NMBDs and Reversals Flashcards
Succinylcholine
MOA:
▾A depolarizing neuromuscular blocking drug
▾Structurally two molecules of acetylcholine bound together and is a partial agonist of nAChR.
• Produces prolonged depolarization of the endplate which results in desensitiziation of nAChR’s, inactivation of VG Na+ channels at the NMJ, and increases K+ permeability in the surrounding membrane, resulting in hyperpolarization, and block. Causes a muscle contraction, then dissociates 4-5 minutes later (length of paralysis)
PK:
▾Only depolarizing NMBD
▾Two Ach molecules linked by acetate methyl groups
▾Rapid onset- Creates intubating conditions in approximately 60 seconds (larynx approximately 34 seconds)
▾Recovery to 90% muscle strength is 9-13 minutes
▾Short action d/t rapid hydrolysis by butyrylcholinesterase (also that only 10% of the administered drug reaches NMJ – St)
▾Recovery occurs as it drifts away from the NMJ down a concentration gradient, into the plasma where it’s metabolized via hydrolysis by butyrylcholinesterase (“plasma cholinesterase”) (“pseudocholinesterase”)
• Breaks down into succinylmonocholine (a weak active metabolite) + choline
▾It is possible that Succs will diffuse across and repeatedly bind to multiple nAChR until it is cleared from the area of the NMJ where it is exposed to plasma cholinesterase and hydrolyzed.
• Elderly – slower onset (d/t ↓ circulation), and prolonged action (less PchE)
• Peds – avoid if <5 yrs old, Duchene, hyperK+ can cause bradycardia, hyperk+ rhabdomyolysis cardiac arrest
PD:
• MSK – muscle fasciculation (contraction) depolarizing block (decrease in twitch tension, no fade), masseter spasm (early indicator for MH, or could also be d/t inadequate dosing of succ), myalgias (body contraction)
• CNS - ↑ IOP (peaks 2-4 minutes, subsides in 6), don’t use in eye injury pts, ↑ ICP - avoid in head injury pts (attenuated with pretx of subtherapeutic dose of nondepolarizing drug so that they have some receptors blocked – smaller fasciculation)
• CV – bradycardia, junctional rhythm, or sinus arrest (acts on cardiac muscarinic receptors). This occurs more if you give a 2nd dose within 5 minutes of 1st, or if given to peds (very PSNS motivated)
• Labs – hyperK+, myoglobinuria (esp in Duchene muscular dystrophy or MH-susceptible pts)
• GI/GU - ↑ intragastric and lower esophageal pressures (no r/f regurgitation)
• Interactions - Beta blockers cause a mild prolongation of succinylcholine (you prob wouldn’t notice it)
Vd: low, base dosing on ideal body weight
Dosing: 1 mg/kg
Half-life: plasma ½ life 2-4 minutes
Extras:
• Dibucaine is a LA that inhibits PchE, dibucaine number reflects the quality of PChE
o Dibucaine has a higher affinity for normal (non-mutated PChE), so a higher dibucaine number = a higher amount of normal PChE. Normal dibucaine number > 70, Block prolonged 1.5-2x longer for dib number 40-60, Severe block prolongation (4-8 hrs) – dibucaine <30.
• Factors decreasing PChE activity include: Advanced liver disease, age, malnutrition, pregnancy, burns, oral contraceptives, MAO inhibitors, echothiophate, cytotoxic drugs, neoplastic disease and anticholinesterase drugs
• MH is a failure of the Ca++ pump (d/t mutation on chromosome 19 – for the ryanodine receptor) which causes sustained muscle contraction, increase in temp
Atricurium
Benzylisoquinolinium
MOA:
▾A non-depolarizing neuromuscular blocking drug
▾Act as competitive antagonists
▾Will bind to one or both alpha subunits, but unlike ACh they lack agonist activity
▾Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel. If enough channels are closed, there is a blockade of neuromuscular transmission.
▾Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate don-depolarizers are used.
PK:
▾Racemic mixture of 10 stereoisomers separated into 3 geometrical isomer groups
▾Intermediate onset
▾Undergoes ester hydrolysis and Hoffman elimination (spontaneous degradation)
▾Laudanosine (tertiary amine) metabolite implicated in convulsions (doses given in anesthesia not capable of producing this)
PD:
• Histamine release! Flushed, tachycardic, hypotensive.
• Respiratory effects - Related to histamine release in patients with reactive airway disease, Increased airway resistance and bronchospasm
Dosing: 0.5mg/kg
Half-life: 17.3-21 minutes (Stoelting p.329) – “20 minutes”
Cisatricurium
Benzylisoquinolinium
MOA:
▾A non-depolarizing neuromuscular blocking drug, competitive antagonist, cis isomer of atracurium
PK:
▾Intermediate onset & action
▾Metabolized by Hoffman elimination (no ester hydrolysis), good for renal/liver failure (PChE produced in the liver)
▾Does not cause histamine release
PD:
Dosing: 0.1 mg/kg, 5x as potent as atricurium (st p799)
Half-life: 26-36 minutes (Nagelhout p. 158), notes say “~1 hr”
Extras:
▾Act as competitive antagonists
▾Will bind to one or both alpha subunits, but unlike ACh they lack agonist activity
▾Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel
▾If enough channels are closed, there is a blockade of neuromuscular transmission.
▾Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate Non-depolarizers are used.
Rocuronium
steroidal compounds
MOA:
▾A non-depolarizing neuromuscular blocking drug, competitive antagonist
• Fast, but least potent
PK:
▾Intermediate-acting NMBD
▾Time to max block-1.7 minutes
▾Faster onset of action than panc or vec (6x less potent than vec)
▾Primarily metabolized in the liver (30% is excreted in the urine)
PD:
Dosing: 0.6 mg/kg
Half-life: 53-71 minutes (Stoelting p.329) [60-120 minutes Nagelhout p. 146] “1 hour”
Extras:
▾A non-depolarizing neuromuscular blocking drug, competitive antagonists
▾Will bind to one or both alpha subunits, but unlike ACh they lack agonist activity
▾Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel. If enough channels are closed, blockade of neuromuscular transmission.
▾Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate Non-depolarizers are used.
Vecuronium
steroidal compounds
MOA:
▾A non-depolarizing neuromuscular blocking drug, competitive antagonist
• Intermediate acting, but still pretty long
PK:
▾Intermediate acting NMBD
▾Onset time to max block- 2.4 minutes, last for an hour before you can give reversal agent
▾Essentially Panc w/o quaternized methyl group (slight decrease in potency, loss of vagolytic properties, molecular instability shorter duration of action, increased lipid solubility)
▾Metabolized principally by the liver (3-OH metabolite has 80% of neuromuscular potency)
PD:
• CV – less stable CV properties bc of loss of vagolytic properties
Dosing: 0.1 mg/kg
Half-life: 53-78 minutes (Stoelting p.329) – “1hour”
Extras:
▾Will bind to one or both alpha subunits, but unlike ACh they lack agonist activity
▾Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel. If enough channels are closed, blockade of neuromuscular transmission.
▾Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate Non-depolarizers are used.
Pancuronium
steroidal compounds
MOA:
▾A non-depolarizing neuromuscular blocking drug, competitive antagonist
PK:
▾Potent long acting NMBD
▾Onset time to max block- 2.9 minutes
• Loooong acting, most potent
▾Vagolytic & butyrylcholinesterase-inhibiting properties
▾Majority cleared by the kidneys (small amt. deacetylated by the liver, accumulation of 3-OH metabolite responsible for block prolongation)
PD:
• CV – maintenance or ↑ of HR, vagolytic (inhibition of muscarinic (ACh) receptors on the heart = vagus nerve/PSNS, so SNS override)
Dosing: 0.08 mg/kg
Half-life: 132 minutes (Stoelting p.329) “2 hours”
Extras:
▾A non-depolarizing neuromuscular blocking drug
▾Act as competitive antagonists
▾Will bind to one or both alpha subunits, but unlike ACh they lack agonist activity
▾Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel
▾If enough channels are closed, there is a blockade of neuromuscular transmission.
▾Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate Non-depolarizers are used.
NMBDs in general
• All muscle relaxants are quaternary ammoniums, majority are synthetic alkaloids
• ACHesterase = true cholinesterase
• Butyrylcholinesterase = plasma cholinesterase = PchE
o Synthesized in the liver
o Hydrolyzes succ in the plasma
o This is what metabolizes all the esters (what else goes through ester hydrolysis? ETOMIDATE)
• Onset of muscle relaxation
o Eye > extremities > trunk > abdominal muscles > diaphragm
o Onset is best measured in the facial nerves (bc they’re the first to relax)
o Recovery is best measured in the hand
• Can have – twitches and have 75% of receptors blocked
• You’re going to do tetany/posttetanic count when you have 0 twitches. Bc you want to see if they’re gonna be ready for a reversal agent soon, or if you’re fucked. If they have some fade you’re close. If they have no fade, then you go on to do posttetanic count to see if you’re kinda close or TRULY fucked.
o Tetany – contraction + fade, you know there’s still NMB competing with the ACh
• Factors that increase potency include:
o Inhalational agents: (amnesia, areflexia, analgesia)
Length of inhalational anesthesia (but you also get relaxation at sufficient doses of inhalation agents)
Type of agent
• desflurane > sevoflurane > isoflurane > nitrous oxide > IV anesthesia
• (propofol – amnestic induction agent. No analgesia, no relaxation.)
o Antibiotics: Aminoglycosides, Clindamycin** (pts with PCN/cephalosporin allergy get this instead)
o Hypothermia
o Magnesium sulfate (calcium antagonist) – calcium tightens things up, mag loosens things up/slow to wake up
o Local anesthetics (block nerve transmission…)
o Quinidine
o (no narcotics, no benzos)
• Factors that decrease potency include:
o Chronic anticonvulsant administration (dilantin, Keppra – might need more drug!)
o Hyperparathyroidism and hypercalcemia (anything that ↑s Ca++ will make your drug work less)
Decreased atracurium sensitivity
• Myasthenia gravis
o Downregulation of receptors
o Need more dosage of succ, need less dosage of nondepolarizers
Reversal Agents: Neostigmine and Edrophonium, Atropine and Glycopyrrulate
MOA: AChE inhibitor, cause a buildup of ACh in the NMJ to compete with NMBDs
PK:
PD:
• Slower onset, sustained effect. (Use with glycopyrrulate)
• Causes muscarinic effects, must give anticholinergic
• Resp – causes bronchoconstriction, ↑ AW resistance, ↑ salivation,
• GI – ↑ bowel motility
• CV - What does ACh do at the heart? Slows down HR via PSNS
o Glycopyrrulate can cause tachycardia bc inhibiting ACh from binding to muscarinic sites, so ≅ vagolytic properties of pancuronium
• Anticholinergics cause - Can’t pee, can’t see, can’t spit, can’t shit. So the muscarinic effects cause the opposite – salivation, lacrimation, urination, defecation
• Atropine – crosses BBB, some sedation
Dosing: max dose
Neostigmine 0.05 mg/kg, onset 5-15 min, half-life 70-80 minutes, duration 45-90 min
Glycopyrrulate dose: 5-10 mcg/kg, onset 2 minutes, duration 2-4 hours
Edrophonium: 1-1.5 mg/kg, onset 5-10 minutes, half-life 2 hrs, duration 30-60 min (faster on, faster off)
Atropine 7-10 mcg/kg, onset 1-2 minutes, duration 1-2 hours
Half-Life:
Extras:
• Must have 4th twitch to use this drug
Sugammadex
MOA: modified gamma-cyclodextrin, circular sugar, which has selective relaxant binding, encapsulates the NMBD. Also encapsulates PO contraceptives
PK:
• Worst best on rocuronium > vecuronium ≫ pancuronium. No use on succinylcholine/depolarizer, or benzylquinoliniums (atricuriums)
PD:
• Interacts with PO contraceptives, encapsulates them for about a week
• Worsens pHTN in peds, ↑ PAP in pts with no hx of pHTN
• Possible allergic reaction and bleeding (↑ ↑ aPTT, PT/INR for about a week after)
Dosing:
TOF >2 –> 2 mg/kg
TOF <2 –> 4 mg/kg
TOF 0 –> 16 mg/kg
Half-Life:
