Central and Peripheral Nervous System
A test is available to detect the MDR-1 genetic deletion that leads to P-glycoprotein deficiencies in collies and related
breeds. This deficiency has been linked to CNS toxicities caused by ivermectin and loperamide as well as (potentially) many
other drugs. Owners of potentially affected dogs should be tested not only to be aware of possible CNS drug toxicities but
also to try to minimize breeding (http://www.vetmed.wsu.edu/announcements/ivermectin/ownerinfo.asp). The sample is a buccal mucosal swab and the cost is approximately $65.
Zonisamide
(Zonegran®; 8 to 12 mg/kg divided twice to three times daily, po) A sulfonamide anticonvulsant approved for use to treat epilepsy
in humans. Zonisamide appears to inhibit neuronal voltage-dependent sodium and T-type calcium channels. Additionally, ZNS
modulates the dopaminergic system and accelerates the release of γ-amino butyric acid (GABA) from the hippocampus. Like phenytoin,
ZNS is less likely to affect normal neuronal activity. A potential advantage of ZNS is free radical scavenging which protects
against the destructive nature of radicals, especially in neuronal membranes. As with most sulfonamides, elimination includes
both a hepatic (induced by Phenobarbital) and renal elimination. Its elimination half-life in dogs is 16 hours; accumulation
in RBC and slow release allows twice daily therapy is reasonable. It can be monitored (see Auburn University), although not
as easily as bromide or Phenobarbital; the therapeutic range recommended in humans is 10 to 40 mcg/ml. It has been used safely
in combination with Phenobarbital for control of refractory seizures in dogs. As with any sulfonamide, at high concentrations
(including those necessary to control seizures in some dogs), thyroid hormone synthesis will be impaired within several weeks
of start of therapy. Function will return to normal but only when therapy is d/c. The protocol for thyroid hormone replacement,
which is probably indicated once hypothyroidism has been documented, has not been well established. Zonisamide has been studied
in normal cats. A single dose of 10 mg/cat resulted in a Cmax of 13 mcg/ml at 4 hr; the elimination half-life of 33 hrs. The
drug was well tolerated. 10 mg/cat (or 2 mg/kg) once daily is a reasonable beginning dose in cats. Levetiracetam (Keppra®) is an anticonvulsant approved for use in humans. Its mechanism of action is not known. It is renally excreted (60%)
and to a lesser degree, metabolized by the liver. However, it has a short half-life (as short as 2 hrs in some dogs and cats)
that necessitates 8 or less hour dosing. However, it is extremely well tolerated in dogs and has been safely used in dogs
and cats as well as an add-on anticonvulsant at 20 mg/kg every 8 hrs po. Its short half-life may indicate CRI for acute management
of seizures. Use for treatment of seizures associated with PSS should be considered.
Control of Pain
(See NSAID, this same proceedings) Tramadol has become a popular analgesic; its mechanism of action results in multimodal
pain control (mu receptor agonist and reuptake inhibitor of serotonin and others). However, the dose necessary to maintain
analgesia in the dog is up to 5 mg/kg every 8 hr. Avoid other drugs which inhibit the uptake of serotonin and taper the dose
to avoid signs of withdrawal if treating longer than several days. Note that tramadol is available in combination with acetaminophen
which is great for dogs but must be avoided in cats (whereas tramadol itself can be used in cats). Amantadine is an N-methylD-aspartate
receptor antagonist (as is ketamine, and to some degree, dextromethorphan) that can be used (3 mg/kp po once daily) in combination
with a wide variety of other oral analgesics. Although use in dogs has not yet been reported, pregabalin (Lyrica®) has been
approved for use in humans to treat chronic (neuropathic) pain. A schedule V drug, its mechanism is similar to gabapentin
and, like gabapentin may also have anticonvulsant activity. Hydromorphone (0.1 mg/kg) was studied SC in cats and compared
to previous reports of IV and IM administration (Robertson 200x FMS). The authors found the drug to cause more side effects,
a longer onset to effect and a shorter duration of antinociception, and thus generally unacceptable. Buprenorphine was studied
in cats and a dose of 0.04 mg/kg was found to provide more analgesia and longer duration of action with no increase in side
effects compared to 0.01 and 0.02 mg/kg/. Meloxicam was demonstrated to be safe (both GI and renal) in cats when administered
at 0.03 mg/kg once daily for 5 to 6 months. However, an analysis of adverse events reported in cats suggests that cats are
more susceptible to renal side effects, and, adverse events reported for meloxicam are more likely to involve the kidney,
compared to carprofen.
