Muscle Relaxants

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Muscle relaxantsAcetylcholine receptor at neuromuscular junction distinct from the nicotinic receptors in autonomic ganglia (which are derived from neural crest) do not readily bind to muscarinic cholinergic agonists or antagonists pentameric transmembrane polypeptide arranged in a "rosette", with a central ion channel 2 -subunits, each MW ~ 40,000 2 1 Dalton 3 slightly larger subunits, , , and only the -subunits carry the recognition sequence for acetylcholine, reversible antagonists, such as d-tubocurarine irreversible antagonists such as -bungarotoxin both -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 -subunit, (not ) synthesis switches to the adult form in response to motor innervation after birth with subunit, conductance increases but channel opening time decreases Receptor activation binding of agonist to the receptor initiates conformational change in the receptor which allows the flux of small cations (Na+, K+, Ca++ ) inward movement of Na+ and outward movement of K+ occur through an ionophore that 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 their electrochemical gradients basis for graded end-plate potentials the duration of channel opening is dependent upon the type of agonist, open channel conductance remains constant radioreceptor binding assay with 131I -bungarotoxin is used to predict the potency of new neuromuscular blockers Other sites of Ach receptors 2nd group located on the prejunctional membrane these receptors augment the release of acetylcholine in response to nerve stimulation and are termed mobilization receptors, Rmob positive feedback antagonism by non-depolarising neuromuscular blocker contributes to fade response with neuromuscular stimulation 3rd group situated on the axon, at the nodes of Ranvier which are responsible for repetitive firing under certain conditions, Rrep

NC Hwang 2008

4th group found in peri-junctional cells and are not normally involved in transmission under certain conditions (prolonged immobilization, more than 24 hours after burns injury), these receptors may proliferate sufficiently to affect neuromuscular transmission Mechanism of neuromuscular transmission Release of acetylcholine increase in nerve membrane gCa++ influx takes place through voltage-gated N-type channels, which have a low sensitivity to the therapeutically used calcium-channel blockers increased intracellular (nerve) Ca++ leads to activation of calmodulin and synapsin I neutralisation of the negatively charged membrane surface and causes the vesicles to approach the junctional membrane (active zone) leading to increases vesicle exocytosis with 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 to depolarize the motor endplateCH3 O + CH3COCH2CH2NCH3--=



Binding of acetylcoline to receptor 2 Ach molecules combine with each specific Ach receptor "activated" receptor then increase membrane gNa+ and gK+ resultant influx of Na+ depolarizes cell endplate potential is produced giving rise to local current sink activation of voltage-gated channels in surrounding muscle cell membrane leads to propagation of muscle action potential Endplate potentials small amounts of acetylcholine are released randomly from 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 unbound acetylcholine decays more rapidly than does the endplate potential one Ach molecule survives long enough to open only one channel acetylcholinesterases are found in nerve terminal, junctional gap, and postsynaptic muscle membrane

Muscle relaxantsReceptor states 3 states resting state or ground state: impermeable to ions activated state: due to interaction of Ach with nicotinic receptor, upon activation opens to a diameter of 6.5 . inactive state due to dissociation of Ach from receptor; this slowly reverts to the ground state due to high efficacy of Ach, a response can be elicited by occupation of only 20-30% of the receptors, the rest constitutes spare receptors (receptor reserve) addition of non-depolarising antagonist to Ach receptor, such as dTC, progressively diminishes the amplitude of the endplate potential non-depolarising muscle relaxant can occupy up to 70% of receptors without noticeable decrease in motor response to nerve stimulation when more than 70% of its initial receptors have been bound, failure to initiate a propagated muscle action potential, this is the safety factor for conduction at any one time, as many as 10-20% of the receptors may be in the inactive state a situation that would lead to a greater increase in the number of receptors in the inactive state can lead to blockade of the neuromuscular junction Substances affecting Ach release local and general anaesthetic agents, tetrodotoxin, saxitoxin and maculotoxin prevent conduction in the axon by blocking the sodium channels and preventing nerve impulses from triggering the Ach release sequence batrachotoxin, ciguatoxin and grayanotoxin block conduction by opening the sodium channels and thereby depolarizing 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) enhances fusion of acetylcholine vesicle membranes to prejunctional membrane, increases the amount of acetylcholine released by an action potential higher concentrations (40-80mM) of ethanol inhibit release of acetylcholine botulinum toxin from bacterial spores of Clostridium botulinium blocks the release of Ach from the vesicles; it kills in very low concentrations by causing paralysis of all muscles, including respiratory muscles black widow spider venom, atraxotoxin and betabungarotoxin disrupt Ach vesicles and deplete the nerve ending of Ach. the vesicles are not subsequently refilled and de novo synthesis of vesicles is required explains why victims initially present with signs of muscle and abdominal cramps followed by relaxation

NC Hwang 2008

History curare used by South American Indians as arrow poison, perhaps before 16th century West used purified curare in patients with tetanus & spastic disorders in 1932 structure was established by King in 1935 one of the N-groups was later found to be tertiary used by Bennett in 1940 as an adjuvant to shock therapy first used for muscle relaxation in 1942 by Griffith and Johnson metocurine synthetic analogue of d-tubocurarine, developed several years later with 3x the potency of dTC gallamine synthesised about 1950 succinylcholine first synthetic neuromuscular blocker introduced into clinical practice in 1952, but actions of which were independently described in Italy, the UK and the USA circa 1949 discovery of its action was delayed many years as it had been used in experiments in conjunction with dTC 1954 Beecher & Todd published their report which showed a 6-fold increase in mortality with the use of muscle relaxants anticholinesterases were not in routine use then but the antagonism of curare by these drugs was described 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 1980s mivacurium & cisatracurium in first half of 1990s rocuronium & rapacuronium in second half of 1990s

Muscle relaxantsDesign 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 quaternary ammonium which is attracted to the negatively charged acetylcholine receptor site, and is essential for neuromuscular activity any neuromuscular blocker has to be structurally similar to acetylcholine to achieve its effectCH3 O + CH3COCH2CH2NCH3-=

NC Hwang 2008



Types of neuromuscular blockers depolarising agents tend to be flexible, enabling free bond rotation used to be classified as leptocurares (Greek leptos = 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 (Greek pachys = thick)

Optimum inter-onium distance , N+ N+ for polymethylene-bis-trimethlyammonium, or "methonium" series 5-6 intervening CH2 groups confer maximal ganglionic blockade (hexamethonium) 10 intervening CH2 groups confer maximal neuromuscular blockade a distance of 1.25 nm may confer optimal depolarising activity decamethonium is a depolarising muscle relaxant with interonium distance of 1.45 nm for rigid non-depolarising agent traditionally, interonium distance thought to be 1.2 to 1.4 nm, (however, not critical) d-tubocurare, gallamine are not bisquaternary fazadinium has a distance of 0.75 nm a distance of 8 Angstroms (0.8 nm) promotes the development of ganglion blocking activity in bisquaternary steroidal compounds neuromuscular blockers developed with interonium distances of m