Tracrium

Atracurium besylate.

Pharmacology: Pharmacodynamics: Atracurium besylate (Tracrium) is a highly selective, competitive or non-depolarising neuromuscular blocking agent.
Atracurium besylate (Tracrium) has no direct effect on intra-ocular pressure, and is therefore suitable for use in ophthalmic surgery.
Pharmacokinetics: Atracurium is inactivated by Hofmann elimination, a non-enzymatic process which occurs at physiological pH and temperature, and by ester hydrolysis catalysed by non-specific esterases.
Tests with plasma from patients with low levels of pseudocholinesterase show that the inactivation of atracurium proceeds unaffected.
Variations in the blood pH and body temperature of the patient within the physiological range will not significantly alter the duration of action of atracurium.
The termination of the neuromuscular blocking action of Atracurium besylate (Tracrium) is not dependent on its hepatic or renal metabolism or excretion. Its duration of action, therefore, is unlikely to be affected by impaired renal, hepatic or circulatory function.
The elimination half-life of atracurium is approximately 20 minutes, and the volume of distribution is 0.16 L/kg. Atracurium is 82% bound to plasma proteins.
Special Patient Populations: Haemofiltration and haemodiafiltration have a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effects of haemodialysis and haemoperfusion on plasma levels of atracurium and its metabolites are unknown.
Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic function (see Precautions). These metabolites do not contribute to neuromuscular block.
Toxicology: Preclinical Safety Data: Mutagenicity: Atracurium has been evaluated in 3 short-term mutagenicity tests. It was not mutagenic in either the in vitro Ames salmonella assay at concentrations up to 1000 μg/plate or in an in vivo rat bone marrow assay at doses up to those which resulted in neuromuscular blockade. In a second in vitro test, the mouse lymphoma assay, mutagenicity was not observed at doses up to 60 μg/mL which killed up to 50% of the treated cells but it was moderately mutagenic at concentrations of 8 μg/mL in the absence of metabolising agent and weakly mutagenic at very high concentrations (1200 μg) when metabolising enzymes were added. At both concentrations over 80% of the cells were killed.
In view of the nature of human exposure to atracurium, the mutagenic risk to patients undergoing surgical relaxation with Atracurium besylate (Tracrium) must be considered negligible.
Carcinogenicity: Carcinogenicity studies have not been performed.

Atracurium besylate (Tracrium) is a highly selective, competitive or non-depolarising neuromuscular blocking agent which is used as an adjunct to general anaesthesia to enable tracheal intubation to be performed and to relax skeletal muscles during surgery or controlled ventilation, and to facilitate mechanical ventilation in Intensive Care Unit (lCU) patients.

Use by injection in adults: Atracurium besylate (Tracrium) is administered by intravenous (i.v.) injection. The dosage range for adults is 0.3 to 0.6 mg/kg (depending on the duration of full block required) and will provide adequate relaxation for 15 to 35 minutes.
Endotracheal intubation can usually be accomplished within 90 seconds from the intravenous injection of 0.5 to 0.6mg/kg.
Full block can be prolonged with supplementary doses of 0.1 to 0.2 mg/kg as required. Successive supplementary dosing does not give rise to accumulation of neuromuscular blocking effect.
Spontaneous recovery from the end of full block occurs in about 35 minutes as measured by the restoration of the tetanic response to 95% of normal neuromuscular function.
The neuromuscular block produced by Atracurium besylate (Tracrium) can be rapidly reversed by standard doses of anticholinesterase agents, such as neostigmine and edrophonium, accompanied or preceded by atropine, with no evidence of recurarisation.
Use as an infusion in adults: After an initial bolus dose of 0.3 to 0.6mg/kg, Atracurium besylate (Tracrium) can be used to maintain neuromuscular block during long surgical procedures by administration as a continuous infusion at rates of 0.3 to 0.6 mg/kg/hour.
Atracurium besylate (Tracrium) can be administered by infusion during cardiopulmonary bypass surgery at the recommended infusion rates. Induced hypothermia to a body temperature of 25°C to 26°C reduces the rate of inactivation of atracurium, therefore full neuromuscular block may be maintained by approximately half the original infusion rate at these low temperatures.
Atracurium besylate (Tracrium) is compatible with the following infusion solutions for the times stated as follows: See table.

Click on icon to see table/diagram/image

When diluted in these solutions to give atracurium besylate concentrations of 0.5 mg/mL and above, the resultant solutions will be stable in daylight for the stated periods at temperatures of up to 30°C.
Use in children: The dosage in children over the age of one month is the same as that in adults on a bodyweight basis.
Use in the elderly: Atracurium besylate (Tracrium) may be used at standard dosage in elderly patients. It is recommended, however, that the initial dose be at the lower end of the range and that it be administered slowly.
Use in patients with reduced renal and/or hepatic function: Atracurium besylate (Tracrium) may be used at standard dosage at all levels of renal or hepatic function, including end stage renal failure.
Use in patients with cardiovascular disease: In patients with clinically significant cardiovascular disease, the initial dose of Atracurium besylate (Tracrium) should be administered over a period of 60 seconds.
Use in Intensive Care Unit (ICU) Patients: After an optional initial bolus dose of Atracurium besylate (Tracrium) of 0.3 to 0.6 mg/kg, Atracurium besylate (Tracrium) can be used to maintain neuromuscular block by administering a continuous infusion at rates of between 11 and 13 μg/kg/min (0.65-0.78 mg/kg/hr). However, there is wide inter-patient variability in dosage requirements. Dosage requirements may change with time. Infusion rates as low as 4.5μg/kg/min (0.27 mg/kg/hr) or as high as 29.5 μg/kg/min (1.77mg/kg/hr) are required in some patients.
The rate of spontaneous recovery from neuromuscular block after infusion of Atracurium besylate (Tracrium) in ICU patients is independent of the duration of administration. Spontaneous recovery to a train-of-four ratio >0.75 (the ratio of the height of the fourth to the first twitch in a train-of-four) can be expected to occur in approximately 60 minutes. A range of 32-108 minutes has been observed in clinical trials.
Monitoring: In common with all neuromuscular blocking agents monitoring of neuromuscular function is recommended during the use of atracurium in order to individualise dosage requirements.

Signs: Prolonged muscle paralysis and its consequences are the main signs of overdosage.
Treatment: It is essential to maintain a patent airway together with assisted positive pressure ventilation until spontaneous respiration is adequate. Full sedation will be required since consciousness is not impaired. Recovery may be hastened by the administration of anticholinesterase agents accompanied by atropine or glycopyrrolate, once evidence of spontaneous recovery is present.

Atracurium is contraindicated in patients known to be hypersensitive to atracurium, cisatracurium or benzenesulfonic acid.

In common with all the other neuromuscular blocking agents atracurium paralyses the respiratory muscles as well as other skeletal muscles but has no effect on consciousness. Atracurium should be administered only with adequate general anaesthesia and only by or under the close supervision of an experienced anaesthetist with adequate facilities for endotracheal intubation and artificial ventilation.
The potential for histamine release exists in susceptible patients during Atracurium besylate (Tracrium) administration.
Caution should be exercised in administering Atracurium besylate (Tracrium) to patients with a history suggestive of an increased sensitivity to the effects of histamine.
Caution should also be exercised when administering atracurium to patients who have shown hypersensitivity to other neuromuscular blocking agents since a high rate of cross-sensitivity (greater than 50%) between neuromuscular blocking agents has been reported (see Contraindications).
Atracurium besylate (Tracrium) does not have significant vagal or ganglionic blocking properties in the recommended dosage range. Consequently, Atracurium besylate (Tracrium) has no clinically significant effects on heart rate in the recommended dosage range and it will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery.
In common with other non-depolarising neuromuscular blocking agents, increased sensitivity to atracurium may be expected in patients with myasthenia gravis, other forms of neuromuscular disease and severe electrolyte imbalance.
Atracurium besylate (Tracrium) should be administered over a period of 60 seconds to patients who may be unusually sensitive to falls in arterial blood pressure, for example those who are hypovolaemic.
Atracurium besylate (Tracrium) is inactivated by high pH and so must not be mixed in the same syringe with thiopentone or any alkaline agent.
When a small vein is selected as the injection site, Atracurium besylate (Tracrium) should be flushed through the vein with physiological saline after injection. When other anaesthetic drugs are administered through the same in-dwelling needle or cannula as Atracurium besylate (Tracrium) it is important that each drug is flushed through with an adequate volume of physiological saline.
Atracurium besylate (Tracrium) is hypotonic and must not be administered into the infusion line of a blood transfusion.
Studies in malignant hyperthermia in susceptible animals (swine) and clinical studies in patients susceptible to malignant hyperthermia indicate that Atracurium besylate (Tracrium) does not trigger this syndrome.
In common with other non-depolarising neuromuscular blocking agents, resistance may develop in patients suffering from burns. Such patients may require increased doses dependent on the time elapsed since the burn injury and the extent of the burn.
Intensive Care Unit (lCU) Patients: When administered to laboratory animals in high doses, laudanosine, a metabolite of atracurium, has been associated with transient hypotension and in some species, cerebral excitatory effects. Although seizures have been seen in lCU patients receiving atracurium, a causal relationship to laudanosine has not been established.
Effect on the ability to drive and use machines: This precaution is not relevant to the use of Atracurium besylate (Tracrium). Atracurium besylate (Tracrium) will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.

Teratogenicity: Animal studies have indicated that Atracurium besylate (Tracrium) has no significant effects on foetal development.
Fertility: Fertility studies have not been performed.
Use in Pregnancy & Lactation: In common with all neuromuscular blocking agents, Atracurium besylate (Tracrium) should be used during pregnancy only if the potential benefit to the mother outweighs any potential risk to the foetus.
Atracurium besylate (Tracrium) is suitable for maintenance of muscle relaxation during Caesarian section as it does not cross the placenta in clinically significant amounts following recommended doses.
It is not known whether Atracurium besylate (Tracrium) is excreted in human milk.

Adverse reactions are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).
Very common, common and uncommon frequencies were determined from clinical trial data. Rare and very rare frequencies were generally derived from spontaneous data. The frequency classification "Not known" has been applied to those reactions where a frequency could not be estimated from the available data.
Clinical Trial Data: Vascular Disorders: Events which have been attributed to histamine release are indicated by a hash (#).
Common: Hypotension (mild, transient}#, Skin flushing#.
Respiratory, thoracic and mediastinal disorders: Events which have been attributed to histamine release are indicated by a hash (#).
Uncommon: Bronchospasm#.
Post-Marketing Data: Immune system disorders: Very rare: Anaphylactic reaction, anaphylactoid reaction.
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.
Nervous system disorder: Not known: Seizures.
There have been reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents.
These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). A causal relationship to laudanosine has not been established. In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.
Skin and subcutaneous tissue disorders: Rare: Urticaria.
Musculoskeletal and connective tissue disorders: Not known: Myopathy, muscle weakness.
There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been seen infrequently in association with atracurium and a causal relationship has not been established.

The neuromuscular block produced by Atracurium besylate (Tracrium) may be increased by the concomitant use of inhalational anaesthetics such as halothane, isoflurane and enflurane.
In common with all non-depolarising neuromuscular blocking agents the magnitude and/or duration of a non-depolarising neuromuscular block may be increased as a result of interaction with: antibiotics, including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin; anti-arrhythmic drugs: propranolol, calcium channel blockers, lidocaine, procainamide and quinidine; diuretics: furosemide and possibly mannitol, thiazide diuretics and acetazolamide; magnesium sulphate; ketamine; lithium salts; ganglion blocking agents: trimetaphan, hexamethonium.
Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to Atracurium besylate (Tracrium) would be consequent on such a development. Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), anti-arrhythmic drugs (procainamide, quinidine), anti-rheumatic drugs (chloroquine, D-penicillamine), trimetaphan, chlorpromazine, steroids, phenytoin and lithium.
The onset of non-depolarising neuromuscular block is likely to be lengthened and the duration of block shortened in patients receiving chronic anti-convulsant therapy.
The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with Atracurium besylate (Tracrium) may produce a degree of neuromuscular blockade in excess of that which might be expected were an equipotent total dose of Atracurium besylate (Tracrium) administered. Any synergistic effect may vary between different drug combinations.
A depolarising muscle relaxant such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarising agents such as atracurium, as this may result in a prolonged and complex block which can be difficult to reverse with anticholinesterase drugs.
Treatment with anticholinesterases, commonly used in the treatment of Alzheimer's disease e.g. donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with atracurium.

Store at temperatures between 2°C and 8°C. Protect from light. Do not freeze.
Any unused atracurium from opened ampoules should be discarded.
Storage precautions: Short periods at temperatures up to 25°C are permissible but ONLY to allow transportation or temporary storage outside of a cold store. It is estimated that a 5% loss of potency would occur if atracurium injection was stored at 25°C for one month.

Neuromuscular Blocking Agents

M03AC04 - atracurium ; Belongs to the class of other quaternary ammonium-containing agents used as peripherally-acting muscle relaxants.

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