ADDITIONAL READING MATERIAL NEUROMUSCULAR BLOCKING …webmedia.unmc.edu/medicine/scholar/NMBD, 2005 .pdf · 1 NEUROMUSCULAR BLOCKING AGENTS Keshore R. Bidasee, Ph.D. Durham Research

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NEUROMUSCULAR BLOCKING AGENTS

Keshore R. Bidasee, Ph.D. Durham Research Center 3047

Phone: 559-9018Email: [email protected]

Spring 2005

ADDITIONAL READING MATERIAL

Chapter 27, Skeletal Muscle Relaxants, Ronald Miller and Betram Katzung, p. 428-446, in Katzung's Basic and Clinical Pharmacology, 9th Edition, 2004

Chapter 9, Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, Palmer Taylor, p. 193-206, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition

OBJECVTIVES OF THIS LECTURE

(1) Identify therapeutic strategies that could be use to block conduction at the neuromuscular junction (NMJ)

(2) Differentiate between competitive (non-depolarizing)blocking and depolarizing agents at the nicotinic acetylcholine receptor receptor (AChR) in the NMJ

(3) Describe the pharmacodynamic and pharmacokinetic properties of neuromuscular blocking agents

(4) Identify precautions, contraindications, and drug-interactions associated with the use of neuromuscular blocking agents

Non-depolarizing blockers

(a) Isoquinoline Derivatives d-Tubocurarine (prototype) Atracurium (Tracrium)Mivacurium (Mivacron)

(b) Steroid DerivativesPancuronium (Pavulon))Vecuronium (Norcuron)Rucoronium (Zemuron)

Depolarizing blockersSuccinylcholine (Anetine)

Acetylcholinesterase inhibitorsNeostigmine (Prostigmin)Edrophonium (Tensilon,

Enlon)

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NEUROMUSCULAR BLOCKING DRUGS ARE ROUTINELY USED

(1) To prevent voluntary or reflex-induced muscle contractions during surgical procedures

(2) To assist with artificial ventilation in unresponsive patients (undergoing antiepileptic therapy)

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WE ARE INTERESTED IN DRUGS THAT

ACT ON NICOTINIC ACETYLCHOLINE

RECEPTORS (nAChR)

AND ALTER Na+ PERMEABILITY

These drugs bear structural resemblance to acetylcholine

bis-quaternaryaminosteroid

Mono-quaternaryaminosteroid

bis-quaternarybenzylisoquinoline

bis-quaternarybenzylisoquinoline

Blockade at the nAChR is accomplished by two ways

(1) Preventing depolarization

Drugs that do this are referred to as

non-depolarizing blockers - d-Tubocurarine (prototype)

(2) Excessive depolarization

Drugs that do this are referred to as

depolarizing blockers - Succinylcholine (prototype)

MECHANISM OF ACTION

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Non-depolarizing (competitive) blocking agents

(1) In low dosages and at low frequencies of stimulation,

they compete with acetylcholine for binding sites on nAChR - competitive blockers or antagonists at nACHR

(2) In larger doses, some of these drugs enter the pore

to cause blockade.

(3) Non-depolarizing agents can also block prejunctional

sodium channels and this interferes with ACh reuptake

at the nerve ending.

nAChRSODIUM CHANNELS

Gated channels

RESTING STATE:upper gate closedlower gate open

nAChR

AcetylcholineNon-depolarizingdrugs

There are two major classes of non-depolarizing agents

(a) isoquinoline derivatives

d-Tubocurarine is the prototype

Atracurium, Mivacurium and Doxacurium

(b) aminosteroids

– Pancuronium, Vecuronium, Rocuronium

Blockage by non-depolarizing blocker can be reversed

by administration of an acetylcholine esterase inhibitor

(neostigmine ann edrophonium)

Blockage of acetylcholine esterase results in a build up of

ACh at the end plate which can then compete with the drug

for binding site on the receptor

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Depolarizing Blocking Agents(a) succinylcholine Phase 1 block

(1) Succinylcholine binds to and activate or open the nicotinic acetylcholine receptor (nAChR)

(2) Opening of the nAChR causes Na+ to enter the muscle and this triggers a cascade of events that result in muscle contraction.

(3) Because succinylcholine is not metabolized effectively by acetylcholinesterase, the depolarized membrane remains depolarized and unresponsive to additional impulses

(4) Since excitation-contraction coupling of the muscle requires end plate repolarization (repriming) and repetitive firing to maintain muscle tension, a flaccid paralysis results.

Depolarizing agents block in two steps

Phase II blockWith continuous exposure to succinylcholine, the initial

end plate depolarization decreases and the membrane

become repolarized. Despite this repolarization, the

membrane cannot easily be repolarized again, i.e.,

it is desensitized.

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Mechanism of Action of depolarizing blocker

nAChRSODIUM CHANNELS

Gated channels

RESTING STATE:upper gate closedlower gate open

DEPOLARIZATIONgates remains open

Blockage by depolarizing blocker cannot be

reversed by administration of an

acetylcholine esterase inhibitor.

MONITORING NEUROMUSCULAR FUNCTION

WHY BOTHER?

•Wide inter-patient variability in dose requirements

•Differentiates type of block

•Allows careful titration to effect

•Allows assessment of readiness for reversal

•Allows assessment of adequacy of reversal

TOF - four pulses are applied at 2Hz and the ratio of the strength ofthe fourth to that of the first is measured

The efficacy of block is usually assessed by stimulating a peripheral nerve and recording evoked contraction

–Peripheral muscles are easily accessible•Ulnar nerve-Adductor Pollicis similar to in vitro NM prep.

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Monitoring Neuromuscular Function

TOF (Train of Four)

• TRAIN OF FOUR (TOF)

– Measures continued relaxation

– No control required

– Identifies phase II block

– Tolerable in awake patients

– Reliability? In visual /tactile

assessment

– measurement 0.7 of 0.9 or 1

Non-depolarizing or competitive blockers areANTAGONISTS at the nicotinic acetylcholine receptors,i.e., they bind but do not activate or open the channel

Blockage by competitive antagonist can be reversed by administration of an acetylcholine esterase inhibitor.

SUMMARIZE

Succinylcholine is NOT metabolized by acetylcholine esterase, (a) persistent depolarization prevents new action potential from occurring (b) K+ leaves the muscle in an attempt to repolarize the

end plate(c) as long a succinylcholine remains binding the

muscle will state in a state of flaccid paralysis

Depolarizing blockers are AGONIST at the nicotinic acetylcholine receptors and there mechanism of action isjust a bit different

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Competitive Block

Depolarizing Block

Action atnicotinic receptorAntagonist Agonist

Effect ofneostigmine

Rate of recovery

Antagonize Augmented

10 - 60 min 4 - 8 min

Phase I Phase II

Antagoniz

>20 min

Initial excitatoryEffect on skeletalmuscle

None Fasciculation None

Comparison of depolarizing and non-depolarizing blockers

Neuromuscular blocking drugs (NMBs) are highly polar

and always administered intravenously by an

anesthesiologist. They are inactive when administered by

mouth.

PHARMACOKINETICS

Non-depolarizing agents

Rate of disappearance of non-depolarizing

agents from the blood is characterized by a rapid initial

distribution, followed by a slower elimination phase.

However, because they are highly ionized they do not cross

membranes (blood brain barrier or the placenta) and have

limited volume of distribution (extracellular fluid volume)

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Non-depolarizing agents can be eliminated

(1) Plasma cholinesterase (butrylcholinesterase)

(2) excreted by the kidney

(3) metabolized by the liver

(4) spontaneous breakdown (Hoffman elimination)

Atracurium is an isoquinoline NMB that is inactivated

mainly by spontaneous elimination (hydrolysis of ester

bond). One of the breakdown products is LAUDANOSINE

which does not possess neuromuscular blocking

properties. However, it is slowing metabolize by the liver

and can cross the blood-brain barrier. At high

concentrations (>17µg/ml), it can cause seizures.

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Atricurium is broken down spontaneously to for

laudanosine

intravenous administration of non-depolarizing agents

will cause skeletal muscles to become totally flaccid and

inexcitable to stimulation.

In general, the larger muscles (those of the trunk) are more

resistance to block and recover more rapidly than the smaller

muscles (e.g., those of the hand). The diaphragm is usually

the last muscle to be paralyzed.

Rapidly moving muscles (eyes, fingers, toes)>limbs>trunk>diaphragm

• SENSITIVITY TO NMBDs’

– Upper airway muscles– Masseter– Abdominal muscles– Peripheral limb muscles– Muscle of the larynx– Muscles of the face– Diaphragm

Increasing resistance

Succinyl choline has an extremely brief duration of action

(5-10 minutes) because it is rapidly hydrolyzed by plasma

cholinesterase (butrylcholinesterase/pseudocholinesterase)

to succinyl monocholine (small amount reaches the NMJ).

Depolarizing agents

The latter is metabolized by the liver to form choline and

succinic acid.

Succinylcholine Succinylmonocholine

Plasma

Cholinesterase

Liver Succinate +

Chloline

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Neuromuscular blockade by succinylcholine can be

prolonged in patients with abnormal invariant of

plasma cholinesterase.

The “dibucaine number” is a test to determine the ability

of patients to metabolize succinylcholine (under standard

conditions, dibucaine inhibits normal enzyme 80% and

abnormal enzyme 20%)

ADVERSE EFFECTS

ISOQUINILONINE TYPE

d-Tubocurarine

(i) hypotension caused by

(ii) releases histamine from mast cells

(can be attenuated with antihistamines)

(iii) ganglion blockage

AMINOSTEROID TYPEPancuronium)

(i) can also block muscarinic acetylcholine receptors

(mACh) in the heart leading to tachycardia and slight

elevation in blood pressure

(ii) block reuptake of norepinephrine (not seen with

Vecronium)

(a) Children:low dosages can stimulate muscarinic receptors in the heart

(b) Adult:high dosages can stimulate the nACh in the autonomic ganglia and this can result in cardiac arrhythmias as well as increases in blood pressure. Can also induce positiveinotropic and chronotrpoic responses

. low dosages can trigger negative inotropic and chronotrpoic responses

DEPOLARIZING BLOCKER

succinylcholine

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ISO

STE

PRECAUTIONS, CONTRAINDICATIONS

(A. Disease affecting muscle contraction where

(i) amount of acetylcholine released at the neuromuscular

junction is abnormal

example: amylotrophic lateral sclerosis

(ii) availability of acetylcholine receptors is abnormal

example: myasthenia gravis

B. Administration of succinylcholine can increases serum

potassium (hyperkalemia) in patients with recent burns

or muscular denervations

E. Succinylcholine may precipitate a malignant hyperthermic crisis in genetically predisposed patients

C. Do not use succinylcholine in patients with atypicalplasma cholinesterase

D. Can increase intraoccular and intragrastric pressure

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Malignant Hyperthermia is a potentially fatal

pharmacogenetic disorder of skeletal muscle.

It is triggered in susceptible individuals by

exposure to commonly used volatile anesthetic

agents such as halothane, isoflurane,

sevoflurane, enflurane or depolarizing muscle

relaxants such as succinylcholine

Malignant Hyperthermia

• ↑ Ca++

• Depletion of high-energy phosphates

• Rapid metabolism• Rigor• Destruction of muscle

cell membrane

Cellular events in muscle

• Plasma – ↓ O2

– ↑ CO2

– ↑ Lactic acid– ↓ pH– ↑ K+

• Tachycardia• ↑ Rate and depth of

respiration• Muscle rigidity• ↑ Body temperature

Clinical Observations

Malignant Hyperthermia is triggered by

mutations on skeletal muscle

ryanodine receptor calcium release

channels

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DANTROLENE

• Given prior to surgery in patient know to carry the

gene (biopsy test)

– Avoid agents which will precipitate an attack

• Not used prophylactically

DRUG-DRUG INTERACTIONS

Drugs which decrease muscle contraction can potentiate the effects of neuromuscular blocking agents, e.g.,(a) antibiotics – large doses particularly

aminoglycosides and polymyxins

(b) general anesthetics and barbiturates potentiate

(c) Quinidine

(d) Ca2+ channel blockers

Drugs that cause or promote desensitization of nAChR

•Volatile Anesthetics

•Antibiotics

•Cocaine

•Alcohols

•Barbiturates

•Agonists

•AChE Inhibitors

•Local Anesthetics

•Phenothiazines

•Phencyclidine

•Ca Channel Blockers

Summary of contraindications and precautions:

Condition Succinylcholine d-Tubocurarine Pancuronium

↓ Muscle contraction ↓ Dose ↓ Dose ↓ Dose

Recent burns DonÕt use Dose No change in dose

High doses of antibiotics ↓ Dose ↓ Dose ↓ Dose

Malignant hyperthermia DonÕt use Use with caution Use with caution

Atypical plasmacholinesterase

DonÕt use Okay Okay