DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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Extrafusal
muscle fibers
Upper
motor
neuron
Ia afferent
Inhibitory
interneuron
SECTION II
NEUROPHARMACOLOGY
Motor nerve efferent
Alpha motor
neuron
Figure 22–8. Monosynaptic muscle stretch reflex with descending control via inhibitory interneurons. Primary Ia afferents (green)
from muscle spindles, activated when the muscle is stretched rapidly, synapse directly on motor neurons (blue) going to the stretched
muscle, causing it to contract and resist the movement. Pyramidal upper motor neurons (aqua) from the cerebral cortex suppress
spinal reflexes and the lower motor neurons indirectly by activating the spinal cord inhibitory interneuron pools (red). When the
pyramidal influences are removed, the reflexes are released from inhibition and become more active, leading to hyperreflexia and spasticity.
Baclofen acts to restore the lost inhibition by stimulating postsynaptic GABA receptors. Tizanidine acts presynaptically to stimulate
GABA release from spinal cord inhibitory interneuron.
of 5-10 mg/day are recommended, which can be increased to as
much as 200 mg/day if necessary. If weakness occurs, the dose
should be lowered. Alternatively, baclofen can be delivered directly
into the space around the spinal cord using a surgically implanted
pump and an intrathecal catheter. This approach minimizes the
adverse effects of the drug, especially sedation, but it carries the risk
of potentially life-threatening CNS depression. Moreover, abrupt
withdrawal of intrathecal baclofen can cause rebound spasticity,
rhabdomyolitis, multi-organ failure, and even death. Intrathecal
baclofen should be used only by physicians trained in delivering
chronic intrathecal therapy.
Tizanidine (ZANAFLEX) is an agonist of α 2
adrenergic receptors
in the CNS. It reduces muscle spasticity and is assumed to act
by increasing presynaptic inhibition of motor neurons. Tizanidine is
primarily used in the treatment of spasticity in multiple sclerosis or
after stroke, but it also may be effective in patients with ALS.
Treatment should be initiated at a low dose of 2-4 mg at bedtime and
titrated upward gradually. Drowsiness, asthenia, and dizziness may
limit the dose that can be administered. Benzodiazepines (Chapter 17)
such as clonazepam (KLONIPIN) are effective antispasticity agents,
but they may contribute to respiratory depression in patients with
advanced ALS. Dantrolene (DANTRIUM) also is approved in the U.S.
for the treatment of muscle spasm. In contrast to the other agents
discussed, dantrolene acts directly on skeletal muscle fibers, impairing
Ca 2+ release from the sarcoplasmic reticulum. Because it can
exacerbate muscular weakness, it is not used in ALS but is effective
in treating spasticity associated with stroke or spinal cord injury and
in treating malignant hyperthermia (Chapter 8). Dantrolene may
cause hepatotoxicity, so it is important to monitor liver associated
enzymes before and during therapy with the drug.
Clinical Summary. ALS is a progressive degenerative
disease of spinal motor neurons leading to weakness and
eventually paralysis. It is the most rapidly progressive
of the common neurodegenerative disorders and often
is fatal within 2-3 years of onset. The only therapy established
to alter the course of ALS is the drug riluzole,
which acts through inhibition of glutamate release as
well as other mechanisms. The effect of this treatment is
modest, prolonging survival by a few months.
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