NDMRs: ROCURONIUM & VECURONIUM

QUESTION 1: Factors that will potentiate nondepolarizing neuromuscular blockade include all of the following EXCEPT:
A. Respiratory acidosis
B. Large body surface area burn
C. Administration of a volatile anesthetic
D. Hypothermia
E. Hypermagnesemia

QUESTION 2: Vecuronium:
A. Has a longer duration in children as compared to adults
B. Has an onset time independent of dose
C. Is totally eliminated by the kidneys
D. Activity is not prolonged by hepatic disease
E. inhibits histamine catabolism

(answers at bottom of post)

HIGHLIGHTS OF NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS:
Categorized in 2 ways:
1) long-, intermediate- and short-acting drugs
2) benzylisoquinoline (-curium) or aminosteroid compounds (-curonium)

Overview:

• Quarternary ammonium group (4 carbon atoms attached to 1 nitrogen atom)--> highly ionized and water-soluble (cannot easily cross lipid membrane barriers such as BBB, renal tubular epithelium, GI epithelium, placenta)
• Lack CNS depressant and analgesic effects
• Competitive antagonists
• NDMR have one positively charged nitrogen atom that binds to one alpha subunit of the postsynaptic cholinergic receptor (which is negatively charged)
• Vec and Roc are monoquarternary
• Aminosteroids lack hormonal activity
• specificity of a drug for autonomic ganglia nicotinic receptors versus the NMJ depends on length of carbon chain separating the 2 positively charged ammonium groups.

 Nicotinic nAChR (ion channel) contains 5 subunits.  2 ACh molecules need to bind to alpha units simultaneously to activate receptor.  1 Succs molecule needed which binds to both alpha units to activate receptor.

Pharmacokinetics/dynamics:

-Not highly bound to plasma protein

Causes of Altered Responses:
Certain drugs can enhance NDMR:

• Volatile Anesthetics: produce dose-dependent enhancement of magnitude and duration of neuromuscular blockade from NDMR.  Anesthetic induced depression of CNS decreases tone of skeletal muscles
• Aminoglycoside antibiotics: decrease release of ACh & stabilize post junctional membranes.  PCNs and cephalosporins do not have this effect.
• Local anesthetics: interfere with prejunctional release of ACh, stabilize membranes and directly depress skeletal muscle fibers.  Ester LA compete for PC (prolonged SCh)
• Cardiac antidysrhythmic drugs: primarily Lidocaine & Quinidine
• Diuretics: Furosemide, decrease release of ACh (inhibition of cAMP), & Azathioprine.  Osmotic diuretics (mannitol) does not influence NDMR
• Magnesium: more with Vec; more important in OB (Mg gtts)
• Lithium
• Cyclosporine

Resistance to NDMR:

• Anticonvulsants: phenytoin and carbamazepine result in resistance to NDMR - higher dose needed; faster recovery

Changes can also occur d/t:

• Hypothermia: prolongs duration d/t decreased clearance and slowed rate of effect site equilibration; also decr degradation by ester hydrolysis and Hofmann elimination
• Acid-base alterations
• Changes in serum potassium concentrations: decr in extracellular K+ increases transmembrane potential, causing hyperpolarization of cell membranes; hypokalemia enhances NDMR
• Adrenocortical dysfunction
• Thermal/burn injury: causes resistance to NDMR; NOT associated with extrajunctional receptors; mechanism is altered affinity of nAChRs for NDMR
• Paresis or Hemiplegia: causes resistance to NDMR d/t proliferation of extrajunctional receptors.  **Place twitch monitor on unaffected side for accurate assessment of twitches**
• Gender: women are more sensitive and require lower dose than men

ROCURONIUM (Zemuron):
Intermediate-acting, monoquaternary aminosteroid

Dose: 0.6-1.2 mg/kg (intubating dose)
Not given as an infusion
Onset: 1-2 min
Duration: 20-35 min

*rapid onset of action is more likely to be achieved with a less potent drug (roc compared to vec) bc of a greater number of molecules being available to diffuse into the NMJ --> may serve as an alternative to SCh in RSI (if SCh is contraindicated)

*laryngeal adductor muscles and diaphragm are more resistant to rocuronium than the adductor pollicis muscles

Metabolism/Excretion: largely excreted unchanged in bile (50%); 30% renal excretion
hepatic deacetylation does not occur
Characteristics:
Generally no CV effects of histamine release; cases of slight vagolytic effects
Prolonged by renal and hepatic dysfunction

VECURONIUM (Norcuron):
Intermediate-acting, monoquaternary aminosteroid

Dose: 0.08-0.15 mg/kg (intubating dose)
Infusion: 1 mcg/kg/min
Onset: 3-5 min
Duration: 20-40 min
Metabolism: hepatic deacetylation
Excretion: 30% unchanged in urine & 40% unchanged in bile
Characteristics:
Prolonged duration in renal dysfunction and hepatic cirrhosis
Devoid of CV effects; no histamine release - vagolytic effect is controversial
large volume of distribution

ANSWER 1:  (B) Patients with burns over a large portion of their body surface area are resistant to nondepolarizing neuromuscular blockade.  The other factors all potentiate such blockade.

ANSWER 2: (E) Vecuronium inhibits hitsmine-N-methyltransferase, the enzyme responsible for degrading histamine.  It has a shorter duration of action in children.  The onset time will be faster if the dose is increased.  About 10% is eliminated through the kidneys and the activity is prolonged by hepatic disease.

dTc inservice.  I wonder who's - I mean - what's for lunch?