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Boards: Pharmacology > NMBA > Flashcards

NMBA Flashcards

1
Q

Clinical Use of NMBAs

A
  • Eliminate laryngeal spasm, RSI, rapid control of airway
  • Central, immobile eye position for ophthalmic sx
  • Sx access; prevention of spontaneous movement for neurologic, cardiothoracic, ophthalmic sx
  • Decreased resistance to controlled ventilation
  • Reduction of SkM tone
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2
Q

NMJ

A

AKA motor end plate
= communication btw nervous system, m – NMBA interfere/block connection

Prejunctional motor nerve ending, postjunctional membrane of skeletal m

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3
Q

Main NT?

A

Acetylcholine

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4
Q

What is the ACh R?

A

Nicotonic ACh R - LG Na channels

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5
Q

Motor Unit

A

Uninterrupted large myelinated N from SC to NMJ/target m divides into many branches to contact many m fibers

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6
Q

Synpatic Cleft

A

Separates nerve from m

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7
Q

ACh in Presynaptic Nerve

A

o ACh synthesized in nerve terminal, stored in vesicles (quanta)
o Readily available ACh: at edge of presynaptic cell, available for exocytosis/release
o Reserve ACh: deeper in pre-synaptic cell, supply of ACh

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8
Q

Structure of the Postsynaptic M Cell

A

o Surface folded, secondary clefts within primary ones –> large surface area
o Shoulders = nAChRs (~5M/junction)
 Safety feature, have far more than need

VG Na channels in clefts
o Proximity btw VG Na channels, LG Na channels helps to propagate AP
 Change in endplate potential –> AP –> stimulation of m cell –> m ctx

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9
Q

Perijunctional Zone

A

o Immediately below NMJ, crucial for functioning
o Mixture of receptors –> enhances capacity of Na channels to propagate wave of depolarization created by nAChRs

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10
Q

NM Transmission

A

o Nerve synthesizes ACh – stored in small vesicles
o Arrival of AP through nerve activates VG Ca channels via AC, production of cAMP
o Increased intracellular Ca –> migration, discharge of vesicles
o Two molecules of ACh bind nAChR 2 molecules ACh required to activate R
o LG Na channels open, trigger opening of VG Na channels  AP on m – all or none
o Depolarization of m cell (=ctx) occurs after Ca from t-tubules
o ACh immediately detaches, destroyed by AChEs
o Note: activation of process to initiate m ctx vs process of m ctx itself

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11
Q

High Margin of Safety

A

o Amt of quanta released = small fraction of that available
o Safety margin/factor = excess in amplitude of EEP over firing threshold
o AP endplate threshold depends on density, state of excitability of Na channels
o Key: release more ACh than need, have more nAChR than need

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12
Q

Amplitude of end-plate potential (EEP)

A

depends on # of quanta released, # of nAChRs
 Excess of ACh released, nAChRs present several folds above what’s necessary
 Sensitivity of postsynaptic membrane to ACh dependent on density of AChR, AChR conductance
 Redundant: if function decreased, maintain NM transmission

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13
Q

Acetylcholinerase

A

very efficient, much of ACh hydrolyzed before reaches post-synaptic cell (~50%)
o Secreted by m cell
o High concentrations in cleft

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14
Q

nAChRs

A

o Synthesized in muscle cells, anchored to motor end plate membrane by rapsyn protein
o Electron microscopy: central pit (ion channel) surrounded by raised area (binding site)
o 5 subunits, passes through muscle membrane – protrudes in/out

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15
Q

Receptor Density in Junctional Folds

A

Receptor density in junctional folds: 10-20,000/microm2

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16
Q

Interaction btw ACh and nAChR

A

o ACh interacts with two a1 subunits – NEEDS TO INTERACT WITH BOTH
 Protein rotates conformation –> ion channel opens –> ion flow
 Small cations only: Na in, K/Ca out

Binding of ligand to R = competitive process, antagonists have advantage bc only need to occupy 1 R

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17
Q

What are the three types of ACh R?

A
  1. presynaptic
  2. Postsynaptic adult
  3. Postsynaptic fetal
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18
Q

Presynaptic nAChR

A

a3b2 subunits

  • Mediates negative/positive FB loops – neg fb to block ACh release, pos fb to prepare nerve cell to release more ACh for next m ctx
  • Development of fade when blocked by non-depolarizing
  • Not inhibited by sux –> no fade during phase 1 block
  • M1/M2 R (GPCR) also modulate pos/neg fb of ACh release from prejunctional cell via modulation Ca influx
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19
Q

Fetal nAChR

A

 Sometimes called extrajunctional, located all over muscle cell surface
During first few weeks of life, gamma subunit replaced by episilon
See in disuse injury, trauma, burns, nerve injury, muscle atrophy
 Humans: usually decreased within 48hr, can appreciate for up to 2yr
 Different affinity for ACh, different opening times

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20
Q

Consequence of More fetal nAChR

A

decreased sensitivity to non-depolarizing/competitive but increased sensitivity to depol/non-compet (sux)
* ACh channels stay open longer –> more K+ efflux –> extreme hyper K+
* Low conductance channel

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21
Q

Causes of Increased Fetal nAChR?

A

-Spinal cord injury
-Stroke
-Burns
-Prolonged immobility
-MS
-Prolonged exposure to NMBAs

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22
Q

Causes of Downregulated nAChR?

A

-MG
-AChE Poisoning
-OP Poisining

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23
Q

Two Structures of Fetal nAChR?

A

fetal R a1a1b1delta-gamma and a7

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24
Q

Consequence of increased fetal nAChR?

A

Increased sensitivity to sux, increased risk hyperkalemia

Decreased sensitivity to non-depor NMBA

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25
Q

Adult nAChR

A

(a1a1b1delta-episilon): mainly responsible for NMB effects – twitch depression
 How weaker/slower muscular twitch becomes
 High affinity binding site btw alpha and episilon, low affinity btw alpha + beta
 High conductance channel

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26
Q

Two Main Hypotheses Assoc with NMBA

A
  1. Desensitized State Hypothesis
  2. Channel Blockade Hypothesis
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27
Q

Desensitized State Hypothesis

A

o Disruption of NM transmission by NMBA
o R bind ACh to alpha subunits but conformational changes, channel opening does not occur
 R said to be “desensitized”
o Agonists, antag, inhalants appear able to switch to desensitized state
 Explains synergistic actions btw inhalants + NMBAs
o Sux, thiopental, Ca channel blockers, LAs, phenothiazines, cyclohexamines, some ABX

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28
Q

Channel Blockade Hypothesis

A

o Cholinergic R binds agonist to each of alpha subunits –> ion channel opens –> molecule becomes stuck within channel
o Mouth of ion channel much wider than TM-spanning region, permits entrance of ions but not crossing
 Entrapped molecules act like plugs
 Interfere with normal passage of ions IRT binding of ACh
o Blocks normal NM transmission by interfering with depolarization process IRT binding of agonist

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29
Q

Why is the channel blockade hypothesis important?

A

paralysis not antagonized by admin of AChE-I
 AChE-I may increase intensity blockade –> opening of more ion channels IRT greater concentration of ACh may provide increase opportunity for offending molecules to become trapped within channel
o Caused by many drugs, including NMBA

Partial explanation: admin of AChE-I to antagonize profound NMB may intensify paralysis

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30
Q

CV Effects of NMBAS

A

o Similarly in structure btw ACh, NMBA – positively charged nitrogen atom
o Stimulation, blocking of cardiac muscarinic R or of sympathetic ganglia = increase/decrease in HR, development of cardiac dysrhythmias

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31
Q

Effect of rapid IV injection of d-Tubocurarine

A

blocked action of ACh at sympathetic ganglia –> decrease in sympathetic tone, hypotension

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32
Q

Effect of rapid IV inj pancuronium:

A

increase HR DT blockade of cardiac muscarinic R –> decrease PNS activity, +/- release of NE from sympathetic nerves
 Effect = inconsistent btw species: dogs, pigs, ponies yes; horses, calves no

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33
Q

Histamine Release

A

o DT quaternary ammonium structure, cross-bridging with IgE in mast cells
 See quaternary ammonium in foods, household chemical products
o Leading cause of hypersensitivity rxn in ax in people
o Vasodilation, decrease BP, +/- increase HR
o Benzylisoquinolines > steroids with low potency
 Biggest offender = d-Tubocurarine
Atra, but at 2.5x ED50 to cause clinically significant histamine release
o Pretreat with H1/H2 R antagonists, slow IV inj, no more than recommended doses

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34
Q

CNS Effects

A

o Large, polar, hydrophilic molecules – do not readily cross cell membranes BUT most gain access to CSF, may be assoc with resultant CNS effects
o No effect on MAC of halothane reduction in people (panc, atra, vec)
o Accidental admin in CSF: myotonia, autonomic effects, sz

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35
Q

What metabolite of NMBA does have CNS effects?

A

Laudanosine easily crosses BBB in dogs, does not reach clinically applicable doses to cause CNS stimulation with clinically used doses of atracurium

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36
Q

What effect does NMBA have on the urethra?

A
  • Unblocking in male cats: urethra contains skeletal muscle, two papers
    o Galluzzi et al JSAP 2012 – Effects of intraurethral administration of atracurium in male cats with urethral plugs
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37
Q

NMBA Protein Binding

A

o ~50%, All = protein bound, unclear clinical significance
o Only unbound fraction available to interact with AChR
o Potentially decreased renal elimination, bc only free/unbound drug filtered at glomerulus
o Amt of NMBA protein-bound in hypoproteinemic patients seems unchanged (human studies)

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38
Q

General MOA of NMBA

A

o Occupation of only one ACh site required for blockade
o Pre-synaptic R responsible for fade –> only sensitive to non-depolarizing
 Binding of non-depolarizing NMBA to pre-synaptic R blocks the feedback loops so that no mobilization of stored/reserve ACh to periphery
 When keep stimulating nerve, runs out of ACh – hence fade on TOF

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39
Q

What is true about NMBA use in birds?

A

WILL CAUSE MYDRIASIS IN BIRDS DT SKELETAL M IN PUPIL

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40
Q

Important Clinical Features of NMBA

A

o Muscles of respiration = paralyzed  must control ventilation
 Diaphragm less sensitive to NMBA than limbs
 Lower density of ACh R in slow muscle fibers in peripheral m vs faster m fibers in laryngeal muscles, etc

Horses: dose required to abolish hoof twitch, facial twitch remains at decreased strength
o Upper airway m very sensitive to NMB
 Humans: if not reversed, 2x as likely to develop pneumonia

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41
Q

Onset/Offset of NMBAs

A

related to blood flow, rate of drug delivery to tissues
 Greater blood flow per g of m: higher peak plasma concentration of drug, rapid redistribution

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42
Q

General Features of NMBAs

A

No sedative, analgesia, or anesthetic properties

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43
Q

Assessment of Ax Depth with NMBAs

A

Assessment of ax depth = more challenging; palpebral reflex, jaw tone, spontaneous movement to assess depth not usable

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44
Q

Speed of Onset of NMBA

A

Inversely proportional to potency

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45
Q

Charge of NMBAs

A

PK markedly different from other agents (propofol, etc): rapid onset, rapid termination DT rapid metabolism, redistribution to skeletal m/adipose tissue

Hepatic metabolism, redistribution to sites other than skeletal m not major mechanisms of action termination

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46
Q

Do NMBAs cross blood brain barrier or blood placental barrier?

A

NO!
* Also DT quaternary ammonium moieties
* No effects on neonates when used in C sections

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47
Q

Other differences with NMBAs vs most other anesthetic agents?

A

o Limited Vd, esp compared to most other ax agents – poor lipid solubility
o Easily excreted by glomerular filtration into urine DT water solubility, generally not reabsorbed by renal tubules
o Neonates: require higher doses —> higher percentage body water, higher vol for water-soluble drugs to distribute into

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48
Q

Two Main Types of NMBA

A
  1. Competitive/Non-depolarizing
  2. Non-competitive/Depolarizing
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49
Q

Two Subcategories of the Non-Depolarizing NMBAs

A

Aminosteroids
* Vecuronium, pancuronium, rocuronium, pipercuronium
Benzylisoquinolinium
* Atracurium, cis-atracurium, mivacurium, doxacurium

MOA: bind to a subunit

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50
Q

Succinylcholine

A

o 2 ACh molecules
 Binds to ACh R –> opens channel, prolonged depolarization of EP = m fasciculations
o Biphasic action: first produces stimulation (m fasciculations), drug stays bound to R, then block
 R unavailable vs refractory period

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51
Q

SE of Succinylcholine

A

Causes changes in HR, BP

All else normal: increase K by 0.5mEq/dL
 Movement of Na into cells, K out of cells
 BAD if metabolic acidosis, hypovolemic – source of K = GI

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52
Q

Use of Sux

A

o Rapid-sequence induction (RSI) in people bc fastest acting, not short acting in some species
 Horses, cats, humans: PChE high, sux broken down quickly
 Dogs: PChE activity mediocre, sux broken down more slowly

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53
Q

Sux Metabolism

A

Broken down by pseudocholinesterases/plasma cholinesterase

Hydrolysis rapid: only 10% of original injected dose survives degradation in plasma to reach site of action

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54
Q

Termination/Accumulation of Sux

A

Termination of sux depends on diffusion of drug away from NMJ, into ECF
* DOA depends on plasma clearance

Minimal accumulation following large or repeated doses
* Metabolite succinylmonocholine much weaker, slower metabolism

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55
Q

PChE

A

 Synthesized in liver
 Very little PChE present in synaptic cleft

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56
Q

Drugs that Will Prolong Succinylcholine Activity

A

Inhibit PChE

esmolol, MAOi, chemotherapeutic agents/cytotoxic drugs, metoclopramide, OP insecticides in horses, bambuterol (prodrug of terbutaline)
* Also liver dz, chronic anemia, malnutrition, burns, pregnancy, old age
* NOT clinically significant: large decreases in PChE activity –> modest increases sux DOA

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57
Q

Do you see fade with Sux?

A

Pre-synaptic ACh R not sensitive to succinylcholine – DO NOT SEE FADE!

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58
Q

Phase I Block

A

end plate depolarization initially stimulates m ctx but sux not degraded by AChE –> remains in NMJ to cause continuous end plate depol/m relax

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59
Q

Phase II Block

A

IV infusion, large dose, repeated doses
* Continuous activation of AChR: ongoing shifts in Na into cell, K out
* Post-junctional membrane potential eventually moves in direction of normal even in presence of sux DT Na-K ATPase pump (K in, Na out)
* R does not respond appropriately to ACh, NMB prolonged

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60
Q

Dibucaine Test

A
  • Test for PCheE function in humans
    -If normal PChE, admin of dibucaine (LA) will interfere with function of normal PChE, abN PChE less inhibited

Single aa substitution/sequencing error at or near active site of enzyme

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61
Q

Normal Genotype for PChE:

A

70-80% PChE inhibition

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62
Q

Heterozygous for PChE:

A

50-60% inhibition, 1-2x prolongation of succ

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63
Q

Homozygous for PChE:

A
  • Homozygous: 20-30% PChE inhibition, up to 8hr prolongation of sux
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64
Q

Dibucaine #

A

% Inhibited

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65
Q

Atypical Cholinesterase

A

won’t break down sux, require plasma transfusion

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66
Q

Cardiac Effects of Sux

A

mimics effect of ACh at cardiac muscarinic R  sinus bradycardia, junctional rhythms, sinus arrest
 Decreases threshold of ventricle to catecholamine-induced dysrhythmias in monkeys, dogs

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67
Q

Effects of Other Autonomic Stimuli on Sux

A

ET intubation, hypoxia, hypercarbia, sx – additive effects

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68
Q

Effects of Sux on other NMBA

A

increase duration of atra, roc if given first but not panc
o Admin of AChE-I following sux will PROLONG DURATION

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69
Q

Non-NM Effects of Sux

A
  1. Hyperkalemia
  2. Increased IOP
  3. Increased intragastric pressure
  4. Increased ICP
  5. Increased m pains
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70
Q

MOA Hyperkalemia with Sux

A
  • Binds to nAChR, not degraded by AChE vs ACh –> persistent state of depolarization + open ion channels
    o K: muscle fibers –> extracellular space
  • Transient increase in K concentrations following sux dose (0.5mEq/mL)
  • Increased density fetal nAChR following nerve injury, etc: increase intracellular K released
    o Risk: 48hr post injury, persists 2-3mo up to 2yr
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71
Q

MOA Increased IOP with Sux

A
  • Transient, peaks 2-4’, remains increased for 6’
  • MOA unknown – dilation of choroidal BV, ctx tonic myofibrils
  • Avoid in veterinary patients with penetrating eye injuries
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72
Q

MOA Increased Intragastric Pressure

A
  • Abdominal skeletal m fasciculations from initial depolarization of motor end plate  abdominal compression, increased intragastric pressure
  • +/- worsen incidence of regurg, may worsen outcome in GDV
  • Variable, patient dependent
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73
Q

MOA Increased ICP with Sux

A
  • Proposed MOA: m fasciculations
  • Humans: prevented by prior admin of d-tubocurarine or another non-depol
  • Avoid in patients with increased ICP
74
Q

M Soreness Following Sux

A
  • Humans: post ax m soreness&raquo_space;> veterinary patients
  • Proposed MOA m fasciculations during initial depolarization of motor endplate, good correlation btw intensity of fasciculations + intensity of pain
    o Reduced by pre-tx with prostaglandin inhibitor
  • Increased CK in humans + myoglobinuria, animals following sux admin
  • Also see masseter m rigidity
75
Q

Pancuronium

A

–Steroid structure
–Onset 5’, DOA 40-60’ in dogs
–Repeated doses = cumulative effect
–Renal&raquo_space;> hepatic metabolism, prolongation of effects in patients with renal insufficiency

Removal of one methyl group/one positive charge = vec

76
Q

Cardiac Effects of Pancuronium

A

o Blocks cardiac muscarinic receptors
 Vagolytic properties DT presence of second positive charges within steroid molecule
 Increased HR
 Varies among species, not always clinically relevant

77
Q

Atracurium

A

o Onset ~5’, DOA 30’ in dogs – noncumulative with repeated doses
o Racemic mixture of ten optical isomers
o Metabolism: Hoffman elimination, plasma esterases

78
Q

Metabolism of Atracurium

A

Metabolism: Hoffman elimination, plasma esterases
–HE not a biologic process, does not require enzyme activity - temp, pH dependent
–Remaining fraction degraded by unknown routes
–Not prolonged in people with renal, hepatic failure

Plasma esterases not related to PChE, DOA not prolonged in presence of AChE-I

79
Q

Storage of Atracurium

A

Refrigerated, pH 3.25-3.65 to slow degradation

80
Q

Effects of Atracurium Metabolism

A

o Following IV admin at physiologic pH/temp, spontaneously decomposes into laudanosine, quarternary monoacrylate
Laudanosine = known CNS stimulant, potential to induce sz
 Hepatic clearance –> concentrations may be elevated in patients with hepatic dz
 Effects unlikely to be problematic unless used for prolonged periods

81
Q

Other Features of Atracurium

A

o Hypothermia: prolong duration, decrease infusion rate needed to maintain NMB
o Risk of histamine release present, less vs d-Tubocurarine
–Several times ED95 required for NMB before appreciable amounts of histamine released

82
Q

Cisatratracurium

A

o 1R-cis, 1R-cis’isomer of atracurium
o 15% racemic atracurium, 4x potency (smaller dose required vs atracurium), decreased histamine release, similar onset/DOA
o Hoffman elimination >50%
 Laudanosine production, less than atracurium
 No ester hydrolysis

83
Q

Vecuronium

A

w/o significant CV effects – no tachycardia, histamine release
o Removal of single methyl group from pancuronium = vec
o Dogs: does not change arterial BP
o Dose-dependent onset of action of ~5’, intermediate duration ~30’
 Don’t see cumulative effect with subsequent doses

84
Q

DOA of Vec

A

o Dose-dependent onset of action of ~5’, intermediate duration ~30’
 Don’t see cumulative effect with subsequent doses

85
Q

Storage/Formulation of Vec

A

Unstable when prepared in solution —> lyophilized powder, add sterile water prior to admin

Stable for 24hr at room temp once reconstituted

86
Q

Metabolism of Vec

A

o More than half drug metabolized by hepatic microsomes, excreted in bile – significant fraction undergoes renal elimination
o Humans: duration slightly prolonged/normal in patients with renal insufficiency; hepatic failure prolongs DOA only if increased doses administered

87
Q

Rocuronium

A

o Derivative of vecuronium, 1/8 potency of vec – similar MWs
o Larger dose  greater # of molecules near NMJ  more rapid onset of NMB
 Optimal conditions for intubation not as rapid as succinylcholine
o DOA: similar to vec, atracurium
o Virtually without CV AEs, no histamine release
o Primary route of admin: hepatic, small fraction eliminated via kidney

88
Q

Pipercuronium

A

o Steroid, derived from pancuronium
o Greatly decreased antimuscarinic effects – free of tachycardiac effects while retaining long DOA
o Hypotension in dogs
o Eliminated primarily by renal route, smaller fraction = biliary excretion

89
Q

Doxacurium

A

o Very potent benzolisoquinolinium
o Long DOA
o No vagolytic properties, no ganglion blockade, no appreciable histamine release
o Minimally metabolized –> excreted unchanged into urine, bile

90
Q

Mivacurium

A

o Not currently available
o Rapid-acting, short-duration – human tracheal intubation
o Potential for histamine release, esp if high dose
o Degraded by plasma PChE, metabolites do not have appreciable NMB activity

91
Q

Mivacurium Metabolism, DOA

A

o Degraded by plasma PChE, metabolites do not have appreciable NMB activity
 Canine PChE enzyme: differing affinity for three primary isomers of mivacurium found in proprietary formulation
 Cats: much shorter DOA than in dogs

92
Q

Mivacurium vs Humans

A

o DOA in humans: 25’
 Marked differences in potency, in duration of action among species
 Potency in dogs&raquo_space;> humans
 1/3 dose in dogs 5x longer than in humans potentially DT differences in circulating quantities of PChE (normal in dogs 19-76% vs humans)

93
Q

Gantacurium

A

o Fumarate
o Rapid-acting, ultra-short duration non-depolarizing NMBA
o Not stable in aqueous solution, provided as lyophilized powder – requires reconstitution

94
Q

Gantacurium Metabolites

A

o Metabolites: CW002 (short acting, 5’), CW011 (intermediate acting, 40’)
 CW bc developed at Cornell Weill 

95
Q

Use/Effects of Gentacurium

A

 IV bolus 0.45-0.54mg/kg (2.5-3x ED95): optimal conditions for intubation in 90s
 Short DOA: 14’ at 0.4mg/kg IV
 Histamine release >2.5x ED95 – clinically significant decrease in BP, increase in HR/facial redness
 Not observed in dogs at 25x ED95

96
Q

Metabolism of Gentacurium

A
  1. pH-sensitive hydrolysis in plasma
  2. Inactivation
    –Binding of non-essential amino acid cysteine to gantacurium ring structure –> endogenous or exogenous cysteine replaces chlorine atom, saturates double bond of fumarate moiety –> inactive, NM transmission resumes
97
Q

Reversal for Depolarizing NMBA

A

o Recovery from Phase I block rapid, spontaneous – sux hydrolysis by plasma esterases
o Potentially delayed recovery in patients with decreased PChE activity
o Admin of AChE-I would prolong NMB
o Phase II block: antagonized similarly to non-depolarizing muscle relaxant, emphasizing importance of determining type of block

98
Q

Role of AChE and Admin of AChE-I in NMJ

A

AChE hydrolyzes ACh into choline, acetic acid

Admin of AChE-I increases concentration of ACh molecules at NMJ –> competes with NMBA for same postsynaptic binding sites

AChE-I is NOT NMBA antagonist - reversal (recovery) is accelerated/enhanced

99
Q

Limitations of reversal

A

Indirect MOA
Ceiling Effect
Cannot reverse deep block with traditional means

100
Q

AChE-I + Anticholinergic Reversal

A

Goal: increase amt of ACh in synaptic cleft, compete with NMBA for binding site

Competition based in favor of relaxant bc binds 1 alpha subunit vs 2
Reversal not instantaneous, usually within 5’

Onset of action: edrophonium < neostigmine < pyridostigmine

101
Q

Edrophonium

A

reversible inhibition by electrostatic attachment to anionic site, hydrogen bonding at esteratic site on AChE

Give anticholinergic first bc onset of action faster than atropine

DOA brief, no covalent bonds formed

ACh can easily compete with edrophonium for access to enzyme
 Human patients: neostig 5.7x more potent than edrophonium

102
Q

Neostigmine, pyridostigmine

A

 Bond lasts longer than ACh+AChE –> prevents AChE from degrading ACh
 Neostigmine = more potent, more severe muscarinic effects

103
Q

Neostigmine metabolism

A

50% hepatic

104
Q

Edrophonium Metabolism

A

30% hepatic

105
Q

Pyridostigmine Metabolism

A

25% Hepatic

106
Q

What happens to AChE-I not metabolized by liver?

A

 Renal excretion of remainder, prolonged elimination in renal failure patients

107
Q

DOA of AChE-I

A

o edrophonium ~ neostigmine, pyridostigmine 40% longer
o Cats: neostigmine 12x more potent than edrophonium

108
Q

Problem with AChE-Is

A

increases ACh accumulation everywhere  muscarinic effects on heart
 Bradycardia, bronchospasm, salivation, lacrimation, miosis, intestinal hyperplasia
 Give atropine or glyco immediately prior to AChE-I
* Humans: usually give as mixed
 Atropine: more rapid onset, glyco onset of action ~ neostigmine

109
Q

Paradoxical Block with Neostigmine

A

 When given alone in non-relaxed patients, can induce NMB
 Mixed evidence: if admin too late during recovery (TOF >0.8), could induce weakness
 Romano, dogs: transient decerease in TOF ratio when neostigmine given at TOF ratio >0.9
* Twitches stronger, but 4th strength increased less than 1st twitch strength

110
Q

Sugammadex

A

SRBA = selective relaxant binding agent
o STEROIDS ONLY
o Primarily used for rocuronium > vecuronium (potency 1:6 – check this)
o Binding efficacy: roc > vec (slightly lower binding affinity)
o gamma-monocyclodextran

111
Q

MOA Sugammadex

A

o Selectively binds roc by encapsulation in plasma –> creates concentration gradient –> pulls roc from NMJ into plasma, increases plasma concentration of roc (free roc + encapsulated roc)
o Can reverse deep block quickly: dogs, ponies 4mg/kg

112
Q

Reversal Agent for Fumarates?

A

L-cysteine

113
Q

Calabadion

A

o Harvard – similar to sugammadex, chelate agents and render useless
o Can use with ANY NMBA
o Problem: can also bind to other substances, might take away other important things (abx)

114
Q

Impaired Metabolism, Excretion

A
  • Hepatic insufficient: potential to alter initial effects DT increased Vd (decreased effect), decreased elimination if hepatic metabolism
    -BDO: decreased clearance
    -Decreased esterase activity slows biotransformation
    -Renal insufficiency
115
Q

Role of Ax Drugs

A

o Inhalants: time, dose dependent enhancement of intensity/duration of NMBA
 Suppression of motor-evoked potentials IRT SC, transcranial stimulation
 Alteration of m contractility
 Variation in regional blood flow: greater fraction of NMBA reaches site of action

116
Q

Potentiation of NMBA by Inhalants

A

o Potentiation: diethyl ether > enflurane > desflurane > sevoflurane > isoflurane > halothane > N2O/barbiturate/opioid or propofol ax
 Greater clinical muscle-relaxing effects produced by less potent ax DT larger aqueous concentrations

117
Q

Proposed MOA of Effect of Inhalants on NMBA

A

 Des, sevo = low blood-gas, low tissue-gas solubility – equilibrium btw end tidal concentration and NMJ reached more rapidly with new ax than older ones
 Proposed MOA: central effect on  motoneurons, inhibition of postsynaptic nAChR, augmentation of antagonist’s affinity at R site
o Can also delay antagonism esp if inhalant ax continued after admin of reversal agent
o Injectables: +/- minimal enhancement – propofol, ketamine, thiopental

118
Q

Effect of AB Disturbances

A

o Resp acidosis - increases intensity of NMB
o Resp alkalosis – decreases intensity of NMB
o Metabolic acidosis, alkalosis – potentiate effects, more difficult to antagonize

119
Q

Effect of Potassium on NMBA

A

Hypokalemia: hyper polarization of end plate, resistant to ACh-induced depolarization
Hyperkalemia: lowered RMP, opposes effects

120
Q

Role of Magnesium on NMBA

A

Increased serum Mg compete with iCa, increased ACh release

Patients admin mag sulfate: DOA of m relaxants increases

121
Q

Effect of Calcium on NMBA

A

Hypocalcemia: increased effect DT decreased ACh
Hypercalcemia: decreased

122
Q

Role of Hypothermia on NMBA

A

o Slows drug elimination, decreases nerve conduction, decreases m ctx
o Hoffman elimination = pH/temp dependent, more dramatic effect of benzylisoquinolones
o 10-15% decrease for every degree <36

123
Q

NMBA in Pediatrics

A

o Youth: receptor immaturity, decreased clearance - increased potency in young
o Very young animals: decreased ECF, larger Vd vs adults – may require higher doses
 Faster onset, faster recovery of NM function
 Lower dose of antagonist required

124
Q

NMBA in Geriatrics

A

o Old age: assoc with increased effect, lower Vd/impaired clearance
 Higher doses for reversal often needed, slower spontaneous recovery

125
Q

NMBA and NM Disorders

A

o Unpredictable responses to depol, non-depol NMBA
o Peripheral neuropathies: increased effect of depol DT proliferation of fetal nAChR, increased risk of sux-induced hyperkalemia

126
Q

Tick Paralysis, Botulism

A

impaired presynaptic release of ACh, increased sensitivity to NMBA

127
Q

Myasthenia gravis

A

autoimmune dz, generalized m weakness from decreased nAChR on motor end plate so ACh released normally but effect on postsynaptic membrane decreased
Resistant to NMB with sux
Extremely sensitive to non-depol NMBA, phase II block with sux
 No increased sensitivity to sux induced hyperkalemia, MH

128
Q

Polymixin

A

depress postsynaptic activity to ACh, enhance channel block

Antagonism with neostigmine, calcium = unreliable

129
Q

Aminoglycosides

A

(gent, neomycin, tobramycin, amikacin, etc): presynaptic site of action, depressed ACh release
 Decreased twitch tension but no change in recovery times in dogs, cats, horses

130
Q

Tetracyclines

A

decreased ACh release via Ca chelation
 Enhanced blockade usually reversible with Ca, not neostigmine

131
Q

Lincosamines

A

o Lincomycin: direct inhibitory effect on muscle, +/- pre/post synaptic activity
 Partially reversed with 4-aminopyridine
Clindamycin&raquo_space;> lincomycin

132
Q

Lithium

A

increased NMB, competes with Na, decreased ACh release

133
Q

Effect of LAs

A

Enhance NMB by both non-depolarizing, depolarizing NMBAs

134
Q

Effect of Steroids

A

prolong, antagonize effects of non-depolarizing agents

135
Q

Monitoring of NMBA

A
  • PNS + way to measure response
    o Check how well nerve able to communicate with muscle, NOT a check of muscle function
    o Observation of spontaneous movements, resp movements or even measurements of respiratory variables not good surrogates
136
Q

MOA of NMBA Monitoring

A
  • Stimulate peripheral motor nerve – fibular/peroneal, ulnar, radial N
    o Short stimulus so that stimulates nerves without stimulating muscle, current such that will stimulate all muscle fibers
137
Q

Duration of NMBA - affected by lot of things

A

o MMF 2014 Recovery from Neuromuscular Block and Spontaneous Ventilation in Dogs
o Parameters of ventilation returned several minutes prior to return of NM function
o Different muscles have different sensitivities to NMBA
 Diaphragm: insensitive to NMBA, returns first (curare cleft on ETCO2)
 In people, larynx btw diaphragm and adductor pollis (thumb) m – what used to monitor NMBA
 Can’t monitor NM function in whole animal, pick group and extrapolate so pick group that most sensitive to monitor

138
Q

Why Should We Monitor NMB?

A

o Redose if need be (1 twitch)
o Determine whether CAN reverse +/- attempt reversal with neostigmine
o Check of residual blockade

139
Q

Hertz

A

1 cycle per second
 1 Hz = 1 stimulus per second
 0.1 Hz = 1 stimuli per 10s

140
Q

Constant Current Stimulator

A

Charge = voltage x duration

141
Q

Stimuli

A

constant – changes attributed to transmission, not stimulus
 Set current constant even if impedance through skin changes (temp, desiccation)
o Usually supramaximal (20-30% higher than maximal)
 Ensures all nerve fibers depolarized, all muscle fibers recruited

142
Q

Type of stimulus and why?

A

o Square wave stimulus, duration: 0.1-0.3msec
 Avoids direct muscle stimulation
 Want NERVE to stimulate the muscle

143
Q

Single Twitch

A

o 0.1Hz (Q10s)
o Not used clinically anymore, used in potency studies
o Baseline needed (Tc) – all subsequent measures expressed as Tw/Tc
 Measure height, force (MMG), AP (EMG) or velocity (AMG)

144
Q

Limitations of Single Twitch

A

o Insensitive to detect residual block
 Could have residual block even if baseline returns to normal
o Does not discriminate btw depolarizing, non-depolarizing
o ACh release decreased by prejunctional effects of relaxant  frequency of single-twitch stimulation should be no greater than Q7-10s
 Stimulus too frequent, resultant twitch response artificially low

145
Q

Single Twitch: Depressed Response

A

not depressed until 75-80% receptors occupied, twitch response abolished when ~90-95% R blocked

146
Q

Train of Four

A

o 4 (supramaximal) stimuli at 2Hz, each TOF separated by 10-20s
 1 stimuli Q0.5s, 2x per second
 Can separate TOF > 10-20s – if <10-20s, will have refractory period

147
Q

Advantages of TOF

A

o No control needed: measurements not expressed in reference to baseline

148
Q

Subjective TOF

A

count (TOFc)
 Fade cannot be subjectively evaluated once TOF >0.5
 Observing or palpating twitches is not sensitive way to determine residual block

149
Q

Objective TOF

A

o If objective, TOF ratio (T4/T1) – compare intensity of fourth twitch to first twitch
o TOF ratio >1.0 (100%) without relaxants
 Following admin of non-depolarizing NMBA, twitches begin to fade when 70% R occupied (4th  3rd  2nd  1st)
 If T4:T1 > 100% following NMBA reversal, know no residual blockade
 If T4:T1 <100%, have some degree of NMB/dysfunction

150
Q

NMBA Recovery per ACVAA Consensus Statement

A

o LJ, ACVAA Consensus Statement (2009): T4:T1 >0.7 assoc with adequate signs of recovery from NMBA; human medicine/MMF >0.9

151
Q

Phase I vs Phase II Block with TOF

A

o Phase I block from depolarizing NMBA: fade absent
 Repeat admin or CRI of sux –> phase II block, will see fade following TOF stimulus

152
Q

Double Burst

A

 2 mini tetanic sequences of 3 stimuli at 50Hz (Q0.02), separated by 750msec
 LJ: 2 minitetanic bursts, 2-4x each
 Can see or measure fade
o Produces two large twitches, ratio of 2nd burst to 1st burst: D2:D1

153
Q

Why use Double Burst?

A

o Attempt for easier observation of fade
o LJ: possibly superior to TOF, correlates highly to TOF when assessed via MMG – fade more readily seen with DBS using both visual, tactile means
 Humans: able to subjectively identify when NMBA at 0.7 vs 0.4-0.5 for TOF
o MMF: Virtually same issues as TOF  in dogs, no better than TOF to identify partial blockade

154
Q

Tetanic Stimulation

A

–Sustained m contraction
–o Most common: 5sec at 50-100Hz ie stimulus Q0.01-0.022s for duration of 5 seconds
 Lot of stimuli given very close together
 No more frequently than Q2-3min bc produces potentiation
 Insufficient ACh released, contraction starts to get weaker - decrease tetanic height

155
Q

Physiological Principles of Tetanic Stimulation

A

Massive influx of Ca into presynapatic cell –> massive immobilization of ACh to periphery –> ACh competes with NMBA –> for short period of time, ACh can displace NMBA from nAChR

156
Q

Use of Tetanic Stimulation

A

o No fade without NMBA, fade with partial NMB from non-depolarizing relaxant admin
o Helpful for detecting residual NMB
o Only with nondepolarizing (or phase 2)
o IT HURTS in lightly anesthetized or conscious patients

157
Q

Post-Tetanic Fasciculation/Post Tetanic Count

A

o When have no twitches on TOF, allows you to monitor depth of blockade and predict return to function
 Applied when TOFc is zero
 Monitor deep blockade

158
Q

MOA PTC

A

Usually consists of 15 single twitches (ST) [not going to produce response bc patient paralyzed BUT will mobilize large amt ACh], then TET, then 15ST – last 15ST represents PTC
 Bc so much ACh, will have twitches with second set of single twitches
 # of ST observed after TET inversely related w/ time to return of T1 (TOFc T1)

159
Q

How Interpret PTC

A

 # of ST observed after TET inversely related w/ time to return of T1 (TOFc T1)
* If only few single twitches, LOT of NMB
* If have many single twitches, not as much NMB
* Ex: if have 12 ST, will get first twitch on TOF back sooner vs if have 3 ST, going to be awhile before first twitch on TOF

160
Q

Why is PTC Beneficial?

A

o Proposed MOA: increased ACh release from nerve terminal
 This large mobilization of ACh is the post tetanic fasciculation
o First clinical indicator of recovery from NMB
o In humans, some procedures require profound blockade –> PTC allows estimation/prediction of time to return to function

161
Q

Ways to Quantify Evoked Responses

A
  1. Mechanomyography
  2. Electromyography
  3. Acceleromyography
162
Q

MMG = mechanomyography

A

 Measurement of isometric force of contraction
 Gold standard
 Cats, horses, dogs, ponies, cows, llamas
 Wire or suture connected to tendon to measure force, cumbersome

163
Q

MOA MMG

A

 Limb must be immobilized, no movement should occur
* Force transducer attached to paw or hoof at a right angle to direction of muscle contraction
* Maximum evoked muscle-twitch tension: resting tension 100-300g should be applied
* Resultant twitch tension can then be quantified

164
Q

EMG = electromyography

A

 Compound AP of muscle fibers contracting during supramaximal stimulus of peripheral motor nerve
 Recording electrode: placed over innervation zone of m, midway btw origin and insertion
 Reference electrode required – over insertion site
 Ground electrode – btw other two electrodes

165
Q

Advantages of EMG

A

requires less or no limb mobilization, no resting tension, more choices as to which muscles may be used

166
Q

Disadvantages of EMG

A

difficult to obtain proper electrode placement for accurate results, particularly in smaller patients

167
Q

Dogs and EMG

A

Dogs: no statistical difference btw MMG, EMG during TOF stimulation for either T1 or T4:T1

168
Q

AMG = Acceleromyography

A

 Most commonly used
 Acceleration  Newton’s Second Law, requires free moving limb
 Piezoelectric crystal

169
Q

Consequences of Post-Operative Residual Curarization

A

o Mild discomfort: diplopia
o Hypoxia: NMBAs interact at carotid bodies, blunt responses to [isocarbic] hypoxia
 No changes IRT hypercarbia
 People: TOFr 0.7-0.8 decreases response (LI Eriksson)
o Aspiration: awake volunteers fail to swallow at TOFr at 0.7-0.8 – without contribution of residual sedatives/hypnotics (LI Eriksson)
o Intraoperative AMG decreases postop negative respiratory events in people (GS Murphy)

170
Q

PORC in Veterinary Medicine

A

almost no info in veterinary medicine
o In dogs, some laryngeal m recover SLOWER than limbs – opposite in people
o Sakai et al, Tseng et al: laryngeal m 5-15’ slower than limbs
o MMF: recover to TOF 1 (100%) + 15’
 If TOF >0.7-0.8, atropine 0.02+neostig 0.02mg/kg
 If TOF >1-2 twitches <0.7, atropine 0.02+neostig 0.04mg/kg (up to 0.07)

171
Q

Horses and NMBA

A

residual NM dysfunction problematic during recovery, want NO degree of residual block but also don’t want to give atropine
 Can give neostig to horses without atropine
 MMF would use edrophonium, use smallest dose of NMBA (atra 0.08mg/kg for ophtho bc eyes so sensitive to NMBA), would use roc/Sugammedex

172
Q

Guanifenesin

A

M relaxant in LA

Therapeutic doses: little effect on resp m or diaphragm
o No analgesia, no antagonist
o Does not produce unconsciousness

173
Q

MOA GG

A

o Disrupt nerve impulse transmission at level of internuncial neurons of SC, BS, subcortical areas of brain

No analgesia, no antagonist, does not produce unconsciousness

174
Q

Formulations of GG

A

powder + sterile water (5, 10, 15%), most commonly 5% in 5% dextrose

Keep warm - will precipitate out

175
Q

SE of GG

A

o IV at high concentrations (>10%, in cows >5%) –> hemolysis, hemoglobinuria, venous thrombosis
 Tissue damage if inadvertent perivascular injection

176
Q

Dantrolene

A

Hydantoin derivative, interferes with E-C coupling –> relaxes skeletal m through decreases in amt of Ca released from SR into cytoplasm

177
Q

Dosing of Dantrolene

A

o Therapeutic doses: do not depress respiration, do not adversely affect CaM or SmM

Under GA: decreased MV DT decreased VT/decreased RR

Doses:
 Dogs, cats 1-5mg/kg IV, 5-6mg/kg PO SID for prophylaxis
 Pigs 1-3mg/kg IV, 2-5mg/kg PO

178
Q

Formulations of Dantrolene

A

o Solutions of reconstituted with 60mL sterile water to 0.33mg/mL = light sensitive, stable for 6h; also have 100mg capsules
 20mg vials in powder + 3g mannitol to improve solubility

179
Q

Prophylactic Use of Dantrolene

A

 Does not guarantee effective blood levels
 Horses: unwanted skeletal m weakness during recovery
 Avoid volatiles, have injectable available if needed – can compound PO preparation for IV use

180
Q

Metabolism of Dantrolene

A

liver through oxidative, reductive pathways

Metabolites, unchanged drug excreted in urine

181
Q

SE Of Dantrolene

A

m weakness, nausea, diarrhea
 Chronic tx in human patients = fatal hepatitis
 Severe myocardial depression if given with verapamil, other Ca channel blockers
 Delayed recovery of NMB with vecuronium

Boards: Pharmacology (9 decks)

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