C. Williams and M.
Leuwer
12 Neuromuscular blocking
agents and skeletal
muscle relaxants
DEPOLARIZING
NEUROMUSCULAR
BLOCKING AGENTS
Suxamethonium (succinylcholine)
[SED-15, 2489; SEDA-32, 273; SEDA-33,
299; SEDA-34, 221]
Immunologic Cardiac arrest shortly after
anesthetic induction for thyroidectomy in
a patient with decompensated thyrotoxico-
sis taking amiodarone was attributed to
suxamethonium; raised plasma tryptase
concentrations conrmed an anaphylactic
reaction (Kounis syndrome) [1A].
Susceptibility factors Genetic The clinical
signicance of genetic variants (K and A) of
the butyrylcholinesterase gene after ECT
has been studied in 13 patients with suspected
prolonged duration of action of suxametho-
nium, 11 of whom had mutations, mostly of
the K variant [2c]. In affected patients the
duration of apnea was 515 minutes, com-
pared with 35 minutes in the published liter-
ature, and there was severe distress during the
recovery phase in two cases. The authors
recommended objective neuromuscular mon-
itoring during the rst episode of ECT.
Side Effects of Drugs, Annual 35
J.K. Aronson (Editor)
ISSN: 0378-6080
http://dx.doi.org/10.1016/B978-0-444-62635-6.00012-7
# 2014 Elsevier B.V. All rights reserved.
Suxamethonium-induced neuromuscular
paralysis has been reported in a patient
with previously undiagnosed butyryl-
cholinesterase deciency [3A].
A 54-year-old-woman due to undergo surgical
drainage of a groin abscess was given intra-
venous propofol 200 mg and suxamethonium
160 mg (1 mg/kg) and 50 minutes later showed
no evidence of spontaneous recovery of respi-
ration. She was successfully weaned from the
ventilator and extubated 11 hours later. Her
butyrylcholinesterase activity was 552 IU/l
(reference range 26736592). Her dibucaine
number was 61% (reference range 8288).
Drugdrug interactions Carbamates Carba-
mates can bind to butyrylcholinesterase and
inhibit the elimination of suxamethonium.
In a severely depressed patient who received
electroconvulsive therapy prolonged apnea
resulted after administration of suxametho-
nium [4A]. The team treating the patient had
not been told that the patient had attempted
suicide by taking an organophosphate based
insecticide.
HMG co-enzyme A inhibitors (statins) The
hypothesis that suxamethonium increases
plasma concentrations of myoglobin, potas-
sium, and creatine kinase more in patients
who take statins than in those who do not
and that suxamethonium-induced post-
operative muscle pain is aggravated in
statin users has been tested in 38 patients
who had taken statins for at least 3 months
and 32 patients who had never used statins
[5C]. After induction of general anesthesia
243
244
with suxamethonium 1.5 mg/kg for intuba-
tion, fasciculations were recorded; blood
samples were obtained before induction
and 5 and 20 minutes and 24 hours after
administration of suxamethonium; the
patients were questioned about myalgia 2
and 24 hours after surgery. Fasciculations
were more intense and at 20 minutes myo-
globin was slightly higher in statin users
than in non-users. However, plasma potas-
sium concentration and creatine kinase
activity were similar in the two groups, as
was muscle pain. These results suggest that
the effect of suxamethonium given to
patients taking statins is small and probably
of limited clinical consequence.
Management of adverse drug reactions
Suxamethonium can cause increased intra-
ocular pressure and may be harmful in
patients with penetrating eye injuries. The
use of dexmedetomidine in preventing the
rise in intraocular pressure associated with
the use of suxamethonium and endotracheal
intubation has been studied in 66 patients,
who underwent non-ophthalmic surgery in a
randomized placebo-controlled comparison
of dexmedetomidine 0.4 and 0.6 micro-
grams/kg given over a period of 10 minutes
before induction [6C]. Dexmedetomidine
caused a fall in intraocular pressure. The pres-
sure then increased after suxamethonium
injection and endotracheal intubation, but
never exceeded the baseline value in those
who had been given dexmedetomidine. The
induction agent used in this study was sodium
thiopental; in a randomized study propofol
lowered intraocular pressure more than thio-
pental, as did supplementary small doses of
each agent before induction [7C].
The effect of remifentanil on
suxamethonium-induced muscle fascicula-
tions has been studied in 40 patients [8c].
Double-blind intravenous pre-treatment with
either remifentanil 1.5 micrograms/kg or intra-
venous saline followed by induction with pro-
pofol and suxamethonium 1 mg/kg showed
that remifentanil pretreatment reduced the
intensity of muscle fasciculations caused by
suxamethonium and reduced the mean maxi-
mum amplitude of muscle action potential.
However, postoperative myalgia, measured
Chapter 12 C. Williams and M. Leuwer
at 24 hours after induction of anesthesia was
not affected.
NON-DEPOLARIZING
NEUROMUSCULAR
BLOCKING AGENTS [SED-15,
2489; SEDA-32, 274; SEDA-33, 301;
SEDA-34, 222]
Rocuronium [SED-15, 3073; SEDA-32,
274; SEDA-33, 301; SEDA-34, 222]
Systematic reviews Because of its fast onset
of action, rocuronium is a potential alterna-
tive to suxamethonium for rapid-sequence
intubation in patients at increased risk of
aspiration. A systematic review of trials com-
paring intubating conditions with either
rocuronium or suxamethonium at 60 seconds
following administration of drug included 37
trials, all of which were randomized con-
trolled trials; 19 were deemed to be ade-
quately concealed, and concealment was
unclear in the other 18 [9M]. The data were
pooled using a random-effects model, and
the results were reported as relative risks with
95% condence intervals (RR 0.88; 95%
CI 0.82, 0.97). The authors concluded that
suxamethonium remains the drug of choice
for rapid sequence induction in emergency
departments, unless there is a contraindica-
tion. However, the ability of sugammadex to
reverse deep neuromuscular blockade of
rocuronium may alter the benet to harm bal-
ance compared with suxamethonium.
Immunologic The occurrence of IgE anti-
bodies in hypersensitivity reactions to rocuro-
nium has been studied in serum samples
from 48 patients with anaphylactic reactions
during anesthesia, using a rocuronium human
serum albumin (rocHSA) conjugate coupled
to a solid phase and a radioallergosorbent
test [10E]. Intradermal skin tests were per-
formed with rocuronium, vecuronium, and
suxamethonium. The effects of patients
serum IgE on histamine release were investi-
gated in vitro in sensitized basophils from
Neuromuscular blocking agents and skeletal muscle relaxants
healthy blood donors. IgE to rocuronium was
found in 23 of 48 serum samples with NMBA
allergy, although only two of these were able
to sensitize basophils to release histamine in
response to rocHSA. IgE responsiveness in
the basophil tests was only observed with con-
jugated rocHSA and not with unconjugated
rocuronium or the other drugs evaluated.
However, unconjugated rocuronium inhib-
ited histamine release induced by rocHSA.
There was a poor correlation between skin-
test reactivity to rocuronium and IgE to
rocuronium. In contrast, there was a striking
correlation between IgE to rocuronium and
skin-test reactivity to suxamethonium.
Management of rocuronium-
induced anaphylaxis with
sugammadex
Following a proposal that sugammadex
might be used to treat rocuronium-induced
anaphylactic reactions [11r], and despite the-
oretical objections [12r], there have been
several reports of its successful use in clinical
practice [13A20A]. The following are illus-
trative cases.
A severe anaphylactic reaction 2 minutes after
an injection of rocuronium 50 mg failed to
respond to 18 minutes of treatment with oxy-
gen, adrenaline, Ringers lactate, and hydroxy-
ethylamidone, and because of persistent
cardiocirculatory failure and bronchospasm a
bolus of 2000 mg (18 mg/kg) of sugammadex
was injected [21A]. There was rapid correction
of arterial hypotension and bronchoconstriction,
starting within a few seconds. Subsequent prick
tests were positive to rocuronium and vecuronium
and negative to propofol, sufentanil, mivacurium,
atracurium, cisatracurium, and suxamethonium.
A 44-year-old woman had an anaphylactic
reaction to rocuronium 80 mg. Her arterial
pressure fell to 50/28 mmHg, with a heart rate
of 130/minute, and an increased ination pres-
sure [22A]. She was given oxygen 100%, a
rapid infusion of 500 ml of crystalloid, and
intravenous adrenaline 0.1 mg. She was then
given sugammadex 1200 mg (12 mg/kg) and
immediately her arterial pressure increased to
180/90 mmHg, the heart rate fell to 95/minute,
and a maculopapular rash appeared. Shortly
afterwards the hypotension and tachycardia
recurred, together with bronchospasm and
Chapter 12 245
desaturation to 85% She was give more adrena-
line and a further dose of sugammadex 400 mg,
bringing the total to 16 mg/kg. Again her arterial
pressure rose to 140/65 mm Hg but this time it sta-
bilized, the heart rate fell to 90/minute, and the
bronchospasm relaxed. She later had positive
screening tests with rocuronium, mivacurium,
and vecuronium, but not suxamethonium, pan-
curonium, atracurium, or cisatracurium.
The second case suggests, not surprisingly,
that it is important to give a dose of sugam-
madex sufcient to reverse the effects of
rocuronium.
Sugammadex has a high binding afnity
and specicity for rocuronium and other
aminosteroid neuromuscular blocking drugs
and sequesters them as an inclusion complex.
The extent to which it competes with IgE anti-
bodies, free and cell bound, for rocuronium
is not known [23R]. Little is known about
how sugammadex interacts with mast cells;
experiments in rats suggest that it may inhibit
mobilization and morphological changes
induced by administration of rocuronium in
pancreatic mast cells [24E]
Objections to the use of sugammadex in
the management of rocuronium-induced
anaphylaxis have appeared. In vitro evi-
dence from experiments in basophil cells
from three patients with rocuronium allergy
and positive skin tests suggested that sugam-
madex could prevent in vitro basophil acti-
vation by rocuronium if applied in advance
but not stop it if applied after initiation of
the reaction [25E].
In a cutaneous model of anaphylaxis in
rocuronium-sensitized patients, sugamma-
dex was not effective in attenuating the type
1 hypersensitivity reaction after it was trig-
gered by rocuronium, although the patients
were anergic to sugammadex-bound rocuro-
nium [26c]. The authors suggested that this
shows that sugammadex can bind an aller-
gen and exclude it from interacting with the
immune system. However, they did not
believe that there is evidence that sugamma-
dex should be used for the treatment of
rocuronium-induced anaphylaxis.
It has been suggested that before sugamma-
dex can be recommended for reversal of
rocuronium-induced anaphylaxis, it should be
discovered whether the allergenic substituted
ammonium groups at each end of the
246
rocuronium molecule in the inclusion complex
with sugammadex are masked within the cavity
or are left exposed, in which case they could
interact with rocuronium IgE antibodies [27R].
A reasonable current strategy in patients
who have anaphylactic reactions would be to
use standard therapy to start with but to use
sugammadex if there is a poor or no response
[28R].
Sugammadex [SEDA-32, 275;
SEDA-33, 301; SEDA-34, 222]
Cardiovascular Hypotension is a rare adverse
reaction to sugammadex [29C] but another
case has been reported in a 33-year old
woman who was given sugammadex 50 mg
after induction of anesthesia; her blood pres-
sure fell to 50/30 mmHg and she recovered
after being given etilephrin and phenyl-
ephrine [30A]. The authors speculated that
pretreatment with propofol and fentanyl
enhances the risk of hypotension due to
sugammadex.
Immunologic Allergic reactions have been
reported in three patients within 4 minutes
of a bolus of sugammadex 100 mg immedi-
ately before extubation; skin testing was
positive in two [31A].
Anaphylactic reactions have also been
reported [32A].
A t 17-year-old man developed a severe aller-
gic reaction to a low dose of intravenous sugam-
madex (200 mg, 3.2 mg/kg) 1 minute after
administration [33A]. He developed intense ery-
thema over the front of the thorax, severe lip and
palpebral edema, and bilateral wheeze. He had a
positive skin prick test to sugammadex.
SKELETAL MUSCLE
RELAXANTS
Systematic reviews The pathophysiology and
epidemiology of spasticity, its pharmacology,
and the efcacy and unwanted effects of dif-
ferent drugs used to treat it have been
Chapter 12 C. Williams and M. Leuwer
reviewed; diazepam, baclofen, and tizanidine
are the most commonly prescribed drugs,
and dantrolene sodium, intrathecal baclofen
and local inltration of botulin toxin are also
used [34r].
Baclofen [SED-15, 408; SEDA-32, 276;
SEDA-33, 302; SEDA-34, 224]
The GABAB receptor is dened pharmaco-
logically by its insensitivity to the GABAA
antagonist bicuculline and its sensitivity to the
GABA analogue baclofen. The G protein-
linked GABAB receptor couples to adenylyl
cyclase, voltage-gated calcium channels, and
inwardly-rectifying potassium channels.
GABAB receptor agonism has been proposed
as a method of treating gastroesophageal
reux disease. There has therefore been a
signicant effort to develop a peripherally-
restricted GABAB receptor agonist that does
not have the nervous system adverse reactions
that are observed with baclofen. The in vivo
and in vitro pharmacology of peripherally-
restricted GABAB receptor agonists and
the preclinical and clinical development of
lesogaberan (3-amino-2-uoropropyl phos-
phinic acid), a potent and predominately
peripherally-restricted GABAB receptor ago-
nist, have been reviewed [35RH].
Preclinical studies have conrmed that
baclofen blocks dopamine release in the
reward-responsive ventral striatum and
medial prefrontal cortex, and consequently
blocks drug motivated behavior [36E].
However, its mechanism of action in
humans is unknown. Continuous arterial
spin-labeled (CASL) perfusion fMRI has
been used to examine the effects of baclo-
fen on blood ow in the human brain in
21 subjects (all smokers, 12 women), who
were randomized to either baclofen
80 mg/day (n 10) or placebo (n 11).
A 5-minute quantitative perfusion fMRI
resting baseline scan was acquired before
dosing and after 21 days. Baclofen reduced
cerebral blood ow in the ventral striatum
and medial prefrontal cortex and increased
it in the lateral prefrontal cortex, which is
involved in suppressing previously rewarded
Neuromuscular blocking agents and skeletal muscle relaxants
behavior. Cerebral blood ow in the insula
was blunted by baclofen. There were no dif-
ferences between the groups in adverse reac-
tions or cigarettes smoked per day. The
authors concluded that baclofens modulatory
actions on regions involved in motivated
behavior in humans are reected in the resting
state and provide insights into the mechanism
underlying its ability to block drug-motivated
behavior and its putative effectiveness as an
anti-craving or anti-relapse agent in humans.
Observational studies In a retrospective
analysis of 25 wheelchair-assisted adults with
cerebral palsy who were receiving intrathecal
baclofen there were complications in eight
and transient interruption of the treatment
or surgical removal of the intrathecal pump
was necessary in four [37c].
In a prospective single-arm open 7-week
study in 20 smokers taking baclofen and
bupropion SR, and having brief counselling
for smoking cessation, there were no serious
adverse reactions [38c]. The most commonly
reported adverse reactions were fatigue
(n 8), disturbance in attention (n 8), dry
mouth (n 7), and insomnia (n 7). With
combination therapy there was one dropout
not attributed to the medication and three
subjects required dosage reductions because
of adverse reactions.
In a retrospective audit of baclofen in the
management of alcohol dependency in
21 patients with psychiatric co-morbidity
adverse reactions that occurred at low doses
included tiredness and sedation; one patient
taking 120 mg/day developed severe revers-
ible back pain, and one taking up to 275 mg/
day developed somnolence, dizziness, and
incontinence [39c]. The use of baclofen in the
treatment of alcohol dependence has been
reviewed [40R].
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled study
of baclofen 30 mg/day over 12 weeks in 80
subjects with alcohol dependence, only two
individuals withdrew because of adverse
events [41c].
In a double-blind, placebo-controlled trial
of a topical poloxamer-based organogel con-
taining baclofen 10 mg, amitriptyline 40 mg,
Chapter 12 247
and ketamine 20 mg for chemotherapy-
induced peripheral neuropathy, there were
no systemic adverse reactions [42c].
Both baclofen and clonidine can improve
the response of symptoms to spinal cord
stimulation. In a double-blind, randomized,
placebo-controlled study in 10 patients with
neuropathic pain and insufcient pain relief
from spinal cord stimulation alone [43c], cloni-
dine, baclofen, and saline were given intra-
thecally by bolus injections in combination
with spinal cord stimulation. In the two
patients with clonidine pumps combined ther-
apy produced pain reductions of 45% and
55% over 15 months. The corresponding
effects with baclofen were 82% and 32% after
7 months.
Metabolism In 10 patients aged 2551 years
and body mass index 3141 kg/m2, who
were given baclofen 15 mg/day increasing
to 30 mg/day in 10 days, and continuing
for 12 weeks there were small but statisti-
cally signicant reductions in both body
weight and waist circumference [44c]. There
were no signicant changes in blood pres-
sure or glucose and lipid metabolism.
Serum leptin concentrations, which possibly
reect the amount of fat stores, were also
signicantly reduced.
Drug withdrawal Baclofen withdrawal is
associated with complications such as respi-
ratory failure, refractory seizures, delirium,
and labile blood pressure [45A]. The various
treatment options include benzodiazepines,
propofol, skeletal muscle relaxants, and
tizanidine. Delirium, extrapyramidal symp-
toms, and autonomic dysfunction occurred
in a 59-year-old man after abrupt with-
drawal of baclofen and tizanidine and
resolved within 24 hours of reintroduction
of baclofen [46A].
Susceptibility factors Renal disease
Baclofen-induced encephalopathy has been
reported in a patient with pre-end-stage
renal disease [47A]. A literature review of
21 case reports involving 41 patients (23
men) showed that about two-thirds were
elderly and two-thirds were on dialysis.
Manifestations of baclofen toxicity usually
started 23 days after the start of treatment,
248
although periods as long as 16 weeks have
been reported. The daily dose of baclofen
was 560 (mean 20) mg. Hemodialysis was
the most common treatment used for drug
elimination. Recovery time ranged from
2 hours in patients who received hemodial-
ysis to 8 days with conservative treatment.
Botulinum toxins [SED-15, 551;
SEDA-32, 276; SEDA-33, 304;
SEDA-34, 226]
Uses The uses of botulinum toxin in pain
management [48R], upper limb hypertonicity
in adults [49R], facial rejuvenation [50R],
neurogenic detrusor overactivity [51R], and
cervical dystonia [52R] have been reviewed.
Observational studies In a 24-month, ran-
domized, single-blind trial of botulinum
toxin A in 10 children aged 314 years
with CharcotMarieTooth disease type 1A
(OMIM 118220) one leg was treated with
intramuscular botulinum toxin A at 6-month
intervals in the tibialis posterior and peroneus
longus muscles; this did not affect the progres-
sion of pes cavus [53c].
In 133 patients with adductor spasmodic
dysphonia who were treated with laryngeal
injections of botulinum toxin 51% had
some breathlessness, and dysphagia to liq-
uids was reported after 14% of treatments
[54c]. The authors considered that an indi-
vidualized dosage regimen helps minimize
adverse reactions and maximize function
and quality of life.
In a retrospective review of 22 children
with Hirschsprungs disease treated with
intrasphincteric injections of botulinum
toxin there were no short-term or long-
term complications [55r].
Sensory systems In a retrospective review
of 46 patients treated with injections of bot-
ulinum toxin in the palpebral lobe of the
lacrimal gland for symptomatic epiphora
due to lacrimal obstruction or gustatory
tearing, there was temporary ptosis in
11% of the patients [56A].
Chapter 12 C. Williams and M. Leuwer
Cyclobenzaprine [SED-15, 1023;
SEDA-33, 305; SEDA-34, 227]
Placebo controlled studies In a double-
blind, randomized, placebo-controlled study
of low-dose bedtime cyclobenzaprine 14 mg
in patients with bromyalgia restorative sleep
was improved [57c].
Drug formulations The pharmacokinetic
prole of an extended-release formulation of
cyclobenzaprine, which delivers a sustained
plasma cyclobenzaprine concentration over
24 hours, allowing once-daily dosing, has
been compared with that of immediate-
release cyclobenzaprine 10 mg tds [58c]. The
extended-release formulation produced a
single daily peak in cyclobenzaprine concen-
tration compared with three peaks for the
immediate-release formulation, but the
systemic exposures were comparable. Sys-
temic exposure to cyclobenzaprine in the
extended-release formulation was increased
by food and in elderly subjects. Steady-state
was achieved by day 7.
Dantrolene sodium [SED-15, 1048;
SEDA-33, 305; SEDA-34, 227]
The pharmacology and pharmacokinetics
of dantrolene have been reviewed [59R].
Observational studies Complications asso-
ciated with the use of dantrolene in malig-
nant hyperthermia have been reported in
an analysis of data submitted to the North
American Malignant Hyperthermia Regis-
try [60C]. Reports of adverse metabolic
and musculoskeletal reactions to anesthesia
(AMRA) were analysed for differences
between subjects with and without compli-
cations attributed to dantrolene. In the full
dataset of 368 subjects, the most frequent
complications associated with dantrolene
were muscle weakness (22%), phlebitis
(9%), gastrointestinal upsets (4.1%), and
respiratory failure (3.8%). There was a
29% increase in the risk of any complica-
tion when the total dose of dantrolene was
doubled, a 144% increase in risk when uid
Neuromuscular blocking agents and skeletal muscle relaxants
administration was part of the treatment,
an 83% reduction in risk in patients under-
going neurosurgery, and a 74% reduction
in risk in patients undergoing oral surgery.
In a subset of 349 patients, omitting those
with complications that were judged likely
to have been due to pre-existing disease
or the event of malignant hyperthermia,
the most frequent complications associated
with dantrolene were muscle weakness
(56%), phlebitis (9.2%), and gastrointestinal
upsets (4.3%); there was a 25% increase in
risk of any complication when the total
dose of dantrolene was doubled, a 572%
increase in risk in patients undergoing
obstetric or gynecological surgery, and a
56% reduction in risk if furosemide was
given; there was no effect of uid adminis-
tration or other types of surgery. The
authors concluded that complications after
dantrolene are common but rarely life-
threatening. Unidentied factors in the sur-
gical environment are associated with
changes in the risks of complications. Fluid
administration, as part of the treatment of
malignant hyperthermia, has an important
association with the risk of complications
after dantrolene administration and should
be monitored closely.
Respiratory High-dose oral dantrolene can
cause severe respiratory insufciency and
may present difculties in the differential
diagnosis of respiratory failure in patients
with high cervical spinal injuries [61A].
A 60-year-old man in the rehabilitation phase
after cervical spine injury developed general-
ized weakness and deteriorating respiratory
function, requiring ventilation. He had bilat-
eral basal lung collapse and a raised dia-
phragm and was taking high-dose oral
dantrolene. Withdrawal of dantrolene resulted
in a dramatic recovery of respiratory function
within 2 days.
Tetrabenazine [SEDA-32, 277;
SEDA-33, 305; SEDA-34, 227]
The use of tetrabenazine in chorea and
other hyperkinetic movement disorders,
Chapter 12 249
including tardive dyskinesia and tics associ-
ated with Tourettes syndrome, has been
reviewed [62R]. Dose-limiting adverse
events consist mainly of sedation, parkin-
sonism, akathisia, and depression, and usu-
ally rapidly abate on dosage reduction.
Placebo-controlled studies In a 12-week,
double-blind, placebo-controlled trial in
patients with Huntingtons disease, oral
tetrabenazine (up to 100 mg/day; n 54)
was signicantly more efcacious than
placebo (n 30) in improving chorea
[63C]. Treatment-emergent adverse events
in those who took tetrabenazine mainly
occurred during the dose-titration phase
and most of the events were mild to moder-
ate and were manageable with dosage
adjustments or drug withdrawal.
Systematic reviews In a systematic review
of three small prospective studies, eight
other trials, one case series, and eight case
reports of the use of tetrabenazine in the
treatment of tardive dyskinesia, limiting
adverse reactions included depression,
parkinsonism, and somnolence [64M].
Tizanidine [SED-15, 3436; SEDA-32,
278; SEDA-33, 307; SEDA-34, 227]
Cardiovascular In patch-clamp experiments
using HERG- or KCNQ1+KCNE1-
transfected cells, tizanidine 0.1100 mmol/l
inhibited the rapid IKr component of the
delayed rectier potassium current with an
IC50 above 100 mmol/l, prolonged repolari-
zation in perfused guinea-pig hearts at a
concentration of 1 mmol/l, and prolonged
the QTc interval in intact guinea-pigs
[65E]. Prolongation of the QT interval by
tizanidine in humans [66A] may therefore
be due to inhibition of IKr channels.
Drugdrug interactions Lisinopril Hypo-
tension and bradycardia associated with
concomitant tizanidine and lisinopril ther-
apy has been reported [67A]. Tizanidine is
a centrally acting a2 agonist and can cause
250
bradycardia and hypotension by reducing
sympathetic outow.
An 85-year-old man developed profound
weakness, a blood pressure of 60/32 mmHg,
and a heart rate of 37/minute after taking
three doses of tizanidine for 2 days in addition
to chlorpromazine, citalopram, nasteride,
lidocaine patches, lisinopril, metformin, prami-
pexole, omeprazole, simvastatin, theophylline,
diclofenac topical gel, hydrocodone + paracet-
amol, and ondansetron. His serum creatinine
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