Anti Convulsant

Kelompok 2 Chyntia frestica Tri prasetya har adi Resa ambun suri Febri lusiana Sherly octiza

Phenytoin
Phenytoin is a hydantoin compound related to the barbiturates that are used for the treatment of seizures. It is effective anticonvulsant for the chronic treatment of tonic-clonic (grand mal) or partial seizures and the acute treatment of generalized status epilepticus. Phenytoin is a type 1B antiarrhythmic and is also used in the treatment of trigeminal neuralgia.

THERAPEUTIC AND TOXIC CONCENTRATIONS

The usual therapeutic range for total (unbound + bound) phenytoin serum concentrations when the drug is used in the treatment of seizures is 1020 g/mL. Phenytoin is highly bound (~90%) to albumin. The suggested therapeutic range for unbound phenytoin concentrations is based on the usual unbound fraction (10%) of phenytoin in individuals with normal plasma protein binding. The generally accepted therapeutic range for unbound phenytoin concentrations is 12 g/mL,

 the therapeutic range (>15 g/mL) some patients will experience minor central nervous system depression side effects (drowsiness or fatigue) Total phenytoin concentrations above 20 g/mL lateral gaze total concentrations exceed 30 g/mL ataxia, slurred speech, and/or incoordination. total phenytoin concentrations are above 40 g/mL mental status changes, including decreased mentation, severe confusion or lethargy, and coma are possible.

 Unbound phenytoin concentrations are an extremely useful monitoring tool when used correctly. Cf = fBC
total concentration (C) unbound or free concentration(Cf) unbound or free fraction (fB).

CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS

Unbound phenytoin serum concentrations should be measured in patients with factors known to alter phenytoin plasma protein binding.

 These factors fall into three broad categories

lack of binding protein where there are insufficient plasma concentrations of albumin displacement of phenytoin from albumin binding sites by endogenous compounds displacement of phenytoin from albumin binding sites by exogenous compounds

Low albumin concentrations (hypoalbuminemia) Albumin is manufactured by the liver so patients with hepatic disease may have difficulty synthesizing the protein.
Albumin concentrations below 3 g/dL are assosited high phenytoin unbound fractions in the plasma.

 albumin concentrations between 2.53 g/dL have phenytoin unbound fractions of 1520% albumin concentrations between 2.02.5 g/dl have unbound phenytoin fractions >20%.

Displacement of phenytoin from plasma protein binding sites by endogenous substances can occur in patients with hepatic or renal dysfunction (mechanism is competition). Total bilirubin concentrations in excess of 2 mg/dL are associated with abnormal phenytoin plasma protein binding. Phenytoin plasma protein binding displacement can also occur due to exogenously administered compounds such as drugs (warfarin, valproic acid, aspirin (>2 g/d), and some highly bound nonsteroidal antiinflammatory agents.)

 The equation for hypoalbuminemia C Normal Binding = C/(X Alb + 0.1)

CNormal Binding : the normalized total phenytoin concentration (g/mL) C : actual measured phenytoin concentration (g/mL) X : 0.2 if protein binding measurements were conducted at 37C or 0.25 if conducted at 25C (X = 0.1 patient has end-stage renal disease, creatinine clearance <1015 mL/min) Alb : albumin concentration (g/dL)

CLINICAL MONITORING PARAMETERS

The goal of therapy with anticonvulsants is to reduce seizure frequency and maximizequality of life with a minimum of adverse drug effects. Patients should be monitored for concentrationrelated side effects Phenytoin serum concentrations should be measured in most patients. Phenytoin serum concentrations are also valuable tools to avoid adverse drug effects. Because phenytoin follows nonlinear or saturable pharmacokinetics, it is fairly easy to attain toxic concentrations with modest changes in drug dose.

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Phenytoin is primarily eliminated by hepatic metabolism (>95%). Hepatic metabolism is mainly via the CYP2C9 enzyme system with a smaller amount metabolized by CYP2C19. Phenytoin follows Michaelis-Menten or saturable pharmacokinetics. rate of metabolism = (Vmax C) / (Km + C)
Vmax : maximum rate of metabolism (mg/d) C : phenytoin concentration (mg/L) Km : substrate concentration (mg/L) rate of metabolism = Vmax /2.

 Michaelis-Menten clearance of phenytoin is not a constant as it is with linear pharmacokinetics, but is concentration- or dose-dependent. dose or concentration of phenytoin increases, the clearance rate (Cl) decreases as the enzyme approaches saturable conditions
Cl = Vmax / (K + C)
m

This is the reason concentrations increase disproportionately after a phenytoin dosage increase.

 Michaelis-Menten equation, to compute the maintenance dose (MD in mg/d) required to achieve a target steady-state phenytoin serum concentration Css (g/mL or mg/L)

when Km>>Css, phenytoin follows linear pharmacokinetics.

Liver Dysfunction
Patients with liver cirrhosis or acute hepatitis have reduced phenytoin clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of CYP2C9 and CYP2C19 available to metabolize the drug and decreases Vmax. The volume of distribution is larger because of reduced plasma protein binding. Protein binding is reduced and unbound fraction is increased due to hypoalbuminemia and/or hyperbilirubinemia (especially albumin 3 g/dL and/or total bilirubin 2 mg/dL) However, the effects that liver disease has on phenytoin pharmacokinetics are highly variable and difficult to accurately predict.

 Child-Pugh Scores for Patients with Liver Disease

The Child-Pugh score consists of five laboratory tests or clinical symptoms: serum albumin, total bilirubin, prothrombin time, ascites, and hepatic encephalopathy. Each of these areas is given a score of 1 (normal) 3 (severely abnormal)

 patient with normal liver function is 5 while the score for a patient with grossly abnormal liver is 15. A Child-Pugh score greater than 8 is grounds for a decrease of 2550% in the initial daily drug dose for phenytoin. Other patients are also prone to hypoalbuminemia : nephrotic syndrome, cystic fibrosis patients, and malnourished individuals.

Pregnancy
Pregnant women taking phenytoin have increased dosage requirements, particularly during the third trimester (>26 weeks) several reasons for this change including
malabsorption of drug resulting in decreased bioavailability increased metabolism of phenytoin decreased protein binding due to low albumin concentrations

An additional concern when administering phenytoin to pregnant patients is the development of fetal hydantoin syndrome by the baby

Elderly
Elderly individuals over the age of 65 years have a decreased capacity to metabolize phenytoin because :
Decreased amounts of CYP2C9 and CYP2C19 Hypoalbuminemia

clinicians tend to prescribe lower initial phenytoin doses for older patients (~200 mg/d).

Renal Dysfunction
End-stage renal disease patients with creatinine clearances <1015 mL/min, these patients tend to have hypoalbuminemia. Unbound phenytoin serum concentration monitoring is very helpful in determining dosage requirements for renal failure patients

Hypoalbuminemia
Other patients are also prone to hypoalbuminemia, including patients with the nephrotic syndrome, cystic fibrosis patients, and malnourished individuals.

Dialysis
Hemodialysis does not remove enough phenytoin that supplemental postdialysis doses are necessary. The typical sieving coefficient during hemoperfusion for phenytoin is 0.45 so in some cases supplemental phenytoin doses could be needed. Because of pharmacokinetic variability, check phenytoin concentrations in patients receiving hemoperfusion.

Hyperalbuminemia
High bilirubin concentrations can also be found in patients with biliary tract obstruction or hemolysis. Unbound phenytoin concentration monitoring should be considered in these patients especially when albumin concentrations are 3 g/dL or total bilirubin concentrations are 2 mg/dL

CARBAMAZEPINE
Carbamazepine is an iminostilbene derivative related to the tricyclic antidepressants, used in the treatment of tonic-clonic (grand mal), partial or secondarily generalized seizures. Carbamazepine is also a useful agent to treat trigeminal neuralgia and bipolar affective disorders.

THERAPEUTIC AND TOXIC CONCENTRATIONS

The accepted therapeutic range for carbamazepine : 412 g/mL (for the treatment of seizures) Carbamazepine plasma protein binding is quite variable among individuals because it is bound to both albumin and 1-acid glycoprotein (AGP). In patients with normal concentrations proteins, plasma protein binding is 7580% resulting in a free fraction of drug of 2025%.

CLINICAL MONITORING PARAMETERS

The goal of therapy is reduce seizure frequency and maximize quality of life with a minimum of adverse drug effects. Patients should be monitored for concentrationrelated side effects. Because carbamazepine has antidiuretic effects associated with reduced levels of antidiuretic hormone, some patients may develop hyponatremia during chronic therapy with carbamazepine, and serum sodium concentrations can be periodically measured.

 Hematologic adverse effects can be divided into two types.

Leukopenia Thrombocytopenia, leukopenia (trend downward in white blood cell count with <2500 cells/mm or absolute neutrophil count <1000 cells/mm ), or anemia are in this category
2 2

Other idiosyncratic side effects include skin rash, Stevens-Johnson syndrome, and systemic lupus-like reactions. Carbamazepine serum concentrations are also valuable tools to avoid adverse drug effects.

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Carbamazepine is primarily eliminated by hepatic metabolism (>99%) mainly via the CYP3A4 enzyme system. Carbamazepine is a potent inducer of hepatic drug metabolizing enzymes, and induces its own metabolism, a process known as autoinduction. At first, patients are started on 1/41/3 of the desired maintenance dose (This exposes hepatic drug metabolizing enzymes to carbamazepine and begins the induction process.) The dose is increased by a similar amount every 23 weeks until the total desired daily dose is ultimately given.

 Therapeutic effect and steady-state carbamazepine serum concentrations can be assessed 23 weeks after the final dosage increase. An injectable form of carbamazepine is not available. For oral use, the drug is available as :
immediate-release tablets (chewable: 100 mg, regular: 100 mg, 200 mg, 300 mg) sustained-release tablets (100 mg, 200 mg, 400 mg) sustained-release capsules (100, 200,300 mg) suspension (100 mg/5 mL).

Liver Dysfunction
Patients with liver cirrhosis/acute hepatitis reduced carbamazepine clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of CYP3A4 available to metabolize the drug and decreases clearance. volume of distribution may be larger because of reduced plasma protein binding. Protein binding may be reduced and unbound fraction maybe increased due to hypoalbuminemia or hyperbilirubinemia (especially albumin 3 g/dL and/or total bilirubin 2 mg/dL) An index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system.

 Carbamazepine serum concentrations and the presence of adverse drug effects should be monitored frequently in patients with liver cirrhosis.

Other Disease and Conditions

Elderly patients have lower carbamazepine oral clearance rates than younger adults so lower initial doses (100 mg/d) may be used in older individuals. During the third trimester of pregnancy, oral clearance of carbamazepine may decrease and require dosage adjustment. Doses of carbamazepine do not require adjustment for patients with renal failure, and the drug is not removed by dialysis. Breast milk concentrations of carbamazepine are about 60% of concurrent serum concentrations.

 The original computation of these doses were based on the pharmacokinetic dosing methods, and modified based on clinical experience In general, the expected carbamazepine Css used to compute these doses was 68 g/mL. Twice daily dosing is initially used until autoinduction takes place. Dosage increases to allow for autoinduction are made every 23 weeks depending on response and adverse effects
8001200 mg/d (adults) 400800 mg/d (children)

INITIAL DOSAGE DETERMINATION METHODS

patient has significant hepatic dysfunction (Child-Pugh score 8), maintenance doses prescribed using this method should be decreased by 2550% depending on how aggressive therapy is required to be for the individual.

USE OF CARBAMAZEPINE SERUM CONCENTRATIONS TO ALTER DOSES

measurement of carbamazepine serum concentrations is conducted for almost all patients to ensure that therapeutic, nontoxic levels are present. to carbamazepine serum concentrations, important patient parameters (seizure frequency, potential carbamazepine side effects, etc.) should be followed to confirm that the patient is responding to treatment and not developing adverse drug reactions.

 Pseudolinear Pharmacokinetics Method

Css new = (D new / D old)Css old
Css new : expected Css from the new carbamazepine dose (g/mL) Cssold : measured Css from the old carbamazepine dose (g/mL) Dnew : new carbamazepine dose to be prescribed (mg/d) Dold : currently prescribed carbamazepine dose (mg/d)

A steady-state trough total carbamazepine serum concentration should be measured after steady state is attained in 23 weeks

BAYESIAN PHARMACOKINETIC COMPUTER PROGRAMS can assist in the computation of pharmacokinetic parameters for patients The most reliable computer programs use a nonlinear regression algorithm that incorporates components of Bayes theorem Unfortunately, these types of computer programs have not been able to give acceptable solutions unless four or more carbamazepine concentrations are available.

Valproic Acid
Valproic Acid is agent that is chemically related to free fatty acids and is used in the treatment of generalized, partial, and absence (petit mal) seizures. It has thewidest spectrum of activity compared to the other currently available antiepileptic drugs. Now available in intravenous, as well as oral, form, valproic acid can be used for the acute treatment and chronic prophylaxis of seizures. also a useful agent for the treatment of bipolar affective disorders and the prevention of migraine headaches. its antiepileptic effect is thought to result from
its ability to increase concentrations of the neuroinhibitor aminobutyric acid (GABA), to potentiate the postsynaptic response to GABA, to exert a direct effect on cellular membranes.

 The generally accepted therapeutic range for total valproic acid Css : 50100 g/mL. some clinicians suggest drug concentrations as high as 175 g/mL with appropriate monitoring of serum concentrations and possible adverse effects. highly protein bound to albumin with typical values of 9095%. Plasma protein binding of valproic acid is saturable within the therapeutic range, which results in less protein binding and higher unbound fraction of drug at higher concentrations.

THERAPEUTIC AND TOXIC CONCENTRATIONS

 The concentration-dependent protein binding of valproic acid causes the drug to follow nonlinear pharmacokinetics (fundamentally different from phenytoin) In the case of valproic acid, when the dose total drug steady-state concentration less than expected, but unbound steadystate drug concentration in a proportional fashion.

 unbound steady-state concentration therapeutic range for valproic acid of 2.510. As is the case with phenytoin, measurement of unbound valproic acid serum concentrations should be considered in patients with factors known to alter valproic acid plasma protein binding. These factors fall into three broad categories :
lack of binding protein where there are insufficient plasma concentrations of albumin displacement of valproic acid from albumin binding sites by endogenous compounds displacement of valproic acid from albumin binding sites by exogenous compounds

Disease States and Conditions that Alter Valproic Acid Plasma Protein Binding

 In the upper end of the therapeutic range (>75 g/mL) some patients will begin to experience the concentration-dependent adverse effects of valproic acid therapy : ataxia, sedation, lethargy, and tiredness. Other concentration-related side effects of valproic acid therapy include:
tremor : concentrations >100 g/mL stupor or coma : concentrations >175 g/mL

 The goal of therapy with anticonvulsants to reduce seizure frequency and maximize quality of life with a minimum of adverse drug effects. Patients should be monitored for concentration-related side effects (local irritation of gastric mucosa) Valproic acid serum concentrations should be measured in most patients. Valproic acid serum concentrations are also valuable tools to avoid adverse drug effects. Patients are more likely to accept drug therapy if adverse reactions are held to the absolute minimum.

CLINICAL MONITORING PARAMETERS

 For parenteral use, valproic acid is available as a 100 mg/mL solution. When given intravenously, it should be diluted in at least 50 mL of intravenous solution, and given over 1 hour (injection rates should not exceed 20 mg/min). For oral use,
a syrup (50 mg/mL) soft capsule (250 mg) enteric coated capsules (125 mg, 250 mg, and 500 mg) sustained-release tablets (250 mg and 500 mg) sprinkle capsule (125 mg, used to sprinkle into foods)

Liver Dysfunction
Valproic acid clearance in patients with liver disease is 34 mL/h/kg, The volume of distribution may be larger because of reduced plasma protein binding (free fraction 29%) Average half-life for valproic acid in patients with liver disease is 25 hours the effects that liver disease has on valproic acid pharmacokinetics are highly variable and difficult to accurately predict. It is possible for a patient with liver disease to have relatively normal or grossly abnormal valproic acid clearance and volume of distribution An index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system to the patient

Other Disease and Conditions

Elderly patients have lower valproic acid oral clearance rates and higher unbound fractions than younger adults so lower initial doses may be used in older individuals. Doses of valproic acid do not require adjustment for patients with renal failure, and the drug is not removed by dialysis. Breast milk concentrations of valproic acid are about 10% of concurrent serum concentrations.

 Aspirin, warfarin, and phenytoin all have plasma protein binding drug interactions with valproic acid, and these drugs have higher unbound fractions when given concurrently with valproic acid. The drug interaction between valproic acid and phenytoin deserves special examination because of its complexity and because these two agents are regularly used together for the treatment of seizures

INITIAL DOSAGE DETERMINATION METHODS

Pharmacokinetic dosing method

CLEARANCE ESTIMATE VOLUME OF DISTRIBUTION ESTIMATE HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS

Literature-Based Recommended Dosing

USE OF VALPROIC ACID SERUM CONCENTRATIONS TO ALTER DOSES
Pseudolinear Pharmacokinetics Method Pharmacokinetic Parameter Method

BAYESIAN PHARMACOKINETIC COMPUTER PROGRAMS

phenobarbital
is a barbiturate and primidone is a deoxybarbiturate that are effective in the ntreatment of generalized tonic-clonic and partial seizures serum concentrations, or primidone plus phenobarbital serum concentrations for those patients receiving primidone therapy, should be measured in most patients. Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis.

 The therapeutic ranges for phenobarbital and primidone are defined by most laboratories as 15 40 g/mL and 512 g/mL When primidone is given, sufficient doses are usually administered to produce therapeutic concentrations of both phenobarbital and primidone. At present, concentrations of the other possible active metabolite of primidone, PEMA, are not routinely measured. While animal experiments indicate that primidone has inherent antiseizure activity, some clinicians believe that phenobarbital is the predominant species responsible for the therapeutic effect of primidone in humans

CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS

Unbound phenytoin concentrations are an extremely useful monitoring tool when used correctly. Cf = fBC total concentration (C) unbound or free concentration(Cf) unbound or free fraction (fB). Unbound phenytoin serum concentrations should be measured in patients with factors known to alter phenytoin plasma protein binding.

 These factors fall into three broad categories

lack of binding protein where there are insufficient plasma concentrations of albumin displacement of phenytoin from albumin binding sites by endogenous compounds displacement of phenytoin from albumin binding sites by exogenous compounds

Low albumin concentrations (hypoalbuminemia) Albumin is manufactured by the liver so patients with hepatic disease may have difficulty synthesizing the protein.
Albumin concentrations below 3 g/dL are assosited high phenytoin unbound fractions in the plasma.

 albumin concentrations between 2.53 g/dL have phenytoin unbound fractions of 1520% albumin concentrations between 2.02.5 g/dl have unbound phenytoin fractions >20%.

Displacement of phenytoin from plasma protein binding sites by endogenous substances can occur in patients with hepatic or renal dysfunction (mechanism is competition). Total bilirubin concentrations in excess of 2 mg/dL are associated with abnormal phenytoin plasma protein binding. Phenytoin plasma protein binding displacement can also occur due to exogenously administered compounds such as drugs (warfarin, valproic acid, aspirin (>2 g/d), and some highly bound nonsteroidal antiinflammatory agents.)

The equation for hypoalbuminemia

C Normal Binding = C/(X Alb + 0.1)
CNormal Binding : the normalized total phenytoin concentration (g/mL) C : actual measured phenytoin concentration (g/mL) X : 0.2 if protein binding measurements were conducted at 37C or 0.25 if conducted at 25C (X = 0.1 patient has end-stage renal disease, creatinine clearance <1015 mL/min) Alb : albumin concentration (g/dL)

 estimated unbound phenytoin concentration (CfEST) = 0.1 C Normal Binding

CfEST = (0.095 + 0.001 VPA)PHT (patients

with concurrent valproic acid administration, PHT (g/mL) VPA (g/mL

 The goal of therapy with anticonvulsants is to reduce seizure frequency and maximizequality of life with a minimum of adverse drug effects. Patients should be monitored for concentration-related side effects Phenytoin serum concentrations should be measured in most patients. Phenytoin serum concentrations are also valuable tools to avoid adverse drug effects. Because phenytoin follows nonlinear or saturable pharmacokinetics, it is fairly easy to attain toxic concentrations with modest changes in drug dose.

BASIC CLINICAL PHARMACOKINETIC PARAMETERS Phenytoin is primarily eliminated by hepatic

metabolism (>95%). Hepatic metabolism is mainly via the CYP2C9 enzyme system with a smaller amount metabolized by CYP2C19. Phenytoin follows Michaelis-Menten or saturable pharmacokinetics. rate of metabolism = (Vmax C) / (Km + C)
Vmax : maximum rate of metabolism (mg/d) C : phenytoin concentration (mg/L) Km : substrate concentration (mg/L) rate of metabolism = Vmax /2.

 Michaelis-Menten : clearance of phenytoin is not a constant as it is with linear pharmacokinetics, but is concentration- or dose-dependent. dose or concentration of phenytoin increases, the clearance rate (Cl) decreases as the enzyme approaches saturable conditions
Cl = Vmax / (K + C)
m

This is the reason concentrations increase disproportionately after a phenytoin dosage increase.

 Phenytoin volume of distribution (V = 0.7 L/kg) is unaffected by saturable metabolism

V = VB+ (fB/fT)VT physiological volume of blood (VB), tissues (VT), the unbound concentration of drug in the blood (fB) and tissues (fT)

t1/2 = (0.693 V)/Cl the time to steady-state serum concentrations is approximately 5 days at a dosage rate of 300 mg/d and 15 days at a dosage rate of 400 mg/d

 Michaelis-Menten equation, to compute the maintenance dose (MD in mg/d) required to achieve a target steady-state phenytoin serum concentration Css (g/mL or mg/L)

when Km>>Css, phenytoin follows linear pharmacokinetics.

 For parenteral use, phenytoin is available in two different dosage forms. Phenytoin sodium, the sodium salt of phenytoin, contains 92% phenytoin by weight. Even though it is a salt of phenytoin, the drug is still relatively insoluble in water. very painful for injection. When given intravenously, injection rates should not exceed 50 mg/min to avoid hypotension. To avoid many of the problems associated with phenytoin sodium injection, a watersoluble phosphate ester prodrug of phenytoin, fosphenytoin, has been developed. With half-life of approximately 15 minutes 100 mg PE of fosphenytoin is equivalent to 100 mg of phenytoin sodium.

 Hypotension during intravenous administration fosphenytoin is much less than with phenytoin sodium. The maximal intravenous infusion rate is 150 mg PE/min. bioavailability via this route of administration is 100%. Fosphenytoin is much more expensive than phenytoin sodium injection. For oral use, capsules contain phenytoin sodium (92% phenytoin, by weight)
Extended phenytoin capsules release phenytoin slowly from the gastrointestinal tract into the systemic circulation. can be given every once or twice daily (available in 30 mg, 100 mg, 200 mg, and 300 mg strengths)

 Prompt phenytoin sodium capsules are absorbed fairly quickly from the gastrointestinal tract because they contain microcrystalline phenytoin sodium which dissolves quicker in gastric juices. must be given multiple times daily .

Phenytoin tablets (50 mg, chewable) and suspension (125 mg/5 mL) for oral use are available as the acid form of the drug.
Both them are absorbed more rapidly than extended phenytoin sodium capsules

The oral bioavailability of phenytoin is very good for capsule, tablet, and suspension dosage forms and approximates 100%.

 The typical recommended loading dose for phenytoin is 1520 mg/kg resulting in 1000 mg for most adult patients. Usual initial maintenance doses are 510 mg/kg/d for children (6 months16 years old) and 46 mg/kg/d for adults. For adults the most prescribed dose is 300 400 mg/d of phenytoin. maximum of 200 mg/d as an initial dose for older patients (>65 years old)

Liver Dysfunction
Patients with liver cirrhosis or acute hepatitis have reduced phenytoin clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of CYP2C9 and CYP2C19 available to metabolize the drug and decreases Vmax. The volume of distribution is larger because of reduced plasma protein binding. Protein binding is reduced and unbound fraction is increased due to hypoalbuminemia and/or hyperbilirubinemia (especially albumin 3 g/dL and/or total bilirubin 2 mg/dL) However, the effects that liver disease has on phenytoin pharmacokinetics are highly variable and difficult to accurately predict.

Pregnancy
Pregnant women taking phenytoin have increased dosage requirements, particularly during the third trimester (>26 weeks) several reasons for this change including
malabsorption of drug resulting in decreased bioavailability increased metabolism of phenytoin decreased protein binding due to low albumin concentrations

An additional concern when administering phenytoin to pregnant patients is the development of fetal hydantoin syndrome by the baby

Elderly
Elderly individuals over the age of 65 years have a decreased capacity to metabolize phenytoin because :
Decreased amounts of CYP2C9 and CYP2C19 Hypoalbuminemia

clinicians tend to prescribe lower initial phenytoin doses for older patients (~200 mg/d).

Renal Dysfunction
End-stage renal disease patients with creatinine clearances <1015 mL/min, these patients tend to have hypoalbuminemia. Unbound phenytoin serum concentration monitoring is very helpful in determining dosage requirements for renal failure patients

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

by hepatic metabolism urine Increasing renal clearance % bound to plasma proteins AB orally 100 % The typical maintenance dose for phenobarbital is 2.55 mg/kg/d for neonates, 34.5 mg/kg/d for pediatric patients (<10 years old) 1.52 mg/kg/d for older patients.4,6 For the acute treatment of status epilepticus intravenous phenobarbital doses of 1520 mg/kg are used

Adverse Effects
Nausea Vomiting Diplopia Dizziness Sedation Unsteadiness Ataxia Generally, slow dosage titration, administration of smaller doses and more frequent dosing of the drug produce relief from these side effects

Clinical Monitoring Parameters

Phenobarbital serum concentrations, or primidone plus phenobarbital serum concentrations for those patients receiving primidone therapy, should be measured in most patients. Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis. Thus, during dosage titration it is difficult to tell if the patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time.

Effects of Disease States & Conditions on Pharmacokinetics and Dosing

Phenobarbital in Renal Dysfunction & Older Patient

Similarly, because phenobarbital is also eliminated by the kidney, patients with renal dysfunction (creatinine clearance <30 mL/min) receiving phenobarbital should be closely monitored. Phenobarbital is significantly removed (~30% of total body amount) by hemodialysis, and supplemental doses may need to be given after a dialysis session. Phenobarbital is significantly removed by hemoperfusion with a sieving coefficient equal to 0.8 The primidone clearance rate (Cl/F) for older patients (12 years old) taking primidone alone is 35 mL/h/kg

Drug Interaction
Drugs That Increase Metabolism and Clearance of Phenobarbital: carbamazepine lamotrigine valproic acid cyclosporin nifedipine diltiazem verapamil oral contraceptives quinidine theophylline warfarin Drugs That Decrease Metabolism and Clearance of Phenobarbital

felbamate
valproic acid

Initial Dosage Determination Methods

Pharmacokinetic Dosing Method

CLEARANCE ESTIMATE VOLUME OF DISTRIBUTION ESTIMATE HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS

Summary
Phenytoin, Carbamazepine, Valproic Acid have narrow therapeutic window so the range between MIC and MTC is very little so the dose must be given correctly For the patients with renal failure and liver disease the elimination and metabolism of drug is abnormal so we mush calculate the appropriate dose.

References
Bauer, Larry A.2008. Applied Clinical Pharmacokinetics Second Edition. Washington : MacGrawHill Medical Bauer, Larry A. 2006. Clinical Pharmacokinetics Handbook. Washington : MacGrawHill Medical