Medication Summary
Medications used in the treatment of Schwartz-Jampel syndrome (SJS) include the following:
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Anticonvulsants - Phenytoin, carbamazepine
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Antiarrhythmic agents - Mexiletine, procainamide, quinidine
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Antimalarials - Quinine
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Neuromuscular blocking agents - Botulinum toxin
Some anticonvulsants appear to reduce excess muscle cell depolarization, while the antiarrhythmics may reduce or regulate the firing rate of skeletal muscle cells, much as they do in cardiac cells. BOTOX® blocks neuromuscular transmission through a multistep process.
The antimalarial drug quinine appears to increase the refractory period for muscle discharge, exerts a curarelike action on the motor endplate, and alters the intracellular calcium distribution in a way that makes the muscle less excitable.
Anticonvulsants, Other
Class Summary
Although the primary use of anticonvulsants is to decrease excessive neuronal discharges seen in epileptic seizures, some of them appear to also reduce excess muscle cell depolarization. The fundamental mechanism in both cases may be the anticonvulsants' ability to reduce the activity of ion channels in the cell membrane. Anticonvulsants are used widely in central pain syndromes. Their use to reduce muscle spasm and cramps is largely empirical and they are not approved by the US Food and Drug Administration (FDA) for this purpose.
Phenytoin (Dilantin, Phenytek)
As an anticonvulsant, phenytoin reduces the rate at which neurons fire by stabilizing the inactive form of neuronal sodium channels and by blocking L-type neuronal calcium channels. It may affect similar channels in muscle to reduce muscle contraction.
Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)
Carbamazepine is a chemical analogue of tricyclic antidepressants (TCAs) and was first developed for depression. It was found to be useful for the relief of pain in depression, and it is used for trigeminal neuralgia. Because trigeminal neuralgia is caused by the rapid firing of nerves, carbamazepine was next tried for rapid neuronal firing seen in seizures and proved very effective. Like phenytoin, carbamazepine probably works by inhibiting neuronal sodium channels and may have direct effects on neurotransmitter systems.
Carbamazepine may inhibit sodium channels or other ion channels in muscle. The adult dose is similar to that used in pain syndromes.
Cardiovascular, Other
Class Summary
Cardiac antiarrhythmics reduce or regulate the firing rate of cardiac cells by a number of mechanisms, the most precisely understood of which are effects on ion channels. That a similar effect may occur in the skeletal muscle should not be surprising. Of the antiarrhythmics, mexiletine is probably the most commonly used for this condition. Procainamide and quinidine also have been listed here for completeness and because they are used by many neurologists to treat muscle stiffness and muscle spasm.
Quinine also can be useful occasionally. Quinine should be classified as an antiarrhythmic because of its similarity to quinidine. However, the most recent classifications list it under "antimalarials." It is therefore discussed under that category.
Mexiletine
As a class IB antiarrhythmic, mexiletine preferentially binds to open or inactivated calcium channels with a rapid association rate. Binding to open channels effectively shortens the action potential (particularly the third phase), and binding to inactivated channels maintains the inactivated (refractory) state. This slows the firing of cells. Presumably, a similar effect may occur in skeletal muscle.
Procainamide
As a class IA antiarrhythmic, procainamide blocks open or inactivated sodium channels with a slower association rate than class IB drugs (eg, mexiletine). This slows the depolarization phase (phase 0) of the action potential and prolongs the overall action potential, thus decreasing the firing rate. Presumably, a similar effect may occur in skeletal muscle.
Procainamide has been listed here because it has been included in discussions of muscle stiffness and muscle spasm. It has never been prescribed by authors for this condition. If it is used for muscle stiffness, then the cardiac dosing regimen should be used, starting with the short-acting form. This is replaced with an equivalent amount of the long-acting form once the medication has proven effective and is well tolerated.
Quinidine
As a class IA antiarrhythmic, quinidine blocks open or inactivated sodium channels with a slower association rate than class IB drugs (eg, mexiletine). This slows the depolarization phase (phase 0) of the action potential and prolongs the overall action potential, thus decreasing the firing rate. Presumably, a similar effect may occur in skeletal muscle.
For SJS, only oral administration of quinidine is known to be used. The use of any other mode of administration is not advised.
Antimalarials
Class Summary
The only drug in this category that is generally used to relieve muscle stiffness is quinine. Quinine appears to increase the refractory period for muscle discharge, exerts a curarelike action on the motor endplate, and alters the intracellular calcium distribution in a way that makes the muscle less excitable.
Quinine (Qualaquin)
Quinine is actually an optical isomer of quinidine; like quinidine, it belongs to the cinchona alkaloid group of drugs. Quinine has effects on the heart similar to those of quinidine and, thus, is subject to similar cautions. Quinine is available in 260-, 300-, and 325-mg capsules. Any of these can be given as a bedtime dose for nocturnal muscle stiffness.
Neuromuscular Blockers, Botulinum Toxins
Class Summary
Agents in this class cause presynaptic paralysis of the myoneural junction and reduce abnormal contractions. BOTOX® is indicated for blepharospasms associated with SJS.
OnabotulinumtoxinA (BOTOX)
This is one of several toxins produced by Clostridium botulinum. It blocks neuromuscular transmission through a 3-step process.
Step 1
BOTOX® binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals.
Step 2
BOTOX® is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal.
Step 3
BOTOX® blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. The toxin does not affect the synthesis or storage of acetylcholine or the conduction of electrical signals along the nerve fiber.
Typically, a 24- to 72-hour delay occurs between the administration of toxin and the onset of clinical effects, which terminate in 2-6 months. This purified neurotoxin complex is a vacuum-dried form of purified botulinum toxin A, which contains 5 ng of neurotoxin complex protein per 100 U. It treats excessive, abnormal contractions associated with blepharospasm.
BOTOX® must be reconstituted with 2 mL of 0.9% sodium chloride diluent. With this solution, each 0.1mL results in a 5-U dose. The patient should receive 5-10 injections per visit. BOTOX® must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative, using the manufacturer's instructions, to provide an injection volume of 0.1 mL. It must be used within 4 hours of storage in a refrigerator at 2-8°C. Preconstituted dry powder must be stored in a freezer at below 5°C.
Reexamine patients 7-14 days after the initial dose of BOTOX® to assess for a response. Increase the dose 2-fold over the previous one for patients experiencing incomplete paralysis of the target muscle. Do not exceed 25 U when giving BOTOX® as single injection or 200 U as a cumulative dose in a 30-day period.
