Pharmacology I: Lecture 7 - Muscle Relaxants

Question 1

Neuromuscular Junction

Answer 1

Question 2

Acetylcholine (Ach)

Answer 2

Synthesized endogenously by the acetylation of choline under the control of choline acetylase

Rapid hydrolysis by acetylcholinesterase (AchE) to acetic acid and choline

Inhibition of AChE leads to increase in ACh at synaptic cleft

Question 3

Nicotinic Ach Receptors

Answer 3

Pentameric unit of five subunits to form a transmembrane pore

3 types 2 post and 1 pre

Question 4

Neuromuscular Transmission

Answer 4

Presynaptic AChR
Release of ACh is triggered by influx of Ca2+
Presynaptic AChRs facilitate this release
Regulated by positive feedback mechanism
Inhibition is detected as ‘fade’

Two Types of Postsynaptic AChR
Localized at neuromuscular endplate
Agonist are ACh and succinylcholine (Succ)
What most ‘our’ MR work on
‘mature’ = 2α1β1δε subunits
Normal healthy
‘immature’ = 2α1β1δγ subunits
Seen when deprivation of neural influence or activity i.e. nerve injury

Question 5

Structure

Answer 5

NDMR
Benzyisoquinolinium
Atracurium, cisatracurium, mivacurium, D-tubocurarine
Aminosteroid
Pan, Pipe, Vec, Roc, Doxa

DMR
Succinylcholine is two acetylcholine (Ach) molecules linked through an acetate methyl group (diacetylcholine)

Question 6

Clinical Pharmacology

Answer 6

A NMB by MR is characterized by a decreased response to stimulation of the respective motor nerve

This blockage is measured by twitches
A twitch of 100% = absence of NMB
0% = complete paralysis
A TOF is a ratio of the 1st twitch vs the 4th

Question 7

Succinylcholine (Anectine© / Quelicin©)
Mechanism of Action

Answer 7

Mimics Ach at one α subunits, causing ion channel opening and depolarization

Other α subunit can be bound by either ACh or Succ or not at all

Noncompetitive block

Partial agonist of nAChE

Elicits only initial depolarization

Binding induces muscle fasciculations – initial phase – followed by relaxation period

Question 8

Phase I Characteristics of Sux

Answer 8

Decrease contraction in response to single twitch & Decrease amplitude to continuous stimulation

Absence of posttetanic facilitation

Onset is accompanied by fasciculations or mini-contractions

DOA 5 – 10 min

Cell membrane beyond perijunctional area is repolarized and thus muscle contraction can be elicited by direct electrical stimulation

Question 9

Phase II Characteristics of Sux

Answer 9

Postjunctional membrane has become repolarized but still does not respond normally to ACh (desensitization neuromuscular blockade).

The mechanism of phase II blockade is unknown but may reflect the development of nonexcitable areas around the end plates that become repolarized but nevertheless prevent the spread of impulses initiated by the action of ACh.

Resemble those of typical NMB by NDMR

DOA 4 – 6 hrs

Can be reversed with a AChE inhibitor

Characterized by a tetanic or TOF fade

Onset due to:
High single dose or cumulative doses of succinylcholine
Lack of or functional inefficiency of pseudocholinesterase

Do not want this, commonly seen on repeated doses of Sux

Question 10

Metabolism of Sux

Answer 10

Short duration of action due to rapid hydrolysis by pseudocholinesterase
Metabolism is so rapid that only a small fraction of the administered dose reaches the neuromuscular junction
Blockade terminated by diffusion into extracellular fluid – must be cleared from NMJ and into the plasma
NMJ only contains AChE

Question 11

Plasma Cholinesterase Activity

Answer 11

Decrease in hepatic production, drug induced decrease, and genetically determined decrease of plasma cholinesterase results in slowed hydrolysis of succinylcholine and corresponding prolongation of the NMB

Question 12

Atypical Plasma Cholinesterase

Answer 12

Presents as an unexpectedly prolonged block from a single dose of succinylcholine

Heterozygous atypical (1/480)
Minimally delay in recovery

Homozygous carries (1/3200)
Experience prolonged block lasting up to 3 – 6 hrs

Question 13

Dibucaine Test

Answer 13

Lower the number, worse the result

Question 14

Side Effects of Sux

Answer 14

Bradycardia
Hyperkalemia (Non-mature Ach receptors is the problem???? Look Up!!!)
Upregulation of extra junctional Ach receptors
Care taken 24 hrs after burns, extensive trauma, spinal cord injury
Myalgia
Masseter spasm
Trigger MH
Histamine release
↑intragastric pressure
↑intraocular pressure
↑intracranial pressure

Question 15

Clinical Considerations of Sux

Answer 15

CV effects are due to stimulation of autonomic ganglia or vagal muscarinic receptors

mAChR of the GPCRs family share the same ligand (ACh) as nAChR in NMJ

Muscarinic side effects include:
Bronchoconstriction
Bradycardia
Increase in salivary secretions

Succ. Dart for Peds mix in 5 cc syringe
1 cc of Atropine – 0.4 mg
4 cc of Succ. – 80 mg
25 g IM needle

This combo allows for quick muscle relaxation in the case of laryngospasm without the concern of bradycardia

Try to avoid in little kids due to muscular dystrophy undiagnosed

Question 16

Packaging & Dosing of Sux

Answer 16

Commercial preparation
20 mg/cc succinylcholine chloride
Dosing
IV: 1 – 2 mg/kg
IM: 2 – 4 mg/kg
Onset: < 1 min
DOA: 5 – 10 min
Pretreat w/ 10%
of NDMR dose

Research shows that the pretreat does not really change anything for what the patient feels after the procedure from all the muscle contractions

Question 17

Non-depolarizing Muscle Relaxants: Mechanism of Action

Answer 17

Competitive antagonism at the α-subunit of the postjunctional nAChR

Occupation of as many as 75% of receptors can occur without showing clinical signs of neurmuscular blockade
Twitch depression

Question 18

Causes of Enhanced Response NDMR

Answer 18

Volatile anesthetics
Dose dependent enhancement in magnitude and duration of NMB
VA induce skeletal muscle relaxation at the level of the spinal cord via nAChR

Question 19

Causes of Altered Response

Answer 19

Aminoglycoside antibiotics
Can stimulate pre-synaptic receptors, causing ↓ release of Ach

Local anesthetics
Interfere with prejunctional release of Ach
Directly depress skeletal muscle fibers
Esters compete for plasma cholinesterase

Quinidine
Depresses prejunctional release of Ach

Diuretics
Furosemide depresses release of Ach

Magnesium
Stabilizes postjunctional membranes

Lithium

Anti-convulsant medications
Increased hepatic clearance of NDMR
Increased protein-binding of NMDR
Increased enzyme induction
Examples
Phenytoin (Dilantin)

Cyclosporines
Depress the release of Ach

Hypothermia
Decreased clearance
Slowed rate of effect site equilibration

Burn injury (>30%)
Altered affinity of receptor for Ach

Prior succinylcholine administration

Question 20

Characteristics of Pancurnium

Answer 20

Aminosteroid
Onset: 3 – 5 minutes
Duration: 60 – 90 minutes
Long DOA
Metabolism: 10 – 20% hepatic
Excretion: 60 – 80% renal, 10% biliary

Other: cardiovascular stimulant via blocking mAChR – Increase in HR

Not used anymore because its used in lethal injection

Question 21

Packaging & Dosing of Pavulon

Answer 21

Commercial preparation
2 mg/cc pancuronium bromide
Dosing
IV: 0.1 – 0.2 mg/kg

Question 22

Characteristics of Vecuronom (Norcuron)

Answer 22

Aminosteroid
Onset: 3 – 4 min
Duration: 30 – 50 min
Metabolism: 30 – 40% hepatic
Excretion: ~ 40% renal and 10 – 20% biliary

Consistent in its predictable

Question 23

Packaging and Dosing of Vecuronom (Norcuron)

Answer 23

Commercial preparation
10 mg lyophilized powder vecuronium bromide
Dilute to 1 mg/cc
Dosing
0.08 – 0.12 mg/kg

Question 24

Characteristics of Cistracurium (Nimbex)

Answer 24

Benzylisoquinolinium compound
Onset: 3 – 5 min
Duration: 30 – 50 min

Metabolism:
Hoffman elimination (extra hepatic and extra renal metabolism)
Renal clearance 10 – 30%

Primarily used for someone with no liver function, so used for a liver transplant

Question 25

Packaging and Dosing of Nimbex

Answer 25

Commercial preparation 2 mg/cc cisatracurium besylate Dosing 0.08 – 0.12 mg/kg

Question 26

Characteristics of Rocuronium (Zemuron)

Answer 26

Aminosteroid Onset: 1 – 2 min Other RSI MR Duration: 20 – 35 min* Metabolism: minimal hepatic Excretion: 30 – 40% renal and 60% biliary

Question 27

Packaging and Dosing of Rocuronium

Answer 27

Commercial preparation 10 mg/cc rocuronium bromide Dosing 0.6 – 1.2 mg/kg Max for induction ~ 50 mg

Question 28

Up-regulation of AChR

Answer 28

Loss of neural influences on muscle cells leads to up regulation of AChR and a spread of these receptors into peri and extrajunctional areas The new receptors are immature and have altered sensitivity and affinity Agonist will depolarize these AChRs more easily and lead to exaggerated cation fluxes Increase requirements of NDMR

Question 29

Down-regulation of AChR

Answer 29

A increase in sensitivity can also be seen in some cases Lower doses of NDMR are required For example: Myasthenia Gravis Organophosphate poisoning Chronic cholinesterase inhibition

Question 30

Histamine Release

Answer 30

A few muscle relaxants release histamine from our MAST cells Easy way to remember them is…. Mivacurium Atracurium Succinylcholine d-Tubocurarine Or MAST

Question 31

Anti-Cholinesterase Drugs Mechanism of Action

Answer 31

Reversible inhibition Edrophonium (Tensilon©) or Enlon Quaternary ammonium Electrostatic attachment to anionic site of acetylcholinesterase Formation of carbanyl esters Includes: Neostigmine (Prostigmin) Pyridostigmine (Mestinon) Physostigmine (Antilirium) Work at the esteratic site of AchE Acts to deactivate AchE Competitive inhibitor of cholinesterase resulting in decreased hydrolysis of acetylcholine Irreversible inactivation Organophosphates Echothiophate Parathion Malathion Bind to AchE esteratic site

Question 32

Kinetics of Anti-Cholinesterase Drugs

Answer 32

Differences in potency are differences in dynamics = all have about the same kinetics

Question 33

Clinical & Non-Clinical Uses of Anti-Cholinesterases

Answer 33

Reversal of neuromuscular blockade Neostigmine and edrophonium are the most commonly used in practice Pyridostigmine has slow onset and long duration DOA = same

Question 34

Clinical & Non-Clinical Uses of Anti-Cholinesterase

Answer 34

Myasthenia gravis treatment “Myasthenia”: muscle weakness (Greek) “Gravis”: serious (Latin) Autoimmune disorder Antibody inhibition of Ach receptors Glaucoma treatment Echothiophate Decreases the resistance to aqueous humor outflow Decreases IOP Central Anticholinergic Syndrome Results from atropine or scopolamine overdose Primarily a dx of exclusion with restless and agitation from insufficient acetylcholine Tx: Physostigmine 15-60 mcg/kg Paralytic ileus Alzheimer’s Disease Shortage of Ach in the brain is associated with Alzheimer’s Drugs used to block AchE to inc Ach Nerve gas Insecticides Malathion is an organophosphate inhibitor selective for many insects Anesthetic somnolence Tx: Physostigmine 2 mg IVP

Question 35

Distribution & Elimination of Anti-Cholinesterase

Answer 35

Lipid solubility Poor: edrophonium, neostigmine, pyridostigmine Good: physostigmine, organophosphates Hepatic hydrolysis and conjugation to inactive metabolites Renal clearance 50-75%

Question 36

Onset & Duration of Anti-Cholinesterase

Answer 36

Onset of action Edrophonium: 1-2 min. Neostigmine: 5-10 min. Pyridostigmine: 10-12 min. Duration of action Edrophonium: 30-60 min. Neostigmine: 45-60 min. Pyridostigmine: 90-120 min.

Question 37

Clinical Considerations of Anti-Cholinesterase

Answer 37

Bradycardia Hyper-peristalsis Increased gastric fluid secretion Increased N/V Mild bronchoconstriction Increased salivation Miosis

Question 38

Packaging & Dosing of Anti-Cholinesterase

Answer 38

Commercial preparation 0.5-1 mg/cc neostigmine methylsulfate 10 mg/cc edrophonium chloride 1 mg/cc pyridostigmine bromide Dosing Neostigmine: 0.04-0.08 mg/kg – MAX 5mg! Edrophonium: 0.5-1.0 mg/kg Pyridostigmine: 0.2-0.5 mg/kg

Question 39

Anti-cholinergic Agents: Commonly Used Agents

Answer 39

Naturally-occurring Atropine Scopolamine Synthetic Glycopyrrolate (Robinul©) History Atropine is a tropane alkaloid extracted from the Atropa belladonna plant A.k.a. Deadly nightshade Used by Cleopatra to dilate her pupils and make her more alluring “Belladonna” = beautiful lady (Italian) Fatally poisonous effect of belladonna led to naming of “atropine” Atropos was the third of three Fates in Greek mythology

Question 40

Mechanism of Action of Anti-Cholinergeric

Answer 40

Mechanism of Action

Question 41

Distribution & Elimination of Anti-Cholinergeric

Answer 41

Atropine and scopolamine are lipid-soluble tertiary amines Glycopyrrolate is a non-lipid soluble quaternary ammonium Varied elimination Glycopyrrolate: unchanged excretion in urine Atropine & scopolamine: hepatic hydrolysis

Question 42

Clinical Uses of Anti-Cholinergeric

Answer 42

Sedation Scopolamine depresses the RAS activity Antisialagogue Bradycardia Asystole PEA Neuromuscular blocking reversal adjunct Atropine with edrophonium Glycopyrrolate with neostigmine Bronchodilation Ipratroprium (Atrovent©) Biliary anti-spasmodic Mydriasis and cycloplegia Motion-sickness / PONV Parkinson’s Disease Organophosphate poisoning Pralidoxime + atropine

Question 43

Central Anti-cholinergic Syndrome

Answer 43

CNS effects are a result of atropine or scopolamine overdose Symptomology: Hallucinations Restlessness Somnolence Unconsciousness Treatment Physostigmine: 15-60 mcg/kg

Question 44

Packaging and Dosing of Anti-Cholinergeric

Answer 44

Commercial preparation 0.1-0.4 mg/cc atropine sulfate 0.2 mg/cc glycopyrrolate HCl 0.2 mg/cc scopolamine HBr Dosing Atropine: 0.01-0.03 mg/kg Glycopyrrolate: 0.01-0.02 mg/kg Scopolamine: 0.2 mg IVP

Question 45

Sugammadex (Bridion©)

Answer 45

New reversal approved this year Drug used to reverse ROC & VEC Reverses pt within 2 min Drug is not metabolized by liver Cleared by the renal system Concentration: 100 mg/ml Dose: 2 mg/kg for pts with TOF of 2/4 4 mg/kg for pts with TOF of 1/4 but a post-tetanic twitch 16 mg/kg for pts who need to be reversed within 3 min of an induction dose of ROC @ 1.2 mg/kg

Question 46

Sugammadex: MOA

Answer 46

Selective relaxant binding agent – Steroids only (VEC and ROC) Forms a complex with NDMR

Question 47

Sugammadex: Adverse Effects

Answer 47

Basically none but small amount of pts have Pain Bradycardia N/V Headache Cough QT prolongation (mild)

Question 48

Sugammadex: Clinical Considerations

Answer 48

Binds to other steroid drugs – hormonal contraceptives No change in dose for geriatric pts No change in diabetic pts Wait times to re-administer NDMR