"Neuromuscular Blockade - PowerPoint"
Neuromuscular Blockade DMED 524 Hazards of Deep Anesthesia In order to achieve muscle relaxation and abolition of reflexes sufficient for deep surgery, dangerous levels of anesthesia are required. This often led to patient death on the operating table. Hazards of Light Anesthesia On the other hand, anesthesia that is too light has its own hazards – mainly for the surgeons. Although first suggested in 1912 by Läwen in Germany, purified extract of curare was introduced to anesthesia in 1941 by H.R Griffith of McGill to allow insensitivity to pain with light anesthesia while blocking reflex muscle movement. Curare was used as a blowdart and arrow poison by indigenous forest peoples of South America to paralyse their prey. The main active ingredient was tubocurarine – the prototype neuromuscular blocking drug. Tubocurarine Mechanism of Action – the Neuromuscular Junction Nerve impulse travels down the nerve fibre and its branches to the terminal. Depolarization opens calcium channels in membrane → inward calcium flux. Calcium promotes discharge of vesicles full of acetylcholine from terminal into synaptic cleft CH3-N- CH2CH2OCCH3 CH3 Acetylcholine + CH3 O The Muscle End Plate The postsynaptic membrane (end plate) is thrown into a series of folds, and the crests of these folds are covered with densely packed acetylcholine receptors. Because they were shown to respond to nicotine in 1896, they originally were designated the “nicotinic receptive substance” – now nicotinic acetylcholine receptors. The Nicotinic Acetylcholine Receptor There are several types:Skeletal muscle Neuronal (various) They differ in subunit composition CH They differ in affinity for drugs. + CH -N- CH Ligands at the receptor need only be CH cations: e.g. tetramethylammonium. Tetramethylammonium Almost all agonists and antagonists are quaternary ammonium compounds 3 3 3 3 The Nicotinic Receptor Molecule The receptor is a rosette of five sub-units spanning the membrane and projecting into the synaptic space. Usually the subunits are mixed. In muscle there are four types, with the α-subunit repeated twice. In nerve there may only be α-subunits, or a mixture of α and β subunits. Molecules of acetylcholine bind to each of the αsubunits. From N.Unwin, Neuron 10(Suppl.), 31-41, 1993 How it works Na+ K+ Gate When acetylcholine binds to its binding site, there is a disturbance in the subunit structure so that the gate opens, allowing ions to pass. At rest, ion flow through the central pore or channel is prevented by a narrowing (gate). 0mV Resting Membrane Potential End Plate Potentials to Action The increase in the Potentials of sodium and permeability potassium caused by End plate potentialreceptor channel opening causes the potential of the end plate to fall, and recover slowly as the acetylcholine is removed – the end plate potential. If the depolarization is great Threshold for enough it activates voltage Action potential sensitive sodium channels to fire a muscle action potential, in turn causing force. Non Depolarizing Block Tubocurarine (and other curariform drugs) are antagonists at the nicotinic receptor. They compete with released acetylcholine to prevent any end plate being large enough to activate muscle contraction. Paralysis is flaccid in all muscles. Since action potentials are all or none, the dose response curves are very steep. Effect of Neuromuscular Blockade Tubocurarine Series of endplate potentials/action potentials in frog muscle under the increasing effect of a concentration of tubocurarine added at b. As endplate potential falls below threshold, action potential fails and there is no mechanical response. Series summarized in h. The Iceberg Effect Not every junction fails at the same point, so there is a period of declining force for the muscle as a whole. Effects are not seen in this muscle (leg muscle) until 75% of receptors are occupied. Duration of effect is shorter than plasma half life/ receptor occupancy Receptor Reserve Percentage of receptors that may be blocked before there is any effect on contraction is the receptor reserve. This is greatest in the muscles of respiration great in muscles of coarse movement (e.g. gastrocnemius) least in the muscles of the face and eyes Lack of facial expression and ptosis are diagnostic of neuromuscular failure. Presynaptic Action The pool of available transmitter in the nerve terminal is finite, and is depleted by each episode of release during a train of closely spaced stimuli. If the same proportion of the pool were released each time, then the amount released by each stimulus would soon fall below the threshold to generate a big enough endplate potential. The proportion of the transmitter pool that is released by second and subsequent stimuli in a train can be enhanced by released acetylcholine acting retrogradely on presynaptic neuronal nicotinic receptors (positive feedback). Contractions Fail as Endplate Currents Fall Trains of 4 stimuli produce diminishing contractile and postsynaptic responses in presence of a neuromuscular blocker. Ionto-phoretically applied ACh produces constant response Bowman et al. Trends Pharmacol. Sci. 9, 16-20, 1988 Clinical Tidbits In anesthetic practice train of four stimuli are applied transdermally to the ulnar nerve and the contractions of the adductor pollicis measured by force transducer to monitor the depth of block. Neuromuscular block can be overcome by Applying a train of impulses (tetanus) first then testing shortly thereafter (post-tetanic potentiation). Applying an anticholinesterase drug to stop the hydrolysis of acetylcholine in the synaptic cleft. Drugs must be injected Adverse Effects Tubocurarine has several drawbacks: It blocks ganglia – loss of control of blood pressure It affects muscarinic receptors – loss of parasympathetic control of heart rate- tachycardia It releases histamine → hypotension, bronchoconstriction and anaphylaxis. Its duration of action is over 30 min – too long for short procedures such as intubation. Better drugs had to be developed. The Newer Drugs Drugs with fewer side effects:Pancuronium – an aminosteroid developed in 1960 Metocurine and alcuronium - semisynthetic derivatives of plant – alkaloids; not popular. Doxacurium – a stable diester drug with a low adverse effect profile and an unusually long duration of action (1-3 hrs). Popular. The Newer Drugs II Aminosteroid drugs with shorter duration of action (designed to replace succinylcholine – see following). Onset time more important than duration of action. No histamine release or vagolysis Vecuronium (most used for general purposes) Onset 3-5 minutes and time to 5% recovery of twitch, 12 minutes. Rocuronium. Very short onset (60-70 sec) but duration of action 28 minutes. The Newer Drugs III Short acting drugs that degrade spontaneously or are metabolized by plasma cholinesterase:Atracurium. Spontaneous chemical disintegration at alkaline pH (Plasma = pH 7.4). Also broken down by plasma cholinesterase. Useful in renal failure patients. Onset 2-3 min. Duration of action 15½ minutes. Associated with histamine release and of limited popularity now Mivacurium. Newest short acting drug. Onset of action 2-3 minutes and duration of action 12 minutes. Metabolized by plasma cholinesterase. Some histamine release but short duration of action limits risk to patient. The Drugs Compared Duration Ganglion 5% block? Recovery Tubocurarine 35 min Yes Pancuronium Metocurine 25 min 30 min No No Vagolytic? Histamine release? Yes Little No Yes No Yes Atracurium Vecuronium Mivacurium Rocuronium Doxacurium 15.5 min 12 min 8 min 28 min 1-3 hrs No No No No No No Little No No No Yes No Yes No No Depolarizing Blocking Agents For muscle with only one innervating nerve (most mammalian muscles) an action potential must be generated before contraction takes place. To generate an action potential, voltage gated sodium channels are first activated and then inactivated by the depolarization. Inactivated channels must first be repolarized before they return to resting state and can be activated again. Prolonging the depolarization by using an agonist drug prevents return to the resting state. No more action potentials: muscle is then paralyzed even though receptors are activated. Depolarizing Blocking Drug Succinylcholine only survivor of its class It is a bisfunctional agonist – two cholines esterified to a central dicarboxylic acid It is resistant to acetylcholinesterase, but susceptible to plasma cholinesterase. Initial depolarization of muscle seen as fasciculations and twitches at onset. Multiply innervated muscles develop contracture – SPASTIC paralysis. Extraocular muscles – exophthalmia Muscle spindle fibres – reflex fibrillation initially. Advantages and Drawbacks Rapid onset – I min Short duration of action (4-5 min) Prolonged application leads to phase II block – desensitization of receptors and delayed recovery. Postoperative pain – especially in extraocular muscles Myotonia patients may experience an attack due to depolarizing effect of succinylcholine Patients with congenital deficiency of plasma cholinesterase experience long lasting block. Malignant Hyperthermia Condition caused by a defect in the molecule (Hyperpyrexia) linking muscle membrane t-tubules to the sarcoplasmic reticulum (ryanodine receptor). Uncontrolled Ca++ release from the S.R. leads to contracture and a rise in body core temperature. Succinylcholine can precipitate an attack even in the absence of halothane like anesthetics. Dantrolene blocks this inappropriate response of the ryanodine receptor and prevents Ca++ loss