Phenytoin
Bioavailability (F):
· Has a good bioavailability (95%), F can range from 0.90-1
· Completely absorbed from most forms
Salt Factor (S):
· 0.92 - Phenytoin Na+ (caps, IV)
· Phenytoin Acid (tabs, suspension)
Volume of Distribution (Vd):
· 0.65 L/Kg: Adults – increased in patients with plasma protein binding
· 0.7 L/Kg: Children
Protein binding: Highly protein bound (90%), mainly bound to albumin, so we would expect issues with patients who have hypoalbuminemia.
Time to Peak:
· 3-12 hours with regular oral dosing
· 20-25 min with IV
Metabolism:
· Undergoes extensive hepatic metabolism ( CYP 2C19 and CYP 2C9). However, it’s a CYP 3A4 inducer. It is also very important to consider that it is capacity limited. So, in other words, Clearance decreases as concentration increases.
Michaelis- Menten Kinetics:
· Initially when we load phenytoin naïve patients, it starts as linear Kinetics but once you reach the saturation point, the plasma concentration increases disproportionally so a small change in the dose would have a big impact on the plasma concentration of phenytoin (it would increase).
Half-Life (t½):
· A function of plasma concentration
· Average - 22 hours (range 8 - 60 hours)
· Not a constant value since the clearance of Phenytoin changes with the plasma concentration. Once it reaches the saturation point, t ½ becomes longer.
Time to Steady State:
· Variable but approximately 5 days.
Elimination:
· Mainly eliminated through the urine
Fosphenytoin:
Time to Peak :
· 20 minutes after a 20 minute infusion
· 30 minutes after an IM injection
Half-Life (t½): 8 minutes. However, we need to remember that it is a prodrug so it does get metabolized to phenytoin which has a half life of 22 hours.
· Based on its PK profile, Fosphenytoin is usually used in patients with poor or absent IV access. It is also important to remember that it does not require propylene glycol for solubilization, which is helpful because propylene glycol can sometimes cause hypotension or tissue necrosis in the case of extravasation.
Fosphenytoin Dosing:
· Loading Dose is 15-20 mg/kg of PE infused at a rate between 50-150 mg of PE / minute.
· Maintenance dose is 4-6 PE/ kg/ day IV
· Maximum IM dose is 5 ml.
Phenytoin Dosing:
· Patients are started with a loading dose
· Loading dose is 15,g/kg ( using ABW) rounded to the nearest 50 mg increment.
· IV infusion rate should not exceed 25-50 mg/ min. In healthy patients, we usually use the 50 mg/ min but in older patients or in patients with concurrent issues, the 25 mg/ min dose is sometimes used.
· If the patient will receive the loading dose orally, we use either the oral solution or the IR formulation, not the ER formulation.
· Oral dose should be administered in 3 divided doses separated every 2-4 hours.
· Doses greater than 400 mg should be separated to avoid prolonged absorption times and risk of GI AE. Therefore, it is important to remember that the maximum oral dose of phenytoin is 400 mg.
· In terms of Maintenance dosing: 5-7 mg/ kg/ day ( using ABW)
· Maintenance dosing beings 8 hours after loading dose, and we utilize the ER capsules. The reason for that is because it can be given only once a day. However, if the IV or oral solution form is used, then we have to give it Tid.
· Again, Doses greater than 400 mg should be separated to avoid prolonged absorption times and risk of GI AE
· When considering dose adjustments, the patient has to be at steady state. It is also important to remember that the maximum change should be no more than 20% of daily dose.
· Phenytoin and Fosphenytoin are sring inducers of several enzymes, including CYP2B6, 2C19, 2C8/9, 3A4, P-gp and UGT1A1; they are substrates of CYP2C19 ( major), 2C9 (major) and 3A4 ( minor).
· Both drugs can also decrease the concetration of many drugs including other anti epileptics, contraceptives, and warfarin.
· Use of an alternative, non hormonal contraceptive is also recommended with chronic phenytoin.
· Since both have high protein binding, they can displace other protein bound drugs or be displaced by other highly protein bound drug, cause an increase in levels that can lead to toxicity
Incremental Dosing Strategy:
· Used when you check the patient’s concentrations and it is not between 10-20
Incremental LD = { (Vd)(Cp desired- Cp initial) } x ABW / ( S*F)
· Important to consider that the Bioavailability is always 1 and that we use the IV or oral solution formulations not the ER capsules.
Monitoring Serum concentrations:
· We sample 2 hours after an IV loading dose
· 5-7 days after a regimen dosing change if the patient is on a maintenance dose ( we usually check trough levels)
· Also check if patient develops any complications such as seizures, signs and symptoms of toxicity, and addition or deletion of feeding tube administration.
· It is also very important to remember that phenytoin is highly Albumin bound (90%), so if there is a drop in serum albumin, there will be an increase in the amount of free phenytoin circulating.
· It is also important to remember that dose adjustments are required in patients with renal dysfunction.
Adjustments:
1) Adjustments for low Albumin (<3.5g/ dL):
Adj concentration = Observed concentration/ (0.2* measured albumin) + 0.1
2) Acute or chronic renal failure (CrCl < 10 ml/min):
Adj concentration = Observed concentration/ (0.1* measured albumin) + 0.1
Phenobarbital
· Phenobarbital is usually administered orally, IM, or IV
· Distribution is less rapid than that of other barbiturates because it is less lipid-soluble, but the drug is found in all tissues and fluids, including adipose tissue and cerebrospinal fluid.
· Only unionized drug crosses the blood brain barrier, therefore, acidosis can increase the pharmacologic effects by increasing the concentration of unionized drug.
· Phenobarbital has a biphasic distribution. In adults, the volume of distribution of the central compartment (to highly perfused organs) is about 0.3 L/kg; the volume of distribution at steady state ranges 0.5 to 1 L/kg (mean: 0.7 L/kg).
· The time to reach steady state phenobarbital levels is 12 to 24 days in the absence of interacting comedication
· About 20 to 45% of phenobarbital is bound to plasma proteins.
· Phenobarbital is the longest acting of all the commercially available barbiturates; the half-life in adults ranges from 50 to 120 hours (mean: 96 hours).
· In the absence of a loading dose, several weeks of therapy may be required to achieve steady-state plasma concentrations.
· Therapeutic plasma concentrations (for anticonvulsant activity) are roughly 10 to 40 mcg/mL.
· Plasma concentrations > 50 mcg/mL may produce coma or respiratory depression; and concentrations > 80 mcg/mL are potentially fatal.
· Roughly 25% of phenobarbital is eliminated unchanged in the urine, but the excretion is pH-dependent.
· Increasing the urinary flow rate or alkalinizing the urine will increase the rate of excretion of unchanged phenobarbital. The remainder of the dose (roughly 75%) is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1.
· Importantly, phenobarbital accelerates the clearance of other drugs metabolized via hepatic enzymes (UGT enzymes, CYP2C-family enzymes, CYP3A-family enzymes, and CYP1A2
· Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1.
· Phenobarbital is also a strong inducer of the P-gp drug transporter.
· Phenobarbital can also decrease hormonal contraceptive levels significantly. Use of an alternative, non hormonal contraceptive is recommended.
Route-Specific Pharmacokinetics:
Oral Route
· Oral bioavailability is generally good; 95% or higher of an oral dose of phenobarbital is absorbed from the GI tract.
· For this reason, total parenteral dosages and oral dosages are often similar on a mg/day basis.
· Oral absorption is delayed by the presence of food. Peak serum concentrations are achieved 8 to 12 hours after oral dosing.
Intravenous Route
· Onset of action after IV administration of phenobarbital is within 5 minutes, reaching a maximum in about 30 minutes.
· The peak brain/plasma concentration ratio occurs slowly about 20 to 40 minutes after an IV dose.
Intramuscular Route
· Onset of action is slightly slower than the less than 5 minutes typical of intravenous administration.
Subcutaneous Route
· Onset of action is slightly slower than the less than 5 minutes typical of intravenous administration.
Rectal route
· Phenobarbital is also generally well-absorbed when administered rectally.
Additional Considerations:
Hepatic Impairment :
· Metabolism of phenobarbital may be impaired in patients with hepatic disease.
Renal Impairment:
· Phenobarbital may accumulate in patients with renal failure or severe renal impairment. Phenobarbital is removed during hemodialysis.
Pediatrics
Infants and Children:
· Peak concentrations are achieved 3 hours after oral administration and 45 minutes to 6 hours after IM administration in infants and children.
· The volume of distribution is approximately 0.6 to 0.9 L/kg in infants and 0.6 to 0.7 L/kg in children.
· The elimination half-life ranges from 47 to 63 hours in infants and 37 to 69 hours in children.
Neonates:
· Higher plasma concentrations of phenobarbital are achieved after IM administration than after oral administration in neonates.
· Little difference has been reported for other pediatric populations.
· Absorption is delayed after oral administration in neonates with a Tmax of 9 hours. After IM administration, the Tmax ranges from 7 to 40 hours in premature neonates and 30 minutes to 27 hours in full term neonates.
· Protein binding is 25 to 50% less in neonates compared to older children and is even lower in hyperbilirubinemic neonates; Which would lead to a higher concentration of free Phenobarb and increase the risk of AE.
· Volume of distribution in neonates is larger than in other populations (approximately 0.7 to 1.2 L/kg), and is not affected by gestational age or birthweight.
· The elimination half-life is highly variable and ranges from 45 to 409 hours.
References:
https://www-clinicalkey-com.ezproxymcp.flo.org/pharmacology/monograph/479?sec=monphar
Glad you like it! Please feel free to post any questions or content that you may have!
Thank you so much man! LOVE THIS
This is very helpful, thank you so much!