POPULATION PHARMACOKINETICS.docx

CLINICAL PHARMACOKINETICS OF PHENYTOIN/FOSPHENYTOIN Discuss the clinical use and mechanism of action of phenytoin Hydantoin, related to barbiturates Anti-convulsant – tonic-clonic, partial seizures, and. Generalized status epilepticus (acute) After IV BZD (diazepam, lorazepam) used to stabilize,...

CLINICAL PHARMACOKINETICS OF PHENYTOIN/FOSPHENYTOIN Discuss the clinical use and mechanism of action of phenytoin Hydantoin, related to barbiturates Anti-convulsant – tonic-clonic, partial seizures, and. Generalized status epilepticus (acute) After IV BZD (diazepam, lorazepam) used to stabilize, then add IV phenytoin or fosphenytoin Type 1B antiarrhythmic Describe the differences between phenytoin and fosphenytoin formulations Fosphenytoin - Water soluble phosphate ester; no pharmacologic activity Rapid and complete conversion to phenytoin (7-15 minutes) dosed using phenytoin sodium equivalents Discuss the phenytoin sodium equivalent (PE) concept 100 mg PE of fosphenytoin = 100 mg phenytoin sodium Compare and contrast between absorption, distribution and elimination of phenytoin vs. fosphenytoin No clinical difference Phenytoin and fosphenytoin are the same (since ester cleaves so fast) Pharmacology – inhibit repetitive firing of action. Potentials; prolonged depolarization Block abnormal discharges from epileptic foci Block post-tetanic potentiation Prolong inactivation of sodium ion channel Pharmacokinetics (nonlinear) – equation given for test $\frac{\text{dx}}{\text{dt}} = \frac{V_{\max}\text{\ x\ }C_{\text{ss}}}{K_{m} + C_{\text{ss}}}$ CYP2C9 metabolism for the most part (same as warfarin) Cannot predict saturation concentration based on this enzyme In the real world, Volume of distribution = 0.65 L/kg, F = 1.0, S = 0.92 (caps, injection), S = 1 (suspension, chew tablets) Identify the differences between Vmax and Km (values given on test) General purposes, Vmax is average of 7 mg/kg/day – how a person metabolizes the drug Km is a unit of concentration, for which the population averages 4 mg/L Different people (ages, etc.) have different Vmax and Km values. Discuss various dosing methods for phenytoin and fosphenytoin Phenytoin – the capsule has a salt factor of 0.92, while the suspension and chewable tablets are 1.0. This means that you have to take into consideration the salt factor when changing dosage form, because an 8% change is significant to the response to phenytoin. Concentration Effect (toxicity) 15-20 ug/mL Minor CNS depression (drowsy, fatigue) 20-30 ug/mL Nystagmus 30-40 ug/mL Ataxia, slurred speech, incoordination (like alcohol poisoning) 40-50 ug/mL Mental status change, severe confusion and lethargy, coma 50-60 ug/mL and over Drug-induced seizure activity