What is the main pharmacological effect of NMB
to interrupt transmission of nerve impulses at the neuromuscular juntion
depolarizing NMB mimic the action of
non-depolarizing NMB interfere with action of
how are pharmacodynamics of NMB determined
by measuring speed of onset and duration of NM blockade
what is a common method for determining the type, speed of onset, magnitude, and duration of NM blockade
to observe or record the skeletal muscle response that is evoked by a supramaximal electrical stimulus that is delivered from a peripheral nerve stimulator
contraction of what muscle using 1 hz of electrical stimulation to the ulnar nerve is used to assess the effect of NMB drugs
- adductor pollicis muscle (muscle in hand that controls movement of the thumb)
- -a single twitch using 1 hz from a peripheral nerve stimulator.
- the dose needed to produce 95% suppression of the single twitch response (1 Hz)
- -this is how potency and effect is measured between all NMB drugs
ED95 represents potency of MNBD in the presence of what
- nitrous oxide-barbiturate-opioid anesthesia.
- -this is always assumed unless stated otherwise
in the presence of volatile anesthetics the ED95 is greatly _______?
- -decreased plasma concentrations of NMBDs is required to produce a given degree of blockade in the presence of VA
What muscles are affected first with NMBD
small rapid moving skeletal muscles (eyes and digits) before those of the abdomen (diaphragm)
the onset of neuromuscular blockade after giving a non-depolarizing NMBD is more rapid but less intense at the _______ muscles than the _______ muscles.
- laryngeal muscles than the peripheral muscles (adductor pollicis)
- -the reason for this is because fast muscle fibers are present in muscle used to close the glottis whereas slow fibers are in the adductor pollicis. The density of Ach receptors is greater in the fast fibers so more receptors need to be occupied to block a fast muscle than a slow muscle
The dose of NMBD necessary to produce a given degree of neuromuscular blockade at the diaphragm is about _____ the required to produce similar blockade of the adductor pollicis muscle.
- -adductor pollicis monitoring is a poor indicator of laryngeal relaxation, whereas facial nerve stimulation and monitoring the response of the orbicularis oculi muscle more closely reflects the onset of neuromuscular blockade at the diaphragm
what is the best muscle to monitor the onset of NMB at the diaphragm
- orbicularis oculi -muscle of the eye via stimulation of the facial nerve- ideal muscle to monitor for blockade of the larynx
- -electrodes place lateral to the eye
- a single pulse that is delivered 1 to every 10 seconds (1-0.1 hz)
- -twitch height is compared to pre NMB baseline
twitch height normal until _____% blockade
twitch height 0 when _____-_____% blockade
train of four
- series of four twitches delivered at 2 Hz every half second for 2 seconds.
- results are expressed as
- train of four ration- ratio of the amplitude of the fourth twitch compared to the first, expressed as a ration (requires all 4 twitches to be present)
- -train of four count- counting the number of twitches
Train of four count
4/4= ___% or less blockade
parasympathetic nervous system
- thoracolumbar segment of spinal cord
- 75% comes from vagus nerve
- CN 3,5,7,9
- Preganglionic fiber (Ach) is long, post is short (Ach)
- muscarinic (cardiac) and nicotinic receptors (two types N2 work at NM junction)
sympathetic nervous system
- cranial caudal nervous system
- cranial and sacral part of spinal cord
- has neuron and nerve fibers synapse (preganglionic) from ganglion goes down more fibers (post ganglionic) to the effector site.
- -preganglionic fibers short (synapse right outside spinal cord) post ganglionic long goes to organ site.
- receptor sites adrenergic (alpha, beta, and dopaminergic) usually NE
striated muscle only has _____ ganglionic neuron
- -goes directly from spinal cord to neuron
dopaminergic 1= ______ synaptic
dopaminergic 2=______ synaptic
- 2 is inhibitory by getting rid of extracellular calcium (should be similar to presynaptic)
a single twitch response evoked by using a peripheral nerve stimulator reflects events at the ________ membrane, whereas continuous stimulation of TOF reflects events at the ______ membrane
- postjunctional membrane
- presynaptic membrane
NMBD are highly _____ _____ soluble compounds at physiological pH
- ionized water
- -possess limited lipid solubility and because of this Vd is limited and is similar to ECF volume
NMB can not cross lipid membrane barriers like what?
BBB, renal tubular epithelium, GI epithelium, or placenta so they do not produce CNS effects or affect the fetus/
what are clearance, Vd, and elimination half times influenced by with NMB
age, VA's, and presence of hepatic and renal disease.
the rate of disappearance of long acting NMB from plasma is characterized by a ______ initial decline (distribution to tissues) followed by a _____ decline (clearance)
potency of NMBD
ED necessary to depress single twitch depression 95% (ED95)
onset of NMBD
time from injection to onset of maximal singe twitch depression
duration of action of NMBD
time of injection to return of singe twitch height to 25% or 95%
recovery index of NMBD
time from 25% return of single twitch height to 75% return of single twitch height
clinical duration of NMBD
time from injection to recovery of the TOF ratio to >/= 0.7 or >/= 0.9
how much of non depolarizing muscle relaxant is often recommended to facilitate tracheal intubation
2 x ED95
how much suppression of single twitch response is considered evidence of adequate drug induced skeletal muscle relaxation
Laryngospasms can be treated with small doses of what
SCh as small as 1mg/kg
A TOF ratio of ______ is considered to reflect adequate return of skeletal muscle strength to permit spontaneous ventilation after either spontaneous recovery or pharmacologic antagonism of the effects of non depolarizing NM blockade
- evidence that pharyngeal dysfunction and greater risk of aspiration is present with TOF ratio is <0.9
clinical indicators or residual NM blockade include
- grip strength
- ability to sustain head lift
- vital capacity measurement
- generation of negative inspiratory pressure
what is sequence of onset of NM blockade
- small muscle (eyes and digits) are affected before trunk and abdomen and finally the intercostals and the diaphragm
- -recovery occurs in reverse order, so diaphragm is first to regain normal function
What is something important to remember about NMB and CNS
- conscious and sensorium remain undisturbed even in the presence of complete neuromuscular blockade ( so patient can still think and hear), patient can also still feel pain
- -therefore these meds can not be substituted for anesthetic drugs.
2 alpha subunits on post synaptic cholinergic recptors
- this where Ach binds and causes channel to open causing depolarization. It takes binding of both alpha subunits to open, if only one is bound thechannel remains closed
- -this is also sites for NMBD
- nondepolarizing bind to one or both (lack agonist activity) cause no change, receptor channel remains closed.
- ****if enough channels remain closed their is a blockade of neuromuscular transmission
NMB drugs are structurally similar to what
NM junction consists of what
prejunctional motor nerve ending separated from a highly folded post junctional membrane of the skeletal muscles fiber by a synaptic cleft.
what is the neurotransmitter at NMJ
arrival of nerve impulse at NMJ causes what
release of hundreds of Ach that bind to alpha subunits of nAChRs (nicotinic acetylcholine receptors) on post synaptic membrane causing a change in membrane permeability to ions decreasing the transmembrane potential. this is when action potential spreads causing skeletal muscles to contract.
Release of Ach is dependent on what
- Calcium levels and is triggered by the concentration of free calcium ions in the nerve terminal .
- CCB can interfere with neuromuscular transmission
what prevents sustained depolarization of the NMJ
- rapid hydrolysis of ACH by acetylcholinesterase
nAChR up regulation caused by
SCI, CVA, thermal injury, prolonged immobility, prolonged exposure to NMBD, MS, Gullian Barre syndrome
When are extrajunctional nAChRs present
- when motor nerves are less active because of trauma or skeletal muscle denervation these receptors will proliferate rapidly.
- -highly responsive to agonists such as ACh or SCh
- -these can account for differences in responses to NMBDs
- influence the release of neurtransmitters
- some drugs work on this, but most drugs of clinical importance work post synaptically
drugs of current clinical significance work where