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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Anaesthetics and Muscle Relaxants

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Neuromuscular Blocking Agents

Adjuvant in surgical anaesthesia to obtain skeletal muscle relaxation.

Neuromuscular Blocking Agents

Uses

·              Adjuvant in surgical anaesthesia to obtain skeletal muscle relaxation.

·              Facilitation of orthopaedic procedures such as correction of dislocations and alignment of fractures. Facilitation of endotracheal intubation, laryngoscopy, bronchoscopy, oesophagoscopy, etc.

·              Prevention of trauma during electroconvulsive therapy.

Mode of Action

·              The essential mechanism of action of all NMBs is inhibition of the effects of acetylcholine (ACH) on nicotinic receptors at the neuromuscular junction (NMJ).

·              The depolarising NMBs (or DNMBs) such as succinyl- choline (suxamethonium) produce muscle depolarisation in the same way as ACH. The action of succinylcholine is prolonged because it is relatively resistant to hydrolysis by true acetylcholinesterase.

·              The nondepolarising NMBs (or NDNMBs) act by competi- tive inhibition of ACH at nicotinic receptors, and their action is in general of shorter duration.

Toxicokinetics

·              The toxicokinetics of commonly used NMBs is summarised in Table 18.3.


·              Succinylcholine is rapidly hydrolysed by plasma pseudocho- linesterase to an intermediate metabolite succinylmonocho- line. This metabolite is weaker in action than succinylcholine, but because of its slower rate of hydrolysis may accumulate and cause prolonged paralysis of the patient.

·              Succinylmonocholine is hydrolysed to succinic acid and choline, neither of which has pharmacologic action.

·              Therapeutic doses produce the following sequence of skel- etal muscle depression: heaviness to the eyelids, difficulty in swallowing and talking, diplopia, progressive weakness of the extremities, the neck, trunk, spine, intercostals, and diaphragm. The paralysis recedes in the reverse.

Adverse Effects

·     Prolonged apnoea and respiratory paralysis.

·              Rapacuronium has been voluntarily withdrawn from the market by the manufacturer, due to reports of an associa-tion with rapacuronium administration and the occurrence of bronchospastic events, including the occurrence of unexplained fatalities.

·              Cardiovascular collapse preceded by tachy- or bradycardia, and hypo- or hypertension. Gallamine has a shorter dura- tion of action than tubocurarine and, due to its blocking of the cardiac vagus, it may cause sinus tachycardia and, occasionally, arrhythmias and hypertension.

·              Histamine-release effects: bronchospasm, hypotension, excessive airway secretions.

·              Hyperkalaemia (with succinylcholine): The potassium may originate from skeletal muscle, released by depolarisation at the neuromuscular junction or from damaged muscle fibres caused by incoordinate contractions The rise in potas- sium usually occurs 3 to 5 minutes after IV administration of succinylcholine, and is usually 0.5 to 1 mmol/L. The increase usually lasts less than 10 to 15 minutes.

·              Bradycardia may occur secondary to severe hyperkalaemia and may progress rapidly to asystole or ventricular fibril- lation in this setting. Use in patients with extensive burns, traumatic muscle injury, paraplegia, hemiplegia, muscular dystrophy, multiple sclerosis, prolonged pharmacologic neuromuscular blockade, upper motor neuron injury or extensive denervation of skeletal muscle can predispose to severe hyperkalaemia and ventricular arrhythmias.

·              Malignant hyperthermia: Malignant hyperthermia (MH) is a rare, genetically influenced, potentially lethal complica- tion associated with the use of inhalational anaesthetics, amino-amide local anaesthetics, and some muscle relaxants (succinylcholine, decamethonium, d-tubocurarine, and gallamine). It can also be precipitated in susceptible indi- viduals by stress, hot environment, emotional excitement, physical exertion, and infection. The genetic susceptibility to MH is due to a mutation of the ryanodine receptor gene located in the region of 12–13.2 of chromosome 19. This is responsible for decreased calcium uptake by the sarcoplasmic reticulum of muscle cells leading to increase in myoplasmic calcium, which is triggered by a nmber of agents. A number of aerobic and anaerobic metabolic processes are set in motion resulting in excessive heat and CO2 and lactic acid production. Indications of MH during anaesthesia include the following:

o     Tachycardia (unexplained).

o     Tachypnoea, cyanosis (unexplained).

o     Rigidity (masseters fail to relax for intubation).

o     Marked hyperthermia (late sign).

o     Hypotension, arrhythmias.

o     Metabolic acidosis.

o     Hyperkalaemia, hypercalcaemia.

o     Electrolyte disturbances.

o     Rhabdomyolysis, disseminated intravascular coagula- tion (DIC), renal failure.

o     Pulmonary oedema.

Early diagnosis can be aided by arterial blood gas analysis (hypoxaemia), electrolyte level estimation, oximetry, and end-tidal CO2 measurement (increased). Death in MH may be due to ventricular fibrillation, DIC, renal failure, cerebral oedema, or pulmonary oedema.

·     Succinylcholine-induced rhabdomyolysis from prolonged fasciculations or malignant hyperthermia can lead to renal failure. Elevated serum levels of creatine phosphokinase (CPK) and myoglobin commonly follow IV administration of succinylcholine.

·     Persistent weakness (especially in critically ill patients subjected to prolonged ventilation) referred to as ICUneuromuscular syndrome. Recovery may take upto 6months. Precautionary measures are necessary to minimise the possibility of this distressing complication.

Drug Interactions

·              Some of the important drug interactions with NMBs are listed in Table 18.4. 



Clinical (Toxic) Features

·      Succinylcholine (succinyldicholine, diacetylcholine, or suxamethonium) is a bis-quaternary ammonium ion composed of two acetylcholine molecules connected by their acetate groups. The dose necessary to produce neuromuscular blockade and respiratory paralysis in adults ranges from 0.3 to 1.1 mg/kg in adults (mean 0.6 mg/kg). Succinylcholine use is sometimes associated with prolonged apnoea which may be due to genetically determined atypical pseudocholinesterase (incidence 1 : 2500), or due to exposure to cholinesterase inhibitors such as organophosphates.

o     Adverse effects of succinylcholine include cardiac arrhythmias, hyperkalaemia, increased intracranial pressure, increased intraocular pressure, increased intra-gastric pressure, myalgia, muscle fasciculation, muscle rigidity (especially masseters), malignant hyperthermia, rhabdomyolysis and myoglobinuria.

o     In children with unsuspected myopathies (especially

Duchenne’s muscular dystrophy), acute rhabdomyol-ysis, severe hyperkalaemia, and cardiac arrest can occur, and hence it is advisable not to use succinylcholine in the paediatric age group (particularly boys under the age of 8 years) except for emergency intubation.

o     Succinylcholine is also well known for causing anaphy-laxis in susceptible individuals (mostly women) which manifests as rapid circulatory collapse without other conventional signs such as skin rash or wheezing.

·      Tubocurarine and all other curariform blocking agents are derived from curare (Fig 18.3), a large vine, found in the canopy of the South American rainforest. Overdose causes complete skeletal muscle paralysis without affecting consciousness. Initially the small muscles of the eyes, ears, fingers, and toes are paralysed, followed by face and neck, upper and lower limbs, and finally the diaphragm and inter-costal muscles, leading to respiratory failure.


o     Metocurine produced by methylation of tubo­curarine is twice as potent while doxacurium is a long-acting NMB without histamine-releasing effects. Unlike the others, it is metabolised rapidly at first to laudanosine, and later to an acrylate moiety both of which do not possess NMB property.

o     cis-Atracurium is a purified atracurium isomer which is much more potent, and unlike its parent compound is not associated with histamine release.

o     Mivacurium is a short-acting drug composed of a mixture of 3 stereo-isomers, but may sometimes cause prolonged block.

o     Pancuronium is a synthetic bis-quaternary aminosteroid which has a selective cardiac antimuscarinic (atropine-like) action resulting in increased heart rate and blood pressure. It is partly metabolised and undergoes some degree of deacetylation in the liver, which is responsible for prolonged effects in the presence of hepatic insuf-ficiency.

o     Vecuronium is a derivative of pancuronium with similar potency, but is less prone to induce tachycardia and hypertension.

o     Pipecuronium is a long-acting analogue producing a block of long duration.

o     Rocuronium is known for its rapid onset of action and does not produce histamine release or significant cardiac effects.

Treatment

·              Reversal of NDNMB block can be achieved by anti-cholinesterases such as neostigmine (0.040–0.080 mg/ kg), pyridostigmine (0.2–0.4 mg/kg), or edrophonium (0.5–1.0 mg/kg), in combination with antimuscarinic agents such as glycopyrrolate (0.01–0.02 mg/kg) or atropine (0.02–0.03 mg/kg).

·            Overdose with depolarising agents such as succinylcho-line cannot be reversed pharmacologically, and must be managed with prolonged assisted ventilation.

·            Physostigmine, neostigmine and other anticholinesterase drugs, including edrophonium, are contraindicated as antidotes to succinylcholine because they actually prolong its action by interfering with metabolism by cholinesterase. Determine pseudocholinesterase activity in patients with unexpectedly prolonged effects. However, many of the patients who react abnormally to succinylcholine have qualitative rather than quantitative defects in plasma pseu-docholinesterase.

·            Maintain patent airway and supply 100% oxygen. Assisted ventilation is usually required. Most patients will recover if adequate airway, ventilation and oxygen-ation are established rapidly.

Treatment of malignant hyperthermia:

o     Discontinue all triggering agents.

o     Hyperventilate with 100% oxygen (10 L/min).

o     Give dantrolene sodium 2 to 3 mg/kg IV bolus, followed by increments upto a maximum of 10 mg/kg. Stop dantrolene when the signs of MH are controlled, and administer it subsequently at 1 mg/ kg IV 6th hourly for 1 to 2 days, and then the same dose orally for 1 more day.

o     Give sodium bicarbonate to correct metabolic acidosis (1 to 2 mEq/kg).

o     Treat hyperthermia with

IV iced saline, 15 ml/kg, q15 min × 3.

Lavage of stomach, bladder and rectum with iced saline.

Skin surface cooling with ice.

o     Treat persistent arrhythmias with standard anti-arrhythmic drugs (except calcium channel blockers which can cause or aggravate hyperkalaemia).

o     Treat hyperkalaemia with hyperventilation, sodium bicarbonate, IV glucose, and insulin. Dangerous hyperkalaemia may necessitate calcium administra-tion (2 to 5 mg/kg of calcium chloride).

o     Ensure adequate urine output (more than 2 ml/kg/hr).

o     Monitor

End-tidal CO2.

Arterial and venous blood gases.

Serum potassium and calcium.

Clotting studies.

Urine output.

·      Treat cardiovascular failure in the usual way.

·      Treat severe hyperkalaemia (associated arrhythmias, QRS widening) aggressively. Monitor ECG continuously during and after therapy.

o     Calcium chloride: Adult: 5 ml IV bolus of a 10% solu-tion over 5 minutes; Child: 0.2 to 0.3 ml/kg of a 10% solution over 5 to 10 minutes (20 to 30 ml/kg /dose).

o     Sodium bicarbonate: Adult or Child: 1–2 mEq/kg IVbolus.

o     Insulin/dextrose: Adult: 5 to 10 units regular insulinIV bolus with 100 ml of D50 IV immediately; monitor serum glucose every 30 minutes; Child: 0.5 to 1 gm/ kg dextrose as D25 or D10 IV followed by 1 unit of regular insulin for every 4 grams of dextrose infused; monitor serum glucose every 30 minutes.

o     Sodium polystyrene sulfonate: Adult 15 to 60 grams by nasogastric tube or rectal enema; Child: 1 gm/kg by nasogastric tube or rectal enema.

·            Pretreatment with 0.125 mg/kg IV succinylcholine followed in 60 seconds by 1 mg/kg IV may reduce postoperative muscle fasciculations and pain in adults. Pretreatment with d-tubocurarine (0.05 mg/kg) may decrease myoglobinaemia.

·            For rhabdomyolysis: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alka-linisation is NOT routinely recommended.

·            In susceptible patients, succinylcholine can produce a rise in ICP that may lead to herniation. Pretreatment with a low dose of a nondepolarising agent such as pancuronium 0.01 mg/kg IV or low dose succinylcholine 0.1 mg/kg IV 3 to 5 minutes prior to administration of full dose succinylcholine, may blunt the rise in ICP.

·             In patients with renal failure, haemodialysis may be effec-tive in reversing prolonged neuromuscular blockade due to tubocurarine or pancuronium. However, dialysis will not be effective for overdose of atracurium or vecuronium since these agents are not renally excreted.

 

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