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71 Cards in this Set

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  • Back
What are the structural defining characteristics of neuromuscular blocking drugs?
Quartenary ammonium groups--highly ionized water-soluble compounds at physiologic pH and possess at limited lipid solubility; not highly bound to plasma proteins (up to 50%)
What are the results of the structural characteristics of NMBDs?
The volume of distrubution is limited (similar to extracellular fluid volume = 200ml/kg). They also cannot easily cross lipid membrane barriers such as the blood-brain barrier, renal tubular epithelium, GI epithelium, or placenta
How is the potency defined in NMBDs?
It is the effective dose necessary to depress single-twitch depression 95% (ED95)
How is the onset of NMBDs defined?
It is the time of injection to onset of maximal single-twitch depression
What is the duration of action of NMBDs?
It is the time from injection to return of single-twitch height to 25% or 95%
How is the recovery index of NMBDs defined?
It is the time from 25% return of single-twitch height to 75% return of single twitch height
What is the clinical duration of NMBDs?
Time from injection to recovery of the train of four to greater than or equal to 0.7 or 0.9
What the principal uses of NMBDs?
To provide skeletal muscle relaxation to facilitate tracheal intubation (2XED95) and to improve surgical working conditions during general anesthesia (90% suppression of single twitch response)
What is the sequence of muscles that the NMBDs affect when it is administered and when it is clearing?
After administration, the small rapidly moving muscles like the eyes and digits are affected before the trunk and abdomen. The last ones to be paralyzed are the interostal muscles and finally the diaphragm. Recovery occurs in reverse with diaphragm gaining movement first. Consciousness and sensorium remain intact!!
Describe the structure of succinylcholine (SCh) and its benefits.
It is two molecules of acetycholine linked through acetate methyl groups--this long slender structure allows it to bind and activate cholinergic receptors. Bulky and rigid molecules as in nondepolarizer cannot activate cholinergic receptors.
What classes are nondepolarizing drugs divided into?
Benzylisoquinoliniums--more likely to release histamine ("urium") and aminosteroids ("uronium")
Describe how length of the carbon chain on NMBDs affect specificity.
The longer the carbon chain the more likely it will affect the neuromuscular junction over the autonomic ganglia nicotinic receptors. Maximal autonomic blockade occurs when the positively charged quaternary ammonium group is separated by 6 carbons whereas neuromuscular blockade occurs when 10 carbon atoms are present (decamethonium)
What is the resting transmembrane potential maintained by skeletal muscle and nerve membranes at the neuromuscular junction?
-90mv and it is maintained by the unequal distribution of potassium and sodium ions across the membrane
How is acetylcholine synthesized?
It is synthesized in the motor nerve ending by the acetylation of choline under the control of the enzyme choline acetylase
When acetylcholine binds to the alpha subunits of nAChRs (nicotinic cholinergic receptors) on postsynaptic membranes there is a decrease in transmembrane potential. What is it called and at what mv does it happen?
It is called the threshold potential and it is at -45mv
The release of acetylcholine is dependent on concentrations of what ion in nerve terminals?
How does a nerve action potential release acetylcholine?
It activates adenylate cyclase in the membranes of nerve terminals leading to the formation of cyclic adenosine monophosphate (cAMP). cAMP opens calcium ion channels causing synaptic vesicles to fuse with the nerve membrane and release acetylcholine.
What is the function of acetylcholinsterase?
Acetylcholinsterase is responsible for the rapid hydrolysis of acetylcholine to acetic acid and choline. Choline can reenter motor nerve ending to again participate in synthesis of acetylcholine.
What are the two types of nicotine acetylcholine receptors on post-synaptic membranes that respond to neuromuscular blocking drugs?
Fetal receptors and Adult receptors
Describe fetal nAChRs.
Consist of 5 subunits designated alpha,gamma,beta, and delta with each receptor being encoded by a separate gene. These receptors when acetycholine is attached and close when acetycholine dissociates. There is a long open period combined with high electrical resistance that allows a SINGLE acetylcholine quanta to elicit action potentials.
What differentiates adult nicotinic acetylcholine receptors and fetal ones?
subunit called episilon exposed by by subsynaptic nuclei; short open periods and higher conductance of sodium, potassium, and calcium ions
When are extrajunctional receptors most active?
With trauma or skeletal muscle denervation they proliferate. Their numbers affect the varying response to NMBDs
What is the duty of prejunctional nAChRs?
They influence the release of neurotransmitters.
What are the benefits of the only depolarizing muscle relaxant?
Succinycholine produces intense paralysis rapidly and effects are likely to wane before a preoxygenated patient becomes hypoxic.
What is the tracheal intubation dose of succinylcholine?
1.0 mg/kg IV traditionally--no literature supporting this
(0.6 mg/kg IV decreases the duration of twitch depression by >90 seconds and associated with acceptable intubation)
If neuromuscular blockage is critical, doses of 1.0-1.5 mg/kg IV may be appropriate.
There is so much variability that there is no single perfect dose!!
How does succinycholine work (mechanism of action)?
It attaches to one or both of the alpha subunits of nicotinic acetylcholine receptors and mimics the action of acetylcholine--> depolarizes postjunctional membrane; compared with acetycholine hydrolysis is slow so there is sustained opening--> neuromuscular blockade develops because the depolarized postjunctional membrane cannot react to more acetycholine
What is another name for depolarizing neuromuscular blockade?
Phase I blockade
What are the characteristics of Phase I blockade?
1. decreased contraction in response to single-twitch stimuli
2. decreased amplitude but sustained response to continuous stimulation
3. TOF ratio> 0.7
4. absence of posttetanic facilitation
5. anticholinsterase drug administration resolves neuromuscular blockade
6. accompanied by muscle fasiculations that reflect generalized postjunctional membrane depolarization
What dose of succinycholine leads to phase II blockade?
>2mg/kg IV, repeated doses or a continuous infusion
What is the duration of action of succinycholine?
3-5 minutes
Succinychole is hydrolyzed by ______
plasma cholinsterase (pseudocholinsterase) enzyme
Where is plasma cholinsterase synthesized?
What stops plasma cholinsterase and then prolongs the effects of succinycholine?
1. decreases in hepatic produciton (liver disease must be severe before this happens)
2. drugs (neostigmine, nitrogen mustard, cyclophosphamide, metoclopramide, high estrogen levels)
3. atypical plasma cholinsterase
Who is resistant to succinycholine?
1. Obese people (increase in plasma cholinsterase activity)
2. Patients with Myasthenia Gravis (decrease in functional acetylcholine endplate receptors)
3. those with juvenile hyaline fibromatosis (normal plasma cholinsterase activity--observed)
What does the dibucaine number represent?
It reflects the QUALITY of cholinsterase enzyme (ability to hydrolyze succinycholine) and NOT QUANTITY of enzyme that is circulating in plasma
What are the adverse side effects that accompany administration of succinycholine?
1. cardiac dysrhythmias
2. hyperkalemia
3. myalgia
4. myoglobinuria
5. increased intragastric pressure
6. increased intraocular pressure
7. increased ICP
8. sustained skeletal muscle contractions
What are the cardiac dysrhythmias associated with succinycholine and why do they happen?
Sinus bradycardia, junctional rhythm and even sinus arrest because action of SCh on cardiac muscarinic cholinergic receptors where it mimics acetylcholine (more likely to occur with second dose which shows a possible role of SCh's metabolites and atropine does not prevent HR slowing)
Hyperkalemia after SCh administration is more likely to result in these patients:
1. clinically unrecognized muscular dystrophy(some avoid using SCh in pediatric patients due to this)
2. unhealed third-degree burns
3. denervation leading to skeletal muscle atrophy (proliferation of extrajunctional cholinergic receptors)
4. severe skeletal muscle injury
5. upper motor neuron lesions
SCh induced myalgia is more prominent where and what population?
It is more likely in young patients undergoing minor surgical procedures that permit early ambulation and and is pain in neck, back, and abdomen, or even a sore throat
SCh induced myoglobinuria is more likely to occur in what population of patients?
Skeletal muscle damage associated with fasciculations more likley to happen in pediatric patients and rare in adults.
What are the characteristics of nondepolarizing neuromuscular blockade?
1. decreased twitch response to a single stimulus
2. unsustained response (fade) during continuous stimulation
3. TOF ratio of <0.7
4. posttetanic potentiation
5. potentiation of other nondepolarizing neuromuscular blocking drugs
6. antagonism by anticholinesterase drugs
7. no skeletal muscle fasciculations
What is the effect of volatile anesthetics on nondepolarizing muscular blockade?
They produce dose-dependent enhancement of magnitude and duration of neuromuscular blockade. It is greatest with enflurane, isoflurane, desflurane, and sevoflurane and the least with nitrous-opiod combinations. Long-acting nondepolarizers have more of an effect than the intermediate acting ones.
Name a prominent type of antibiotics that enhance the effect produced by nondepolarizing neuromuscular drugs. What can this effect be antagonized by?
Aminoglycosides. The antagonism by anticholinsterase drugs or calcium is unpredictable but calcium can transiently antagonize the antibiotic induced enhanced neuromuscular blockade.
Which antibiotics have no effect on neuromuscular blockade by nondepolarizers?
Penicillins and Cephalosporins
What is the effect of local anesthetics on nondepolarizers?
Dose dependent with small doses enhancing neuromuscular blockade and large doses blocking neuromuscular transmission.
What is the effect of lidocaine on neuromuscular blockade? What is the effect of quinidine?
Lidocaine can enhance pre-existing blockade. Quinidine can potentiate effects by nondepolarizers and depolarizers.
How does Furosemide 1mg/kg enhance nondepolarizing neuromuscular blockade?
Furosemide inhibits cAMP production leading to decreased prejunctional output of acetylcholine. Conversely large doses may inhibit phosphodiesterase making more cAMP available and leading to antagonism of nondepolarizing neuromuscular-blocking drugs. (Azathioprine inhibits phosphodiesterase and not only inhibits nondepolarizer but also depolarizers)
What is the effect of chronic anticonvulsant use on nondepolarizer blocking effects?
Phenytoin, Carbamazepine are resistant to pancuronium vecuronium, rocuronium, cistracurium, pipecuronium, doxacurium but not mivacurium and atacurium
Name the long-acting nondepolarizing neuromuscular drugs.
onset of action?
duration of action?
ED95= 70 micrograms/kg
onset of action= 3-5 minutes
duration of action= 60-90 minutes
_______ acidosis enhances pancuronium induced neuromuscular blockade.
Respiratory (neostigmine may not reverse neuromuscular blockade effects)
How much of pancuronium is eliminated in urine unchanged?
What are the cardiovascular effects of Pancuronium?
10-15% increase in HR (blocks vagal muscarinic receptors in SA node), MAP, and CO
onset of action?
duration of action?
ED95= 30 micrograms/kg
onset of action= 4-6 minutes
duration of action= 60-90 minutes
*renal clearance like pancuronium
onset of action?
duration of action?
ED95= 50-60 micrograms/kg
onset of action= 3-5 minutes
duration ot action= 60-90 minutes
*dependence on renal clearance like pancuronium
*potency increased and duration of action shortened in infants compared with children and adults
*hepatic cirrhosis does not influence pharmacokinetics or pharmacodynamics
Name the intermediate-acting nondepolarizing neuromuscular-blocking drugs.
What is the priming principle?
Administration first of a small subparalyzing dose (10% of ED95) followed by the larger dose (2-3X ED95) 4 minutes later to accelerate speed of onset.
onset of action?
duration of action?
protein binding?
ED95= 0.2 mg/kg
onset of action= 3-5 minutes
duration of action= 20-35 minutes
Protein binding= 82% to albumin
*acidic solution that degrades if exposed to alkaline solution (like barbituates)
*potency at room temperature decreases 5% every 30 days
How is atracurium metabolized?
Spontaneous nonenzymatic degradation at normal body temperature and pH by a base catalyzed reaction termed Hoffman elimination. Also through hydrolysis by nonspecific plasma esterases.Laudanosine is the major by-product.
onset of action?
duration of action?
ED95= 50 micrograms/kg
onset of action= 3-5 minutes
duration of action= 20-35 minutes
*unstable in solution, supplied as a lyophilized powder that must be dissolved in sterile water before use
*onset of action more rapid in infants over children but duration of action is longest in infant and shortest in children
*prolonged duration of action in obese, in immediate postpartum period, clearance increased in late pregnancy d/t stimulation of hepatic microsomal enzymes by progesterone
How is vecuronium metabolized and excreted?
High lipid solubility--> hepatic metabolism and renal excretion (30% appears unchanged or as metabolites in first 24 hours in urine)
onset of action?
duration of action?
Ed95= 0.3mg/kg
onset of action= 1-2 minutes
duration of action= 20-35 minutes
*only nondepolarizer that serves as an alternative to SCh (4xEd95)
Where is rocuronium excreted?
Bile - up to 50% unchanged in 2 hours
ranal excretion- >30% in 24 hours
*renal impairment and liver disease prolong duration of action (newly transplanted liver does not)
*prolonged duration of action in elderly
What are the cardiovascular effects of rocuronium?
-absence of histamine release
-unlike other aminosteroid neuromuscular blocking drugs may produce a slight vagolytic effect (useful in pts undergoing surgeries that may have vagal stimulation like laps--no reflex bradycardia)
Onset of action?
Duration of aciton?
ED95= 50 micrograms/kg
onset of action= 3-5 minutes
duration of action= 20-35 minutes
*slower onset than atracurium and less histamine releasing effect
How is cistracurium metabolized and eliminated?
Degradation by Hoffman elimination at physiologic pH and temperature to form laudanosine and monoquaternary acrylate; nonspecific plasma esterases are not involved
elimination: 77% by Hoffman elimination and 16% by renal excretion
Name the short-acting nondepolarizing neuromuscular drugs.
Mivacurium is the only clinically useful one.
onset of action?
duration of action?
ED95= 80 micrograms/kg
onset of action= 2-3 minutes
duration of action= 12-20 minutes
*consists of 3 stereoisomers of which two are the most active and equipotent--> cis-trans, tran-trans (cis-cis is only 1/10 as active as first two)
*duration of action increased in pts with atypical plasma cholinsterase
*clearance more rapid in children so need higher infusion requirements
*good for burn patients (dont need a higher dosage)
How is mivacurium metabolized?
Hydrolyzed by plasma cholinsterase which produces inactive metabolites at neuromuscular junction
What are the cardiovascular effects of mivacurium?
*Histamine releaser
3xED95 over 10-15 seconds decreases MAP by 13-18%, hypotension is more pronounced and frequent in hypertensive rather than normotensive patients
What is GW280430A?
A representative of a new class of nondepolarizing neuromuscular drugs characterized as a mixed-onium chlorfurmarate. Rapid breakdown in plasma by hydrolysis and inactivation by cysteine adduction.
ED95= 0.19 mg/kg
onset of action= 1.3-2.1 min
duration of action= 4.7-10.1 minutes
when 3xED95 given there was transient histamine release