Chapter 12: NMBD and Reversal agents Flashcards
1
Q
What is the state of the acetylcholine receptor in its resting state?
A
- Is closed when in its resting state
2
Q
How is the acetylcholine receptor channel opened?
A
- Simultaneous binding of two acetylcholine molecules to the receptor alpha subunits.
- Causes a conformational change to open the channel
3
Q
How do Nondepolarizing muscle blockers work?
A
- They produce competitive antagonism by binding a single molecule
4
Q
What is the action of Succinylcholine on the neuromuscular endplate?
A
- Produces prolonged depolarization of the endplate region
5
Q
Where is acetylcholinesterase found and what is its role?
A
- Acetylcholinesterase (true cholinesterase) is present at the neuromuscular junction
- Responsible for the hydrolysis of released acetylcholine to acetic acid and choline.
6
Q
What is the role of Butyrylcholinesterase?
A
- Butyrylcholinesterase (plasma cholinesterase, pseudocholinesterase), synthesized in the liver, catalyzes the hydrolysis of succinylcholine mainly in the plasma
- Metabolizes :mivacurium, cocaine, procaine, and chloroprocaine.
7
Q
What are the characteristics of a Depolarizing block?
A
- Also known as phase I block
- The only type of depolarizing neuromuscular blocking drug (NMBD) in clinical use.
- Often preceded by muscle fasciculations resulting from antidromic action potentials
8
Q
What is the purpose of precurarization in depolarizing blocks?
A
- Administration of a small dose of nondepolarizing neuromuscular blocker (precurarization)
- Helps prevent fasciculations
- Increases intraocular pressure
9
Q
Is masseter spasm consistently associated with malignant hyperthermia (MH)?
A
- May be an early indicator of MH but is NOT consistently associated with it
10
Q
How are nondepolarizing neuromuscular-blocking drugs (NMBDs) classified?
A
Nondepolarizing NMBDs are classified based on:
1. Chemical class (steroidal or benzylisoquinolinium)
2. Duration of action
11
Q
How is Atracurium metabolized and what are its characteristics?
A
- Metabolized by Hofmann elimination and ester hydrolysis.
- Atracurium is a racemic mixture of 10 stereoisomers.
- It is eliminated 70% in bile and the remainder in urine.
- Elimination impaired by biliary obstruction.
12
Q
What are the key properties of Cisatracurium?
A
- Cisatracurium is a more potent isomer of atracurium.
- Metabolized by Hofmann elimination,
- Produce less laudanosine
- Does not cause histamine release
13
Q
How is Mivacurium metabolized?
A
- Metabolized by butyrylcholinesterase at a rate similar to succinylcholine.
- Consit of three (3) stereoisomers.
- May produce histamine release if administered rapidly.
14
Q
What are the key characteristics of Pancuronium?
A
- Is a potent, long-acting NMBD.
- Has vagolytic properties
- Blocks Norepinephrine reuptake
- Blocks Butyrylcholinesterase-inhibiting properties.
15
Q
What is the significance of ED95 in the context of neuromuscular blockade?
A
- ED95 is the dose resulting in 95% depression of twitch height.
- It is used to determine the appropriate dose for tracheal intubation and to maintain neuromuscular blockade.
16
Q
What is the difference between steroidal and benzylisoquinolinium NMBDs?
A
- Steroidal NMBDs are generally monoquaternary compounds.
- Benzylisoquinolinium NMBDs, like curare derivatives, are bisquaternary ammonium compounds.
17
Q
Which steroidal neuromuscular-blocking drugs (NMBDs) does Sugammadex work best with?
A
- Sugammadex is most effective with Rocuronium.
- followed by Vecuronium.
- Least effective with Pancuronium.
18
Q
What is the primary action of Acetylcholinesterase Inhibitors in the context of NMBDs?
A
- They antagonize the residual effects of nondepolarizing NMBDs.
- Causes acetylcholine to accumulate at the neuromuscular junction and compete for available sites.
19
Q
What is the effective dose range for neostigmine?
A
- The effective dose range is 60 – 80 mcg/kg
20
Q
What is the effective dose range for Edrophonium?
A
- The effective dose range is 1 – 1.5 mg/kg
21
Q
What are the common side effects associated with acetylcholinesterase inhibitors?
A
- Bronchoconstriction.
- Increased airway resistance.
- Increased salivation.
- Increased bowel motility.
Muscarinic effects must be blocked by Atropine or Glycopyrrolate.
22
Q
Describe the chemical structure of Sugammadex.
A
- Is a modified γ-cyclodextrin compound.
- With a structure resembling a hollow truncated cone or doughnut.
- Has a hydrophobic cavity and a hydrophilic exterior.
23
Q
How does Sugammadex work to reverse neuromuscular blockade?
A
- Forms tight complexes with steroidal NMBDs.
- Particularly Rocuronium, independent of the depth of the neuromuscular block.
24
Q
What are the key pharmacokinetic properties of Sugammadex?
A
- Sugammadex is biologically inactive.
- Does not bind to plasma proteins.
- Primarily eliminated through the urine (75%).
- 59%-80% excreted in urine within 24 hrs post administration
- In patients with renal impairment, clearance of Sugammadex and rocuronium is affected.
25
What are the primary purposes of monitoring neuromuscular function?
* Allows for appropriate dosing,
* Ensures adequate recovery (TOFR ≥ 0.9).
* Helps avoid risks of residual paralysis (upper airway obstruction, aspiration, and hypoxemia).
26
What does subjective evaluation of neuromuscular blockade involve?
* Includes visual and tactile assessment of evoked responses.
* Assessing the degree of blockade, but is considered unreliable.
27
What is electromyography (EMG) and how is it used in neuromuscular monitoring?
* EMG involves stimulating a peripheral nerve and measuring the muscle action potential.
* It is the oldest form of neuromuscular monitoring but is subject to electrical interference.
* Does not analyze muscle movement.
28
Why is Mechanomyography considered the gold standard in neuromuscular blockade monitoring?
* It measures the force of muscle contraction in response to electrical stimuli.
* Is the GOLD STANDARD due to its accuracy.
* Its clinical use is limited by stringent preparation requirements.
29
What is the principle behind Acceleromyography in neuromuscular monitoring?
* Is based on Newton's second law (force = mass x acceleration).
* Measures the acceleration of a muscle, usually the adductor pollicis.
* Its use may be limited by surgical positioning
30
How does a Kinemyographic device function in neuromuscular monitoring?
* Uses a mechanosensor strip that generates an electrical signal proportional to the magnitude of bending.
* The results may not consistently correlate with the gold standard MMG
31
How do **Depolarizing** and **Nondepolarizing** blockades differ in response to peripheral nerve stimulation (PNS)?
* **Depolarizing block** shows absence of fade and posttetanic potentiation.
* **Nondepolarizing block** shows fade after repeated stimulation and can cause posttetanic potentiation
32
What are the characteristics of a Depolarizing (Phase I) Block?
32
How do different muscle groups respond to NMBDs?
* **Vessel-rich central muscle groups** like the diaphragm are more susceptible to NMBDs, become paralyzed before peripheral muscles, and recover faster.
* The **adductor pollicis** is one of the last muscles to recover from NMBD-induced paralysis
33
What are the characteristics of a Non-Depolarizing (Phase II) Block?
34
What is Suggamadex's affinity in numbers for Rocuronium?
* **4,723** more affinity to Rocuronium than Atracurium.
35
What are the doses of Suggamdex?
36
**Sugammadex** should be avoided in patients with Creatinine clearance of:
< 30 mL/min
37
What are the common clinical signs of Recovery from a Neuromuscular Blockade?
38
What discovery refuted the electrical theory of neuromuscular transmission?
* The discovery of the role of acetylcholine in neuromuscular transmission refuted the electrical theory, leading to Dale and Loewi's Nobel Prize in 1936 for this discovery.
39
When and by whom was curare first successfully administered for surgical relaxation?
* The first successful administration of curare was in 1912 by Arthur Läwen, who used a partially purified preparation for surgical relaxation.
40
When was a significant milestone in the use of NMBDs in clinical anesthesia, and what happened?
* A significant milestone was on January 23, 1942, when Enid Johnson, under Harold Griffith’s instructions, administered curare intravenously for an appendectomy, marking a turning point in the use of NMBDs in anesthesia.
41
What are the two chemical classifications of neuromuscular-blocking drugs?
* **Depolarizing NMBDs** which act as agonists at nicotinic acetylcholine receptors causing prolonged membrane depolarization.
* **Nondepolarizing NMBDs**, which compete with acetylcholine at the receptors and are competitive antagonists.
42
What is an example of a depolarizing NMBD currently in clinical use?
* Succinylcholine is the only depolarizing NMBD currently used in clinical practice.
43
What is the state of the acetylcholine receptor ion channel in the resting state?
* The ion channel of the acetylcholine receptor is closed.
44
How is the acetylcholine receptor ion channel activated?
* Activation occurs when two acetylcholine molecules bind to the α subunits.
* Causing conformational changes that open the channel.
45
How do nondepolarizing neuromuscular-blocking drugs (NMBDs) work?
* **Nondepolarizing NMBDs** bind to one α subunit of the acetylcholine receptor, sufficient to produce neuromuscular block as competitive antagonists.
46
What is the mechanism of action of succinylcholine at the neuromuscular junction?
* Succinylcholine **causes prolonged depolarization** of the endplate, resulting in desensitization of nicotinic acetylcholine receptors.
* Inactivation of voltage-gated sodium channels.
* Increased potassium permeability.
* Hyperpolarization
* Neuromuscular transmission blockade.
47
What enzymes hydrolyze **Choline Esters** and where are they found?
* **Acetylcholinesterase** (true cholinesterase) is at the neuromuscular junction and hydrolyzes acetylcholine.
* **Butyrylcholinesterase** (plasma cholinesterase) is in the plasma, hydrolyzing succinylcholine and other substances like mivacurium and local anesthetics.
## Footnote
Butyrylcholinesterase : Succinylcholine, Mivacurium, Cocaine, Procaine,
48
What distinguishes succinylcholine in clinical use?
* Succinylcholine, also known as **suxamethonium**
* Is the only depolarizing neuromuscular-blocking drug (NMBD) used in clinical practice.
49
What causes muscle fasciculations after succinylcholine administration?
* May result from **antidromic conduction of action potentials** activating parts of the motor unit, leading to variable fasciculations among patients.
50
What is the purpose of precurarization before administering succinylcholine?
* Precurarization, using a small dose of nondepolarizing neuromuscular blocker.
* is intended to prevent succinylcholine-induced side effects.
* Its effectiveness is inconsistent across studies.
51
Describe the structure of succinylcholine.
* Succinylcholine is a long, thin, flexible molecule.
* Made up of two acetylcholine molecules linked through the acetate methyl groups.
52
How does succinylcholine act on cholinergic receptors?
* Succinylcholine stimulates cholinergic receptors at the neuromuscular junction and at nicotinic and muscarinic autonomic sites.
Causes side effects like:
1. **Increased intraocular**
2. **Increased intragastric pressure**.
3. **cardiac arrhythmias** by opening the ionic channel in the acetylcholine receptor.
53
What is the elimination half-life of succinylcholine?
* 47 seconds and follows first-order kinetics.
54
What is the usual dose of succinylcholine for tracheal intubation, and what are its effects?
* Is 1.0 mg/kg. This dose results in complete suppression of neuromuscular response in about 60 seconds.
* Recovery to 90% muscle strength in 9 to 13 minutes in those with normal butyrylcholinesterase activity.
55
How does the dose of succinylcholine influence intubating conditions?
* Doses larger than 1.5 mg/kg do not provide significant advantages.
* A dose of 2.0 mg/kg does not guarantee excellent intubating conditions in all patients.
* Intubating conditions depend on the depth of anesthesia, airway anatomy, and the anesthesiologist's experience.
56
How is succinylcholine metabolized?
* Is rapidly hydrolyzed by butyrylcholinesterase to succinylmonocholine (a weaker agent) and choline.
* Only 10% of the administered drug reaching the neuromuscular junction.
57
What is the role of butyrylcholinesterase in the action of succinylcholine?
* Butyrylcholinesterase controls the onset and duration of succinylcholine's action by hydrolyzing the drug in plasma before it reaches and after it leaves the neuromuscular junction.
* Recovery occurs as the drug diffuses away from the junction.
58
Where is butyrylcholinesterase synthesized and what is its function?
* Is synthesized by the liver
* It's found in the plasma, and is responsible for metabolizing drugs like:
1. succinylcholine
2. mivacurium
3. several local anesthetics
59
What factors can decrease butyrylcholinesterase activity?
* **Factors include**:
1. Liver disease
2. Aging
3. Malnutrition
4. Pregnancy
5. Burns
6. Certain medications
7. Neoplastic disease
8. High estrogen levels.
60
How does butyrylcholinesterase activity affect neuromuscular block induced by succinylcholine?
* A reduction in butyrylcholinesterase activity prolongs the neuromuscular block induced by **succinylcholine or mivacurium.**
61
What is the effect of esmolol on butyrylcholinesterase activity?
* Esmolol inhibits butyrylcholinesterase, causing only a **minor prolongation of succinylcholine block**.
62
How does liver disease affect butyrylcholinesterase activity?
* In severe liver disease, plasma cholinesterase activity can be reduced to 20% of normal.
* Significantly increasing the duration of succinylcholine-induced apnea.
63
How do anticholinesterase drugs like neostigmine affect butyrylcholinesterase activity?
* Neostigmine and similar drugs can cause a profound decrease in butyrylcholinesterase activity.
* Leading to prolonged neuromuscular blockade after succinylcholine administration.
64
What effect does pregnancy have on butyrylcholinesterase activity?
* High estrogen levels in pregnancy can decrease butyrylcholinesterase activity by up to 40%,
* This does not typically prolong the action of succinylcholine-induced paralysis.
65
How do genetic variants of butyrylcholinesterase affect neuromuscular block induced by succinylcholine or mivacurium?
* Genetic variants can significantly prolong the neuromuscular block induced by succinylcholine or mivacurium.
66
How is butyrylcholinesterase phenotype determined?
* Is determined using specific enzyme inhibitors like **Dibucaine or Fluoride**.
* Which produce phenotype-specific dibucaine or fluoride numbers.
67
What do different dibucaine numbers indicate about butyrylcholinesterase genotypes?
* A Dibucaine number of 70 or higher indicates the usual genotype (E1uE1u).
* Numbers less than 30 indicate homozygous atypical genes (E1aE1a).
* Heterozygous atypical variants (E1uE1a) have Dibucaine numbers between 40 to 60.
68
How does butyrylcholinesterase genotype affect the duration of neuromuscular block?
* In Homozygous atypical genotypes (E1aE1a), the block can last 4 to 8 hours.
* In Heterozygous atypical genotypes (E1uE1a), it can be 1.5 to 2 times longer than in individuals with the usual genotype.
69
What is the recommended treatment for a prolonged neuromuscular block?
* Keep the patient sedated.
* Maintaining artificial ventilation until the train-of-four ratio (TOFR) recovers to 0.9 or more.
70
What does measuring butyrylcholinesterase activity reveal?
* Shows the efficiency of the enzyme in hydrolyzing succinylcholine or mivacurium
* Which can be influenced by genotype.
71
How do certain butyrylcholinesterase variants affect enzyme activity?
* Some rare variants are associated with increased enzyme activity, **leading to resistance to succinylcholine and mivacurium.**
72
What cardiac effects can succinylcholine cause?
* Sinus bradycardia
* Junctional rhythm
* Sinus arrest
Reflecting its action on cardiac muscarinic cholinergic receptors.
73
When are cardiac dysrhythmias most likely to occur with succinylcholine administration?
* More likely when a second dose of succinylcholine is given.
* About 5 minutes after the first dose.
## Footnote
**Children** will have dysrhythmias at the first dose.
74
In whom is sinus bradycardia frequently seen following succinylcholine administration?
* Is common in **children and adults** after a repeated dose of succinylcholine.
## Footnote
Due to stimulation of cardiac muscarinic receptors.
75
How is succinylcholine-induced bradycardia treated or prevented?
* **Atropine** is effective in treating or preventing succinylcholine-induced bradycardia.
76
What contrasting effects does succinylcholine have on the autonomic nervous system?
Succinylcholine can cause Ganglionic stimulation, leading to **increases in**:
1. **Heart rate**
2. **Systemic blood pressure**
Similar to acetylcholine's physiologic effect at autonomic ganglia.
77
What can cause ventricular dysrhythmias after succinylcholine administration?
* May be due to autonomic stimuli associated with laryngoscopy and tracheal intubation.
78
How does succinylcholine administration affect plasma potassium levels?
* Potassium **Increase of 0.5 mEq/dL** in plasma concentration in healthy individuals.
* Usually without causing dysrhythmias.
79
Are patients with renal failure more susceptible to hyperkalemia from succinylcholine?
* Patients with renal failure **are not more susceptible** to an exaggerated hyperkalemic response to succinylcholine than those with normal renal function.
80
Which patients are at risk of severe hyperkalemia from succinylcholine?
Patients at risk of severe hyperkalemia:
1. Burns
2. Severe abdominal infections
3. Severe Metabolic acidosis
4. Closed head injuries
5. Conditions causing upregulation of extrajunctional acetylcholine receptors.
81
Is succinylcholine recommended for use in children?
**Is not recommended except** for emergency tracheal intubation, due to the risk of:
* Rhabdomyolysis
* Hyperkalemia
* Death
In children with undiagnosed muscle disease, succinylcholine.
82
What does the occurrence of myoglobinuria indicate after succinylcholine administration?
* Suggests **skeletal muscle damage.**
* Especially in pediatric patients
83
What conditions are often found in patients with Rhabdomyolysis and Myoglobinuria after succinylcholine administration?
Are often found to have:
1. **Malignant Hyperthermia**.
2. **Occult Muscular Dystrophy.**
84
How does succinylcholine affect intraocular pressure?
* Usually causes an increase in intraocular pressure.
* peaking at 2 to 4 minutes post-administration
* Returning to normal by 6 minutes.
85
Is succinylcholine recommended for use in open eye injuries?
* The use is controversial
* It was shown to cause no adverse events in a study of patients with penetrating eye injuries.
86
What is the efficacy of precurarization in attenuating increases in intraocular pressure following succinylcholine administration?
* In reducing succinylcholine-induced **increases** in **Intraocular pressure** is controversial.
87
How does succinylcholine affect intragastric pressure?
* Succinylcholine causes a variable increase in intragastric and lower esophageal sphincter pressures.
* Related to the intensity of fasciculations of abdominal skeletal muscle and an increase in vagal tone.
88
Does succinylcholine predispose patients to regurgitation?
* Succinylcholine does **not typically** predispose to regurgitation in patients with an **intact lower esophageal sphincter**
* As the increase in intragastric pressure usually doesn't exceed the "barrier pressure."
89
What is the effect of succinylcholine on intracranial pressure?
* It can **increase intracranial pressure**.
* This increase can be **attenuated** or prevented by pretreatment **with** a **nondepolarizing NMBD**.
90
What are the characteristics of postoperative myalgias induced by succinylcholine?
## Footnote
Think "NBA"
Can cause postoperative skeletal muscle myalgia, especially in the:
1. **N**eck
2. **B**ack
3. **A**bdomen
It occurs more frequently in:
* Young adults undergoing minor surgeries
* Ambulatory patients
* Particularly women > men
91
How common is succinylcholine-induced myalgia, and what might cause it?
* The incidence varies widely, from 0.2% to 89%.
* The cause is not fully understood
* May be related to muscle damage from fasciculations or involve prostaglandins and cyclooxygenases.
92
How can succinylcholine-induced myalgias be prevented?
* Using muscle relaxants
* Lidocaine
* Nonsteroidal anti-inflammatory drugs.
* Prostaglandin inhibitors like Lysine acetyl salicylate or Diclofenac.
93
What is the relationship between succinylcholine, masseter spasm, and malignant hyperthermia?
* While succinylcholine can trigger malignant hyperthermia,
* **Masseter spasm may be an early indicator but is not consistently associated with this condition.**
94
Why might masseter spasm be more common in children given succinylcholine?
* Might be due to inadequate dosing of succinylcholine.
95
How do Nondepolarizing Neuromuscular-Blocking Drugs (NMBDs) work?
* Act as **competitive antagonists** by binding to the **α subunits** of the nicotinic acetylcholine receptor.
96
What are the bases for classifying nondepolarizing NMBDs?
Are classified based on:
1. Chemical class (**steroidal, Benzylisoquinolinium**)
2. Duration of action (long-acting, intermediate-acting, or short-acting).
97
What are the general characteristics of nondepolarizing NMBDs?
* Nondepolarizing NMBDs are positively charged
* And relatively large molecules.
98
What are the typical dosing strategies for nondepolarizing NMBDs?
* Generally, a dose of **2 to 3 times the ED95** is used for tracheal intubation.
* **10%** of the ED95 is used to **maintain** neuromuscular blockade.
99
What inspired the development of Benzylisoquinoline-type relaxants?
* The arrow poisons used by South American Indians.
* **Known as curare**, served as the basis for developing benzylisoquinoline-type relaxants like **Tubocurarine.**
100
Why is Tubocurarine, a benzylisoquinolinium compound, no longer in use?
* Is not currently used anymore due to its side effects
* Tubocurarine was initially introduced as an NMBD for surgical anesthesia.
101
What is the composition of **Atracurium**?
* Is a racemic mixture of 10 stereoisomers,
* Divided into cis-cis, cis-trans, and trans-trans isomer groups
* In a ratio of approximately 10:6:1.
102
How does Atracurium degrade in the body?
* Undergoes spontaneous degradation through **Hofmann elimination**
* Produce **Laudanosine** **monoquaternary acrylate**
* Can also undergo **Ester Hydrolysis.**
103
What is Hofmann elimination, and what are the metabolites of atracurium?
* Hofmann elimination **is a chemical process that degrades atracurium into laudanosine and a monoquaternary acrylate.**
* Both metabolites of atracurium.
104
How is Laudanosine cleared from the body, and what are its effects?
* About **70%** of laudanosine is excreted in the **bile** and the remainder in urine.
* It crosses the blood-brain barrier
* Has CNS stimulating properties
* Its seizure threshold in humans is unknown.
105
Are high blood levels of laudanosine a concern for patients in intensive care?
* In intensive care patients, blood levels of laudanosine can reach 5.0 to 6.0 μg/mL.
* However, there is no evidence that prolonged administration of atracurium leads to concentrations capable of causing convulsions.
106
What is the plasma elimination half-life of laudanosine in patients with normal and impaired renal function?
* Is similar in patients with normal and impaired renal function
* 197 ± 38 min normal renal function
* 234 ± 81 min impaired renal function
107
What is **Cisatracurium** and how potent is it compared to **Atracurium**?
* Cisatracurium is the 1R cis–1'R cis isomer of Atracurium.
* Comprising 15% of the atracurium mixture by weight but over 50% in terms of neuromuscular-blocking activity.
108
How is **Cisatracurium** metabolized?
* Is metabolized by Hofmann elimination to laudanosine and a monoquaternary alcohol metabolite, without undergoing ester hydrolysis.
109
What are the clinical advantages of Cisatracurium over Atracurium?
* Cisatracurium, being more potent, produces less laudanosine.
* Does not cause histamine release, unlike Atracurium.
110
What is **Mivacurium**, and how is it metabolized?
* Is a mixture of three (3) stereoisomers
* Metabolized by **Butyrylcholinesterase to a Monoester and a Dicarboxylic acid**
* Similar to succinylcholine.
111
Does Mivacurium cause histamine release?
* Mivacurium may produce histamine release, especially when administered rapidly.
112
What is significant about the structure of steroidal neuromuscular-blocking drugs?
* Steroidal compounds possess onium centers
* It is essential for one of the nitrogen atoms in the molecule to be quaternized for effective interaction with nicotinic acetylcholine receptors.
113
What role does the acetyl ester play in steroidal compounds?
* Facilitates the interaction of steroidal compounds with nicotinic acetylcholine receptors at the postsynaptic muscle membrane.
| The acetyl ester, resembling an acetylcholine-like moiety
114
What are the key **properties of Pancuronium**?
* Is a potent long-acting NMBD with vagolytic, direct sympathomimetic stimulation
* Blocks Norepinephrine reuptake
* Butyrylcholinesterase-inhibiting properties.
* 40-60% cleared by the kidney
* 11% is excreted in the bile
* 15%-20% is metabolized, mainly by deacetylation in the liver.
* The metabolites 3-OH, 17-OH, and 3,7-di-OH
115
How is Pancuronium metabolized and excreted?
* About **40% to 60%** of pancuronium is cleared by the **kidneys**
* **11%** excreted in **bile**
* **15%-20%** metabolized, **mainly by deacetylation** in the **liver**
* Its metabolites are less potent NMBDs and excreted in urine.
116
Why might clinicians opt for other NMBDs over **Pancuronium**?
* Due to its prolonged effect
* The risk of postoperative residual paralysis
* Associated morbidity
clinicians often prefer other NMBDs for achieving neuromuscular blockade.
117
What are the key characteristics of vecuronium?
* Vecuronium is a monoquarternary NMBD with intermediate action duration
* Less potent than pancuronium
* With virtually no vagolytic properties
* Increased lipid solubility leading to greater biliary elimination.
118
How does vecuronium differ from pancuronium?
* Vecuronium lacks the quaternizing methyl group present in pancuronium
* Leading to a slight decrease in potency
* Loss of vagolytic properties
* Molecular instability in solution
* Increased lipid solubility.
119
How is Vecuronium metabolized and excreted?
* Vecuronium is metabolized in the liver into metabolites like 3-OH vecuronium,
* Around 30%- 40% excreted in bile as the parent compound
* 30% excreted in urine. (Renal)
* Its Neuromuscular block duration depends mainly on hepatic function.
120
How stable is vecuronium in solution?
* Vecuronium is less stable in solution
* Prepared as a lyophilized powder
* Cannot be prepared as a ready-to-use solution with a long shelf life.
121
What are the properties of Rocuronium?
* Rocuronium is an intermediate-acting monoquarternary NMBD with a
* Faster onset than vecuronium or pancuronium
* Is about 6 times less potent than vecuronium.
122
How is Rocuronium eliminated and how stable is it?
* **Primarily** eliminated by the **liver**
* Excreted in bile
* 30% is excreted unchanged in urine.
* It is stable at room temperature for 60 days.
* Pancuronium is stable for 6 months.
123
How is the potency of nondepolarizing NMBDs expressed?
* Is expressed as ED50 and ED95
* indicating the doses required for 50% or 95% depression of twitch height, respectively.
124
How does the potency of nondepolarizing NMBDs affect their speed of onset?
* The speed of onset of nondepolarizing NMBDs is inversely proportional to their potency.
* Low-potency drugs have a rapid onset
* High-potency drugs have a slow onset.
125
What is the relationship between molar potency and onset time in NMBDs?
* Molar potency (ED50 or ED95 in μM/kg) is predictive of the time to onset of effect
* Lower molar potency drugs like rocuronium having a rapid onset compared to higher potency drugs.
126
Why do low-potency drugs have a faster onset than high-potency drugs?
* Low-potency drugs have a higher number of molecules for an equipotent dose
* Creating a greater diffusion gradient to the neuromuscular junction and a faster transfer rate from plasma to biophase.
127
What is "buffered diffusion," and how does it affect NMBD recovery?
* Buffered diffusion, seen in high-potency drugs,
* Is where **drug diffusion is impeded due to binding to high-density** receptors within a restricted space.
* It causes repetitive binding and unbinding from receptors, lengthening the duration of effect.
128
How do inhalational anesthetics affect the potency of nondepolarizing NMBDs?
* Inhalational anesthetics potentiate the neuromuscular-blocking effect of nondepolarizing NMBDs
* Reduce the required dosage
* Prolongs both action duration and recovery time.
129
What factors influence the potentiation of NMBDs by inhalational anesthetics?
* The potentiation depends on the duration of inhalational anesthesia
* The specific anesthetic used, and
* Its concentration.
**Des > Sevo > Iso > Halothane> N2O**
| Nitrous oxide have varying degrees of potentiation.
130
How do certain antibiotics potentiate neuromuscular blockade?
* Aminoglycoside antibiotics, polymyxins, lincomycin, and clindamycin **inhibit acetylcholine release and depress receptor sensitivity**
* **Tetracyclines** exhibit postjunctional activity.
## Footnote
Aminoglycosides = Gentamicin, Amikacin, Trobamycin, Neomycin, Streptomycin
131
How do hypothermia and magnesium sulfate affect neuromuscular blockade?
* They potentiate the blockade
* **Hypothermia** increasing recovery time
* **Hypermagnesemia** inhibits calcium channels at presynaptic nerve terminals.
132
What effect do local anesthetics and antidysrhythmic drugs have on neuromuscular block?
* Large doses of local anesthetics and antidysrhythmic drugs like quinidine potentiate neuromuscular block
* Smaller doses of local anesthetics have no significant effect.
133
How does chronic anticonvulsant therapy affect resistance to nondepolarizing NMBDs?
* Chronic anticonvulsant therapy can lead to resistance to nondepolarizing NMBDs (except mivacurium and atracurium)
* Requiring increased doses for complete neuromuscular blockade and resulting in accelerated recovery.
134
What are the possible causes of resistance to nondepolarizing NMBDs?
* May be due to increased clearance
* Increased binding to α1-acid glycoproteins
* Upregulation of neuromuscular acetylcholine receptors.
135
How does hyperparathyroidism affect the sensitivity to nondepolarizing NMBDs?
* In hyperparathyroidism, hypercalcemia decreases sensitivity to NMBDs like atracurium, tubocurarine, and pancuronium,
* leading to a **shorter duration of neuromuscular blockade**.
## Footnote
**THINK: Hyperthyroidism = Decreases A-T-P**
136
What is the significance of NMBDs in adverse reactions during anesthesia?
* NMBDs are responsible for a significant proportion of adverse drug reactions
* Deaths during anesthesia, with 10.8% of adverse reactions and 7.3% of deaths attributable to them.
137
How do neuromuscular-blocking agents affect the autonomic nervous system?
NMBDs interact with nicotinic and muscarinic cholinergic receptors in the sympathetic and parasympathetic systems causing effects like:
* Ganglion blockade
* Hypotension
* Reflex tachycardia
* Bronchospasm.
138
What are the specific autonomic effects of tubocurarine?
* Causes ganglion blockade leading to hypotension
* Can trigger histamine release, resulting in flushing, reflex tachycardia, and bronchospasm.
139
What is the vagolytic effect of pancuronium?
* Pancuronium has a direct vagolytic effect
* can block muscarinic receptors on sympathetic postganglionic nerve terminals
* affecting catecholamine release modulation.
140
How does pancuronium influence catecholamine release?
* May stimulate catecholamine release from adrenergic nerve terminals
* Influences the sympathetic nervous system.
141
Which neuromuscular-blocking compounds cause histamine release and what are the effects?
Benzylisoquinolinium compounds like **Mivacurium, Atracurium, and Tubocurarine can cause histamine release, leading to**:
* Skin flushing
* Decreases in blood pressure
* Increased pulse rate
* Systemic vascular resistance changes
142
Do steroidal NMBDs cause histamine release?
* In typical clinical doses, are not associated with histamine release.
| **Steroidal compounds: P-V-R**
143
What are the clinical effects and duration of histamine release from NMBDs?
* The effects of histamine release, such as skin flushing and hypotension, occur with rapid drug administration, usually last 1-5 minutes
* Are dose-related.
* They can be clinically insignificant in healthy patients but
* May cause bronchospasm in those with hyperactive airway disease.
144
How does histamine affect the cardiovascular system?
* Can cause peripheral vasodilatation,
* Leading to hypotension and reflex responses
* Has positive inotropic and chronotropic effects on myocardial H2 receptors.
145
What considerations should be made when choosing NMBDs for hemodynamically compromised patients?
* In such patients, it's better to use drugs with less or no histamine release, like cisatracurium, vecuronium, or rocuronium
* Administer benzylisoquinolinium NMBDs slowly or with prophylactic histamine H1- and H2-receptor antagonists.
146
How often do life-threatening anaphylactic reactions occur during anesthesia?
* Anaphylactic reactions occur in approximately 1 in 1,000 to 1 in 25,000 anesthesia administrations,
* With a mortality rate of about 5%.
147
What are the most common causes of anaphylaxis during anesthesia?
1. NMBDs (58.2%)
2. Latex (16.7%)
3. Antibiotics (15.1%).
148
What is the difference between anaphylactic and anaphylactoid reactions?
* **Anaphylactic reactions** are immune-mediated involving IgE antibodies
* **Anaphylactoid reactions** are exaggerated pharmacologic responses, not immune-mediated.
149
What can nondepolarizing NMBDs cross-react with?
* Food
* Cosmetics
* Disinfectants
* Industrial materials
150
Do steroidal NMBDs cause significant histamine release?
* Steroidal NMBDs (e.g., rocuronium, vecuronium) do not cause significant histamine release but still can cause anaphylaxis.
151
What is the recommended treatment for anaphylactic reactions during anesthesia?
* 100% oxygen
* Intravenous epinephrine (10-20 mcg/kg)
* Early tracheal intubation (Angioedema)
* Fluids (crytalloids/colloids)
* potentially norepinephrine or a sympathomimetic drug like Phynelephrine
* Treatment for dysrhythmias.
The use of antihistamines and steroids is controversial.
152
What is the function of acetylcholinesterase at the neuromuscular junction?
* Acetylcholinesterase rapidly hydrolyzes released acetylcholine at the neuromuscular junction
* About 50% hydrolyzed before reaching nicotinic receptors.
153
How do acetylcholinesterase inhibitors work to reverse nondepolarizing neuromuscular blockade?
* Increase acetylcholine concentration at the neuromuscular junction,
* **Compete with nondepolarizing NMBDs for receptor sites and accelerating recovery**.
154
What is the ceiling effect of acetylcholinesterase inhibitors?
* Once maximum inhibition of acetylcholinesterase is reached additional doses won't increase acetylcholine concentration further.
155
What are the maximum effective doses of neostigmine and edrophonium?
* The maximum effective dose for neostigmine is 60 to 80 μg/kg
* Edrophonium, it is 1.0 to 1.5 mg/kg.
156
How widely used is neostigmine in clinical practice?
* Neostigmine is the most widely used anticholinesterase agent by anesthesiologists worldwide.
157
When should neostigmine be administered for optimal effect?
* It should ideally be administered when there is partial spontaneous recovery from a nondepolarizing NMBD,
* Using a small dose if fade cannot be detected on TOF stimulation.
158
What are the elimination half-lives and routes of excretion for edrophonium, neostigmine, and pyridostigmine?
* Edrophonium, neostigmine, and pyridostigmine have similar elimination half-lives,
* With renal excretion
* Accounting for 50% for neostigmine
* About 75% for pyridostigmine and edrophonium.
* Renal failure decreases their plasma clearance.
159
What are the general side effects of acetylcholinesterase inhibitors?
* Increases acetylcholine concentration at all synapses,
* Affecting both nicotinic and muscarinic receptors.
160
How are the cardiovascular side effects of acetylcholinesterase inhibitors managed?
* Anticholinergic agents like atropine or glycopyrrolate are coadministered to block muscarinic effects.
* Atropine matches the action of edrophonium
* Glycopyrrolate matches that of neostigmine and pyridostigmine.
161
What are the pulmonary and alimentary side effects of acetylcholinesterase inhibitors?
These inhibitors can cause:
* Bronchoconstriction
* Increased airway resistance
* Increased salivation
* Increased bowel motility
Anticholinergics help reduce these effects.
162
Does neostigmine increase the incidence of postoperative nausea and vomiting?
* There is no evidence that neostigmine increases postoperative nausea and vomiting.
* It may have antiemetic properties or no effect on the incidence of these conditions.
163
What is a common postanesthetic issue associated with acetylcholinesterase inhibitors?
* Incomplete reversal and residual postoperative weakness are frequent
* With studies reporting a high incidence of postoperative residual neuromuscular blockade
164
What was the reported incidence of postoperative residual neuromuscular blockade in a 2003 study?
* In 2003, Debaene and colleagues reported a 45% incidence of this condition in patients arriving in the postanesthesia care unit.
165
How does practitioner overconfidence affect the management of NMBDs?
* Most practitioners are overconfident in their knowledge and ability to manage NMBDs,
* often not knowing what constitutes adequate recovery from neuromuscular blockade
166
What are the limitations of using nerve stimulators and reversal agents for NMBDs?
* Lack of routine use of quantitative nerve stimulators and the ceiling effect of reversal agents when administered at a deep level of neuromuscular blockade.
167
Does the use of reversal agents and nerve stimulators eliminate critical respiratory events postoperatively?
* Despite using nerve stimulators and neostigmine, critical respiratory events in the postoperative care unit remain significant, indicating a need for changes in clinical care.
168
What are cyclodextrins and their natural forms?
* Cyclodextrins are cyclic dextrose units from starch, with natural forms being α-, β-, or γ-cyclodextrin, comprising 6-, 7-, or 8-cyclic oligosaccharides, respectively.
* They have a hydrophobic cavity and hydrophilic exterior
169
What is the composition and structure of sugammadex?
* Is a modified γ-cyclodextrin with an eight-membered ring
* Designed to encapsulate steroidal NMBDs.
* It has extended cavity and negatively charged carboxyl groups for better binding to rocuronium.
170
How does sugammadex work to counteract steroidal neuromuscular-blocking agents?
* Sugammadex forms tight 1:1 complexes with steroidal NMBDs, particularly rocuronium, through van der Waals forces
* Hydrogen bonds, and hydrophobic interactions, resulting in a high association rate and very low dissociation rate.
171
Which neuromuscular-blocking agents does sugammadex bind to most effectively?
* Is **most effective at binding with Rocuronium**
* Followed by Vecuronium
* Has much less affinity for Pancuronium.
**Rocuronium > Vecuronium > Pancuronium**
172
Is sugammadex biologically active and does it bind to plasma proteins?
* Sugammadex is biologically inactive
* Does not bind to plasma proteins.
* Its metabolism is minimal, with most of it eliminated through urine.
173
How is sugammadex eliminated from the body?
* About 75% is eliminated in the urine
* 59% to 80% of the dose excreted within 24 hours after administration.
174
How does renal impairment affect the clearance of sugammadex and rocuronium?
* In patients with significant renal impairment, clearances of sugammadex and rocuronium decrease considerably
* Their elimination half-lives increase.
* Sugammadex is **not recommended** for patients with a **creatinine clearance of <30 mL/min.**
175
Can dialysis effectively remove sugammadex and rocuronium from plasma?
* The effectiveness of dialysis in removing sugammadex and rocuronium from plasma has not been consistently demonstrated.
176
How does sugammadex affect the elimination of rocuronium?
* Rocuronium is mainly eliminated by biliary excretion
* When bound to sugammadex, this route becomes unavailable, decreasing rocuronium clearance to a value close to the glomerular filtration rate.
177
What is the capability of Sugammadex in reversing neuromuscular blockade?
* Sugammadex can reverse any depth of neuromuscular blockade induced by rocuronium or vecuronium to a Train-of-Four Ratio (TOFR) of ≥0.9 within 3 minutes.
178
How does Sugammadex work to reverse neuromuscular blockade?
* Sugammadex removes free rocuronium or vecuronium from plasma,
* creating a concentration gradient that moves remaining molecules from the neuromuscular junction back into plasma, where they are encapsulated by Sugammadex.
179
What are the recommended doses of Sugammadex for different levels of blockade?
* For TOF count ≥2, use 2 mg/kg;
* For deeper levels (only posttetanic twitches), use 4 mg/kg
* For rapid reversal of 1.2 mg/kg rocuronium, use 16 mg/kg.
180
Is Sugammadex effective in "cannot intubate, cannot ventilate" (CICV) situations?
* Sugammadex should not be relied upon in CICV situations
* It may not ensure immediate return of spontaneous ventilation, especially in obese patients.
181
Against which neuromuscular-blocking drugs is sugammadex ineffective?
* Succinylcholine
* Benzylisoquinolinium NMBDs like mivacurium, atracurium, and cisatracurium, as it cannot form inclusion complexes with these drugs.
182
How does sugammadex interact with oral contraceptives?
* Inhibit oral contraceptives.
* Patients are advised to use alternative contraceptive methods for 7 days after exposure to sugammadex.
183
What is the incidence of anaphylactic reactions to sugammadex, and how is it diagnosed?
* The incidence is about 0.04%,
* Similar to that with rocuronium.
* Diagnosis involves estimating plasma tryptase concentrations during the acute event and repeating it 2-6 hours and 24 hours later.
184
What cardiac arrhythmias can occur post-sugammadex administration?
* **Bradycardia and asystole**, may occur after sugammadex administration.
* Continuous electrocardiogram monitoring and readiness with **atropine and vasoactive drugs are necessary**.
185
What serious cardiac adverse events have been reported with sugammadex?
* From 2009 to 2017, serious events like bradycardia, cardiac arrest, ventricular fibrillation, and tachycardia were reported, including 138 cases with nine deaths.
186
Does sugammadex affect blood coagulation times?
* May cause small increases in aPTT and PT
* But clinically significant bleeding has not been reported.
187
What are the primary purposes of monitoring neuromuscular function in clinical settings?
* The purposes are to administer appropriate doses of NMBDs
* To ensure adequate recovery from their residual effects
* Guaranteeing patient safety.
188
What are the complications associated with residual postoperative paralysis?
1. Upper airway obstruction
2. Aspiration
3. Hypoxemia.
189
Why are clinical bedside criteria considered inadequate for assessing neuromuscular recovery?
* Bedside criteria like a 5-second head lift are insensitive indicators of neuromuscular recovery, as they don't accurately reflect residual neuromuscular blockade
190
What is the difference between subjective and objective neuromuscular monitoring?
* **Subjective monitoring** relies on qualitative evaluation of muscular responses
* **Objective (quantitative) monitoring** involves real-time measurement of the TOFR.
191
Why is quantitative monitoring essential in neuromuscular function assessment?
* Accurately measures TOFR in real time
* Crucial for assessing neuromuscular recovery
* Prevents residual blockade.
192
What are the limitations of subjective evaluation using a Peripheral Nerve Stimulator (PNS) for neuromuscular blockade?
* Is unreliable for determining recovery from neuromuscular blockade and may miss residual weakness.
* It struggles to assure readiness for tracheal extubation (TOFR ≥0.90)
* Often fails to detect fade at TOFR approaching 0.40.
193
How is subjective neuromuscular monitoring performed?
* It involves using a PNS to stimulate a nerve observing the number
* Strength of muscle twitches (TOFC) by tactile or visual means.
194
What are the different objective techniques for neuromuscular blockade monitoring?
* Electromyography (EMG)
* Mechanomyography (MMG- is Gold standard)
* Acceleromyography
* Kinemyography
Each with distinct methods and limitations.
195
What is Electromyography (EMG) and how is it used in neuromuscular monitoring?
* EMG measures muscle action potentials in response to nerve stimulation
* Is subject to electrical interference
* Does not analyze muscle movement.
196
Why is Mechanomyography (MMG) considered the gold standard in neuromuscular blockade monitoring?
* MMG measures force from muscle contraction in response to electrical stimuli
* Is considered the gold standard, but its clinical use is limited due to preparation requirements.
197
How are Acceleromyography and Kinemyography used in neuromuscular monitoring?
* **Acceleromyography:** measures muscle acceleration and requires free thumb movement, limiting its use.
* **Kinemyography:** uses a mechanosensor strip but may not correlate well with MMG.
198
How do responses to nerve stimulation differ between depolarizing and nondepolarizing NMBD blockades?
* **Depolarizing block** (succinylcholine) shows no fade or posttetanic potentiation
* **Nondepolarizing blockades** exhibit fade and can cause posttetanic potentiation.
199
How do different muscle groups respond to NMBDs?
* Central muscles like the diaphragm are more susceptible to NMBDs and recover faster compared to peripheral muscles like the adductor pollicis.
200
Which muscle group should be monitored for assessing neuromuscular blockade recovery?
* The adductor pollicis muscle, in response to ulnar nerve stimulation, is recommended for monitoring to exclude residual weakness.
201
How do laryngeal and diaphragmatic muscles respond to NMBDs?
* These muscles are more resistant to NMBDs
* Develop blockade faster
* Recover quicker than peripheral muscles like the adductor pollicis
202
Is monitoring facial muscles reliable for assessing neuromuscular blockade?
* Monitoring facial muscles, like the corrugator supercilii or orbicularis oculi, **is less reliable** than monitoring the adductor pollicis muscle.
203
What is the difference in residual paralysis incidence when monitoring facial muscles vs. hand muscles?
* Monitoring eyebrow responses showed a 52% incidence of residual paralysis
* compared to 22% with hand muscle monitoring.
204
Name the Monoquaternary compounds:
1. Tubocurarine
2. Vecuronium
3. Rocuronium
205
Majority of Nondepolarizing NMBD are considered:
- Bisquaternary Ammonium Compounds.
206
The parasympathetic nervous systems uses Acetylcholine as:
- Preganglionic and Postganglionic neurotransmitter.
207
Chronic anticonvulsant therapy can lead to resistance to nondepolarizing NMBDs except:
- Mivacurium
- Atracurium
