J Clin Pharm Ther. Renal function and therapeutic concentrations of phenytoin. Mabuchi H, Nakahashi H. A major inhibitor of phenytoin binding to serum protein in uremia. The clinical pharmacokinetics of phenytoin.
Removal of phenytoin by hemodialysis in uremic patients. Appropriateness of sampling times for therapeutic drug monitoring. Am J Hosp Pharm. Accuracy of two equations in determining normalized phenytoin concentrations.
Time for phenytoin concentration to peak: Due to its large surface area, the small intestine is the main site of phenytoin absorption. Phenytoin may be given intravenously to patients who cannot receive the drug orally or who require rapid onset of drug effect. Phenytoin distributes into the body tissues, including the brain, within 30 to 60 minutes after reaching the systemic circulation.
The drug is highly bound to both plasma proteins mostly albumin and to tissue components. A decrease in plasma protein binding, hence an increase in the volume of distribution , occurs in conditions reducing the amount of serum albumin such as hepatic failure and the nephrotic syndrome , in the presence of other drugs or during the accumulation of endogenous substances competing for the albumin binding sites as in renal failure.
See also Overview of Pharmacokinetics. The liver is the principal site of drug metabolism. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even more so than the parent compound.
An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively.
It is frequently coadministered with phenytoin for control of complex seizure disorders and with valproic acid for complex parietal seizures. Phenobarbital has a long half-life of 96 hours, with no known active metabolites.
Sedation is common at therapeutic concentrations for the first 2 to 3 weeks of therapy, but this side effect disappears with time. Toxicity due to phenobarbital overdose is characterized by CNS sedation and reduced respiratory function. Death usually occurs due to respiratory arrest when pulmonary support is not supplied manually.
There are no known drug interactions that significantly affect the pharmacokinetics of phenobarbital; conversely, phenobarbital affects the pharmacokinetics of other drugs significantly because it induces the synthesis of enzymes associated with the hepatic cytochrome P metabolic pathway. Vitamin D deficiency , as well as low calcium and phosphate in the blood cause decreased bone mineral density. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin.
Patients should be cautioned against concomitant use of antacids and phenytoin. Consider using other options if possible. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady state inactivation.
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