Neuromuscular Physiology and Pharmacology Flashcards
Depolarizing Muscle Relaxant
Succinylcholine, Mimics the action of ACh
Depolarizing Muscle Relaxant
Succinylcholine, Mimics the action of ACh
Succinylcholine Metabolism
Hydrolyzed by plasma cholinesterase
• AKA pseudocholinesterase or butyrocholinesterase – not present in the NMJ, drug must be cleared from
plasma
NM ‘blockade’ occurs because…(DMR, Sux)
the depolarized post‐junctional membrane cannot respond to additional agonist (Ion flux is an important consideration)
Clearance from the junctional cleft occurs by…(DMR, Sux)
diffusion (Sux molecules can repeatedly bind to receptors until the diffuse away from the NMJ)
Desensitization
Occurs when agonists bind to α subunits but do not cause a conformational change to open the Na+ pore (These receptors are unable to transmit the chemical signal to the muscle membrane)
Closed channel blockade
Drug reacts around the mouth of the channel and prevents passage of ions
– Seen with cocaine, some antibiotics, quinidine, etc.
Open channel blockade
Drug enters an open channel but does not pass all the way through (“gets stuck”)
– Impedes the flow of ions – Ex. NDMRs in large doses
Extrajunctional Receptors (number)
Normally not present in large numbers
– Synthesis is suppressed by normal neural activity
• May proliferate if normal neural activity is decreased
– Trauma,sepsis,prolongedbedrest,burninjury,spinalcordinjury,etc.
Extrajunctional Receptors (Differ from nAChRs)
-change in the epsilon
subunit—structurally different from nAChRs
-stay open longer (AllowlargeramountsofK+effluxafteradministrationofDMR • Hyperkalemic arrest is well documented after SCh adm)
-Spread across the entire muscle membrane (not just at the NMJ)
Succinylcholine Metabolism
Hydrolyzed by plasma cholinesterase
• AKA pseudocholinesterase or butyrocholinesterase – not present in the NMJ, drug must be cleared from
plasma
Succinylcholine (activity termination)
Activity is terminated by diffusion of the drug away from the NMJ
NM ‘blockade’ occurs because…(DMR, Sux)
the depolarized post‐junctional membrane cannot respond to additional agonist (Ion flux is an important consideration)
Clearance from the junctional cleft occurs by…(DMR, Sux)
diffusion (Sux molecules can repeatedly bind to receptors until the diffuse away from the NMJ)…sustained opening
Desinsitization
Occurs when agonists bind to α subunits but do not cause a conformational change to open the Na+ pore (These receptors are unable to transmit the chemical signal to the muscle membrane)
Closed channel blockade
Drug reacts around the mouth of the channel and prevents passage of ions
– Seen with cocaine, some antibiotics, quinidine, etc.
Open channel blockade
Drug enters an open channel but does not pass all the way through (“gets stuck”)
– Impedes the flow of ions – Ex. NDMRs in large doses
Extrajunctional Receptors (number)
Normally not present in large numbers
– Synthesis is suppressed by normal neural activity
• May proliferate if normal neural activity is decreased
– Trauma,sepsis,prolongedbedrest,burninjury,spinalcordinjury,etc.
Extrajunctional Receptors (Differ from nAChRs)
-change in the epsilon
subunit—structurally different from nAChRs
-stay open longer (AllowlargeramountsofK+effluxafteradministrationofDMR • Hyperkalemic arrest is well documented after SCh adm)
-Spread across the entire muscle membrane (not just at the NMJ)
Extrajunctional Receptors (agonist/antagonists)
Highly sensitive to agonists, but less sensitive (resistant) to antagonists
Prejunctional Receptors
nAChRs on prejunctional membranes
• Believed to regulate release of ACh from presynaptic membrane
Stimulation of Prejunctional Receptors
inhibits release of ACh from presynaptic
membrane
– May stimulate production of more ACh in the nerve terminal
nAChRs vs. mAChRs
All cholinergic receptors are responsive to acetylcholine
Nicotinic receptors are located…
-At the synapse betw preganglionic and postganglionic
parasympathetic nerves
-At the synapse betw preganglionic and postganglionic sympathetic nerves
-At the NMJ
Muscarinic receptors are located…
At the synapse betw postganglionic parasympathetic nerves and the end organ/tissue
Drugs which have affinity for cholinergic receptors may produce effects at….
mAChRs or nAChRs… or both ( This explains many of the side effects of many NDMRs and DMR outside the NMJ
• E.g., autonomic side effects)
primary pharmacologic effect of NMBAs is to…
interrupt transmission of nerve impulses at the NMJ (NMDR or DMR)
All NMBAs…
- Contain quaternary ammonium groups
- Limited Vd
- Do not cross the BBB
- Do not cross the placenta
- No CNS effects
- Oral administration not effective
- Minimal renal reabsorption
- Ionized Water-soluble, Limited lipid solubility
NMBA P‐kinetics: Vd and E 1/2T influences by…
Age,
Hepatic or renal disease
NMBA Vd
Generally, NMBAs have a Vd that is equivalent to the extracellular compartment (~14L) (not highly protein bound)
NDMR (effect)
Antagonize the effects of ACh
NMDR Long Acting
Pancuronium, Pipecuronium, Doxacurium
NMDR Intermediate Acting
Atracurium, Rocuronium, Vecuronium, Cisatracurium
NMDR Short Acting
Mivacurium
NMBA and Volatile Anesthetics (halothane, des, iso, sevo) PK
Do not directly alter the p‐kinetics of NMBAs
NMDR and Volatile Anesthetics (halothane, des, iso, sevo) PD
NDMRs are enhanced via pharmacodynamic action of VA
• Volatile anesthetics potentiate the effects of NDMRs via Ca++ channels
• Decreased dosing required for NDMRs in the presence of VAs
Clinical Uses NMBA
– Facilitate tracheal intubation
– Enhance surgical conditions
– Decrease oxygen utilization in critically ill patients who have limited reserve
– Treat laryngospasm (suxtiny dose!)
– Treat truncal rigidity associated with large doses of opioids
ED95
– The dose necessary to produce 95% suppression of a single twitch in response to peripheral nerve stimulator
– 2xED95 for NDMRs is the recommended dose to facilitate tracheal intubation (intubating dose)
• 90% depression is adequate for surgical relaxation
Choice of relaxant is determined based on…(4 things)
– Speed of onset
– Duration of action
– Side effect profile of the drug
– Patient’s health history
Inadequate return of function (residual paralysis)
- Difficulty focusing/diplopia
- Inability to swallow/dysphagia • Unable to protect airway
- Ptosis
- Weakness of mandibular muscles
- Low VT (hypoxia)
- floppy
All NMBAs (structure)
– Are structurally similar to ACh – Are compounds that have at least one N which binds to the α subunit of the AChR • Quaternary ammonium group – Are ionized – Have Vd similar to Extracellular Fluid
cause the majority of anaphylactic reactions during anesthesia
NMBAs…The biggest offenders are Succinylcholine and Rocuronium
Benzylisoquinoliniums (NDMR classification)
- Atracurium
- Cisatracurium
- Mivacurium
More likely to evoke histamine release d/t tertiary amine
Aminosteroids (NDMR classification)
- Pancuronium • Vecuronium
- Rocuronium
Do not possess any hormonal activity
Electrostatic attraction between AChRs(‐) and NH4+ groups
Occurs at all cholinergic sites including cardiac mAChRs and autonomic ganglion nAChRs which may cause cardiac side effects
the length of the carbon chain separating the + ammonium groups influences the degree of CV effects (structure/activity relationship)
-Longer chains are more specific to the nAChRs of the NMJ
– Maximal autonomic blockade when NH4+ groups are
separated by 6 Cs (hexamethonium)
– NM blockade is maximal when 10 Cs are present (decamethonium)
Succinylcholine chloride (intubation dose)
– 1‐1.5 mg/kg
• General dosing for tracheal intubation
• 1.5 mg/kg is the dose for rapid sequence intubation
Sux MOA
• Attaches to one or both α subunits of the nAChR where it mimics the actions of ACh
• Hydrolysis by pseudocholinesterase in the plasma is slow
– Depolarization is sustained and the depolarized membrane/receptors cannot respond to additional agonist
• This is referred to as Phase I blockade
• Fasciculations occur due to sustained depolarization
Sux and K
• Sustained depolarization is associated with leakage of K+ from the muscle cell
– plasma K+ increases 0.5 mEq/L (nrl response)
Sux Overdose
• A single large dose, repeated doses, or an infusion may cause postjunctional membranes to respond abnormally to ACh (overdose)
– Mechanism for this is unclear
• May be due to desensitization, ion channel blockade, or entry of Sux into skeletal muscle cytoplasm. Blockade characteristics change to Phase II Blockade
Phase I Blockade with SCh
- Decreased contractile force in response to a single twitch
- Sustained tetany with decreased amplitude
- TOF ratio >0.7 (~1.0)
- No Post Tetanic Facilitation
- Fasciculations
- Augmentation after admin anticholinesterase
Phase II Blockade with SCh
- Decreased contractile force in response to a single twitch
- Decreased amplitude and tetanic fade to sustained stimulus
- TOF ratio <0.7
- No fasciculations
- Can be antagonized by anticholinesterase
- Abrupt onset manifests as tachyphylaxis and increased dose requirements
Sux—Phase II (te)
Tetanic stimulation before & after administration of a LARGE dose of Sux is similar to the normal response to a NDMR
POST TETANIC FACILITATION
Sux—Phase I (te)
Tetanic stimulation before and after administration of an DMR
NO POST TETANIC FACILITATION
Post Junctional Receptor Agonists
ACh, Sux (depolarizing)
Post Junctional Receptor Antagonists
NDMRs (non-depolarizing)
cholinesterase inhibitors
inhibit acetylcholinesterase enzyme activity (reverse NDMR, prolong Sux)
fade
nondepolarizing block (d/t decrease in ACH from prejunctional receptors) OR phase II block Sux
parasympathetic (ganglionic fibers)
long pre-ganglionic fiber, short post-ganglionic fiber
sympathetic (ganglionic fibers)
short pre-ganglionic fiber, short post-ganglionic fiber
Sux metabolized by _____________ to produce ____________ and ______________.
- plasma cholinesterase
- succinylmonocholine and choline (succinic acid and choline)
plasma cholinesterase in sysnthesized by the….
liver
Sux duration of action is prolonged d/t…
- decreased synthesis of plasma cholinesterase, drug induced inhibition of the enzyme, atypical plasma cholinesterase
- <75% normal serum levels necessary to prolong plamsa cholinesterase
Atypical Plasma Cholinesterase
• Often discovered after administration of SCh produces prolonged effect
• Several variants of the enzyme exist
– Dibucaine‐related variants are most clinically
important
– Dibucaine “test” permits diagnosis of atypical plasma cholinesterase
Dibucaine
• Anamidelocal anesthetic
Dibucaine # 80
Significance
• Inhibitstheactivityof normal plasma cholinesterase by approximately 80%
Confirms normal plasma cholinesterase enzyme
• Inhibitstheactivityof atypical plasma cholinesterase by ~20%
- 80: Confirms normal plasma cholinesterase enzyme
- 40-60: Indicates heterozygous for atypical plasma cholinesterase (1:480). Modest increase in DOA
- 20: Indicates homozygous for atypical plasma cholinesterase (1:3200). NMB may last hours
resistance to SCh may be seen in patients with…
Myasthenia Gravis…d/t decrease in functional nAChRs
Sux AE (histamine)
- histamine release (large, rapid dose)
- face/trunchal flushing, bronchospasm, reduction in blood pressure, anaphylaxis/anaphylactoid reactions
Sux AE (cardiac dysrhythmias)
– Sinus bradycardia, junctional rhythm, and sinus arrest have been observed
• Due to stimulation of cardiac postganglionic mAChRs
• More common after a second dose of Sux is
administered soon after the first or in pediatric pop
• Pretreatment with a NDMR or atropine decreases the incidence
– Increases in HR and BP may occur
• Reflect activity at sympathetic ganglia
Sux AE (hyperkalemia)
– Occurs reliably in patients with
• Muscular dystrophy, 3rd degree burns, denervation injurymuscle atrophy, trauma, sepsis, upper motor neuron lesions, prolonged bed rest/mechanical ventilation…
– Due to proliferation of extrajunctional receptors
– Cardiac arrest may occur
– Pretreatment with NDMR does not protect against hyperK+ and related sequelae
– Using a smaller dose of Sux DOES NOT attenuate hyperkalemic response.
Sux AE (myalgia)
• Myalgia
– Esp. neck, back, abdomen, pharynx
– Apparently due to fasciculations
– Young, healthy, athletic more susceptible
– Pretreatment with a NDMR (a defasciculating dose) can reduce the severity
– May be treated with NSAIDS (if approp) – IV NSAID (ketorolac)
Sux AE (IOP)
• Increased IOP
– Onset: 2‐4 min after administration – Duration: 5‐10 min
– Unknown mechanism
– Theoretical basis
• Some avoid sux in patients with open globe injury to prevent extrusion of ocular contents
Suz AE (ICP)
• Increased ICP
– Not a consistent observation
Sux AE (intragastric pressure)
• Increased intragastric pressure
– Possible risk of aspiration
– Probably due to fasciculations and abdominal
muscle contraction
– May be prevented by defasciculating doses of NDMRs
Sux AE (sustained muscle contraction)
• Sustained muscle contraction
– Esp. masseter muscle (Trismus) • Common in children
• Sux is NOT recommended in peds
– Must be differentiated from Malignant Hyperthermia
Sux AE (malignant hyperthermia)
• Malignant Hyperthermia
– Rare, life‐threatening Autosomal Dominant pharmacogenetic disorder involving defective ryanodine receptors which control release of Ca++ in the sarcoplasmic reticulumhypermetabolism
– Often discovered after administration of a trigger (Sux or volatile anesthesics)
– Manifests as muscle rigidity, hyperpyrexia, hypermetabolism and 02 consumption, hypercarbia, tachycardia, metabolic acidosis, rhabdomyolysis
– Prompt diagnosis and treatment with dantrolene decreases mortality significantly
NDMRs (MOA)
– Bind to nAChRs in the NMJ without causing activation of the ion channel. Compete with ACh at the α subunits. Hi doses can cause channel blockade
– 70% receptor occupation does not produce evidence of NM blockade by single twitch
– 80‐90% receptor occupation required to interrupt transmission of the chemical signal
-steep dose response curve
Characteristics of NDMR blockade
– Decreased twitch to single stimulus – Tetanic fade – TOF ratio < 0.7 – Post‐tetanic facilitation TOF TOF – Potentiation of other NDMRs – Antagonism by anticholinesterase drugs -resembles phase II
NMDR SE (CV)
CV effects related to
– Histamine, prostacyclin release
– Antagonism of muscarinic receptors and/or nicotinic receptors in the ANS
Autonomic Margin of Safety
the difference between the required dose for NM blockade and the dose for circulatory effects
- pancuronium has very narrow autonomic margin of safety
- Vec, roc, and cis have much wider autonomic margins of safety
NMDR interactions (VA)
• Volatile anesthetics (not nitrous)
– Cause dose‐dependent potentiation of NDMRs (not sux)
• Iso=Des=Sevo>Halo>N2O(none)
• Long‐acting > intermediate‐acting
• Perhaps due to VA interaction with Ca++ channelsdecreased sensitivity of post junctional membrane to depolarization
– Pharmacodynamic, not p‐kinetic interaction
NMDR interactions (drugs…)
• Antibiotics – Aminoglycosides enhance NDMRs (& DMR) • May decrease prejunctional release of ACh by competing with Ca++ • Local Anesthetics enhance NDMRs(&DMR) • Antidysrhythmics enhance NDMRs (&DMR) • Diuretics enhance NDMRs – Furosemide inhibits cAMP↓ACh output • Magnesium enhances NDMRs (esp.vec) (hypermagnesia- competes with calcium at the motor end plate) • Lithium enhances NDMRs (&DMR) • Phenytoin decreases NDMR effect • Cyclosporin prolongs NDMRs • Ganglionic blockers delay onset and prolong DOA of NDMRs • Hypothermia enhances NDMRs • Increased K+enhances DMR, causes resistance to NDMRs • Decreased K+resistance to DMRs and enhances NDMRs 
NMDR interactions (injury)
- Thermal injury resistance to NDMRs after 10 days (not r/t prolif of ejrs)
- Paresis/hemiplegia resistance to NDMRs on the affected side
NMDR and NMDR interaction
- Some NDMRs have synergistic effects with other NDMRs
- Panc + dTC or metocurine
- Vec + dTC
- Males are less sensitive to NDMRs than women – Women require 22% less vec than men!
- d/t mucsle mass
Pancuronium Bromide (structure)
• Long‐acting,bisquaternaryaminosteroid
Pancuronium Bromide DOA
60-90min (long) – Prolonged with renal dz, cirrhosis, biliary obstr, aging
Pancuronium Bromide Metabolism/Elimination
• Renalelimination(80%unΔinurine) • Hepaticdeacetylation(10‐40%)
– 3‐desacetylpancuronium is 50% as potent as panc • Cumulative effects may occur with repeat dosing
Pancuronium Bromide CV effects
• CV effects
– ↑HR, MAP, CO
• Due to antagonism of cardiac mAChRs (SA node)
• More profound increases with AV conduction abns • Increased myocardial O2 consumption
– Can contribute to ischemia in pts with CAD
• No histamine release
• No ganglionic blockade
Intermediate acting NDMR
• Efficiently cleared
– Less cumulative effects than long‐acting
• Speed of onset can be hastened by administration of a priming dose
– ~10% of the ED95 prior to induction
– After induction, the balance of the intubating dose is adm
• Onset of intubating conditions is faster • Defasciculating dose (on the other hand)
– ~10% of the ED95 of NDMR prior to induction – However, a larger dose of Sux is required
Vecuronium Bromide (structure)
intermediate acting, monoquaternary aminosteroid
Vecuronium Bromide (metabolism, elimination)
• RenalandHepaticelimination
– Deacetylation to 3‐desacetylvecuronium which is 50‐70% as potent as vec
– Prolonged in patients with renal and/or hepatic disease
Vercuronium Bromide (facts…)
• Does not antagonize mAChRs
• Does not cause mast cell degranulation
• Unstableinsolution
– Supplied as a powderrequires reconstitution
• Cumulative effects (esp. with renal dz) – Panc > Vec > atracurium
Vecuronium Bromide (peds, elderly)
• Pediatric considerations – Similar potency c/t adults
– More rapid onset in infants – Longer DOA in infants
• Elderly consideration
– Prolonged DOA d/t lower clearance
Rocuronium Bromide (structure)
Intermediate‐acting monoquaternary aminosteroid
Rocuronium Bromide (excretion)
• ExcretedunΔinbile
• Renalexcretion(>30%)
– Liver and/or renal dz can prolong effects
• The only NDMR which can serve as an alternative to Sux when rapid onset is needed for RSI
Rocuronium Bromide….– Quality of relaxation is less than with Sux but still adequate.
Rocuronium Bromide SE
- No CV effects
- No histamine release
- Highest incidence of anaphylaxis among NMBAs—actually among all drugs used perioperatively!
Atracurium Bromide (structure)
Intermediate-acting bisquaternary benzylisoquinolinium (mixture of 10 stereoisomers in solution)
Atracurium Bromide (metabolism, elimination)
• Cleared by Hofmann Elimination & hydrolysis by non‐specific plasma esterases
– Both pathways produce laudanosine
• CNS stimulant
– Increases MAC in animal models
– May be epileptogenic
– Laudanosine cleared renally !
Atracurium Bromide (CV effects)
• CVeffects
– Rapid administration of >2x ED95 results in ↑HR and ↓BP • Facial and truncal flushing accompany histamine release at 3x ED95
Atracurium Bromide (pediatric, elderly considerations)
• Pediatric considerations – Infants 1‐6 mos, decrease dose by 50% for same effect as full dose in adults – Recovery is more rapid in infants • Elderly considerations – No change in pharmacokinetics
Cisatracurium Bromide (structure)
• Intermediate‐acting benzylisoquinolinium
– Purified form of one of the 10 stereoisomers of atracurium
-Similar NM blocking profile to atracurium except slower onset and no histamine release
Cisatracurium Bromide (elimination)
- Hofmann elimination at physiologic temp and pH to laudanosine (less than atracurium)
- No metabolism by nonspecific esterases
- May be adm to patients with renal/he pdz w/o prolonged effect.
Cisatrabromide (CV effects)
• CV Effects
Cisatracurium bromide
– No histamine release
– Indistiguishable from the CV effects of vec in patients with CAD
Mivacurium (structure)
Short‐Acting NDMR—Mivacurium
• BenzylisoquinoliniumNDMR
– Mixture of 2 stereoisomers
– Trans‐trans and cis‐trans are most active and are equipotent
– Cis‐cis is 1/10 as potent as the others
drug no longer available
Mivacurium (hydrolysis)
• Hydrolyzed by plasma cholinesterase
Mivacurium (CV effects)
• CV effects
– Minimal at clinically relevant doses
– Rapid administration of 3x ED95 produces
histamine release↓MAP (transiently)
Defective receptor is malignant hyperthermia
Ryanodine
Treatment malignant hyperthermia
Dantrolene
