Neuromuscular Physiology and Pharmacology Flashcards Preview

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Flashcards in Neuromuscular Physiology and Pharmacology Deck (108):
1

Depolarizing Muscle Relaxant

Succinylcholine, Mimics the action of ACh

2

Depolarizing Muscle Relaxant

Succinylcholine, Mimics the action of ACh

3

Succinylcholine Metabolism

Hydrolyzed by plasma cholinesterase
• AKA pseudocholinesterase or butyrocholinesterase – not present in the NMJ, drug must be cleared from
plasma

4

NM ‘blockade’ occurs because...(DMR, Sux)

the depolarized post‐junctional membrane cannot respond to additional agonist (Ion flux is an important consideration)

5

Clearance from the junctional cleft occurs by...(DMR, Sux)

diffusion (Sux molecules can repeatedly bind to receptors until the diffuse away from the NMJ)

6

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)

7

Closed channel blockade

Drug reacts around the mouth of the channel and prevents passage of ions
– Seen with cocaine, some antibiotics, quinidine, etc.

8

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

9

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.

10

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)

11

Succinylcholine Metabolism

Hydrolyzed by plasma cholinesterase
• AKA pseudocholinesterase or butyrocholinesterase – not present in the NMJ, drug must be cleared from
plasma

12

Succinylcholine (activity termination)

Activity is terminated by diffusion of the drug away from the NMJ

13

NM ‘blockade’ occurs because...(DMR, Sux)

the depolarized post‐junctional membrane cannot respond to additional agonist (Ion flux is an important consideration)

14

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

15

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)

16

Closed channel blockade

Drug reacts around the mouth of the channel and prevents passage of ions
– Seen with cocaine, some antibiotics, quinidine, etc.

17

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

18

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.

19

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)

20

Extrajunctional Receptors (agonist/antagonists)

Highly sensitive to agonists, but less sensitive (resistant) to antagonists

21

Prejunctional Receptors

nAChRs on prejunctional membranes
• Believed to regulate release of ACh from presynaptic membrane

22

Stimulation of Prejunctional Receptors

inhibits release of ACh from presynaptic
membrane
– May stimulate production of more ACh in the nerve terminal

23

nAChRs vs. mAChRs

All cholinergic receptors are responsive to acetylcholine

24

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

25

Muscarinic receptors are located...

At the synapse betw postganglionic parasympathetic nerves and the end organ/tissue

26

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)

27

primary pharmacologic effect of NMBAs is to...

interrupt transmission of nerve impulses at the NMJ (NMDR or DMR)

28

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

29

NMBA P‐kinetics: Vd and E 1/2T influences by...

Age,
Hepatic or renal disease

30

NMBA Vd

Generally, NMBAs have a Vd that is equivalent to the extracellular compartment (~14L) (not highly protein bound)

31

NDMR (effect)

Antagonize the effects of ACh

32

NMDR Long Acting

Pancuronium, Pipecuronium, Doxacurium

33

NMDR Intermediate Acting

Atracurium, Rocuronium, Vecuronium, Cisatracurium

34

NMDR Short Acting

Mivacurium

35

NMBA and Volatile Anesthetics (halothane, des, iso, sevo) PK

Do not directly alter the p‐kinetics of NMBAs

36

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

37

Clinical Uses NMBA

– Facilitate tracheal intubation
– Enhance surgical conditions
– Decrease oxygen utilization in critically ill patients who have limited reserve
– Treat laryngospasm (suxtiny dose!)
– Treat truncal rigidity associated with large doses of opioids

38

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

39

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

40

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

41

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

42

cause the majority of anaphylactic reactions during anesthesia

NMBAs...The biggest offenders are Succinylcholine and Rocuronium

43

Benzylisoquinoliniums (NDMR classification)

• Atracurium
• Cisatracurium
• Mivacurium

More likely to evoke histamine release d/t tertiary amine

44

Aminosteroids (NDMR classification)

• Pancuronium • Vecuronium
• Rocuronium

Do not possess any hormonal activity

45

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

46

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)

47

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

48

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

49

Sux and K

• Sustained depolarization is associated with leakage of K+ from the muscle cell
– plasma K+ increases 0.5 mEq/L (nrl response)

50

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

51

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

52

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

53

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

54

Sux—Phase I (te)

Tetanic stimulation before and after administration of an DMR

NO POST TETANIC FACILITATION

55

Post Junctional Receptor Agonists

ACh, Sux (depolarizing)

56

Post Junctional Receptor Antagonists

NDMRs (non-depolarizing)

57

cholinesterase inhibitors

inhibit acetylcholinesterase enzyme activity (reverse NDMR, prolong Sux)

58

fade

nondepolarizing block (d/t decrease in ACH from prejunctional receptors) OR phase II block Sux

59

parasympathetic (ganglionic fibers)

long pre-ganglionic fiber, short post-ganglionic fiber

60

sympathetic (ganglionic fibers)

short pre-ganglionic fiber, short post-ganglionic fiber

61

Sux metabolized by _____________ to produce ____________ and ______________.

-plasma cholinesterase
-succinylmonocholine and choline (succinic acid and choline)

62

plasma cholinesterase in sysnthesized by the....

liver

63

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

64

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

65

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

66

resistance to SCh may be seen in patients with...

Myasthenia Gravis...d/t decrease in functional nAChRs

67

Sux AE (histamine)

-histamine release (large, rapid dose)
-face/trunchal flushing, bronchospasm, reduction in blood pressure, anaphylaxis/anaphylactoid reactions

68

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

69

Sux AE (hyperkalemia)

– Occurs reliably in patients with
• Muscular dystrophy, 3rd degree burns, denervation injurymuscle 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.

70

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)

71

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

72

Suz AE (ICP)

• Increased ICP
– Not a consistent observation

73

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

74

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

75

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 reticulumhypermetabolism
– 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

76

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

77

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

78

NMDR SE (CV)

CV effects related to
– Histamine, prostacyclin release
– Antagonism of muscarinic receptors and/or nicotinic receptors in the ANS

79

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

80

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++ channelsdecreased sensitivity of post junctional membrane to depolarization
– Pharmacodynamic, not p‐kinetic interaction

81

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

82

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

83

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

84

Pancuronium Bromide (structure)

• Long‐acting,bisquaternaryaminosteroid

85

Pancuronium Bromide DOA

60-90min (long) – Prolonged with renal dz, cirrhosis, biliary obstr, aging

86

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

87

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

88

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

89

Vecuronium Bromide (structure)

intermediate acting, monoquaternary aminosteroid

90

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

91

Vercuronium Bromide (facts...)

• Does not antagonize mAChRs
• Does not cause mast cell degranulation
• Unstableinsolution
– Supplied as a powderrequires reconstitution
• Cumulative effects (esp. with renal dz) – Panc > Vec > atracurium

92

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

93

Rocuronium Bromide (structure)

Intermediate‐acting monoquaternary aminosteroid

94

Rocuronium Bromide (excretion)

• ExcretedunΔinbile
• Renalexcretion(>30%)
– Liver and/or renal dz can prolong effects

95

• 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.

96

Rocuronium Bromide SE

• No CV effects
• No histamine release
• Highest incidence of anaphylaxis among NMBAs—actually among all drugs used perioperatively!

97

Atracurium Bromide (structure)

Intermediate-acting bisquaternary benzylisoquinolinium (mixture of 10 stereoisomers in solution)

98

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 !

99

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

100

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

101

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

102

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.

103

Cisatrabromide (CV effects)

• CV Effects
Cisatracurium bromide
– No histamine release
– Indistiguishable from the CV effects of vec in patients with CAD

104

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

105

Mivacurium (hydrolysis)

• Hydrolyzed by plasma cholinesterase

106

Mivacurium (CV effects)

• CV effects
– Minimal at clinically relevant doses
– Rapid administration of 3x ED95 produces
histamine release↓MAP (transiently)

107

Defective receptor is malignant hyperthermia

Ryanodine

108

Treatment malignant hyperthermia

Dantrolene