PHENYTOIN

• Phenytoin


  Hydantoin-derivative anticonvulsant
• FDA-approved Indications for Phenytoin


  • Generalized tonic-clonic (grand mal) seizures
  • Complex partial seizures
  • Seizure prophylaxis following head trauma and neurosurgery

  
• Phenytoin also exhibits antiarrhythmic properties similar to those of lidocaine but is seldom if ever used as an antiarrhythmic
• Loading dose


  When a rapid therapeutic concentration is desired, a loading dose is recommended
• Because of the slow absorption characteristics of phenytoin, the loading dose is often administered by the intravenous (IV) route

  
• Absorption of Phenytoin


  • All dosage forms of phenytoin, including generic products, are assumed to have a bioavailability of 100%
  • Phenytoin has a capacity-limited metabolism; as a result, bioavailability studies are difficult to interpret
  • Drug products with the same fraction absorbed but having different rates of absorption can appear to have different bioavailabilities
  • The time to achieve peak concentration is both product- and dose-dependent
  • The suspension and chewable tablets appear to be absorbed more rapidly than capsules
  • Single Dilantin extended capsule doses of 400, 800, and 1,600 mg achieve peak concentrations at approximately 8, 13, and 30 hr after administration, respectively
  • Peak concentrations following these oral doses are on average only about half of what would be expected after administration of single IV doses
  • The reduced peak concentration following large oral doses is most likely the result of slow absorption rather than a reduced extent of absorption

  
• Bioavailability of Phenytoin


  • The rate and extent of absorption are highly dependent on the size of the phenytoin particles entering the intestine
  • Different dosage forms of phenytoin have widely different bioavailabilities
  • Clinicians and Pharmacists should be careful when switching patients whose seizures are controlled from one phenytoin preparation to another because even small increases or decreases in bioavailability can significantly change the steady-state plasma concentration during chronic therapy

  
• Volume of distribution (Vd) for Phenytoin


  • The volume of distribution (Vd) for phenytoin is calculated in part by using plasma concentrations
  • Any factor that alters plasma protein binding can alter the concentration and, therefore, the apparent Vd
  • The phenytoin that is displaced from the albumin binding sites, while a large percent of the plasma concentration, is only a small percent of the total amount of phenytoin in the body
  • The "extra" phenytoin that is not bound to the albumin is rapidly distributed into the tissues; as a result, the bound concentration decreases but the unbound concentration, tissue concentrations, and pharmacologic effect are relatively unchanged
  • Therefore, no change in loading dose is required in patients with altered plasma binding

  
• A 44 year old male patient is 66 inches tall and weighs 95kg. Calculate the Vd of Phenytoin in this patient.

  
• Protein binding of Phenytoin


  • Phenytoin is bound primarily to albumin in the plasma (fraction bound in plasma equals 0.9)
  • Most clinical assays measure the total (total = bound + unbound) phenytoin concentration
  • Alterations in plasma binding require adjustment for the change in the bound concentration
  • The two factors most commonly associated with altered phenytoin plasma protein binding are hypoalbuminemia and end-stage renal failure [dialysis]
  • Phenytoin concentrations reported (Creported) in these patients can be adjusted to represent the phenytoin concentration anticipated under normal plasma protein binding (Cnormal binding) conditions
  • Phenytoin is 90 percent bound to plasma albumin, and the free form (10%) is the pharmacologically active drug responsible for efficacy and toxicity
  • A smaller portion is bound to alpha-1-acid glycoprotein
  • When phenytoin levels are reported, they represent the unbound (free or active) and bound (inactive) phenytoin level, often referred to as phenytoin observed
  • In patients with normal albumin level and renal function, the fraction of unbound phenytoin (fup) is 0.1
  • Hence, a total phenytoin concentration of 10–20 mg/L represents a fup of 1–2 mg/mL

  
• Sheiner-Tozer equation


  A correction formula that uses the plasma albumin concentration to predict the free fraction of phenytoin using the total phenytoin observed

  
• Analysis carried out at 37oC, most labs conduct this at 25oC
• Phenytoin's binding affinity to albumin (Ka) is less likely to be affected if the calculated creatinine CrCl is >25 mL/min. However, once the CrCl is 10–25 mL/min, Ka is likely to be decreased to an unknown extent.

  
• Calculating for the corrected phenytoin level in patients with hypoalbuminemia when the serum phenytoin test is performed at 37°C

  1. Step 1: Calculate creatinine clearance

  2. Step 2: Calculate for the corrected phenytoin level using the Sheiner-Tozer equation

  
• This patient has a corrected serum phenytoin concentration of 17.5 mg/L. Although this patient's corrected serum phenytoin concentration is within the target range of 10–20 mg/dL, she is experiencing phenytoin-induced CNS adverse effects. The patient should be monitored for other CNS and non-CNS signs and symptoms of phenytoin toxicity. In order to mitigate the phenytoin induced CNS-adverse effects, the medical team may consider administering the entire phenytoin dose at bedtime, or a reduced phenytoin daily dose.