Tubocurarine Chloride
The chloride of (+)-tubocurarine. It may be obtained from ex
tracts of the stems of Chondodendron tomentosum (Menis-
pennaceae) and is one of the active principles of curare, by
which name it is sometimes referred to in anaesthetic litera-
ture. Is a white or slightly yellowish-white or greyish-white.
crystalline powder.
Ph. Eur. solubilities are: soluble in water and in alcohol; prac-
tically insoluble in acetone and in ether; dissolves in solutions
of alkali hydroxides. USP solubilities are: soluble I in 20 of
water and I in 45 of alcohol. A I % solution in water has a ph
of 4.0 to 6.0. Store in airtight containers.
Adverse Effects, Treatment, and Precautions : As for competitive neuromuscular blockers in general like atracurium whose details are given below :
PRECAUTIONS:
GENERAL: Although TRACRIUM is a less potent histamine releaser than d-
tubocurarine or metocurine, the possibility of substantial histamine release in
sensitive individuals must be considered. Special caution should be exercised in
administering TRACRIUM to patients in whom substantial histamine release would
be especially hazardous (e.g., patients with clinically significant
cardiovascular disease) and in patients with any history (e.g., severe
anaphylactoid reactions or asthma) suggesting a greater risk of histamine
release. In these patients, the recommended initial TRACRIUM dose is lower (0.3
to 0.4 mg/kg) than for other patients and should be administered slowly or in
divided doses over 1 minute.
Since TRACRIUM has no clinically significant effects on heart rate in the
recommended dosage range, it will not counteract the bradycardia produced by
many anesthetic agents or vagal stimulation. As a result, bradycardia during
anesthesia may be more common with TRACRIUM than with other muscle relaxants.
TRACRIUM may have profound effects in patients with myasthenia gravis, Eaton-
Lambert syndrome, or other neuromuscular diseases in which potentiation of
nondepolarizing agents has been noted. The use of a peripheral nerve stimulator
is especially important for assessing neuromuscular block in these patients.
Similar precautions should be taken in patients with severe electrolyte
disorders or carcinomatosis.
Multiple factors in anesthesia practice are suspected of triggering malignant
hyperthermia (MH), a potentially fatal hypermetabolic state of skeletal muscle.
Halogenated anesthetic agents and succinylcholine are recognized as the
principal pharmacologic triggering agents in MH- susceptible patients; however,
since MH can develop in the absence of established triggering agents, the
clinician should be prepared to recognize and treat MH in any patient scheduled
for general anesthesia. Reports of MH have been rare in cases in which TRACRIUM
has been used. In studies of MH-susceptible animals (swine) and in a clinical
study of MH-susceptible patients, TRACRIUM did not trigger this syndrome.
Resistance to nondepolarizing neuromuscular blocking agents may develop in burn
patients. Increased doses of nondepolarizing muscle relaxants may be required in
burn patients and are dependent on the time elapsed since the burn injury and
the size of the burn.
The safety of TRACRIUM has not been established in patients with bronchial
asthma.
LONG-TERM USE IN INTENSIVE CARE UNIT (ICU): When there is a need for long-term
mechanical ventilation, the benefits-to-risk ratio of neuromuscular block must
be considered. The long- term (1 to 10 days) infusion of TRACRIUM during
mechanical ventilation in the ICU has been evaluated in several studies. Average
infusion rates of 11 to 13 mcg/kg/min (range 4.5 to 29.5) were required to
achieve adequate neuromuscular block. These data suggest that there is wide
interpatient variability in dosage requirements. In addition, these studies have
shown that dosage requirements may decrease or increase with time. Following
discontinuation of infusion of TRACRIUM in these ICU studies, spontaneous
recovery of four twitches in a train-of-four occurred in an average of
approximately 30 minutes (range 15 to 75 min) and spontaneous recovery to a
train-of- four ratio >75% (the ratio of the height of the fourth to the first
twitch in a train-of-four) occurred in an average of approximately 60 minutes
(range: 32 to 108 min).
Little information is available on the plasma levels and clinical consequences
of atracurium metabolites that may accumulate during days to weeks of atracurium
administration in ICU patients. Laudanosine, a major biologically active
metabolite of atracurium without neuromuscular blocking activity, produces
transient hypotension and, in higher doses, cerebral excitatory effects
(generalized muscle twitching and seizures) when administered to several species
of animals. There have been rare spontaneous reports of seizures in ICU patients
who have received atracurium or other agents. These patients usually had
predisposing causes (such as head trauma, cerebral edema, hypoxic
encephalopathy, viral encephalitis, uremia). There are insufficient data to
determine whether or not laudanosine contributes to seizures in ICU patients.
WHENEVER THE USE OF TRACRIUM OR ANY NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED
IN THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED
CONTINUOUSLY DURING ADMINISTRATION WITH THE HELP OF A NERVE STIMULATOR.
ADDITIONAL DOSES OF TRACRIUM OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD
NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO T1 OR TO THE FIRST TWITCH.
IF NO RESPONSE IS ELICITED, INFUSION ADMINISTRATION SHOULD BE DISCONTINUED UNTIL
A RESPONSE RETURNS.
Hemofiltration has a minimal effect on plasma levels of atracurium and its
metabolites, including laudanosine. The effects of hemodialysis and
hemoperfusion on plasma levels of atracurium and its metabolites are unknown.
ADVERSE REACTIONS:
OBSERVED IN CONTROLLED CLINICAL STUDIES: TRACRIUM was well tolerated and
produced few adverse reactions during extensive clinical trials. Most adverse
reactions were suggestive of histamine release. In studies including 875
patients, TRACRIUM was discontinued in only one patient (who required treatment
for bronchial secretions), and six other patients required treatment for adverse
reactions attributable to TRACRIUM (wheezing in one, hypotension in five). Of
the five patients who required treatment for hypotension, three had a history of
significant cardiovascular disease. The overall incidence rate for clinically
important adverse reactions, therefore, was 7/875 or 0.8%. The table below
includes all adverse reactions reported attributable to TRACRIUM during clinical
trials with 875 patients.
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TABLE 1: PERCENT OF PATIENTS REPORTING ADVERSE REACTIONS
ADVERSE REACTION INITIAL TRACRIUM DOSE (MG/KG)
-----------------------------------------------------------------------------------------------------------------
0.00-0.30 0.31-0.50* >/= 0.60 Total
(n = 485) (n = 366) (n = 24) (n = 875)
---------------------------------------------------------------------------------------------------------------------------------
Skin Flush 1.0% 8.7% 29.2% 5.0%
Erythema 0.6% 0.5% 0% 0.6%
Itching 0.4% 0% 0% 0.2%
Wheezing/
Bronchial
Secretions 0.2% 0.3% 0% 0.2%
Hives 0.2% 0% 0% 0.1%
----------------------------------------------------------------------------------------------------------------------------------
*Includes the recommended initial dosage range for most patients.
Most adverse reactions were of little clinical significance unless they were
associated with significant hemodynamic changes. Table 2 summarizes the
incidences of substantial vital sign changes noted during clinical trials of
TRACRIUM with 530 patients, without cardiovascular disease, in whom these
parameters were assessed.
TABLE 2: PERCENT OF PATIENTS SHOWING > 30% VITAL SIGN
CHANGES FOLLOWING ADMINISTRATION OF TRACRIUM
VITAL SIGN CHANGE INITIAL TRACRIUM DOSE (MG/KG)
-------------------------------------------------------------------------------------------------------------
0.00-0.30 0.31-0.50* >/= 0.60 Total
(n = 365) (n = 144) (n = 21) (n = 530)
-------------------------------------------------------------------------------------------------------------------------------
Mean Arterial Pressure
Increase 1.9% 2.8% 0% 2.1%
Decrease 1.1% 2.1% 14.3% 1.9%
Heart Rate
Increase 1.6% 2.8% 4.8% 2.1%
Decrease 0.8% 0% 0% 0.6%
-------------------------------------------------------------------------------------------------------------------------------
*Includes the recommended initial dosage range for most patients.
OBSERVED IN CLINICAL PRACTICE: Based on initial clinical practice experience in
approximately 3 million patients who received TRACRIUM in the U.S. and in the
United Kingdom, spontaneously reported adverse reactions were uncommon
(approximately 0.01% to 0.02%). The following adverse reactions are among the
most frequently reported, but there are insufficient data to support an estimate
of their incidence:
GENERAL: Allergic reactions (anaphylactic or anaphylactoid responses) which, in
rare instances, were severe (e.g., cardiac arrest)
MUSCULOSKELETAL: Inadequate block, prolonged block
CARDIOVASCULAR: Hypotension, vasodilatation (flushing), tachycardia, bradycardia
RESPIRATORY: Dyspnea, bronchospasm, laryngospasm
INTEGUMENTARY: Rash, urticaria, reaction at injection site
There have been rare spontaneous reports of seizures in ICU patients following
long-term infusion of atracurium to support mechanical ventilation. There are
insufficient data to define the contribution, if any, of atracurium and/or its
metabolite laudanosine. (See PRECAUTIONS: Long-Term Use in Intensive Care Unit
(ICU)).
A transient fall in blood pressure commonly occurs, due in part to ganglionic blockade and
the release of histamine; there may be an increase in heart rate
Tubocurarine has a greater propensity to cause histamine re
lease than other competitive neuromuscular blockers in clini
cal use. Tubocurarine should be used with caution in patient
with renal impairment. Resistance lo the effect of tubocurar
ine may occur in patients with hepatic impairment.
Interactions
For interactions associated with competitive neuromuscular blockers like Atracurium whose details are given below :
DRUG INTERACTIONS:
Drugs which may enhance the neuromuscular blocking action of TRACRIUM include:
enflurane; isoflurane; halothane; certain antibiotics, especially the
aminoglycosides and polymyxins; lithium; magnesium salts; procainamide; and
quinidine.
If other muscle relaxants are used during the same procedure, the possibility of
a synergistic or antagonist effect should be considered.
The prior administration of succinylcholine does not enhance the duration, but
quickens the onset and may increase the depth, of neuromuscular block induced by
TRACRIUM. TRACRIUM should not be administered until a patient has recovered from
succinylcholine-induced neuromuscular block.
(See Also PRECAUTIONS)
Pharmacokinetics
Tambourine chloride is a quaternary ammonium compound
and absorption from the gastro-intestinal tract following oral
administration is extremely poor Absorption is slow and ir
regular when given intramuscularly. Following intravenous
injection tubocurarine is widely distributed throughout body
tissues: less than 50% is bound to plasma proteins. Following
a single dose extensive redistribution to tissues is responsible
for the termination of activity, but after a large single dose or
repeated small doses tissue saturation occurs and renal excre
tion becomes the main determinant of duration. When given
in usual doses it does not pass the blood-brain barrier, and
does not appear to cross the placenta in significant amounts
Up to 75% of a dose is excreted unchanged in the urine in 24
hours, and up to 12% in bile. Biliary excretion is increased in
renal impairment. A small proportion of a dose is metabolised
in the liver.
Uses and Administration
Tubocurarine is a benzylisoquinolinium competitive neuro-
muscular blocker (see Atracurium. Following in
travenous injection of tubocurarine chloride neuromuscular
block appears within one minute and lasts for about 30 min-
utes: the maximum effect is attained within 2 to 5 minute.
Tubocurarine chloride has been used similarly to other com
petitive neuromuscular blockers to produce muscle relaxation
in various procedures but has largely been replaced by other
dnigs with fewer cardiovascular effects and a lower potential
for histamine release.
Doses used have varied according to the degree of muscle re-
laxation required. In the UK initial doses of 15 to 30 mg have
been given intravenously to adults with additional doses of 5
to 10 mg given at intervals of 25 to 60 minutes if required to
maintain muscle relaxation. In the USA lower doses have
generally been used. An initial dose of 6 to 9 mg intravenous
ly has been suggested followed by 3 to 4.5 mg after 3 to 5
minutes if necessary; additional doses of 3 mg may be given
as required for prolonged procedures. Tubocurarine should be
given with caution in reduced doses to patients with renal im-
pairment. if large or repeated doses are given neuromuscular
block may be prolonged. Tubocurarine chloride has also been
used to control the muscle spasms of tetanus.