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Muscle Relaxants

Muscle Relaxants

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Published by: anaeshkl on Apr 07, 2012
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Acetylcholine receptor at neuromuscular junction
distinct from the nicotinic receptors in autonomicganglia (which are derived from neural crest)
do not readily bind to muscarinic cholinergicagonists or antagonists
pentameric transmembrane polypeptide arranged in a"rosette", with a central ion channel
2
α
-subunits, each MW ~ 40,000Dalton
3 slightly larger subunits,
β
,
δ
, and
ε
only the
α
-subunits carry the recognition sequence for
acetylcholine,
reversible antagonists, such as d-tubocurarine
irreversible antagonists such as
α
-bungarotoxin
both
α
-sites must be occupied for activation
binding exhibits positive co-operativity
binding at one site facilitates the other
bound to cytoskeleton by a binding protein, rapsyn
foetal receptor has a
γ
-subunit, (not
ε
)
synthesis switches to the adult form in response to motorinnervation after birth
with
ε
subunit, conductance increases but channelopening time decreases
Receptor activation
binding of agonist to the receptor
initiates conformational change in the receptorwhich allows the flux of small cations (Na
+
, K
+
,Ca
++
)
inward movement of Na
+
and outwardmovement of K
+
occur through an ionophorethat appears not to be ion-specific
increasing the concentration of agonist
the greater the number of ionophores that are‘open’
increases the frequency of channel opening
larger the ion fluxes down theirelectrochemical gradients
basis for graded end-plate potentials
the duration of channel opening
is dependent upon the type of agonist, openchannel conductance remains constant
radioreceptor binding assay with
131
I
α
-bungarotoxin isused to predict the potency of new neuromuscularblockers
Other sites of Ach receptors
2nd group
located on the prejunctional membrane
these receptors
augment
the release of acetylcholine in response to nerve stimulationand are termed mobilization receptors, Rmob
positive feedback
antagonism by non-depolarising neuromuscularblocker contributes to “fade”response withneuromuscular stimulation
3rd group
situated on the axon, at the nodes of Ranvierwhich are responsible for repetitive firing undercertain conditions, Rrep
4th group
found in peri-junctional cells and are notnormally involved in transmission
under certain conditions (prolongedimmobilization, more than 24 hours after burnsinjury), these receptors may proliferatesufficiently to affect neuromusculartransmission
Mechanism of neuromuscular transmission
Release of acetylcholine
increase in nerve membrane gCa
++
influx takes place through voltage-gated N-typechannels, which have a low sensitivity to thetherapeutically used calcium-channel blockers
increased intracellular (nerve) Ca
++
leads to
activation of calmodulin and synapsin I
neutralisation of the negatively chargedmembrane surface and causes the vesicles toapproach the junctional membrane (active zone)
leading to increases vesicle exocytosiswith release of Ach into synapse
each nerve action potential releases
60 vesicles, with
10,000 acetylcholine molecules each
10 x the amount of Ach required todepolarize the motor endplate
Binding of acetylcoline to receptor
2 Ach molecules combine with each specific Achreceptor
"activated" receptor then increase membrane gNa
+
andgK
+
resultant influx of Na
+
depolarizes cell
endplate potential is produced giving rise to localcurrent sink
activation of voltage-gated channels in surroundingmuscle cell membrane
leads to propagation of muscle action potential
Endplate potentials
small amounts of acetylcholine are released randomlyfrom the resting nerve cell
each produces a minute depolarization spike,or miniature endplate potential
the amplitude of these mepp's is about 0.5 mV
the number of quanta released varies,
increases directly with the extracellular [Ca
++
]
decreases with the increasing extracellular[Mg
++
]
Termination of endplate potential
hydrolysis by membrane-bound acetylcholinesterases
the synaptic concentration of unboundacetylcholine decays more rapidly than does theendplate potential
one Ach molecule survives long enough toopen only one channel
acetylcholinesterases are found in nerveterminal, junctional gap, and postsynapticmuscle membrane
Muscle relaxants
α
2
α
1
β δ
CH
3
 –C–O–CH
2
 –CH
2
 –N–CH
3
OCH
3
CH
3
+
      =
acetylcholine
    -    -    -    -
NC Hwang 2008
 
Receptor states
3 states
restingstate or groundstate: impermeable toions
activatedstate: due to interaction of Ach withnicotinic receptor, upon activation opens to adiameter of 6.5 Å.
inactivestate due to dissociation of Ach fromreceptor; this slowly reverts to the ground state
due to high efficacy of Ach, a response can be elicitedby occupation of only 20-30% of the receptors, the restconstitutes spare receptors (receptor reserve)
addition of non-depolarising antagonist to Achreceptor, such as dTC, progressively diminishesthe amplitude of the endplate potential
non-depolarising muscle relaxant can occupyup to 70% of receptors without noticeabledecrease in motor response to nerve stimulation
when more than 70% of its initial receptorshave been bound, failure to initiate a propagatedmuscle action potential, this is the safety factorfor conduction
at any one time, as many as 10-20% of the receptorsmay be in the inactive state
a situation that would lead to a greater increase in thenumber of receptors in the inactive state can lead toblockade of the neuromuscular junction
Substances affecting Ach release
local and general anaesthetic agents, tetrodotoxin,saxitoxin and maculotoxin prevent conduction in theaxon by blocking the sodium channels and preventingnerve impulses from triggering the Ach release sequence
batrachotoxin, ciguatoxin and grayanotoxin blockconduction by opening the sodium channels and therebydepolarizing the axon membrane
Ca
++
increases release
Mg
++
and aminoglycosides decreases release of Ach,probably by modifying the Ca
++
channels
ethanol
at low concentrations (5-20mM) enhancesfusion of acetylcholine vesicle membranes toprejunctional membrane, increases the amountof acetylcholine released by an action potential
higher concentrations (40-80mM) of ethanolinhibit release of acetylcholine
botulinum toxin from bacterial spores of Clostridiumbotulinium blocks the release of Ach from the vesicles; itkills in very low concentrations by causing paralysis of all muscles, including respiratory muscles
black widow spider venom, atraxotoxin and beta-bungarotoxin disrupt Ach vesicles and deplete the nerveending of Ach.
the vesicles are not subsequently refilled and denovo synthesis of vesicles is required
explains why victims initially present withsigns of muscle and abdominal cramps followedby relaxation
History
curare
used by South American Indians as arrowpoison, perhaps before 16th century
West used purified curare in patients withtetanus & spastic disorders in 1932
structure was established by King in 1935
one of the N-groups was later found to betertiary
used by Bennett in 1940 as an adjuvant toshock therapy
first used for muscle relaxation in
1942
byGriffith and Johnson
metocurine
synthetic analogue of d-tubocurarine,
developed several years later with 3x thepotency of dTC
gallamine
synthesised about 1950
succinylcholine
first synthetic neuromuscular blockerintroduced into clinical practice in
1952
, butactions of which were independently describedin Italy, the UK and the USA circa 1949
discovery of its action was delayed many yearsas it had been used in experiments inconjunction with dTC
1954 Beecher & Todd published their report whichshowed a 6-fold increase in mortality with the use of muscle relaxants
anticholinesterases were not in routine use thenbut the antagonism of curare by these drugs wasdescribed by Pal in Vienna in 1900
most potent of all curare alkaloids are the toxiferines
obtained from Strychnos toxifera
semisynthetic derivative, alcuronium chloride(1961) ; N,N`-diallylnortoxiferinium dichloride
introduction of other muscle relaxants
pancuronium in 1967
atracurium & vecuronium in 1980’s
mivacurium & cisatracurium in first half of 1990’s
rocuronium & rapacuronium in second half of 1990’s
Muscle relaxants
NC Hwang 2008
 
Design of neuromuscular blockers
Incorporation of acetylcholine structure
Quaternary ammonium group
Interonium distance
Depolarising or non-depolarising
Muscarinic activities
Bisquaternary compound
Metabolism
Structure activity relationship
acetylcholine has a positively charged quaternaryammonium which is attracted to the negatively chargedacetylcholine receptor site, and is essential forneuromuscular activity
any neuromuscular blocker has to be structurally similarto acetylcholine to achieve its effect
Types of neuromuscular blockers
depolarising agents tend to be flexible, enabling freebond rotation
used to be classified as leptocurares (Greekleptos = thin)
non-depolarising agents are bulky rigid molecules
the double Ach structure is concealed in one of 2 types of bulky, relatively rigid ring systems:isoquinoline derivatives and steroids
used to be classified as pachycurares (Greekpachys = thick)
Quaternary ammonium group
makes muscle relaxants poorly lipid-soluble
prevents entry into the CNS, but, attraction of quaternary group extends to other acetylcholine receptorsas well
nicotinic receptors in autonomic ganglia andadrenal
muscarinic receptors at vagal nerve endings
specificity of the compound for either ganglionic orneuromuscular receptor is partly determined by thedistance between the 2 positively charged groups(interonium distance)
high potency dependent upon the presence of 2positively charged areas
low potency drug associated with rapid onsettime and short duration of action (mivacurium)
majority of non-depolarising muscle relaxants have 2quaternary ammonium groups
exceptions: d-tubocurare (1), gallamine (3)
Optimum inter-onium distance , N
+
  ̶  ̶
N
+
for polymethylene-bis-trimethlyammonium, or"methonium" series
5-6 intervening CH
2
groups confer maximalganglionic blockade (hexamethonium)
10 intervening CH
2
groups confer maximalneuromuscular blockade
a distance of 1.25 nm may confer optimaldepolarising activity
decamethonium is a depolarisingmuscle relaxant with interoniumdistance of 1.45 nm
for rigid non-depolarising agent
traditionally, interonium distance thought to be1.2 to 1.4 nm, (however, not critical)
d-tubocurare, gallamine are notbisquaternary
fazadinium has a distance of 0.75 nm
a distance of 8 Angstroms (0.8 nm) promotes thedevelopment of ganglion blocking activity inbisquaternary steroidal compounds
neuromuscular blockers developed with interoniumdistances of more than 10 Angstroms (1 nm)
alcuronium (1.0nm)
pancuronium (1.0nm)
vecuronium (1.2nm)
atracurium (1.8nm)
mivacurium (2.1nm)
structure rigidity of the steroid nucleus
allows for a relatively fixed and optimumdistance between the 2 positively chargedregions of the molecule
interonium distance of 1.05 nm
in the correct range to produce highneuromuscular blocking potency but too large tocause ganglionic blockade
addition of bulky groups ensures development of non-depolarizing agent
Muscle relaxants
CH
3
 –C–O–CH
2
 –CH
2
 –N–CH
3
OCH
3
CH
3
+
      =
acetylcholine
    -    -    -    -
NC Hwang 2008

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