > Isoflurane
- Onset as early as 30 minutes.
- Thought to occur due to solubility allowing rapid movement into muscular partition/compartment. Possible dose dependent inhibition of the nACh-R
What drug classes and/or drugs will enhance or prolong neuromuscular blockade?
How does this work?
- Diuretics
- Corticosteroids
- Metoclopramide
- Local Anesthestics
- They increase ACh release
- Depress cholinesterase activity
- Depress nerve conduction.
How does Magnesium effect non-depolarizing blockers and SCh?
Why is this thought to occur?
Enhances blockade
- ↓prejunctional release of ACh (for non-depol)
- ↓sensitivity to postjunctional membranes (for non-depol)
- MOA for SUX is unlcear but thought to be due to a more rapid shift to a phase II block (oversedation with SUX).
How will sympathomimetics such as ephedrine or epinephrine affect NMBDs?
↓ onset time (Drug works faster) due to an increase in CO and skeletal muscle flow.
How will sympatholytics such as esmolol affect NMBDs?
↑ onset time (Drug works slower)/ delays onset of drug
How does Hypothermia affect non-depolarizing blockers?
Does this occur for CYP450 metabolism or hoffman elimination?
- Hypothermia will increase NMBD duration. Even mild hypothermia will double the duration of Panc and Vec.
- MOA = temperature slowing of hepatic enzyme activity.
This occurs whether the process is CYP450 dependent (ester hydrolysis) or hoffman elimination dependent
How does acute hypokalemiaaffect non-depolarizing blockers?.
- Hyperolarizes the cell membrane creating an even more negative VrM.
- Resistance to depolarizing NMBDs
- increased Sensitivity to non-depolarizing NMBD’s
How does acute hyperkalemia affect non-depolarizing blockers?
- partially depolarizes or hypolarizes the cell membrane casuing an increase in VrM.
- Sensitivity to depolarizing NMBDs;
- Resistance to non-depolarizing NMBDs
With ↑K⁺ we are sensitive to succ & resistant to roc
How do burns affect non-depolarizing blockers?
What is the MOA?
- Resistanance to non-depol NMBDs begins at 10 days post burn and declines after 60 days post burn.
- MOA = altered affinity of nACh-R, not related to altered density/number of receptors.
What percentage of the body needs to be affected by burns to cause altered response/resistance to non-depolarizing blockers?
- 30% BSA or >
For a patient with burns needing intubation, how can we offset the resistance to non-depolarizing blockers the burn causes?
1.2 mg/kg dose of Rocuronium
Explain how paresis/paralysis will affect neuromuscular blocking drugs effects.
What is the MOA?
The more “paralyzed” = more resistant
Ex. Paralyzed leg (most resistant) > unaffected side of a person who suffered a stroke > person who never had a stroke or any paresis whatsoever.
MOA = proliferationof extrajunctional nACh-Rs.
Which depolarizing/non-depolarizing blocker is the most likely to cause allergic reactions? Which is least likely to cause reaction?
SCh (most) > Pancuronium, Vecuronium, Rocuronium > Cisatracurium (least)
What organic functional group makes a cross sensitivity reaction possible for depolarizing/non-depolarizing blockers?
- Quaternary ammonium group
How can a patient get an allergic reaction from a depolarizing/non-depolarizing blocker on their 1st exposure?
Due to prior sensitization (from 1st exposure to the drug) →Soaps/cosmetics (women > men)
How does Gender affect non-depolarizing blockers? MoA?
- Women more sensitive (need 22% less Vec or 30% less Roc) and have greater drug duration.
- MoA: likely less muscle mass in women
What is the most common long acting NMBD?
Pancuronium (Pavulon)
What is the intubating dose, onset and duration of Pancuronium?
- Dose: 0.1mg/kg;
- Onset: 3-5 minutes;
- Duration: 60-90 minutes
How is the majority of Pancuronium eliminated?
- 80% eliminated unchanged in urine
What patients would you not want to use pancuronium on?
Liver and Kidney cases, and elderly (prolonged elimination and metabolism).
What changes in metabolism of Pancuronium do we see with a liver disease patient?
- Increased VD
- Larger initial dose is needed
- Prolonged E½ time
What CV effects do we see with Pancuronium?
Sympathomimetic:
- ↑ HR;
- ↑ MAP;
- ↑ CO;
- Mostly at the SA node
- BP increased due to increased HR
- No change in SVR or inotropy
- NO HISTAMINE RELEASE
What occurs with norepinephrine after pancuronium administration?
- ↑NE release presynaptically
- ↓NE reuptake due to blockade
What are the 4 types intermediate acting non-depolarizing NMBDs?
- Vecuronium (aminosyeroid)
- Rocuronium (aminosteroid)
- Cisatrscurium (Benzylisoquinolone)
- Atracurium (Benzylisoquinoline)
Compared to pancuronium, what duration of action do intermediate-acting NMBDS have?
Approximately 1/3 duration of action
Compared to pancuronium, what cardiovascular effects do intermediate-acting NMBDS have?
Minimal/absent cardiovascular effects
After administering any intermediate-acting neuromuscular blocker, when will you be able to reverse its effects via an cholinesterase-inhibitor?
Approximately 20min post administration
What is the intubating dose, onset, and duration of Vecuronium?
- Intubating Dose: 0.1 mg/kg
- Onset: 3-5 minutes
- Duration: 20-35 minutes
- What is the main way Vecuronium is metabolized?
- What is the metabolite produced?
- How is Vec excreted?
- What type of patients should you use caution in?
- CYP450’s in the liver (70%)
- 3-desacetylvecuronium 50-80% as potent (but rapidly converted to metabolite with 1/10 the effects)
- 30% is unchanged and renally excreted.
- Use caution in renal dysfunction because it can prolong the elimination half time.
Repeated doses or continuous infusion of vec will cause what?
Cumulative effects
How does metabolism of Vecuronium change with the elderly?
- ↓ volume of distribution (because they have less muscle mass);
- ↓ plasma clearance (less hepatic flow / delayed recovery with infusions)
Is vecuronium a great drug for those with liver or kidney problems?
Nope
- Hepatic metabolism
- Renal dysfunction = ↑E½
How does metabolism of Vecuronium change with an obstetric patient?
- Insignificant effects to fetus;
- ↑ clearance in 3rd trimester (progesterone);
- ↑ duration in early postpartum (use IBW)
What will respiratory acidosis Pre administration of vecuronium do?
What will respiratory acidosis post administration of vec do?
*Pre - no prolonged blockade
* Post - Prolong NMJ blockade. Activity is inversely proportional to the bound drug, acidosis decreases tthe bound amount. A change ionization at the receptor increases attachment time. There is a concern for post op hypoventilation.
When is respiratory acidosis that occurs after Vecuronium administration a concern?
With post-operative hypoventilating patients (ex. post-opioid administration)
What are the CV effects of vec?
- Essentially none
- no histamine release
What is the normal intubating dose, onset and duration of Rocuronium?
- Dose: 0.6 mg/kg
- Onset: 3-5 minutes
- Duration: 20-35 minutes
What is the RSI intubating dose, onset and duration of Rocuronium?
- Dose: 1.2 mg/kg
- Onset: 1-2 minutes
- Duration: 60-90 minutes
What do larger doses of Roc parallel?
- Onset of SUX
- Offset of panc
How is Rocuronium excreted?
Unchanged in bile
Why will Rocuronium have a longer DoA in the elderly or with liver failure patients?
Due to ↓ clearance and ↑ Vd
What percentage of Rocuronium is excreted renally?
10-30% → only marginally affected by renal failure
Roc is good for CKD patients?
What are the CV effects of Roc?
- Essentially none
- No histamine release
What is the intubating dose, onset and duration of Cisatracurium?
- Intubating Dose: 0.1 mg/kg;
- Onset: 3-5 minutes;
- Duration of action: 20-35 minutes
What is unique about the metabolism of Cisatracurium?
Recovery from infusion is NOT affected by time.
How is cisatracurium metabolized?
Hoffman Elimination
What changes occur in Cisatracurium when used in an elderly patient? What changes occur in an obese patient?
- Elderly: Slight delay in onset by 1 minute d/t CO;
- Obese:Duration of action prolonged IF dosed at actual body weight d/t ↑ Vd
What are the CV effects of Cisatracurium?
- Essentially none
- no histamine release
What is the only short acting non-depolarizing NMBD?
Mivacurium
What is the intubating dose, onset and duration of Mivacurium?
- Intubating Dose: 0.15 mg/kg;
- Onset: 2-3 minutes (Conditions less desirable);
- Duration: 12-20 minutes
How is mivacurium cleared from plasma?
Via Plasma cholinesterases
Which two non-depolarizing NMBDs cause histamine release?
- Atracurium
- Mivacurium (with massive overdoses)
What are the 3 sterioisomers of mivacurium?
Which of the 3 sterioisomers have NM blocking activity?
- Cis-cis
- cis-trans
- trans-trans
- cis-trans and trans-trans
Is mivacurium currently on the market?
no
What are the CV effects of mivacurium?
- Minival CV effects
- Does have histamine release >3 times the ED95, you will have a transient MAP drop. This is more common with rapid large doses. MAP will drop more in hypertensive patients than in hypotensive patients.
