Neuromuscular Blocking Drugs Flashcards
Physio-chemical properties of muscle relaxants
- Highly H20 soluble/ Relatively hydrophilic
- Easily excreted in urine (and bile)-watch renal pts.
- DOES NOT cross lipid membranes (BBB, most cells, placenta)
- Small Vd
- Relatively less actively metabolized by liver than lipophilic compounds
How are Neuromuscular Blocking Drugs classified
- By Mechanism (Depolarizing, Non depolarizing)
- By Duration (Short, intermediate, or long acting)
- By structure (Aminosteroid, Benzylisoquinolinium)
***Depolarizing Muscle Relaxation
- Depolarizing block-Action same as Ach, only longer r/t slower hydrolysis by plasma (pseudocholinesterase)
- Reacts with nicotinic receptors to open channel & cause depolarization @ end plate
- Phase 1 &2 blockade
- Succinylcholine (Sux) is only one available in U.S
Phase 1 depolarizing MOA
- accompanied by fasiculations
- desired/ expected block
How is phase 1 Neuromuscular Blockade reversed
hydrolysis
**Effect of anticholinesterase agent during phase 1 depolarizing block
-block is augmented (enhanced) not reversed. (Ach levels will increase which will cause depolarization therefor increasing the effect)
***Cause and characteristics of phase 2 block
- From continued Sux exposure (high dose or inadequate hydrolysis)
- Characteristic nearly identical to NDMB (r/t sux blocking receptors)
- Reversible by anticholinesterase drugs (pt. gets better)
Cause of inadequate hydrolysis of Sux
Pseudocholinesterase deficiency
***How is Succinylcholine broken down. Any metabolites
- Rapid hydrolysis in plasma (Pseudocholinesterase)
- weakly active metabolite: succinylmonocholine which is broken down to succinic acid and choline
Where is Pseudocholinesterase produce. What will effect its production? What can effect the degree of activity
- Produced in liver
- Advance liver disease will will effect production
- Degree of activity may be effected by genetics (pts w/ atypical Pseudocholinesterase)
- What is the most important genetic variation of pseudocholinesterase enzyme and why?
- What is the effect of having this variant?
-Atypical pseudocholinesterase-Dibucaine-related variant
inhibits normal enzyme function by 80% and atypical by 20%
Prolong effects of Sux
***The dibucaine number effects______ of the enzyme not _____of available enzyme
- quality
- not quanity
*****Dibucaine numbers r/t effects
80= normal (96%) 60-79= slightly prolonged response (1:200-480) 20-45(59)= greatly prolonged response (1:20,000)
***Cardiac side effects of Sux
- BRADYCARDIA, sinus arrest due to muscarinic stimulation (worst after subsequent doses); worst in pediatric pts.
- Hyperkalemia (contraindication)
Possible causes for hyperkalemia
- result of proliferation of extrajunctional cholinergic receptors in nerve damage or denervated states providing sites for K+ to leak from cell during depolarization
- Pt. with muscular dystrophy, unhealed 3rd degree burns, denervation states, motor neuron lesions, severe skeletal muscle trauma
Succinylcholine is a trigger for this life-threatening state and its effects are also confused with this condition
Malignant hyperthermia
***Cause of Malignant hyperthermia (MH). How is it diagnosed
- Autosomal dominant inherited skeletal muscle disorder
- Dx. by muscle biopsy
**2 biggest triggers of MH
- Volatile agents
- Succinylcholine
signs of symptoms of MH crisis
- Increased HR, ET CO2, Temperature (comes later)
- Muscle rigidity (Masseter muscle may be 1st sign)
- Decrease CO2
- Hyperkalemia, acidosis
Safe anesthetic to give to pt. with hx. of MH
- Regional
- N2O
- TIVA
Medication given to treat MH, action, and dose
- Dantrolene (impairs Ca releasefrom sarcoplasmic reticulum causing relaxation)
- 2.5mg/kg IV. Can add up to 9-10mg/ kg
Succinylcholine: How supplied? Dose?
- 20mg/ ml (also 500mg powder for infusion)
- 0.7-1mg/ kg IV (1.5 if pre-treated); 2.5-4mg/ kg IM
- Infusion: 0.5-10mg/ min titrated (<5mg/kg avoids phase 2 block)
Nondepolarizer MOA
- Competitive antagonist @ nicotinic receptors, no intrinsic activity
- Competes with Ach @ post junctional receptor. At high doses may block ion receptor channel
**How much of receptors can be occupied by a NMBD before evidence of a blockade will show on blockade monitor
***Up to 70% can be occupied before it shows on monitor.
(0-70% will look the same on monitor/ train of four. Up to 70% of drug can still be in symptom and pt. appears reversed on monitor)
Cardiovascular effects of NDMB drugs. Why
-Decrease B/P r/t histamine release and other vasoactive substances
**Only NDMB drug that increases HR. Why?
- Pavulon
- May block cardiac muscarinic receptors. (atropine-like efects)
Other physiology that can enhance effect of NMBD
- **hypothermia
- hypotension
- hypokalemia
- acidosis
How is the speed of onset and duration of neuromuscular blockade measured
monitoring response to skeletal muscle to an electrical stimulus (peripheral nerve stimulator, PNS)
What muscle is usually monitored by PNS (peripheral nerve stimulator) and by what nerve?
adductor pollicis muscle via ulnar nerve
***How are potency comparisons of neuromuscular blocking drugs made?
The amount of drug needed to produce a 95% block when given with the barbiturate, opiate, and N2O (ED95)
**What type of muscles are effected by NMBD before the diaphragm
small, rapidly moving muscles (diaphragm may take 2x the dose)
9ex. onset rapid to the vocal cords)
Body muscles sensitivity to NDMR from most resistant to least.
Diaphragm> Face> larynx> peripheral limb> abdomen> masseter> upper airway muscles
Why monitor NMBD?
- **Assessment of reversal readiness
- Wide inter-patient variability in dose requirement
- Differentiate block type (Depolarizing phase 1 vs. 2, Non-depolarizing)
- Careful titration to effect
- Assessment of reversal adequacy
Which nerve/ muscles are better to asses cord paralysis, why?
- Orbicularis oculi muscle (facial nerve)
- Effects are short acting and can be minimum by the time drugs reaches the ulna ( adductor Pollicis)
(5)Types of stimulation patterns (monitors)
- Single Impulse/ twitch
- Train of Four (TOF)
- Tetany
- Double burst Simulation (DBS)
- Post Tetanic Count (PTC) after tetany
Tetanus monitoring facts, including amount of frequency
***50 Hz, fade with NDMR's 100 Hz w/out NDMR's -sensitive indicator of residual block -PAINFUL -can't repeat too soon (underestimates block)
ST (single twitch) PNS characteristics
- Single impulse/ twitch 1Hz lasting 0.1-0.2 mSec
- Onset depends on frequency recovery
- Twitch magnitude decreases @ 75% block until gone @ 100%
- Control REQUIRED, may still have residual paralysis
Tetanus PNS
- 50 Hz fade with NDMR (100Hz w/out NDMR)
- **sensitive indicator of residual block
- Painful
- Can’t repeat to soon r/t underestimates block (receptors flooded)
***Train of Four
- 2 Hz x4
- Measures continued relaxation
- Identifies phase 2 block
- No control required (no need to know what pt. looked like before)
- Tolerable in awake pts.
- Questionable visual reliability
- allows good titration
***Double Burst Stimulation
- ** 2 burst of 50 Hz, separated by 750mSec
- each burst has 3, 0.3mSec duration pulses
- Measured fade correlates with TOF
- Tactile&visual evaluation response superior to TOF
Post Tetanic Count (PTC)
- 50Hz for 5 sec, followed in 3 sec by ST @ 1-2Hz
- Shouldn’t repeat more frequently than 6 minute
- ***used to MONITOR INTENSE BLOCK
- predicts optimal time for reversal
***Percentage of block with 4 TOF twitches & clinical significance
0-75%blocked
May be able to move with weakness. Can be reversed (may not need it)
***Percentage of block with 3 TOF twitches & clinical significance
75%
May need additional drug to prolong relaxation. Short or intermediate acting agents may be reversed (pt. doesn’t have good relaxation)
***Percentage of block with 2 TOF twitches & clinical significance
80%
Suitable short term relaxation as well as LONG TERM MECHANICAL VENTILATION
***Percentage of block with 1 TOF twitches & clinical significance
90%
- Condition for short term procedures like INTUBATION and long term MECHANICAL VENTILATION
- Can reverse, but 2 twitches better
***Percentage of block with 0 TOF twitches & clinical significance
100%
- Intubation conditions. long term saturation may lead to prolonged effects
- CAN NOT REVERSE
How many twitches on TOF is optimal for reversal
2
Neuromuscular function extubation criteria(5)
- Head lift >5 sec
- Sustained hand grips
- NIP -50cm H20 ADULTS (-30 PEDS)
- Vital capacity 15ml/ kg
- Absence of nystagmus/ diplopia
PNS (peripheral nerve stimulator) Criteria for extubation
1-2 twitches prior to reversal
sustained tetany to 50 Hz
No fade on DBS
Anticholinergic only offset_____receptors
Muscarinic (Not nicotinic)
When are NDMR used
- Intubation
- Bolus dose after Sux
- Intermittent boluses
- Continuous infusion
Prototype of NDMR
Curare
What is a defasiculating dose and when is it given
small dose of NDMR given before Sux
Drug structure of Curare
Isoquinolinium
***Pancuronium structure, length of action, cardiac effects, histamine release, where it’s metabolized
- Bi-isquarternary aminosteroid
- long acting
- Increases HR (selective vagal blockade)L slight increase in B/P
- 55-70% unchanged in urine, remainder in Hepatic metabolism to active metabolites (PROLONGED ELIMINATION)
- Rare histamine release
Atracurium (Tracrium)
Structure, length of action, metabolism/ metabolite, heart effects, histamine release
- Benzylisoquinolinium
- intermediate acting (on shorter side)
- Hoffman & Plasma (ester) hydrolysis
- Metabolite= LAUDANOSINE, CNS stimulate excreted via kidney
- Histamine release
Cisatracurium (Nimbex)
Structure, length of action, metabolism/ metabolite, heart effects, histamine release
- Benzylisoquinolinium
- Intermediate (slower onset than atracurium)
- Hoffman metabolism; some ester hydrolysis
- ? metabolite (none mentioned) though Atracurium isomer
- Cardiac stable
- Little/ no histamine release
Vecuronium (Norcuron) Structure, length of action, metabolism/ metabolite, heart effects, histamine release
-Monoquaternary aminosteroid
-Intermediate acting
-Hepatic metabolism
-Active Metabolite (1/2 of parent drug activity)
-30% renal excretion, 40-70% biliary (Considered safe for renal7 liver pts.)
-Cardiac stable w/ some bradycardia
No signif. histamine release
-Doesn’t significantly cross placenta
-No change in IOP
Rocuronium (Zemron)
Structure, length of action, metabolism/ metabolite, heart effects, histamine release
- Monoquaternary Amine
- Intermediate acting (faster onset, less potent than vecuronium)
- Recommended for RSI
- Liver metabolism to inactive metabolites (safe in renal pts)
- Prolonged effects in liver pts.
- Cardiac stable
- Rare, if any histamine release
- Large bile excretion
Mivacurium (Mivacron)
Structure, length of action, metabolism/ metabolite, heart effects, histamine release
- Benzylisoquinolinium
- Short acting (? availability/ discontinuance)
- Plasma hydrolysis (cholinesterase). Effects can prolong with atypical pseudocholinesterase
- Histamine release
- Minimal cardiac effects
- Increased doses has less impact on DOA r/t rapid hydrolysis
***Pharmokinetic rational for choosing drug (muscle relaxant)
- **METABOLISM & ELIMINATION
- Vd
- Clearance
- Elimination 1/2 life
Pharmacodynamic rational for choosing drug (muscle relaxant)
dose- response
plasma level- response
effect compartment- response
***Considerations for choosing a Muscle relaxant
- onset time
- DOA
- Pharmacokinetic profile
- Cardiovascular effects
- need for reversal
- Disease states (Liver, Cardiac, Renal)
- Elimination route
How blood flow and cardiac output effects onset
- Increased blood flow (& increase dose)= faster onset
- Decrease CO = slower onset
Cardiac stable muscle relaxants
- Cisatracurium (Nimbex)
- Vecuronium (Norcuron)
- Rocuronium (Zemuron)
- Mivacurium (Mivacron)
Dugs that release histamine
- Mivacurium (Mivacron)
- Atracurium
- Pancurium (Rarely)
- D-Tubocurarine (Curare)
Drugs that aren’t cardiac stable
- Succinylcholine (Bradycardia/ sinus arrest)
- Pancurium (Pavulon): Increase HR, Increase B/P (r/t HR)
- Atracurium (Tracurium): hypotension r/t histamine release
- Vecuronium (Some incidence of bradycardia, but cardiac stable)
Drugs that don’t release histamine
- Pancuronium (Pavulon): rare histamine release
- Vecuronium (Norcuron)
- Rocuronium (Zemuron): rare, if any
- Cisatracurium (Nimbex): little to no
Pt. population to monitor when using NMBD and why?
Renal patients. Drug easily excreted through urine (and bile). Relatively hydrophilic & highly water soluble.
What are the 2 structures of NMBD
- Aminosteroid
- Benzylisoquinolinium
Patient populations to use caution/ avoid with Succinylcholine
- Neuro pts.
- Eye injury
- Increased ICP
Causes of altered response to NDMR (decreased effect)
- Hyperkalemia (Resistance to NDMR)
- Burn injury (Resistance to NDMR)
- Paresis (may cause resistance r/t proliferatiom of extrajunctional receptors)
- Men> resistant than women
Mnemonic for sensitivity to NDMR resistance (Toy’s made up) from Greatest resistance to least.
Down For Long Periods And Moving Up
Diaphragm>Face(muscles)> Larynx (muscles)> Peripheral limbs> Abdominal muscles> Masseter> Upper airway
Benzylquinolinium Structured NDMR
*-Atracurium (Tracrium)
*-Cisatracurium (Nimbex)
*-Mivacurium (Mivacron
(Doxacurium)
Biisoquaternary aminosteroid structured Drugs
- Pancuronium (Pavulon)
- (Pipercurion)
Monoquaternary Aminosteroid sructured NDMR
- Rocuronium (Zemron)
- Vecuronium (Norcuron)
NMBD that release histamine (M.A.D.S)
- Mivacurium (Mivacron)
- Atracurium (Tracrium)
- DTC/D-Tubocurarine (Curare)
- Succinylcholine
Major metabolite of Atracurium and where its excreted
- Laudanosine
- Kidney excretion (Not good for renal Pts)
Best reversal to use with Mivacurium (Mivacron)
-Edrophonium (Enlon)
Neostigmine, theoretically, increases effects
Which muscle relaxant has the fastest onset?
Succinylcholine
What is the “self-taming” technique to administering a NDMR
20% of planned Sux dose given first followed by the rest later. (after propofol)
