J Anaesth Clin Pharmacol 2010; 26(2): 223-228
Ropivacaine- The Latest Local Anaesthetic in the Indian Market
Ankit Agarwal, R.K. Verma, Shivika Srivastava
Regional anaesthesia has come to occupy an important
part in clinical anaesthesiology. As with other fields, regional
anaesthesia too, has undergone major developments, both
in techniques and drug availability. Ropivacaine, an amide
based local anaesthetic, though available internationally
for long, has only recently been launched in the Indian
market.
Ropivacaine is a new long acting local anaesthetic
drug belonging to the amino amide group. Ropivacaine,
bupivacaine and mepivacaine belong to pipecoloxylidides
group of local anaesthetics. Though bupivacaine and
mepivacaine have been in use for more than 30 years,
ropivacaine is unique. The name ropivacaine refers to both
the racemate and the marketed S-enantiomer.1 Historically,
bupivacaine was used clinically as it had a long duration
of action. Subsequently it was found that 'propyl' derivatives
of pipecoloxylidides were less toxic than butyl derivatives
(bupivacaine). Ropivacaine thus was developed after
bupivacaine was noted to be associated with significant
number of cardiac arrests. Cardiotoxicity of ropivacaine is
less than bupivacaine as ropivacaine causes lesser
depression of cardiac contractility.2 It is used for local
anaesthesia including infiltration, nerve block, epidural and
intrathecal anaesthesia in adults and children over 12 years.
It is also used for peripheral nerve block and caudal epidural
in children 1-12 years for surgical pain.
Chemical structure
Ropivacaine is a member of the amino amide class of
local anesthetics chemically described as S-(-)-1-propyl-
2',6'-pipecoloxylidide hydrochloride monohydrate. The IUPAC
name is (S)-N-(2,6-dimethylphenyl)-1-propylpiperidine-2-
carboxamide. The drug substance is a white crystalline
powder, with a molecular formula of C17H26N2OoHCloH2O
and a molecular weight of 328.89. The structural formula
is represented in Figure 1.
Physical properties
At 25°C ropivacaine HCL has a solubility of 53.8 mg/mL in
water, a distribution ratio between n-octanol and phosphate
buffer at pH 7.4 of 14:1 and a pKa of 8.07 in 0.1 M KCl
solution. The pKa of ropivacaine is approximately the same
Drs. Ankit Agarwal, Assistant Professor, R.K. Verma, Associate Professor, Shivika Srivastava, Resident, Deptt. of Anaesthesiology
& Critical Care, Banaras Hindu University (BHU), Varanasi, India
Correspondence: Dr. Ankit Agarwal, Email: drankit80@gmail.com
223
Figure 1
as bupivacaine (8.1) and is similar to that of mepivacaine
(7.7). However, ropivacaine has an intermediate degree of
lipid solubility compared to bupivacaine and mepivacaine.
Usually sodium hydroxide or hydrochloric acid is added to
adjust pH of the compound. Ropivacaine is preservative
free and is available in single dose containers in 2 (0.2%),
5 (0.5%), 7.5 (0.75%) and 10 mg/mL (1%) concentrations.
The specific gravity of solutions range from 1.002 to 1.005
at 25°C.
Mechanism of action
Ropivacaine reversibly interferes with the entry of sodium
in nerve cell membranes, leading to deceased membrane
permeability to sodium and thus blocks generation and
conduction of nerve impulses, and also slows the
propagation of the nerve impulse, and reduces the rate of
rise of the action potential.3 Small unmyelinated C fibres
and small myelinated A fibres transmit pain impulses
whereas large A fibres transmit motor impulses. Most local
anaesthetics block C fibres at approximately the same
rate, but the rate of blockade of A fibre depends on the
physicochemical properties of the individual drugs, high
pKa and low lipid solubility. The pKa of bupivacaine and
ropivacaine are identical but ropivacaine is less lipid
soluble, envisaging that ropivacaine will block A fibres more
slowly than bupivacaine and this has been confirmed
clinically. Thus ropivacaine would cause less motor block
than bupivacaine. Studies of lumbar extradural block in
humans have confirmed that equal volumes and
concentrations of ropivacaine and bupivacaine produce a
similar pattern of sensory block but motor block is slower
in onset, less in intensity and shorter in duration with
ropivacaine. Clinically, the order of blockade of nerve fibres
is autonomic, sensory and motor, disappearing in the
AGARWAL A ET AL: ROPIVACAINE
reverse order, and the order of loss of nerve function is (1)
pain, (2) temperature, (3) touch, (4) proprioception, and (5)
skeletal muscle tone.
Uses of Ropivacaine
Ropivacaine is indicated for local or regional anesthesia
for surgery and for acute pain management.
Surgical Anesthesia: It may be administered as epidural
block for surgery including cesarean section, or alternatively
as major nerve block or local infiltration
Acute Pain Management: It may be given as continuous
epidural infusion or intermittent bolus for postoperative
analgesia or labor analgesia.
Pharmacokinetics4
Absorption: The systemic concentration of ropivacaine is
dependent on the total dose and concentration of drug
administered, the route of administration, the patient's
hemodynamic condition, and the vascularity of the
administration site. Ropivacaine, from the epidural space,
shows complete and biphasic absorption. The half-lives of
the 2 phases (mean ±SD) are 14±7 minutes and 4.2±0.9
h, respectively.
Distribution: After intravascular infusion, ropivacaine has a
steady state volume of distribution of 41±7 liters. It is 94%
protein bound, mainly to a1-acid glycoprotein. Ropivacaine
readily crosses the placenta.
Metabolism: Ropivacaine is extensively metabolized in the
liver, predominantly by aromatic hydroxylation mediated by
cytochrome P4501A to 3-hydroxy ropivacaine. After a single
IV dose, approximately 37% of the total dose is excreted in
the urine as both free and conjugated 3-hydroxy ropivacaine.
Low concentrations of 3-hydroxy ropivacaine have been
found in the plasma. An additional metabolite, 2-hydroxy-
methyl-ropivacaine, has been identified but not quantified
in the urine. N-de-alkylated metabolite of ropivacaine and
3-OH-ropivacaine are the major metabolites excreted in the
urine during epidural infusion.
Elimination: The kidney is the main excretory organ for
most ropivacaine metabolites. In total, 86% of the
ropivacaine dose is excreted in the urine after intravenous
administration of which only 1% relates to unchanged drug.
After intravenous administration ropivacaine has a mean
±SD total plasma clearance of 387 ±107 mL/min, an
unbound plasma clearance of 7.2 ±1.6 L/min, and a renal
clearance of 1 mL/min. The mean ±SD terminal half-life is
1.8 ±0.7 h after intravascular administration and 4.2 ±1.0
h after epidural administration.
224
Ropivacaine in Clinical trials
Ropivacaine was studied as a local anaesthetic both for
surgical anesthesia and for acute pain management. The
onset, depth and duration of sensory block were, in general,
similar to bupivacaine but, the depth and duration of motor
block, were less than that with bupivacaine.
Epidural Administration in Surgery5: There were 25 clinical
studies performed in 900 patients to evaluate ropivacaine
epidural injection for general surgery in doses ranging
from 75 to 250 mg. In doses of 100-200 mg, the median
onset time to achieve a T10 sensory block was 10 (5-13)
minutes and the median duration at the T10 level was 4
(3-5) hours. Higher doses produced a more profound block
with a greater duration of effect.
Epidural Administration in Cesarean Section6,7: A total of
12 studies were performed with epidural administration of
ropivacaine for cesarean section. Eight of these studies
involved 218 patients using the concentration of 5 mg/mL
(0.5%) in doses up to 150 mg. Median onset measured at
T6 ranged from 11 to 26 minutes. Median duration of
sensory block at T6 ranged from 1.7 to 3.2 h, and duration
of motor block ranged from 1.4 to 2.9 h. Ropivacaine
provided adequate muscle relaxation for surgery in all cases.
Epidural Administration in Labor and Delivery8: A total of
9 double-blind clinical studies, involving 240 patients were
performed to evaluate ropivacaine for epidural block for
management of labor pain. When administered in doses
up to 278 mg as intermittent injections or as a continuous
infusion, ropivacaine produced adequate pain relief. A
prospective meta-analysis on 6 of these studies provided
detailed evaluation of the delivered newborns and showed
no difference in clinical outcomes compared to bupivacaine.
There were significantly fewer instrumental deliveries in
mothers receiving ropivacaine as compared to bupivacaine.
Epidural Administration in Postoperative Pain
Management9: There were 8 clinical studies performed in
382 patients to evaluate ropivacaine 2 mg/mL (0.2%) for
postoperative pain management after upper and lower
abdominal surgery and after orthopedic surgery. The studies
utilized intravascular morphine via PCA as a rescue
medication and quantified as an efficacy variable. Epidural
anesthesia with ropivacaine 5 mg/mL, (0.5%) was used
intraoperatively for each of these procedures prior to
initiation of postoperative ropivacaine. The incidence and
intensity of the motor block were dependent on the dose
rate of ropivacaine and the site of injection. Cumulative
doses of up to 770 mg of ropivacaine were administered
J Anaesth Clin Pharmacol 2010; 26(2): 223-228
over 24 hours (intraoperative block plus postoperative
continuous infusion). The overall quality of pain relief, as
judged by the patients, in the ropivacaine groups was rated
as good or excellent (73% to 100%). The frequency of
motor block was greatest at 4 hours and decreased during
the infusion period in all groups. At least 80% of patients
in the upper and lower abdominal studies and 42% in the
orthopedic studies had no motor block at the end of the 21-
hour infusion period. Sensory block was also dose rate-
dependent and a decrease in spread was observed during
the infusion period. Thus experience indicates that a
cumulative dose of up to 770 mg ropivacaine administered
over 24 hours is well tolerated in adults when used for
postoperative pain management: ie a total of 2016 mg
ropivacaine. It must be used cautiously when administered
for prolonged periods of time, ie > 70 hours in debilitated
patients.
Continuous epidural infusion of ropivacaine 2 mg/mL
(0.2%) during up to 72 hours for postoperative pain
management after major abdominal surgery was studied
in 2 multicenter, double-blind studies. A total of 391 patients
received a low thoracic epidural catheter, and ropivacaine
7.5 mg/L (0.75%) was given for surgery, in combination
with GA. Postoperatively, ropivacaine 2 mg/mL (0.2%), 4-14
mL/h, alone or with fentanyl 1, 2, or 4 µg/mL was infused
through the epidural catheter and adjusted according to the
patient's needs. Clinical studies with 2 mg/mL (0.2%)
ropivacaine have demonstrated that infusion rates of 6-14
mL (12-28 mg) per hour provide adequate analgesia with
nonprogressive motor block in cases of moderate to severe
postoperative pain. In these studies, this technique resulted
in a significant reduction in patients' morphine rescue dose
requirement. For treatment of postoperative pain, the
technique recommended is : if regional anesthesia was
not used intraoperatively, then an initial epidural block with
5 to 7 mL ropivacaine is induced through an epidural
catheter. Analgesia is maintained with an infusion of 2 mg/
mL (0.2%) ropivacaine. With this technique a significant
reduction in the need for opioids was demonstrated. Clinical
studies support the use of ropivacaine epidural infusions
for up to 72 hours.
Peripheral Nerve Block:10,11 Ropivacaine, 5 mg/mL (0.5%),
was evaluated for its ability to provide anesthesia for surgery
using the techniques of Peripheral Nerve Block. There were
13 studies performed including a series of 4
pharmacodynamic and pharmacokinetic studies performed
on minor nerve blocks. Ropivacaine was used in doses up
to 275 mg. When used for brachial plexus block, onset
depended on technique used. The median onset of sensory
block produced by ropivacaine 0.5% via axillary block ranged
225
from 10 minutes (medial brachial cutaneous nerve) to 45
minutes (musculocutaneous nerve). Median duration
ranged from 3.7 hours (medial brachial cutaneous nerve)
to 8.7 hours (ulnar nerve).
Local Infiltration: A total of 7 clinical studies were performed
to evaluate the local infiltration of ropivacaine to produce
anesthesia for surgery and analgesia in postoperative pain
management. In these studies 297 patients who received
ropivacaine in doses up to 200 mg (concentrations up to
5 mg/mL, 0.5%) were evaluable for efficacy. With infiltration
of 100-200 mg ropivacaine, the time to first request for
analgesic was 2-6 hours. When compared to placebo,
ropivacaine produced lower pain scores and a reduction of
analgesic consumption.
Dosage
The dose of ropivacaine varies with the anaesthetic
procedure, the area to be anesthetized, the vascularity of
the tissues, the number of neuronal segments to be
blocked, the depth of anesthesia and degree of muscle
relaxation required, the duration of anesthesia desired,
individual tolerance, and the physical condition of the patient.
Patients in poor general condition due to aging or other
compromising factors such as partial or complete heart
conduction block, advanced liver disease or severe renal
dysfunction require special attention although regional
anesthesia is frequently indicated in these patients.12,13 To
reduce the risk of potentially serious adverse reactions,
dosage should be adjusted accordingly. The various
recommended dosage guidelines for ropivacaine are
depicted in Table 1. Ropivacaine has limited solubility above
a pH of 6.0, and precipitation might occur if mixed with
alkaline solutions.
Adverse effects
Reactions to ropivacaine may be associated with excessive
plasma levels, which may be due to overdosage,
unintentional intravascular injection or slow metabolic
degradation. The mean doses at which CNS symptoms of
toxicity begin to occur in human beings are 4.3 and 0.6 µg/
ml of total and free plasma concentrations respectively.
When prolonged blocks are used, either through continuous
infusion or through repeated bolus administration, the risks
of reaching a toxic plasma concentration or inducing local
neural injury are increased. Ropivacaine has also not been
approved for intraarticular infusions. There have been
reports of chondrolysis in patients receiving intraarticular
local anaesthetic infusions. Such reports are with infusions
lasting 48-72 hrs, but information is still deficient for shorter
duration infusions.
AGARWAL A ET AL: ROPIVACAINE 226

Table 1
Dosage of Ropivacaine

Conc. Volume mL Dose mg Onset min Duration

mg/mL (%) hours

SURGICAL ANAESTHESIA
Lumbar Epidural 5.0 (0.5%) 15-30 75-150 15-30 2-4
Administration 7.5 (0.75%) 15-25 113-188 10-20 3-5
Surgery 10.0 (1.0%) 15-20 150-200 10-20 4-6
Thoracic Epidural 5.0 (0.5%) 5-15 25-75 10-20 n/a
Administration 7.5 (0.75%) 5-15 38-113 10-20 n/a
Major Nerve Block 5.0 (0.5%) 35-50 175-250 15-30 5-8
(eg, brachial plexus block) 7.5 (0.75%) 10-40 75-300 10-25 6-10
Field Block (eg, minor nerve blocks and infiltration) 5.0 (0.5%) 1-40 5-200 1-15 2-6

LABOR PAIN MANAGEMENT

Lumbar Epidural Administration
Initial Dose 2.0 (0.2%) 10-20 20-40 10-15 0.5-1.5
Continuous infusion 2.0 (0.2%) 6-14 mL/h 12-28 mg/h n/a n/a
Incremental injections (top-up) 2.0 (0.2%) 10-15 mL/h 20-30mg/h n/a n/a

POSTOPERATIVE PAIN MANAGEMENT

Lumbar Epidural Administration
Continuous infusion 2.0 (0.2%) 6-14 mL/h 12-28 mg/h n/a n/a0
Thoracic Epidural Administration 2.0 (0.2%) 6-14mL/h 12-28 mg/h n/a n/a
Continuous infusion
Infiltration 2.0 (0.2%) 1-100 2-200 1-5 2-6
(eg, minor nerve block) 5.0 (0.5%) 1-40 5-200 1-5 2-6

The various possible side effects include
Application Site Reactions - injection site pain
Cardiovascular System - vasovagal reaction, syncope,
postural hypotension, nonspecific ECG abnormalities14
Gastrointestinal System - fecal incontinence,
tenesmus, neonatal vomiting
General and Other Disorders - hypothermia, malaise,
asthenia
Hearing and Vestibular - tinnitus, hearing abnormalities
Liver and Biliary System - jaundice
Metabolic Disorders - hypomagnesemia
Musculoskeletal System - myalgia
Nervous System - tremor, Horner's syndrome, paresis,
dyskinesia, neuropathy, vertigo, coma, convulsion,
hypokinesia, hypotonia, ptosis, stupor, vision abnormalities15.
Due to a depressant effect of ropivacaine on medulla,
excitatory stage of CNS toxicity might not occur.
Psychiatric Disorders - agitation, confusion,
somnolence, nervousness, amnesia, hallucination,
emotional lability, insomnia, nightmares
Skin Disorders - rash, urticaria
Urinary System Disorders- urinary incontinence,
micturition disorder
Vascular - deep vein thrombosis, phlebitis, pulmonary
embolism
Ropivacaine should only be administered in
incremental doses and is not recommended for emergency,
where a fast onset of surgical anesthesia is necessary.
Management of complications- The administration of
ropivacaine should be discontinued at the first sign of
toxicity. Since no specific antidote is yet available,
symptomatic and supportive management should be
promptly done. Any change in mentation necessitates
oxygen administration. If there is slightest of respiratory
depression, immediate establishment of a secure airway
and assisted ventilation must be done. If toxicity leads to
convulsions, barbiturates, specific anticonvulsants or
neuromuscular blockers must be used. In case of a cardiac
arrest, prolonged resuscitative efforts might be required.
Drug Interactions
Ropivacaine should be used with caution in patients
receiving other local anesthetics or agents structurally
related to amide-type local anesthetics, since the toxic effects
of these drugs are additive. Cytochrome P4501A2 is involved
in the formation of 3-hydroxy ropivacaine, the major
metabolite. Strong inhibitors of cytochrome P4501A2, such
as fluvoxamine, can interact with ropivacaine leading to
increased ropivacaine plasma levels.16 Possible
interactions with drugs known to be metabolized by CYP1A2
via competitive inhibition such as theophylline and
imipramine may also occur.
J Anaesth Clin Pharmacol 2010; 26(2): 223-228 227

Ropivacaine in pregnancy17,18 motor block which makes it a better choice for use in
There are no adequate or well-controlled studies in pregnant obstetrics and postoperative pain relief. As compared to
women of the effects of ropivacaine on the developing bupivacaine, it produces less intense motor block, and of
fetus. It should only be used during pregnancy if the benefits shorter duration, permitting earlier mobilization & discharge.
outweigh the risk. Teratogenicity studies in rats and rabbits It has a lower systemic toxicity than bupivacaine and a
did not show evidence of any adverse effects on better cardiotoxic profile. Both bupivacaine and ropivacaine
organogenesis. Local anesthetics, including ropivacaine, have a chiral center. Commercial bupivacaine is a racemic
rapidly cross the placenta, and when used for epidural mixture of the S- and R-enantiomers. The R-enentiomer
block can cause varying degrees of maternal, fetal and has a greater affinity and dwell time at the voltage-gated
neonatal toxicity. The incidence and degree of toxicity sodium channels, and this is the cause of greater
depend upon the procedure performed, the type and cardiotoxicity of bupivacaine. Also, the R-enantiomer binds
amount of drug used, and the technique of drug 3 times more firmly to the sodium channel, and unbinds
administration. Adverse reactions in the parturient, fetus 4.4 times as slowly. R-bupivacaine is also more
and neonate involve alterations of the central nervous arrhythmogenic, and slows ventricular conduction 4.6 times
system, peripheral vascular tone and cardiac function. as much as S-bupivacaine. The cardiotoxicity of bupivacaine
Maternal hypotension has resulted from regional anesthesia has been termed as treatment resistant. This is not so with
with ropivacaine for obstetrical pain relief. The fetal heart ropivacaine. Ropivacaine is the pure S-enantiomer. Thus
rate also should be monitored continuously, and electronic has a lesser cardiotoxicity.
fetal monitoring is highly advisable. Adverse reactions in
fetuses have also been reported when ropivacaine was CONCLUSION
used used for regional anaesthesia before delivery (Table Ropivacaine is a new amide local anaesthetic, available
2). as a pure S-enantiomer. It has a profile similar to euipotent
Table 2 doses of bupivacaine. It provides excellent postoperative
Adverse fetal reactions with ropivacaine as compared to analgesia by epidural or perineural approach. The
bupivacaine
primary benefit of ropivacaine is its lower cardiotoxicity
Adverse Reaction Ropivacaine Bupivacaine following accidental intravascular injection. The higher
total N=639 total N=573 therapeutic index is leads to a better safety profile over other
N (%) N (%)
local anaesthetics.
Fetal bradycardia 77 (12.1) 68 (11.9)
Neonatal jaundice 49 (7.7) 47 (8.2)
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