7.5
Nondepolarizing (Competitive) Neuromuscular Blockers: Pharmacokinetics
All neuromuscular blocking agents are injected intravenously because they are poorly absorbed from the GI tract. Rapid onset is achieved with intraven…
All nondepolarizing blockers are polar compounds with two or more quaternary amines. When given orally, these drugs cannot cross the cell membrane and are minimally absorbed by the intestinal villi. So they are administered intravenously.
These blockers are rapidly distributed via blood to muscles, causing neuromuscular blockade.
Most nondepolarizing blockers are not metabolized, and their actions are terminated by redistribution to the liver and kidneys. The duration of the blockade depends on the drug's elimination half-life, which is the time taken to reduce the initial drug concentration to half.
Some drugs are excreted unchanged in the urine. These drugs have a longer half-life and action duration than drugs that are metabolized and eliminated in the liver.
The liver metabolizes steroidal relaxants into 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products. Other drugs remain unchanged and are excreted through the bile.
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Q1: Why are nondepolarizing neuromuscular blockers administered intravenously instead of orally?
Nondepolarizing blockers are polar compounds with quaternary amines that cannot cross cell membranes and are minimally absorbed by intestinal villi when taken orally. Intravenous administration ensures rapid distribution via blood to muscles, achieving effective neuromuscular blockade. This route bypasses poor gastrointestinal absorption and delivers the drug directly to target tissues.
Q2: How does blood flow affect the speed of neuromuscular blockade in different muscles?
Muscles with greater blood supply and higher blood flow receive nondepolarizing blockers faster than muscles with lesser blood supply. Since these highly ionized drugs are transported by blood to different tissues, well-perfused muscles experience blockade onset more rapidly. This differential distribution explains why some muscles are blocked before others during anesthesia.
Q3: What determines the duration of action for nondepolarizing neuromuscular blockers?
The duration of blockade is directly correlated to the drug's elimination half-life, which is the time required to reduce initial drug concentration to half. Drugs excreted unchanged in urine have longer half-lives and action durations exceeding 60 minutes. Conversely, drugs metabolized in plasma or liver have shorter half-lives and action durations lasting only 20 to 40 minutes.
Q4: How are steroidal nondepolarizing blockers metabolized in the liver?
The liver metabolizes steroidal relaxants into 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy metabolites. Although these metabolites retain half the activity of the parent drug, they are typically not produced in amounts sufficient to cause additional blockade. This hepatic metabolism contributes to the shorter action duration of these agents compared to drugs excreted unchanged.
Q5: Which nondepolarizing blockers undergo spontaneous ester hydrolysis and what is its significance?
Drugs like atracurium and cisatracurium undergo spontaneous ester hydrolysis in plasma, resulting in shorter elimination half-lives and action durations of 20 to 40 minutes. This plasma metabolism is independent of liver or kidney function, making these agents advantageous in patients with hepatic or renal impairment. Their rapid breakdown provides predictable, shorter blockade periods.
Q6: How do nondepolarizing competitive neuromuscular blockers mechanism of action relate to their pharmacokinetic properties?
Nondepolarizing blockers competitively antagonize acetylcholine at the neuromuscular junction, and their pharmacokinetic properties determine how long this blockade persists. Drug redistribution to other tissues terminates the blockade, while elimination through urine, bile, or hepatic metabolism determines overall duration. Understanding both mechanism and kinetics is essential for predicting clinical effects and recovery times.
Q7: What is the difference between drugs excreted unchanged versus those metabolized in terms of action duration?
Drugs like pancuronium and d-tubocurarine are excreted unchanged in urine with elimination half-lives producing action durations exceeding 60 minutes. In contrast, vecuronium and rocuronium are hepatically metabolized with shorter half-lives and action durations of 20 to 40 minutes. Some drugs are also excreted unchanged through bile, affecting their elimination pathways and clinical duration.