This document discusses the pharmacokinetics of the anticonvulsant medication phenytoin. It covers phenytoin's indications, dosing, adverse effects, bioavailability, volume of distribution, and methods for calculating loading doses. Phenytoin has multiple therapeutic uses and dosage forms but also significant drug interactions and adverse side effects that require monitoring like hepatotoxicity and cardiac issues. Loading doses aim to quickly achieve therapeutic phenytoin concentrations in patients who are new to or have subtherapeutic levels of the drug.
This document discusses the pharmacokinetics of the anticonvulsant medication phenytoin. It covers phenytoin's indications, dosing, adverse effects, bioavailability, volume of distribution, and methods for calculating loading doses. Phenytoin has multiple therapeutic uses and dosage forms but also significant drug interactions and adverse side effects that require monitoring like hepatotoxicity and cardiac issues. Loading doses aim to quickly achieve therapeutic phenytoin concentrations in patients who are new to or have subtherapeutic levels of the drug.
This document discusses the pharmacokinetics of the anticonvulsant medication phenytoin. It covers phenytoin's indications, dosing, adverse effects, bioavailability, volume of distribution, and methods for calculating loading doses. Phenytoin has multiple therapeutic uses and dosage forms but also significant drug interactions and adverse side effects that require monitoring like hepatotoxicity and cardiac issues. Loading doses aim to quickly achieve therapeutic phenytoin concentrations in patients who are new to or have subtherapeutic levels of the drug.
This document discusses the pharmacokinetics of the anticonvulsant medication phenytoin. It covers phenytoin's indications, dosing, adverse effects, bioavailability, volume of distribution, and methods for calculating loading doses. Phenytoin has multiple therapeutic uses and dosage forms but also significant drug interactions and adverse side effects that require monitoring like hepatotoxicity and cardiac issues. Loading doses aim to quickly achieve therapeutic phenytoin concentrations in patients who are new to or have subtherapeutic levels of the drug.
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Phenytoin Pharmacokinetics
Northern Border University
Faculty of Pharmacy Department of Clinical Pharmacy Overview • Phenytoin is an anticonvulsant medication that was first discovered in 1908 by Heinrich Biltz at the University of Kiel in Germany. • Today, it is FDA-approved for the management of generalized tonic clonic (grand mal) seizures, complex partial seizures, and for the prevention of seizures after head trauma and neurosurgery. • Phenytoin also has multiple unlabeled indications including the management of trigeminal neuralgia, syndrome of inappropriate antidiuretic hormone (SIADH), torsade de pointes, and arrhythmias (as a Class IB antiarrhythmic). • Topical phenytoin has also been used to heal multiple acute and chronic wounds. Dosing • Phenytoin is available in multiple dosage forms including an injectable formulation, extended- release capsule, oral suspension, and chewable tablet. • Intramuscular (IM) administration of phenytoin is not recommended due to its erratic absorption and pain on injection. • Intravenously (IV), phenytoin may be administered by IV push or IV piggyback using a 0.22 micron filter. • Due to the rate-limited gastrointestinal (GI) absorption of phenytoin no more than 400 mg should be administered at a time. • A target level is achieved within 6–10 hours. • A serum phenytoin concentration of 10–20 mg/L is considered within therapeutic range. Adverse Events • Phenytoin adverse effects can be common and chronic, and include hepatotoxicity, osteoporosis, megaloblastic anemia, gingival hyperplasia, hirsutism, and peripheral neuropathy. • Phenytoin may cause gastrointestinal adverse effects such as nausea and vomiting. • Phenytoin can cause central nervous system (CNS) adverse effects such as dizziness, confusion, drowsiness, and ataxia • Phenytoin may cause a rash that presents as the antiepileptic hypersensitivity syndrome (AES). • Hypotension is listed as a boxed warning in the package insert of phenytoin. Adverse Events • Due to the cardiotoxicity associated with phenytoin (e.g., bradycardia, hypotension, QRS prolongation, ventricular fibrillation) • All patients receiving IV phenytoin must have continuous cardiac monitoring. • Phenytoin is pregnancy category D because it crosses the placenta and has been associated with congenital malformations. • Phenytoin enters the breast milk and it is not recommended to be used by lactating women. Bioavailability • The bioavailability of phenytoin varies significantly among the different dosage forms. • Due to the acidity of the stomach, phenytoin sodium changes to free phenytoin acid that precipitates after it dissolves. • For this reason, the different dosage forms of phenytoin have widely different bioavailability's. • Numerous case studies report a decrease in phenytoin absorption when it is co-administered with enteral feedings. Volume of Distribution
• Phenytoin has an apparent volume of distribution
of 0.6–0.7 L/kg adults and children and 1.2 L/kg in infants and neonates. • Phenytoin distributes rapidly to the brain where plasma and brain concentrations achieve equilibrium within 20 minutes. Loading Dose • There are two scenarios whereby loading dose of phenytoin is required. • First, when a newly diagnosed patient who is phenytoin-naïve is to be started on phenytoin • Second, when a patient who is already receiving phenytoin has a phenytoin level that is below the desired concentration. • Loading doses allow such patients to achieve target levels quickly. • When calculating for a loading dose, it is important to determine the target peak phenytoin concentration (Cp) and the formulation of phenytoin that is to be used for the loading. Loading Dose • Typically, for phenytoin-naïve patients, the target Cp is 20 mg/L. • The oral suspension and the intravenous formulations are the most commonly used dosage forms for loading • phenytoin because they have been associated with the most rapid increase in serum concentration as compared to the tablet and capsule formulations. • The following formula is used when calculating the loading dose in phenytoin- naïve patients. Loading Dose • Under normal Ka and fup, the estimated volume of distribution (Vd) falls between 0.6 and 0.7 L/kg, with an average of 0.65 L/kg. • All phenytoin formulation has a bioavialability (F) of 1. • Phenytoin sodium, available as interavenous and as capsule, has a salt factor (S) of 0.92. • Phenytoin acid on the other hand is available as suspension and chewable tablets, and has a salt factor of 1. Loading Dose • The phenytoin loading dose equation (Equation 4) must be changed for patients who are currently on phenytoin and the observed phenytoin level is below target. • The newly revised formulation accounts for the presence of the phenytoin already in the patient's plasma.
