Page 501 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 27 Skeletal Muscle Relaxants 487

are no reports of baclofen directly causing human fetal malforma- agonist and has active metabolites, including GABA itself.
tions, animal studies using high doses show that it causes impaired Glycine is another inhibitory amino acid neurotransmitter
sternal ossification and omphalocele. (see Chapter 21) that appears to possess pharmacologic activity
Oral baclofen has been studied in many other medical condi- when given orally and readily passes the blood-brain barrier.
tions, including patients with intractable low back pain, stiff per- Idrocilamide and riluzole are newer drugs for the treatment of
son syndrome, trigeminal neuralgia, cluster headache, intractable amyotrophic lateral sclerosis (ALS) that appear to have spasm-
hiccups, tic disorder, gastroesophageal reflux disease, and cravings reducing effects, possibly through inhibition of glutamatergic
for alcohol, nicotine, and cocaine (see Chapter 32). transmission in the CNS.

TIZANIDINE BOTULINUM TOXIN

As noted in Chapter 11, α -adrenoceptor agonists such as cloni- The therapeutic use of botulinum toxin (BoNT) for ophthalmic
2
dine and other imidazoline compounds have a variety of effects purposes and for local muscle spasm was mentioned in Chapter 6.
on the CNS that are not fully understood. Among these effects This neurotoxin produces chemodenervation and local paralysis
is the ability to reduce muscle spasm. Tizanidine is a congener of when injected into a muscle. Seven immunologically distinct tox-
clonidine that has been studied for its spasmolytic actions. Tiza- ins share homologous subunits. The single-chain polypeptide
nidine has significant α -agonist effects, but it reduces spasticity BoNT has little activity until it is cleaved into a heavy chain
2
in experimental models at doses that cause fewer cardiovascu- (100 kDa) and a light chain (50 kDa). The light chain, a zinc-
lar effects than clonidine or dexmedetomidine. Tizanidine has dependent protease, prevents release of acetylcholine by interfer-
*
approximately one tenth to one fifteenth of the blood pressure- ing with vesicle fusion, through proteolytically cleaving SNAP -25
lowering effects of clonidine. Neurophysiologic studies in animals (BoNT-A, BoNT-E) or synaptobrevin-2 (BoNT-B, BoNT-D,
and humans suggest that tizanidine reinforces both presynaptic BoNT-F). Local facial injections of botulinum toxin are widely
and postsynaptic inhibition in the cord. It also inhibits nocicep- used for the short-term treatment (1–3 months per treatment) of
tive transmission in the spinal dorsal horn. Tizanidine’s actions are wrinkles associated with aging around the eyes and mouth. Local
believed to be mediated via restoration of inhibitory suppression injection of botulinum toxin has also become a useful treatment
of the group II spinal interneurons without inducing any changes for generalized spastic disorders (eg, cerebral palsy). Most clinical
in intrinsic muscle properties. studies to date have involved administration in one or two limbs,
Clinical trials with oral tizanidine report efficacy in relieving and the benefits appear to persist for weeks to several months after
muscle spasm comparable to diazepam, baclofen, and dantrolene. a single treatment. BoNT has virtually replaced anticholinergic
Tizanidine causes markedly less muscle weakness but produces medications used in the treatment of dystonia. More recently,
a different spectrum of adverse effects, including drowsiness, FDA approval was granted for treatment of incontinence due to
hypotension, dizziness, dry mouth, asthenia, and hepatotoxicity. overactive bladder and for chronic migraine. Most studies have
The drowsiness can be managed by taking the drug at night. Tiza- used several formulations of type A BoNT, but type B is also
nidine displays linear pharmacokinetics, and dosage requirements available.
vary considerably among patients. Treatment is initiated at 2 mg Adverse effects include respiratory tract infections, muscle
every 6–8 hours and can be titrated up to a maximum of 36 mg/d. weakness, urinary incontinence, falls, fever, and pain. While
Dosage must be adjusted in patients with hepatic or renal impair- immunogenicity is currently of much less concern than in the
ment. Tizanidine is involved in drug-drug interactions; plasma past, experts still recommend that injections not be administered
levels increase in response to CYP1A2 inhibition. Conversely, more frequently than every 3 months. Studies to determine safety
tizanidine induces CYP11A1 activity, which is responsible for of more frequent administration are underway. Besides occasional
converting cholesterol to pregnenolone. In addition to its effec- complications, a major limitation of BoNT treatment is its high
tiveness in spastic conditions, tizanidine also appears to be effec- cost. Future research developing other serotypes such as BoNT-
tive for management of chronic migraine. C and BoNT-F is expected to result in the development of new
agents that can provide chemodenervation with long-term ben-
efits and at lower cost.
OTHER CENTRALLY ACTING
SPASMOLYTIC DRUGS DANTROLENE

Gabapentin is an antiepileptic drug (see Chapter 24) that has Dantrolene is a hydantoin derivative related to phenytoin that has
shown considerable promise as a spasmolytic agent in several a unique mechanism of spasmolytic activity. In contrast to the
studies involving patients with multiple sclerosis. Pregabalin is a centrally acting drugs, dantrolene reduces skeletal muscle strength
newer analog of gabapentin that may also prove useful in reliev- by interfering with excitation-contraction coupling in the muscle
ing painful disorders that involve a muscle spasm component. fibers. The normal contractile response involves release of calcium
Progabide and glycine have also been found in preliminary
studies to reduce spasticity. Progabide is a GABA and GABA * SNAP, Soluble N-ethylmaleimide sensitive factor Attachment Protein.
B
A