Single- vs Multiple-Dose Pharmacokinetics of Clozapine in Psychiatric Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.     

Effects of carbamazepine on plasma haloperidol levels

Plasma haloperidol levels were monitored in three schizophrenic patients when carbamazepine was either added or discontinued. The percent decrease in plasma haloperidol levels due to concomitant carbamazepine therapy was between 59% and 61%. The effects of carbamazepine on plasma haloperidol levels were noted to occur in 2 to 3 weeks. Although no adverse effects occurred in the patients during therapy, careful monitoring of clinical symptoms and plasma haloperidol levels is recommended.     

Respiratory arrest following retrobulbar anesthesia

Respiratory arrest is a serious complication of retrobulbar anesthesia. We have prospectively followed 3123 retrobulbar injections to determine the incidence of respiratory arrest and identify possible risk factors. Injections contained either 2% or 4% lidocaine with 0.75% bupivacaine (Marcaine) in a 50:50 mixture by volume (total 10 cc.) to which a 1 ml ampule of hyaluronidase (150 NF units) was added. Use of 4% lidocaine gave a significantly higher incidence of respiratory arrest than 2% lidocaine (0.79% vs. 0.09%; P = 0.003, Fisher's exact test). Serum levels of lidocaine and bupivacaine of patients who arrested were not elevated significantly compared to 20 control patients. All levels were well below accepted levels of toxicity. Thus, 4% lidocaine increases the risk of respiratory arrest. These results suggest the mechanism is not direct intravascular or central nervous system injection.