Tizanidine, a clonidine derivative, is a centrally acting skeletal muscle relaxant with alpha-2 adrenergic activity. It reduces muscle tone associated with spasticity, but has no effect on muscle force, tendon reflexes or Babinski sign. This drug is indicated for the acute and intermittent management of increased muscle tone associated with spasticity. The reduction in muscle tone usually occurs at one to two hours after dosing and dissipates within three to six hours post-administration. Use should be individualized to correspond to activities and times when relief of spasticity is most important and titrated to avoid intolerance. It has been primarily studied in the treatment of spasticity associated with a variety of causes. Tizanidine undergoes extensive first pass metabolism, resulting in an oral bioavailability of only 40%. Plasma protein binding is low (30%). The elimination half-life on tizanidine is approximately 2.5 hours, while the terminal half-life based on total radioactivity of the compound and metabolites is 22 hours. The clearance of tizanidine is reduced by more than 50% in elderly patients with renal insufficiency (CrCl < 25 ml/min) compared to healthy elderly subjects.   

    In patients with multiple sclerosis, comparative studies between tizanidine (12 to 24 mg/day) and baclofen (15 to 60 mg/day) demonstrated no difference in mobility improvement, spasticity, spasms, and overall efficacy in those completing the study. In comparative trials of tizanidine, baclofen and diazepam, muscle tone was decreased to a similar extent in patients with spasticity from multiple causes.

    Tizanidine is contraindicated in patients taking other alpha-2 adrenergic agonists (e.g., clonidine). Tizanidine can produce hypotension, and has caused 20% reduction in either diastolic or systolic blood pressure in single dose studies. Reductions were observed within one hour, peaks at two to three hours and may be associated with bradycardia, orthostatic hypotension, lightheadedness and syncope. These effects appear to be dose related and minimized by dose titration. This drug should be used with caution in patient receiving concurrent antihypertensive therapy. The most common adverse reactions include drowsiness and dry mouth. Tolerance to sedation does not occur.

    A single oral dose of 8 mg reduces muscle tone in patients with spasticity for several hours. Treatment should begin with a single oral dose of 4 mg and increased in 2 to 4 mg increments as needed. Doses can be repeated at 6 to 8 hour intervals, although the manufacturer recommends a maximum of three doses in 24 hours. The total daily dose should not exceed 36 mg daily. Lower initial doses are recommended in patients with renal insufficiency and in women taking oral contraceptives.

    Tiagabine is a gamma aminobutyric acid (GABA) uptake inhibitor, indicated for the adjunctive treatment of partial epilepsy in adults and children older than 12 years of age. The exact mechanism of action of tiagabine is unknown but is believed to be related to its ability to enhance GABA activity, the major neurotransmitter in the CNS, via post-synaptic neuronal uptake. Absorption of tiagabine is rapid, with peak plasma concentrations occurring approximately 45 minutes after oral dosing. It has an absolute bioavailability of about 90%. Tiagabine is 96% bound to plasma proteins and is metabolized by Cytochrome P450 isoenzyme 3A. This drug is not affected by renal impairment, but clearance is reduced by 60% in patients with hepatic failure.

    In comparative trials, tiagabine was more effective than placebo as add-on therapy in a total of 951 patients with refractory partial seizures. It was also more effective than placebo in decreasing the frequency of complex partial seizures and secondary generalized seizures. Efficacy with tiagabine appears to be dose related with patients receiving higher daily doses have a greater response rate. Studies with monotherapy are limited and monotherapy with this drug is not recommended at this time.

    Tiagabine should be given with caution when coadministered with valproate which significantly decreased tiagabine protein binding and increased free tiagabine concentrations by 40%. Dosage adjustments may be required when tiagabine is given concomitantly with carbamazepine, phenytoin and phenobarbital which increase clearance by 60%. Tiagabine did not affect theophylline, warfarin, digoxin or oral contraceptives. The most common adverse reactions associated with tiagabine are dizziness, asthenia, somnolence, nervousness, nausea, and CNS effects including impaired coordination, speech or language problems.

T    he recommended daily dose for adolescents 12 to 18 years of age is 4 mg once daily initially then increased by 4 mg at beginning of week 2. Tiagabine doses can then be increased weekly by 4 to 8 mg until clinical efficacy is achieved. The total daily doses should be divided into two to four times daily. The maximum recommended dose is 32 mg daily. In adults, the initial recommended dose is 4 mg daily and may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or until a maximum daily dosage of 56 mg is obtained in two to four divided doses. Patients with hepatic dysfunction may require reduced initial and maintenance doses and/or longer intervals between dosing.

    The diclofenac sodium/misoprostol product is indicated for the treatment of signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID induced gastric ulcers and duodenal ulcers and their complications. Diclofenac is a phenylacetic acid derivative NDAID used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and some acute pain conditions. Misoprostol is a prostaglandin E1 analog used to treat and prevent NSAID induced gastric and duodenal ulcers. These tablets contain diclofenac in an enteric coated core surrounded by misoprostol in an outer mantle.

    Diclofenac is completely absorbed following oral administration, reaching a peak level within 1 to 4 hours. First pass metabolism results in 50% bioavailability of the absorbed dose. The mean terminal half-life is 1to 2 hours. Diclofenac is more than 99% plasma protein bound. Peak concentrations of misoprostol acid, the active moiety, are achieved within 12 minutes.

    Several studies have demonstrated comparable efficacy between diclofenac sodium 50 mg/ misoprostol 200 mcg and diclofenac 50 mg alone. There were no differences in joint tenderness, pain, duration of morning stiffness or functional capacity between the two study groups. Among 290 patients with rheumatoid arthritis, gastroduodenal ulcers were discovered in approximately 4.4% of patients taking the combination product as opposed to 11.1% of the patients taking diclofenac alone. In addition, the incidence of erosive lesions or ulcers and the incidence of duodenal ulcers was significantly lower in the combination product. The incidence of gastric ulcers did not differ between the two groups.

    Diclofenac/misoprostol is contraindicated in patients with asthma or allergic urticaria with aspirin or other NSAIDS, and in pregnant women. Misoprostol is pregnancy category X. This drug should only be prescribed if: (1) a negative serum pregnancy test is obtained within 2 weeks prior to initiation of therapy, (2) the patient is able to comply with contraceptive measures, (3) the patient has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger of childbearing potential should the drug be taken by mistake and (4) will begin combination product only on the second or third day of the next normal menstrual period.

    Elevations in transaminase levels have occurred in about 15% of diclofenac treated patients. The most common side effects of diclofenac/misoprostol include abdominal pain, diarrhea, nausea, dyspepsia, headache, and flatulence. The incidence of gastrointestinal side effects is higher with the combination product as compared to the incidence observed with diclofenac alone. The incidence of diarrhea can be minimized by administering the product with food.

    The manufacturer recommended dosage of diclofenac/misoprostol is 50 mg/200 mcg three times daily for the treatment of osteoarthritis. For patients unable to tolerate this dose the 75 mg/200 mcg or 50 mg/200 mcg can be administered twice daily but is less effective in preventing ulcers. The maximum recommended dose of diclofenac is 150 mg daily for osteoarthritis and 225 mg daily for rheumatoid arthritis. The total dose of misoprostol should not exceed 800 mcg daily and no more than 200 mcg can be administered per dose. This product should be swallowed whole and not chewed, crushed or dissolved.

    Fomepizole is a competitive inhibitor of alcohol dehydrogenase (ADH), the enzyme which catalyzes the oxidation of ethanol to acetaldehyde and the initial steps in the metabolism of ethylene glycol and methanol to their toxic by-products. Fomepizole is the only approved antidote for ethylene glycol poisoning or for suspected ethylene glycol ingestion. Fomepizole is approved, and intended, for intravenous use, but single acute oral doses (7-50 mg/kg) are rapidly absorbed, reaching maximum plasma concentrations within 1-2 hours after dosing. Elimination occurs by Michaelis-Menton kinetics following acute doses and saturable kinetics occurring at therapeutic blood levels (8.2-24.6 mg/L). Autoinduction of fomepizole following multiple dosing occurs via the Cytochrome P450 system resulting in a significant elimination rate increase after 30-40 hours.

    Fomepizole has only been studied in uncontrolled, non-comparative trials. These trials demonstrated that initiation of fomepizole therapy produced rapid reductions in plasma glycolate levels in all patients and urinary oxalate levels returned to baseline. A majority of patients in these trials were alive at the end of treatment, however some patients had sequelae; such as acute renal failure, pleural effusion, renal insufficiency and anemia, from the intoxication.

    Drugs that inhibit or induce the cytochrome P450 system may interact with concurrent use of fomepizole. Fomepizole is a pregnancy category C and it is not known whether it is excreted in human breast milk. The adverse events that occurred in patients and healthy volunteers most frequently were headache, nausea, dizziness, and smell and taste disturbances.

    Treatment should be initiated immediately upon suspicion of ethylene glycol poisoning based on patient history, anion gap, metabolic acidosis, increased osmolar gap, oxylate crystals in the urine, or documented serum ethylene glycol level greater than 20 mg/dL. A loading dose of 15 mg/kg should be administered, followed by 4 doses of 10 mg/kg every 12 hours, then 15 mg/kg every 12 hours thereafter until ethylene glycol levels fall below 20 mg/dL. All doses are slow intravenous infusions over 30 minutes. Fomepizole is dialyzable, therefore frequency should be increased to every 4 hours during hemodialysis (Table 1).