Pharmacokinetics and bioavailability roland gugler m. Subsequently, phenytoin loglinear elimination kinetics after a 10 mgkg i. The effect of phenytoin on the pharmacokinetics of. Concepts and applications by malcolm rowland clinical pharmacokinetics and pharmacodynamics. Phenytoin pharmacokinetics in burned rats and plasma protein. Pharmacokinetics, pharmacodynamics, and pharmacogenomics. 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. Download pdf wintersbasicclinicalpharmacokinetics free.
Phenytoin and its sodium salt are reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals. Phenytoin induced toxicity leads to ataxia, nystagmus, gingival hypertrophy, nodular skin lesions and hirsutism. At that time, his phenytoin serum concentration was 8 mcgml. Casebook in clinical pharmacokinetics and drug dosing. Clinically important displacement can be caused by bilirubin and.
The objectives for this study were to model the time. Phenytoin was given as an intravenous loading dose of 15 mgkg followed by an initial maintenance dose of 6 mgkgday in 10 adult critically ill trauma patients. Phenytoin pht, sold under the brand name dilantin among others, is an antiseizure medication. Efficacy of levetiracetam compared with phenytoin in. If im administration is required, fosphenytoin is preferred. Dec 15, 2012 phenytoin diphenylhydantoin is still the most commonly used anticonvulsant drug. Clinical pharmacology is a fast moving subject and the present edition has been completely revised and updated. Chandler medical center at the university of kentucky under the preceptorship of dr. Dec, 2012 phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt. Her phenytoin plasma concentration was found to be 27. Phenytoin diphenylhydantoin is still the most commonly used anticonvulsant drug. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or. Concepts and applications 4th edition 122909 handbook of basic. The pharmacokinetics of phenytoin was studied in 66 epileptic chinese children and adults.
Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in scandinavia. Phenytoin may cause slight decreases in urinary 17hydroxycorticosteroids and 17ketosteroids while urinary 6. Phenytoin pharmacokinetics in critically ill trauma. Table i phenytoin pharmacokinetics in adults and children mean t s. W comparative evaluation of six techniques for determining the michaelismenten parameters relating phenytoin dose and steadystate serum concentrations. Phenytoin is often used to control status epilepticus, but its water. Applied clinical pharmacokinetics 3e pdf book library. Nonlinear pharmacokinetics in other words, time or dose dependences in pharmacokinetic parameters can arise from factors associated with absorption, firstpass metabolism, binding, excretion and biotransformation. Varelas, jan claassen, seizures in critical care, 2017, 121crossref.
Pdf phenytoin pharmacokinetics in critically ill trauma. Phenytoin is 90% bound to serum proteins, mainly albumin, and does not show any concentrationdependent binding within the therapeutic range. Clinical pharmacokinetics and clinical research units, the upjohn company. The text emphasizes the practical aspects of drug dosing for agents that have serum concentrations.
Calculate a maintenance dose, loading dose, and dosage interval for a patient given values of clearance, volume of distribution, and halflife. A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient. This essential reference continues to focus on the basics of clinical pharmacology for the development, evaluation, and clinical use of pharmaceutical products. The treating physician increased his dose to phenytoin 100 mg 3 capsules po bid. Joseph c fleishaker, phd, clinical pharmacokinetics unit, 7215. 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. He also completed an ashpaccredited hospital pharmacy residency 1980 specializing in clinical pharmacokinetics from a. These assumptions guide clinical decisions, such as the frequency of recommended daily dosing of phenytoin and calculations of dosing changes to achieve targeted serum levels.
The patients neurologic status improved slowly over a period of 10 days and correlated best with the rise and fall of phenytoin plasma concentrations. In order to be as clinically relevant as possible, the book not only discusses drugs with readily available therapeutic serum levels, but places. Phenytoin may increase risk of suicidal thoughts or behavior. Content organized for fast reference to specific drugs the latest on dosing in obese and overweight patients dosing considerations for. Click download or read online button to wintersbasic clinical pharmacokinetics book pdf for free 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.
Phenytoin pharmacokinetics in critically ill trauma patients. The policyprocedure manual outlines standard guidelines which should be followed when providing clinical pharmacokinetic monitoring of the following drugs. Pharmacokinetics pharmacodynamics adherance distribution elimination figure 1. Clinical pharmacokinetics service along with pharmacy practice residents and py4 pharmacy students as part of a residentstudent rotation in clinical pharmacokinetics. Patients with serum drug concentrations on noncovered services are identified on a daily basis utilizing sunrise clinical manager scm. In parallel, the anticonvulsant effect and the electroencephalogram eeg effect were used to determine the. The pharmacokinetics of phenytoin is fairly well studied and the impact of genomic variation on plasma drug levels and metabolism has been studied in healthy populations and patients with epilepsy. The clinical relevance of pharmacokinetics and drug interactions with anti epileptic drugs department of clinical pharmacology and therapeutics, university of malta email. Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patients drug therapy. Applied clinical pharmacokinetics 3e kindle edition by. Dilantin phenytoin sodium food and drug administration. Due to its large surface area, the small intestine is the main site of phenytoin absorption. However, fewer studies have shown how these alterations in metabolism affect drug response, resistance and adrs.
This site is like a library, use search box in the widget to get ebook that you want. Jul 29, 2015 clinical pharmacokinetics of 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. Phenytoin is often used to control status epilepticus, but its watersoluble prodrug, fosphenytoin, may be more useful as it is easier to administer. He has experienced several seizures since that time. Phenytoin is a imidazolidine2,4dione that consists of hydantoin bearing two phenyl substituents at position 5. Biopharmaceutics and pharmacokinetics by venkateswarlu pdf. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and or any thoughts or behavior of suicide. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins.
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 gain access to this resource from offcampus. Serial plasma levels of phenytoin, primidone, and phenobarbital were determined in a patient following a massive overdose of phenytoin and primidone. For dilantin capsules, peak serum levels occur 4 to 12 hours after administration. Clinical pharmacokinetics of phenytoin springerlink. We remind clinicians that phenytoin toxicity can easily mimic a cerebellar lesion or alcohol intoxication, and suggest that in accordance with national institute for clinical excellence nice guidelines phenytoin. An understanding of their pharmacokinetics and pharmacology is important for clinical therapeutics. The intravenous form is used for status epilepticus that does not improve with benzodiazepines. Phenytoin may produce lower than normal values for the metyrapone tests b.
Frequency distribution of plasma phenytoin concentrations in 200 adult outpatients taking phenytoin 300 mg daily. Bauer is a fellow of the american college of clinical pharmacology and the american college of clinical pharmacy. As the editors state in the preface, the fourth edition has retained the books original goal to provide a rigorous, yet practical, text. There were 780 steadystate phenytoin concentrations and. After 5 days of therapy, she presented to the hospitals emergency department with marked ataxia. Introduction to pharmacokinetics and pharmacodynamics.
Clinical pharmacology and toxicology center, departments of medicine and pharmacology, university of kansas medical center, college of health sciences and hospital, kansas city, kan. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Possibly partially influenced by cyp2c9 and cyp2c19 variations. Phenytoin is a hydantoin compound related to the barbiturates that are used for the treatment of seizures. The medicine is chosen on the basis of an evidencebased approach to clinical practice and assured to be compatible with. Phenytoin is available in multiple dosage forms including an injectable formulation, extendedrelease capsule, oral suspension, and chewable tablet. A significant reduction in the frequency of epilepsy was observed in the group receiving the active drug up to the 10th postoperative week. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p. It has certain physicochemical characteristics which make it liable to bioavailability problems.
In this chapter the following anti epileptic drugs are considered. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. It may also be used for certain heart arrhythmias or neuropathic pain. Highlights of paper phenytoin causes dose related side effects at normal doses on chronic use. Phenytoin is poorly soluble in water and is therefore commonly given as phenytoin sodium salt, which dissolves more readily.
Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcgml, although some mild cases of tonicclonic grand mal epilepsy may be controlled with lower serum levels of phenytoin. Bauer, a nationally recognized leader in the field of pharmacokinetics has conceived a text for today and tomorrows pharmacy student and practitioner. Pdf pharmacokinetic study of phenytoin in malaysian. Furthermore, each critically ill patient is distinct, with a differing. Pharmacokinetics and clinical effects of phenytoin and. Amitava dasgupta, in clinical challenges in therapeutic drug monitoring, 2016. Phenytoin case history after inpatient evaluation for a generalized seizure, a 28yearold woman was discharged on phenytoin therapy at a dose of 300 mgday. The clinical relevance of pharmacokinetics and drug. Pharmacokinetics, pharmacodynamics, and pharmacogenomics by simon w. The clinical application of pharmacokinetics and pharmacodynamics of cns agents has made significant progress over the past 50 years and new information is reported by numerous publications in psychiatry, neurology, and pharmacology. Applied clinical pharmacokinetics 3 e download ebook pdf.
Click download or read online button to get applied clinical pharmacokinetics 3 e book now. Oct 28, 2019 phenytoin may produce increased serum. 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 most current, handson book in the field, applied clinical pharmacokinetics the perfect textbook for pharmacy students learning the clinical application of pharmacokinetics, which is the mathematical tools for modifying doages. Unexpectedly low serum phenytoin levels occurred in burned epileptic patients, suggesting the possibility of altered phenytoin disposition. Clinical pharmacokinetics 4 practical focus 4 pharmacodynamics 5. Textbook of clinical pharmacology and therapeutics 5th. Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Now the fully updated 5th edition brings to experienced practitioners and students alike the fresh information they need most. However, many published papers have indicated that free phenytoin concentration correlates better with therapeutic efficacy as well as toxicity compared to total phenytoin. It differs from the fourth edition in that it concentrates exclusively on aspects that students should know and understand, rather than including a. Routine clinical pharmacokinetic data collected from out. Patients need to be prescribed appropriate medicines for a clinical condition. In the complex field of pharmacokinetics, one reference guide has an identity all its own.
Clinicians all know that, in general, the halflife of phenytoin is about 22 hours and that the volume of distribution of phenytoin is about 0. Previously reported routine phenytoin clinical pharmacokinetic data from japan, england, and germany were analysed to estimate population pharmacokinetic parameters. There are 23 first and second antiepileptic drugs in current usage, 15 of which were licensed since 1989. Improving upon and updating the information and format of the leading competing clinical pharmacokinetic text, dr. Clinical data from other patient populations with animal data and known developmental pharmacology of neonates to determine best guess for drug and dosing regimens maturation of organ systems leads to differences in dosing needs throughout spectrum of. Our understanding of the interrelationship between these medications, receptors, drug transporters, as well as. Professor and executive dean, south carolina college of pharmacy, the university of south carolina, columbia, medical university of south carolina, charleston, south carolina. The clinical use of drugs applied therapeutics kodakimble clinical pharmacokinetics and pharmacodynamics. A doubleblind trial of phenytoin therapy following craniotomy was performed to test the hypothesis that phenytoin is effective in reducing postoperative epilepsy. Acute phenytoin and primidone intoxication a pharmacokinetic. The data were analysed by the population approach, using the nonlinear mixed effect model, in the multi. It is useful for the prevention of tonicclonic seizures and focal seizures, but not absence seizures. We applied such an integrated approach to characterize the pharmacokineticpharmacodynamic relationship of phenytoin. Steadystate pharmacokinetics of phenytoin from routinely.
Phenytoinfosphenytoin applied clinical pharmacokinetics. In this study a pharmacokineticpharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. However, serum drug levels should only be taken when there is a clear indication to. 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. Bauers specialty area is in clinical pharmacokinetics, and he teaches courses and offers clinical clerkships in this area. Pharmacokinetics and anticoagulation service uk healthcare.
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