Phenytoin is 90% bound to serum proteins, mainly albumin, and does not show any concentrationdependent binding within the therapeutic range. Due to the dose dependent metabolism of phenytoin and to its narrow therapeutic range even small changes in the bioavailability can cause major changes in serum phenytoin concentration and have serious clinical. Phenytoin may be given intravenously to patients who cannot receive the drug orally or who require rapid onset of drug effect. Clearance is the most important pharmacokinetic parameter because it determines the steadystate concentration for a given dosage rate. Clinical pharmacokinetics pharmacy handbook is the first therapeutic drug. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and or any thoughts or behavior of suicide. Frequency distribution of plasma phenytoin concentrations in 200 adult outpatients taking phenytoin 300 mg daily.
Editorial project manager, books and elearning courses. It is an effective anticonvulsant for the chronic treatment of tonicclonic grand mal or partial seizures and the acute treatment of generalized status epilepticus table 101. The fifth edition of a textbook of clinical pharmacology and therapeutics is accompanied by an. Due to zero order kinetics, dosage should not be increased by more than 50100mg increments. In order to be as clinically relevant as possible, the book not only discusses drugs with readily available therapeutic serum levels, but places. An understanding of their pharmacokinetics and pharmacology is important for clinical therapeutics. Phenytoin pharmacokinetics and clinical effects in african children. However, many published papers have indicated that free phenytoin concentration correlates better with therapeutic efficacy as well as toxicity compared to total phenytoin. It is an effective anticonvulsant for the chronic treatment of tonicclonic grand mal or partial seizures and the acute treatment of generalized status epilepticus. Essential topics for pharmaceutics, pharmacokinetics, therapeutics, and clinical pharmacy courses or can be. Apr 20, 2009 ml in blood sf 2008, medlineplus 2009. The clinical pharmacokinetics service and anticoagulation. Phenytoin oral capsule is used to treat tonicclonic and complex partial seizures in people with epilepsy.
Routine prophylaxis with phenytoin in a dosage of 5 to 6 mgkgday would seem to be indicated, particularly in highrisk patients and, where possible, this treatment should be started 1 week preoperatively. Calculate a maintenance dose, loading dose, and dosage interval for a patient given values of clearance, volume of distribution, and halflife. This site is like a library, use search box in the widget to get ebook that you want. T1 pharmacotherapeutics, pharmacokinetics, and pharmacodynamics. Phase i includes firstinhuman trials that provide information about the safety tolerability and pharmacokinetics pk of a new drug. Amitava dasgupta, in clinical challenges in therapeutic drug monitoring, 2016. Seizure control is best when therapeutic levels of phenytoin are maintained. Pharmacokinetics and clinical effects of phenytoin and fosphenytoin. Improving upon and updating the information and format of the leading competing clinical pharmacokinetic text, dr. An exception is digoxin where monitoring free digoxin is clinically very useful to assess success of digibind or digifab.
Up to 90% of phenytoin is metabolized to phpph and then glucuronidated and excreted into urine 17576806. This chapter provides an overview of the clinical drug development process, which includes the clinical proof of mechanism, the clinical proof of concept, and the characterization of clinical safety. Asian journal of pharmaceutical and clinical research vol. Dec 15, 2012 phenytoin diphenylhydantoin is still the most commonly used anticonvulsant drug. With its clear, straightforward presentation, this text enables you to grasp all the fundamental concepts of pharmacokinetics and pharmacodynamics.
Phenytoin, formerly known as diphenylhydantoin, is perhaps the most commonly used major anticonvulsant agent, and is a rare but well known cause of acute idiosyncratic drug induced liver disease that can be severe and even fatal. Phenytoin pharmacokinetics in therapeutic plasmapheresis. Applied clinical pharmacokinetics 3 e download ebook pdf. Some patientrelated factors eg, renal function, genetic makeup, sex, age can be used to predict the pharmacokinetic parameters in populations. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus.
Oct 02, 2012 principles of clinical pharmacology is a successful survey covering the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development. Overview of pharmacokinetics clinical pharmacology merck. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants. Aug 31, 2002 phenytoin is often used to control status epilepticus, but its watersoluble prodrug, fosphenytoin, may be more useful as it is easier to administer. Drug challenge courses in therapeutics and disease state management. Phenytoin is poorly soluble in water and is therefore commonly given as phenytoin sodium salt, which dissolves more readily. The medicine is chosen on the basis of an evidencebased approach to clinical practice and assured to be compatible with. We applied such an integrated approach to characterize the pharmacokineticpharmacodynamic relationship of phenytoin.
In recent years, little has been added to the knowledge of the pharmacokinetics of phenytoin. Phenytoinpharmacokineticspopulation pkepilepsynonlinear. Total and free serum phenytoin concentrations and net phenytoin removal were examined in two stable patients henceforth referred to as patient d. As an anticonvulsant, phenytoin works by increasing the efflux and decreasing. Vancomycin, phenytoin, carbamazepine, valproic acid, phenobarbitone, digoxin. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Phenytoin does not demonstrate a proportional relationship between drug levels and dose. Bauer, a nationally recognized leader in the field of pharmacokinetics has conceived a text for today and tomorrows pharmacy student and practitioner. Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus bernhards r ogutu, 1, 2 charles r j c newton, 1, 3 simon n muchohi, 4 godfrey o otieno, 1 geoffrey edwards, 5, 6 william m watkins, 5 and gilbert o kokwaro 2, 4. In parallel, the anticonvulsant effect and the electroencephalogram eeg effect were used to determine the pharmacodynamics. Possibly partially influenced by cyp2c9 and cyp2c19 variations. Phenytoin pharmacokineticspopulation pkepilepsynonlinear. In this study a pharmacokineticpharmacodynamic model is proposed for drugs with nonlinear elimination kinetics.
This chapter provides references cited mainly for more recently established facts. A textbook of clinical pharmacology and therapeutics. This will allow you to understand the time course of drug response and dosing regimen design. Phenytoin is primarily metabolized to the inactive hydroxyphenytoin, 54hydroxyphenyl5phenylhydantoin or phpph article. Pharmacotherapeutics, pharmacokinetics, and pharmacodynamics. Basic clinical pharmacokinetics download ebook pdf, epub.
Furthermore, phenytoin demonstrates nonlinear pharmacokinetics even within the therapeutic range. Clinical models for concentration and response are described and built from the basic concepts presented in earlier chapters. Introduction to pharmacokinetics and pharmacodynamics. Primary goals of clinical pharmacokinetics include. The intravenous form is used for status epilepticus that does not improve with benzodiazepines. For strongly protein bound drugs such as phenytoin and valproic acid, measuring free drug concentration in. Bauers specialty area is in clinical pharmacokinetics, and he teaches courses and offers clinical clerkships in this area. Chapter 1 pharmacokinetics and therapeutic drug monitoring. Jul 29, 2015 clinical pharmacokinetics of phenytoin. Pharmacokinetics of a drug depends on patientrelated factors as well as on the drugs chemical properties.
Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patients drug therapy. M, department of pharmacology, al shifa college of pharmacy, kizhattur,poonthavanam p. Clinically important displacement can be caused by bilirubin and. Phenytoin was also found as an undeclared drug in several weightloss products marketed as dietary supplements fda 2009b. Pharmacokinetics and bioavailability roland gugler m. In this chapter the following anti epileptic drugs are considered. Pharmacokinetics, pharmacodynamics, and pharmacogenomics. Department of pharmacology, materia medica and therapeutics.
Phenytoin would be a suitable alternative to phenobarbitone due to its long elimination halflife at the usual therapeutic doses. Pharmacokinetics pharmacodynamics adherance distribution elimination figure 1. This essential reference continues to focus on the basics of clinical pharmacology for the development, evaluation, and clinical use of pharmaceutical products. The solution is in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to ph 12 with sodium hydroxide. Due to the ratelimited gastrointestinal gi absorption of phenytoin, no more than 400 mg. Clinical pharmacokinetics of phenytoin springerlink. As a general rule, hold therapy 1 day for every 20umoll over 80umoll.
If your institution subscribes to this resource, and you dont have a myaccess profile, please contact your librarys reference desk for information on how to. The enzyme system involved in phenytoin metabolism gradually becomes saturated, resulting in a decrease in the rate of elimination of phenytoin as the dose is increased4. Phenytoin may increase risk of suicidal thoughts or behavior. Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin is a highly effective anticonvulsant medication that is considered to be the treatment of choice for generalized major motor and focal epileptic seizures. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins. Pharmacokinetics and clinical effects of phenytoin and. Patients need to be prescribed appropriate medicines for a clinical condition. In 2009, 48 clinical trials involving phenytoin were in progress or recently completed, including 22 that were recruiting patients in the united states clinicaltrials 2009. Phenytoin the treatment of epilepsy wiley online library. Clinical pharmacokinetics is the discipline that describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy. Home books casebook in clinical pharmacokinetics and drug dosing. However, many published papers have indicated that free phenytoin concentration correlates better with.
Table i phenytoin pharmacokinetics in adults and children mean t s. Phenytoin is a imidazolidine2,4dione that consists of hydantoin bearing two phenyl substituents at position 5. Estimation of phenytoin pharmacokinetic parameters in saudi. It is useful for the prevention of tonicclonic seizures and focal seizures, but not absence seizures. Pharmacokinetics, pharmacodynamics, and pharmacogenomics by simon w. Hold dosage until levels are back within the therapeutic range then reduce dosage as per above. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in scandinavia. Due to its large surface area, the small intestine is the main site of phenytoin absorption. It may also be used for certain heart arrhythmias or neuropathic pain. There are 23 first and second antiepileptic drugs in current usage, 15 of which were licensed since 1989. The text emphasizes the practical aspects of drug dosing for agents that have serum concentrations commonly available from. Numerous interactions between phenytoin and endogenous substances and co. Click download or read online button to get applied clinical pharmacokinetics 3 e book now. He is the author of applied clinical pharamcokinetics mcgrawhill, 2001 his research interests include the pharmacokinetics and pharmacodynamics of drug interactions, the effects of liver disease and age on drug.
Digoxin, phenytoin, carbamazepine, theophylline, cyclosporine, tacrolimus, and. Phenytoin is a hydantoin compound related to the barbiturates that are used for the treatment of seizures. Dec 11, 2018 dilantin phenytoin sodium injection, usp is a sterile solution of 50 mg phenytoin sodium per milliliter for intravenous or intramuscular administration. Its available as a generic drug and as the brandname drugs phenytek and dilantin. Casebook in clinical pharmacokinetics and drug dosing. Phenytoin may produce lower than normal values for the metyrapone tests b. Click download or read online button to get basic clinical pharmacokinetics book now. Clinical pharmacology and toxicology center, departments of medicine and pharmacology, university of kansas medical center, college of health sciences and hospital, kansas city, kan. Applied clinical pharmacokinetics, 3e accesspharmacy. It has certain physicochemical characteristics which make it liable to bioavailability problems. Dec, 2012 phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt.
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