Neuromuscular Blockers (NMBs)
NMB Sequence of Paralysis
- Larger muscles are more resistant to paralysis - Small, rapidly moving muscles (eye) > limbs, neck, trunk, masseter and upper airway > intercostal muscles, larynx and face > diaphragm **Want larger diaphragm to be more resistant so it can come back more quickly so you can breathe again - Offset of paralysis occurs in reverse order - Sequence of paralysis is same for non-depolarizing and depolarizing NMBs
NMB Therapeutic Uses
Facilitation of endotracheal intubation (succinylcholine, rocuronium) Facilitation of skeletal muscle relaxation for surgical procedures or as an adjuvant to anesthesia (non-depolarizing NMBs) Facilitation or maintenance of synchrony in mechanically ventilated patients (non-depolarizing NMBs) Anti-shivering during hypothermia protocol (non-depolarizing NMBs)
NMB Reversal
Non-Depolarizing (Competitive) NMBs antagonize the action of ACh in a competitive manner and therefore, if the concentration of ACh is increased, it has a higher chance of occupying the receptor sites than the non-depolarizing NMBs. Reversal of this NMB inhibition can occur through Acetylcholinesterase (AChE) Inhibitors, which leads to more available ACh to overcome the NMB inhibition. ▪ AChE inhibitors (neostigmine, pyridostigmine, edrophonium) ▪ Decrease breakdown of ACh and reverse NMB block ▪ Need 4/4 twitches on TOF (not effective for deep block) ▪ Time to reversal = 15 up to 30 minutes (variable) ▪ Muscarinic sides effects (N/V, bradycardia, miosis, QTc prolongation, bronchoconstriction, increased intestinal tone) ▪ Co-administered with antimuscarinic agent such as glycopyrrolate or atropine (cause tachycardia) ▪ If you give an AChE inhibitor to a patient on succinylcholine, you will just get more of a blockade because more ACh will be available, therefore no reversal Sugammadex is a modified cyclodextrin that selectively binds rocuronium (more potent) and vacuronium (less potent) and removes from receptors. It is effective for moderate to deep block (reverses in 3 minutes) but is not effective against benzylisoquinoline NMBs. It has minimal side effects compared to AChE inhibitors, but need to use Ach inhibitors for benzylisoquinolones. May interact with oral contraceptives so females on birth control may have interactions due to steroidal structure that might theoretically bind to this drug
Reversal of NMB Blockade
▪ Also termed postoperative residual curarisation (PORC) ▪ Current estimates show that around 40% of post-operative patients (who have been paralyzed) arrive in PACU with TOF ratio < 0.9 and 12% with TOF ratio < 0.7 ▪ A rough estimate of 1-3% of patients experiencing residual NMB blockade develop clinically apparent events (Table 1) ▪ New gold standard for acceptable postoperative recovery is TOF ratio > or = 0.9 and this ratio should be achieved before tracheal extubation ▪ Physiologic changes include impaired muscle tone and coordination that can result in difficulty/impaired breathing via dysfunctional airway and respiratory muscles ▪ Clinical changes include difficulty breathing/speaking (signs of muscle weakness), postoperative hypoxemia and upper airway obstruction (immediate critical respiratory events in PACU), and prolonged ventilator weaning (later respiratory events)
NMB Characteristics
◦ Cause paralysis of skeletal muscles ◦ Do not alter level of consciousness or alter pain sensation, therefore need a "balanced approach" to anesthesia or sedation practices or can lead to PTSD if patient is still conscious but paralyzed during procedure ◦ All have poor oral absorption and must be given intravenously ◦ Ionized and do not cross blood-brain-barrier therefore no CNS effects Non-depolarizing NMBs: 1. Pancuronium - onset of 4-6 mins, duration of 120-180 mins and is prolonged with liver/renal failure 2. Rocuronium - onset of 1-2 mins, duration of 30-67 mins and is prolonged with liver/renal failure 3. Vecuronium - onset of 2-4 mins, duration of 20-60 mins and is prolonged by liver failure and slightly by renal failure **These first three are steroidal agents that get metabolized in the liver and also eliminated in the kidney, therefore if you have dysfunction in either of these organs it will lead to prolonged action. In this case, you want either a lower dosage of the drug or to use a different drug that doesn't go through these organs. Most used is vecuronium. Pancuronium has very long onset and duration which is probably not good if you want to unblock them therefore it is not used a lot. 4. Atracurium - onset of 2-4 mins, duration of 30-40 mins, and is not prolonged with liver/renal failure 5. Cisatracurium - onset of 2-5 mins, duration of 30-70 mins, and is not prolonged with liver/renal failure **Benzylisoquinoline Derivatives go through organ-independent elimination (use these drugs when patient has kidney or liver failure) via Hoffman elimination, pH degradation, blood esterase degradation. Most used is cisatracurium Depolarizing NMBs: 1. Succinylcholine - onset of 20-30 seconds, duration of 5-10 mins, and is not prolonged with liver/renal failure. Succinylcholine also uses organ-independent elimination.
NMB Monitoring, Train-of-Four
- The number of contractions observed reflects the degree of blockade achieved. If you have 4 twitches, you are anywhere from 0-75% blocked (need over 75% to have blockade so may be blocked a little or not at all). 3 twitches = 80% blockade, 2 twitches =85% blockade, 1 twitch = 90% blockade. If you have no twitches, you are 100% blocked (generally no procedures where you want this). Want patients between 85-95% so want to keep 1 or 2 out of 4 twitches. - Recommended to achieve 1 - 2 / 4 twitches (TOF count) - Also recorded as ratio of magnitude of 4th and 1st twitches (TOF ratio) (cut-off = <0.7 or <0.9 depending on practice). Twitch height records TOF ratio which is magnitude of 4th and 1st twitches, old cutoff was 0.7 or less then you are too blocked and don't take tube out or you will get reblocked and have respiratory arrest, changed it to 0.9 so you are less blocked.
NMB Drug Interactions
1. Inhalation anesthetics ▪ Reduction of post-synaptic receptor sensitivity to ACh, decreased muscle contractility ▪ Examples: desflurane>sevoflurane>isoflurane>halothane >nitrous oxide 2. Antibiotics ▪ Decreased pre-synaptic Ach release, reduction of post-synaptic nAChR sensitivity, impairment of ion channels ▪ Examples: Aminoglycosides, Colistin, Clindamycin, Tetracyclines 3. Calcium channel blockers and local anesthetics ▪ Decreased pre-synaptic Ach release, decreased muscle contractility
Mechanism of Action
Acetylcholine (ACh) is the neurotransmitter responsible for physiologic transmission of nerve impulses from pre-ganglionic and post-ganglionic neurons of the cholinergic (parasympathetic) nervous system, preganglionic adrenergic (sympathetic) neurons, multiple nerve endings in the central nervous system and the neuromuscular junction in skeletal muscles. There are two types of ACh receptors: Nicotinic (nAChR) (main site of activity for NMBs) and muscarinic (mAChR). Mechanism includes: ▪ Motor neuron depolarization causes action potential to travel down never fiber to the neuromuscular junction (1) ▪ Depolarization of the axon terminal causes an influx of Ca2+(2) which triggers fusion of the synaptic vesicles (3) and release of the neurotransmitter ACh (4) ▪ Ach diffuses across the synaptic cleft of the neuromuscular junction and binds to post-synaptic nAChR located on the muscle fibe at the motor end-plate (5) The nAChR is a pentamer with two α-subunits and one β, γ and δ-subunit in which two ACh molecules must bind in a specific confirmation to produce agonistic action ▪ Binding of ACh to nAChR opens the channels causing an influx of Na+(5), depolarization of the sarcolemma that travels down the t-tubules (6) and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum leading to contraction ▪ Unbound ACh in the synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) (7) Post-synaptic nAChR Activity - Need two ACh molecules to bind to receptor at the alpha subunit. Once ACh binds to postsynaptic receptors, causes Ca2+ voltage channels to open and cause action potential propogation. AChE is breaking down remaining ACh in synapse. Each vesicle contains 2000-10,000 ACh molecules (equals 1 "quanta"), and depolarizing nerve impulse releases 300-500 "quanta". Each motor end plate has about 10 million receptors, and only 25-30% of AChRs are needed for transmission, with remaining 70-75% representing a safety margin that would need to be overcome for any molecule to be considered a NMB (usually takes ≥70% blockade of nAChR to see a paralytic response).
NMB Adverse Effects
Adverse effects also determine which drug we use for a patient. Non-Depolarizing (Competitive) NMBs ▪ Tachycardia and hypertension due to vagolytic and sympathomimetic properties, Pancuronium and Rocuronium (if elevated dosage) cause this. Vacuronium is devoid of these side effects (thermodynamically neutral). ▪ Histamine release potentially leading to: hypotension, reflex tachycardia, flushing, urticaria, and bronchospasm which is very hard to treat and disrupts ventilation. Atracurium and its metabolite laudansoine causes these symptoms, laudansoine can also cause seizures as it is a CNS stimulant. Cisatracurium does not cause histamine release and has 1/10 amount of laudansoine metabolite compared to atracurium, very good NMB but cannot be used for rapid blocking because slower onset. ▪ All can cause acute quadriplegic myopathy syndrome (AQMS, "post-blocker/weakness blockade"). When you are unblocked, some patients have residual blockade/weakness which can take months to recover or never recover, rule is to use the lowest amount of drug possible for shortest amount of time, most commonly seen in ICU patients. Risk is greater with concomitant steroid use as NMBs enhance corticosteroid-induced myosin degradation. Depolarizing NMBs ▪ Hyperkalemia ▪ Bradycardia ▪ Masseter muscle rigidity ▪ Malignant hyperthermia ▪ Delayed muscle pain ▪ Prolonged paralysis (pseudocholinesterase deficiency) ▪ Anaphylaxis **Reasons why we don't use succinylcholine. If you're a burn patient or cardiac patient, can cause cardiac arrest (hyperkalemia). Some have genetic predisposition to malignant hyperthermia by some trigger such as succinylcholine, it is when you have fevers and rigidity and can quickly lead to death. Number of people complain of delayed muscle pain for 1-2 hours unblocking. Kinetically a good drug but side effects are very bad, pretty much no longer used anymore
Non-Depolarizing NMBs
Aminosteroid Derivatives: 1. Pancuronium 2. Rocuronium 3. Vecuronium Benzylisoquinoline Derivatives: 1. Atracurium 2. Cisatracurium 3. D-tubocurarine (no longer on market) **these derivatives all have quaternary structure at nitrogen
Neuromuscular Blockers (NMBs)
Drugs that block neural transmission at the neuromuscular junction causing paralysis of the affected skeletal muscles. All NMBs cause relaxation of skeletal muscles resulting in paralysis. All NMBs are structurally related to Ach, and all useful NMBs structurally contain one or two quaternary nitrogens. Succinylcholine is the only depolarizing one we need to know, basically two ACh stuck together but use of this drug has practically stopped due to many reasons described later
Non-Depolarizing NMBs Mechanism
Non-Depolarizing (Competitive) NMBs mainly antagonize the action of ACh in a competitive manner at the post-synaptic nAChR leading to flaccid paralysis. Only one NMB molecule is needed to block the nAChR. Block pre-junctional receptors resulting in failure of ACh mobilization. Manifests as "Fade Phenomenon" in which there is a reduction in twitch height with successive stimuli. **"Fade Phenomenon" property is useful for monitoring degree of neuromuscular blocking. Take electricity called Train of Four which involves 4 twitches due to electricity. Each time you elicit response, you get twitch response that is a little bit less each time. If you have no drug, twitch hike should be the same each time. If non-depolarizing, every successive twitch is less and can use ratio between twitches to determine how much ACh inhibition is going on.
Depolarizing NMBs Mechanism
Phase I Block - ▪ Succinylcholine is comprised of two ACh molecules and is fairly resistant to AChE (metabolized by butyrylcholinesterase) ▪ Membrane is depolarized by opening nAChR channels causing a brief period of muscle fasciculation followed by a block in neurotransmission leading to flaccid paralysis ▪ Succinylcholine produces a prolonged refractory period ▪ Phase I blockade involves similar succinylcholine that noncompetitively binds and causes prolonged depolarization because it is metabolized by butyrlcholinesterase that is not readily available in synapse, when you block succinylcholine you will see brief muscle contractions/twitching followed by eventual flaccid paralysis. ▪ ACh cannot propagate an action potential on an already depolarized end-plate ▪ Does not occur with ACh due to short duration of action (msec) because AChE is readily available to degrade. Phase II Block - ▪ End-plate eventually repolarizes, but because succinylcholine is not metabolized like Ach, it continues to occupy the nAChRs to "desensitize" the end-plate ▪ Similar to non-depolarizing NMBs ▪ Occurs with prolonged use: 30 - 60 minutes of paralysis **Twitch height is reduced in a constant manner with no "Fade" during Phase I block since succinylcholine acts just like ACh, and thus we cannot measure ACh inhibition. Pre-junctional activity associated with fasciculations. During phase II block though, you will see fade response but we don't typically allow phase II block to occur.
