Pharm- Depolarizing and non-depolarizing blockade

List the most common SE of Succ

• Dysrhythmias- bradycardia

• Myalgia from fasciculations

• Hyperkalemia

• Myoglobinuria- presence of an excess amount of myoglobin in the urine. It is mostly caused by muscle breakdown, releasing a high amount of myoglobin in the blood. Myoglobinuria can lead to acute kidney injury

• INC Intragastric Pressure

• INC IOP

• INC ICP

• Malignant Hyperthermia trigger

Sequence of neuromuscular blockade [1st paralyzed to last paralyzed]

• Eyes and digits→trunk and abdomen→intercostal muscles and diaphragm[more junctional receptors]

discuss the SE of Bradycardia w/ Succ

• mimics Ach at the M2 receptors, muscarinic receptors of SA node, and pre-ganglionic nicotinic receptors and causes:

  • brady, junctional rhythm or sinus arrest

• More prominent in patients with high sympathetic tone, such as children

• Pretreatment with NDNMB can diminish this

Discuss the SE myalgia w/ succ administration

• Prominent in neck, back, & abdomen

• Generalized depolarization → unsynchronized contraction (fasciculations)

• PreTx with ND NMBD 

  • (1/10 ED95 NDNMB)

  • If visible muscle contractions DEC , then myalgia DEC 

  • Defasciculation 

    • Small amount of NDP is given to bind to alpha subunits to prevent a dramatic depolarization when SCh arrives

  • This technique may prolong the onset time of SCh but this can be overcome by increasing the intubating dose of SCh

INC ICP w/ succ

• Increased CBF & ICP with SCh not consistently observed but is due to fasciculations when it occurs

• Intracranial tumors or head trauma

• If increased ICP is detrimental 

  • Pretreatment with ND is effective

  • Prior hyperventilation to vasoconstrict vessels in the brain 

  • Lidocaine IV prior to intubation

hyperkalemia and Succ

pt. at risk:

• Clinically unrecognized muscular dystrophy & myopathies

  • Duchenne’s muscular dystrophy

• Burn injury > 24 hrs post injury

• Denervation → skeletal muscle atrophy [in bed for long time] 

• Severe skeletal muscle trauma >72 hrs

• Upper motor neuron lesions

  • Guillain-Barre

• Prolonged immobilization

• Crush or burn injuries have high serum potassium levels from significant muscle injury (rhabdomyolysis) which is compounded with SCh administration

  • PreTx with ND NMBD,  NO effect on magnitude of K+ release

avoid succ in peds < _______ y/o

and especially in ____ pt b/c Hyperkalemia that results leads to cardiac arrest and death

• 10

• Duchenne muscular dystrophy

Discuss extrajunctional receptors SE seen w/ Succ

• Up-regulation of extrajunctional ACh receptors

  • INC # of receptors→ INC  depolarization

  • They stay open 4 X longer than normal–< Significantly INC K levels

• Occurs with

  • muscle atrophy

  • Myopathies

  • Denervation injuries

  • Prolonged immobilization

• discuss INC Intragastric Pressure seen w/ Succ- [not a huge issue]

• GE sphincter opens > 28 cm H20 which is hard to overcome 

  • 15 cm H2O in pregnant patients

• Increased intensity of fasciculations results in increased intragastric pressure

• Causes in increase in lower esophageal sphincter tone.

• PreTx with ND NMBD

  • If visible muscle contractions DEC  , aspiration risk DEC esp with concomitant cricoid pressure

INC IOP SE seen w/ Succ

• Striated muscle of the eye contains several motor end plates

• SCh INC  IOP 2 - 4 min post injection

  • Lasts only 5-10 minutes

• Theory: SCh may cause extrusion of global contents if patient has open eye injury

  • Never been substantiated

  • pretx w/ NDNMB

  • Legal issue- b/c patient can go blind and sue ur ass 

metabolism of Succ

how is it metabolized and what is the metabolite?

• Plasma cholinesterase (pseudocholinesterase) rapidly hydrolyzes SCh

  • Not found in significant amounts at NM junction

  • Quality & quantity important

  • Small fraction SCh reaches NMJ 

• Succinylmonocholine – only active metabolite that is 1/20th to 1/80th as potent

• SCh action terminated primarily by _________

• Degraded via hydrolysis by plasma cholinesterase aka _____

• diffusion away from NMJ

• pseudocholinesterase 

Phase 1 depolarizing block

• general info

• Sustained opening of ion channels

• Depolarization occurs

  • Fasciculation: a small local contraction of muscles, visible through the skin, representing a spontaneous discharge of a number of fibers innervated by a single motor nerve filament

• Intracellular; K+ leakage  serum K+[ ] an average of 0.5 mEq/L

Phase 1 specific characteristics

• Dose Related DEC in intensity of contraction in response to a single twitch

• DEC Amplitude but sustained response to continuous stimulation [NO FADE]

• TOF ratio > 0.7 or No fade

• Absence of posttetanic facilitation

• Fasciculations

• Augmentation of block by anticholinesterase (AChase) drugs

phase II block w/ succ

• Like Non-Depolarizing blockade

  • Dose related decrease in twitch height

  • DEC TOF twitch height with fade

  • Tetanus fades

  • Post-tetanic facilitation present

Succ characteristics

• class

• preparation

• onset

• DOA

• indications

• The only one in this class used in the U.S.

• Di-quaternary ammonium compound

• Unstable-refrigeration required

• Preparation:

  • 2% solution; 20 mg/ml in 10 ml vials

• Rapid onset: 30-60 sec

  • Low lipid solubility

• Duration: 4-8 min 

  • Rapidly hydrolyzed in the body

• Useful for rapid tracheal intubation [RSI]

Common structure in all muscle relaxants

• Highly ionized at physiologic pH= lipid insoluble

• Quaternary ammonium groups- in NMB

• Other NMB commonalities :

  • Sevo can potentiate the actions of the NMB

  • Water soluble

  • Can’t cross BBB or placenta

    • Lipid membrane barriers

    • Limited lipid solubility

  • NOT ANESTHETICS

  • They do not provide amnesia, analgesia, or narcosis

Succ is CI in these conditions:

• myasthenia gravis

• congenital myasthenia syndromes [CMS]

• Lambert-Eaton myasthenic syndrome [LAMS]

• presence of extrajunctional receptors- pt w/ injuries or unuse

• muscular dystrophies

• low plasma cholinesterase

• Examples of conditions that can cause Low PChase 

• Burns

• Cancer

  • Certain neoplasms and cancer drugs

• Pregnancy

• Certain Drugs

  • Echothiophate – glaucoma eye drops – stop 4 wks prior to surgery

• DEC Hepatic production of Plasma Cholinesterase (PChase)

  • Severe liver disease

• Drug induced DEC of PChase

  • Neostigmine, but not edrophonium

  • Glaucoma/myasthenia gravis treatment

• Genetic atypical PChase → slowed or absent hydrolysis of SCh

  • These patients usually remain intubated until further testing is done and or the Succ wears off 

Atypical Plasma Cholinesterase

what is it and how is it dx

• Genetically acquired 100 fold lower affinity for the substrate [reaction cannot occur] 

• Prolonged NM blockade b/c there is not enough enzyme to metabolize the drug

• may require postop ventilation

• Identified/Dx using Dibucaine (local anesthetic)

  • Amide

discuss the Dibucaine number test

• Dibucaine

  • A local anesthetic that inhibits normal PChase by ~ 80 %, compared to ~ 20% inhibition of the activity of atypical enzyme

  • 40-60 is considered heterozygous [U/A]

  • <20 atypical homozygous [A]

• Dibucaine # of 80 reflects 80 % inhibition of enzyme activity

  • Confirms normal Pchase

• Quality not quantity

  • Quantity DEC in liver disease

  • (normal Dibucaine #)

hereditary variants of PChase

• Congenital Myasthenic Syndromes (CMS)

• Presynaptic – Defects in ACH synthesis or release

• Synaptic – Endplate ACE deficiency

• Postsynaptic – Abnormal ACH receptor or Na Channels

• Difficult to predict clinical effects d/t variants

• Myasthenia Gravis

• Postsynaptic – Autoimmune destruction of ACH receptor

• Demand problem – plenty of ACH, but no ACHR to work on

• Resistant to Sux, sensitive to NDMR

• Lambert-Eaton Myasthenic Syndrome (LAMS)

• Presynaptic – Autoimmune destruction of voltage-gated Ca++ channel that triggers release of Ach

  • affects the communication between nerves and muscles

• Sensitive to both Succ and NDMR

• LEMS can be caused by a paraneoplastic syndrome or a primary autoimmune disorder. [Most cases are associated with small-cell lung cancer]

AE of ND NMB

• Anaphylactic reactions

• Airway compromise (if not supported)

• Respiratory arrest (if not supported)

• Histamine release (mivacurium and atracurium) [Hilarious Monkey Antics]

  • Avoid in asthmatics

• Cholinergic blockade (pancuronium and rocuronium) [Comically Performing Resuscitation]

  • Avoid in patients who cannot tolerate elevated HR or BP

Contraindications for NMRs

• Equipment not available to manage airway/sustain ventilation

• Patient is dependent on negative intrathoracic pressure to maintain airway patency or cardiac output

  • Ex: cardiac tamponade pt 

• Anaphylaxis to specific agent

• Movement during surgery (conscious or evoked) is needed)

describe NDMR MOA

• Competitive antagonist-affinity but no intrinsic activity

• compete for Ach receptors sites on the pre-and post junctional receptors

• Blocks AcH postsynaptically from binding α subunits of the α2βγδ receptor on motor endplate inhibiting depolarization→ skeletal muscle paralysis

• Blocks AcH presynaptically (α3β2 type AcH receptors), decreasing mobilization down the axon or fusion with the cleft membrane of AcH vesicles. 

aminosteroid NDMR include:

• Intermediate Acting

  • Vecuronium (Norcuron)*

  • Rocuronium (Zemuron)*

• Long Acting

  • Pancuronium (Pavulon)*

  • Pipecuronium (Arduan)

• End in “-Curonium”

QUINOLINIUM NDMRs include:

BENZYLISOQUINOLINE

• Intermediate Acting

  • Atracurium (Tracrium)*

  • Cisatracurium (Nimbex)*

• Long Acting

  • d-Tubocurarine (Curare)

  • Doxacurium (Nuromax)

TETRAHYDROISOQUINOLINIUM

• Short Acting

  • Mivacurium

  • Rapacuronium- removed from the market b/c it caused bronchospasm in 1/100 pt

characteristics of pancuronium

• Bisquaternary aminosteroid drug (2 quaternary amines)

• First aminosteroid in clinical use (1968)

• Duration: Long (86-100 minutes)

• Undergoes minimal hepatic metabolism, extensive renal excretion (prolonged duration in renal failure)

• Some affinity for muscarinic receptors (anticholinergic properties) [inc HR by~35% and C.O.]

clinical uses for pancuronium

• not really used anymore…but still test us on it…..

• Long cases on patients with intact renal function, or who did not need to be extubated

• For decades was the NDMR of choice for heart surgery (anticholinergic properties offset bradycardia in high dose opiate cases)

• Also drug of choice in execution protocols

vecuronium characteristics

• Quaternary aminosteroid drug (1 quaternary amine)

• Like pancuronium but missing a methyl group 

  • allowing easier hepatic metabolism via deacetylation

• Duration: Intermediate (~40 minutes) until twitch back

• Majority is excreted unchanged in the bile (40%) or urine (20-30%)

  • 3 possible by-products of metabolism → 3-Desacetylvecuronium only active one [50% active]

    • Can build up and make it hard for the kidneys to filter and eventually regain muscle movement 

    • 17- Desacetylvecuronium and 3, 17-desacetylvecuronium are inactive

clinical uses of Vecuronium

• avoid w/ _____

• good b/c it has no ____release or _____ properties

• Inexpensive

• Good for any surgery longer than 45 minutes (adjust intubation dose)

• No histamine release, no cholinergic properties (can give large doses to accelerate onset of intubating conditions)

• Avoid if biliary obstruction/hepatic failure, renal failure (use atra/cisartacurium)

Rocuronium characteristics

• Quaternary aminosteroid drug (1 quaternary amine)

• Only nondepolarizer recommended for RSI (at 2 x ED95 intubating conditions occur in ~2 minutes)

• Duration: Intermediate (~40 minutes) [esp w/ high doses]

  • The smaller the dose, the slower the onset 

• Majority is excreted unchanged in the bile (80-90%) or urine (10-20%)

  • Hepatic dysfunction will prolong duration of the drug [not b/c of metabolism but b/c of the fact that it is excreted in the bile] 

• Duration prolonged by coadministration with sevoflurane; most implicated NDMR in anaphylaxis

clinical uses for rocuronium

• Inexpensive (now)

• Good for any surgery longer than 20-30 minutes (adjust intubation dose)

• No histamine release, mild (if any) anticholinergic properties (can give large doses to accelerate onset of intubating conditions)

• Avoid if biliary obstruction/hepatic failure, renal failure (use atra/cisartacurium)

• Atracurium characteristics

  • class

  • SE

  • DOA

  • metabolism

• Benzylisoquinolinium (2 quaternary amines)

  • 4 stereocenters, mixture of 10 stereoisomers d/t central plane of symmetry

• Histamine release limits speed of administration [ not great for induction ]

• Duration: Intermediate (30-60 minutes)

• Undergoes Hoffman elimination (33%)/ester hydrolysis (66%)  by nonspecific esterases (not butrylcholinesterase aka plasma cholinesterase)

• Metabolites (inc. Laudanosine) renally/hepatically excreted

• Degrades spontaneously at room temperature-refrigerate

  • Loses 10-15% of its potency each week it's not refrigerated

Cisatracurium

• class

• DOA

• metabolism

• Benzylisoquinolinium (2 quaternary amines)

• Single stereoisomer version of atracurium (1 R-cis, 1’R-cis variant)

  • Does not release histamine

• Duration: Intermediate (30-60 minutes)

• Undergoes Hoffman elimination (77%)/ ester hydrolysis (~7-10%)  by nonspecific esterases (not butrylcholinesterase!)

  • Metabolites (inc. Laudanosine) renally/hepatically excreted

• Degrades spontaneously at room temperature-refrigerate

clinical uses for Cisatracurium

• Inexpensive (now)

• Good for any surgery longer than 40 minutes (adjust intubation dose), where rapid airway control is not needed

• Cisatracurium can be safely used in asthmatics

• Drugs of choice in renal/hepatic failure/obstruction (terminated by metabolism, not elimination!)

• Mivacurium characteristics

  • class

  • SE

  • DOA

  • metabolism

• Isoquinalone (2 quaternary amines)

• Clinical drug is composed of 3 of the 20 possible  stereoisomers

• Histamine release limits speed of administration; must be administered over at least 30 seconds for intubation

• Duration: short (~20 minutes)

• Benefit: Undergoes ester hydrolysis (~100%) via butrylcholinesterase (plasma cholinesterase) → gives it a short DOA 

  • Metabolites are physiologically inactive and renally/hepatically excreted

• Mivacurium clinical uses and when to avoid use

• Good for short surgery, where securing airway quickly not a concern [drug of choice for kid tonsils] 

• Best avoided in asthmatics [b/c of histamine release]

• Good drug in renal/hepatic failure/obstruction (terminated by metabolism, not elimination!)

• Avoid in atypical plasma cholinesterase, or if patient recently received neostigmine

• Succinylcholine: intubation dose:

• Pancuronium: intubation dose:

• Vecuronium :Intubation dose:

• Cisatracurium Intubation dose:

• Mivacurium Intubation dose:

• Atracurium Intubation dose:

• Rocuronium Intubation dose:

• Succinylcholine: intubation dose: 1-1.5 mg/kg

• Pancuronium: intubation dose: 0.08-0.12 mg/kg 

• Vecuronium :Intubation dose: 0.1 mg/kg (relatively potent)

• Cisatracurium Intubation dose: 0.1 mg/kg (potent)

• Mivacurium Intubation dose: 0.2 mg/kg (moderate/high potency)

• Atracurium Intubation dose: 0.5 mg/kg (moderate potency)

• Rocuronium Intubation dose: 0.6 mg/kg (low potency)

"Silly Penguins Venture Carelessly, Making Awkward Ruckus"- increasing dose = lower potency

general comparisons of aminosteroids and quinoliniums

Aminosteroid metabolism

• Hepatic metabolism- very minimal

• Only active metabolite is vecuronium→ 3-desacetyl vecuronium 

• Aminosteroids are dependent on hepatic and/or renal elimination, and so will be prolonged in patients with impairment/obstruction

Quinolinium metabolism

Hoffman and/or ester hydrolysis metabolism- extensive metabolism

describe Hoffman elimination and hoffman products for cisatracurium

• pH and temperature-dependent degradation [not organ dependent] 

• elimination reaction that breaks down an organic compound into simpler substances by removing a weak acid under the influence of a strong base

• Favored by proton-poor and warm conditions

• Essentially a reversal of how quaternerary ammonium ions are made.

• Hoffman Products:

  • ​​For cisatracurium, approximately 80% of the drug is metabolized into laudanosine (~20 excreted unchanged via hepatic/renal routes)

  • Laudanosine levels from cisatracurium are ~1/5 that of atracurium d/t smaller doses and differences in hydrolyzed fractions

  • Laudanosine is the metabolite that can cause seizures in high concentrations! 

• _________ is metabolized by butrylcholinesterase (like succinylcholine), so is subject to the same caveats about metabolism which include:

• Mivacurium

• Prolonged by atypical butrylcholinesterase

• Might be prolonged by neostigmine administration (not significant once NM function has returned)

Benzylisoquinoliniums metabolism

are terminated by metabolism, not elimination, so are good choices for patients with organ impairment

more extensive metabolism than aminosteroids.

Metabolized by hoffman elimination and plasma esterases