What's new in drug therapy for small animals? (Proceedings)
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.