Anti Convulsant

Anti ConvulsantGroup 7Class ARifka Uljannah1211012007Lora Rahmatika1211012020Vonny kurnia utama1211012026Fadhila Ulfa Irawan1211013011Phenytoin adalah senyawa hidantoin yang digunakan untuk pengobatan serangan jantungAntikonvulsan ini efektif untuk mengobati penyakit jantung kronik atau serangan akut dengan status epilepticusPhenytoin adalah tipe 1B aritmik dan juga digunakan untuk mengobati trigeminal neuralgia.PhenytoinTHERAPEUTIC AND TOXIC CONCENTRATIONSRentang terapeutik yang biasa (bebas + berikatan) konsentrasi serum fenitoin yang digunakan untuk serangan jantung adalah 1020 g/mL.Phenytoin terikat tinggi (~90%) dengan albumin.Rentang terapeutik yang dianjurkan untuk fenitoin bebas 10% dari fenitoin normal yang terikat dalam proein plasma.Secara umim terapeutik fenitoin bebas 12 g/mL,Rentang terapi (>15 g/mL) pada beberapa pasien akan memberikan efek samping depresi sistem saraf pusat Konsentrasi fenitoin diatas20 g/mL menyebabkan lateral gazeTotal konsentrasi melebihi 30 g/mL kehilangan keseimbangan,susah menelan, dan atau kehilangan koordinasi.Total konsentrasi fenitoin diatas 40 g/mL perubahan status mental,termasuk penurunan mental,kelesuan,dan koma

CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONSUnbound 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 categorieslack of binding protein where there are insufficient plasma concentrations of albumindisplacement of phenytoin from albumin binding sites by endogenous compoundsdisplacement of phenytoin from albumin binding sites by exogenous compoundsLow 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 hypoalbuminemiaC 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 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 conditionsCl = Vmax / (Km + C)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 metabolismV = VB+ (fB/fT)VTphysiological volume of blood (VB), tissues (VT), the unbound concentration of drug in the blood (fB) and tissues (fT)t1/2 = (0.693 V)/Clthe 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/dMichaelis-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 minutes100 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 capsulesThe 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 300400 mg/d of phenytoin.maximum of 200 mg/d as an initial dose for older patients (>65 years old)EFFECTS OF ALTERED PLASMA PROTEIN BINDING ON PHENYTOIN PHARMACOKINETICSa decrease in plasma protein binding and increase in unbound fraction increase clearance (Cl = fBClint) and volume of distribution [V = VB + (fB / fT)VT]half-life will not substantially change [t1/2 = (0.693 V) / Cl]Clinicians need to be on the outlook for situations because the total drug concentration (bound + unbound) can be misleading and cause an unwarranted increase in drug dosage.

EFFECTS OF DISEASE STATES AND CONDITIONS ON PHARMACOKINETICS AND DOSINGAdults without the disease states with normal liver and renal function as well as normal plasma protein binding (~90%)Vmax of 7 mg/kg/d (range: 1.514 mg/kg/d)Km of 4 g/mL (range:115 g/mL)Michaelis-Menten parameters for younger children (6 months6 years)Vmax = 12 mg/kg/dKm = 6 g/mLfor older children (716 years)Vmax = 9 mg/kg/dKm = 6 g/mL

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.Liver DysfunctionChild-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.Trauma and burn patients have an increased ability to metabolize phenytoin beginning 37 days after their initial injury. At this time, these patients become hypermetabolic in order to repair damaged tissue, and the Vmax for phenytoin increases due to this general increase in metabolic rate. If caloric needs are not met during this phase of recovery for trauma patients, many become hypoalbuminemic, and phenytoin plasma protein binding decreases resulting in an increased unbound fraction. Phenytoin dosage requirements are increased while trauma patients are in their hypermetabolic phase, and unbound concentration monitoring is indicated when patients have low albumin concentrations (especially for albumin levels 3 g/dL).Trauma/BurnsPregnant women taking phenytoin have increased dosage requirements, particularly during the third trimester (>26 weeks)several reasons for this change includingmalabsorption of drug resulting in decreased bioavailabilityincreased metabolism of phenytoindecreased protein binding due to low albumin concentrationsAn additional concern when administering phenytoin to pregnant patients is the development of fetal hydantoin syndrome by the babyPregnancyElderly individuals over the age of 65 years have a decreased capacity to metabolize phenytoin because :Decreased amounts of CYP2C9 and CYP2C19Hypoalbuminemiaclinicians tend to prescribe lower initial phenytoin doses for older patients (~200 mg/d).ElderlyRenal DysfunctionEnd-stage renal disease patients with creatinine clearances 2 g/d), some NSAID, and warfarin displace phenytoin from plasma protein binding sites need monitoring of unbound phenytoin concentrations.INITIAL DOSAGE DETERMINATION METHODSPharmacokinetic Dosing MethodPhenytoin serum concentration monitoring, including unbound concentration measurement if altered plasma protein binding is suspected, is an important component of therapy for this drug.Use Child-Pugh parameter. MICHAELIS-MENTEN PARAMETER ESTIMATES (last slide)VOLUME OF DISTRIBUTION ESTIMATEpatients with normal phenytoin plasma protein binding 0.7 L/kg for adults.obese individuals 30% or more above their ideal body weightV = 0.7 L/kg [IBW + 1.33(TBW IBW)]IBW : ideal body weight (kg)IBWfemales (kg) = 45 + 2.3(Ht 60)IBWmales (in kg) = 50 + 2.3(Ht 60)Ht : height (inches)TBW : total body weight (kg)LD = Css V (loading dose)Css : desired total phenytoin concentration (mg/L) mg/L = g/mLV : volume of distribution (L)SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONSMichaelis-Menten pharmacokinetic equation that computes the average phenytoin steady-state serum concentration (Css in g/mL = mg/L) is widely used and allows maintenance dosage calculation :

S : fraction of the phenytoin salt form that is active phenytoin (0.92 for phenytoin sodium injection and capsules, 0.92 for fosphenytoin)Vmax : maximum rate of metabolism (mg/d)MD : maintenance dose of the phenytoin salt (mg/d)

Css : phenytoin concentration (mg/L = g/mL)Km : substrate concentration (mg/L = g/mL)rate of metabolism = Vmax/2LD = (Css V)/SSTEADY-STATE CONCENTRATION SELECTIONThe generally accepted therapeutic ranges for total and unbound phenytoin concentrations 1020 g/mL and 12 g/mL.fB = Cf/Cunbound fraction (fB)C : total phenytoin concentration (g/mL)Cf : unbound, or free, phenytoin concentration (g/mL)Literature-Based Recommended DosingSuggested phenytoin maintenance doses are 46 mg/kg/d for adults and 510 mg/kg/d for children (6 months16 years old). Phenytoin loading doses are 1520 mg/kg.For obese individuals (>30% over ideal body weight), adjusted body weight (ABW) should be used to compute loading doses: ABW (in kg) = IBW + 1.33(TBW IBW) where IBW is ideal body weight in kilograms [IBWfemales (in kg) = 45 + 2.3(Ht 60) or IBWmales (in kg) = 50 + 2.3(Ht 60)], Ht is height in inches, TBW is total body weight in kilograms.64USE OF PHENYTOIN SERUM CONCENTRATIONS TO ALTER DOSESmeasurement of phenytoin serum concentrations is conducted for almost all patientsn to ensure that therapeutic, nontoxic levels are present. empiric dosing method (adjust phenytoin doses with one or more steady-state concentrations)Graves-Cloyd method (adjustment of phenytoin doses using one steady-state concentration)Vozeh-Sheiner method (to individualize phenytoin doses using a single steady-state concentration, using graph)Mullen method (same as Vozeh-Sheiner method)Ludden method (uses standard graph paper)Bayesian pharmacokinetic computer programs (used in difficult case)

Single Total Phenytoin Steady-State Serum Concentration MethodsEmpiric Phenytoin Dosage Increases Based on a Single Total Steady-State Concentration

DOSING STRATEGIES

Karbamazepin adalah derivat iminostilben yang terhubung pada antidepresan trisiklik, yang digunakan pada terapi tonic klonik, parsial maupun serangan kejang.Karbamazepin juga berguna sebagai agen terapi untuk trigeminal neuralgia dan gangguan bipolar. CARBAMAZEPINETHERAPEUTIC AND TOXIC CONCENTRATIONSrange terapetik yang diterima untuk karbamazepin: 412 g/mL (untuk penanganan kejang)Ikatan protein plasma carbamazepin sangat bervariasi tiap individu karena karbamazepin berikatan pada albumin dan juga 1-acid glykoprotein (AGP).Pada pasien dengan konsentrasi protein normal, protein plasma yang terikat 75-80% sedangkan fraksi obat yang bebas sebanyak 20-25%AGP diklasifikasikan sebagai fase akut protein reaktan yang muncul dalam jumlah yang sedikit pada setiap individu, tetapi disekresikan dalam jumlah banyak dalam merespon pada keadaan stress dan tahapan penyakit (Trauma, gagal jantung, dan infark miokardium)Pada pasien dengan tahap awal penyakit, karbamazepin terikat pada AGP yang dapat menghasilkan lebih besar fraksi yang tidak terikat sampai rendah 10-15%Karbamazepin-10, 11-epoksida merupakan metabolit aktif yang berkontribusi baik secara terapeutik maupun efek toksik dari obat, dan dapat diukur pada sampel serum sejumlah kasus epilepsi yang terbatas. Konsentrasi epoksida cenderung lebih tinggi pada pasien yang mengkonsumsi obat-obat enzim penginduksi dan rendah konsentrasinya pada pasien yang mengkonsumsi enzim inhibitor.Rentang terapi karbamazepin-10, 11-epoksida belum diketahui tapi rentang yang disarankan 0.4-4 g/mL yang biasanya digunakan pada kebanyakan penelitian. Rentang teratas pemakaian karbamazepin untuk terapi (> 8 g/mL) pada beberapa pasien akan mengalami efek timbal balik konsentrasi dari terapi karbamazepin. Karena karbamazepin menginduksi metabolisme hepatik obat itu sendiri, efek kurang baik dapat dilihat segera mungkin selama periode titrasi dosis setelah dosis dinaikkan.Parameter Monitoring Klinik Tujuan terapi adalah untuk mengurangi frekuensi kejang-kejang dan memaksimalkan kualitas hidup dengan memperkecil efek buruk obatPasien sebaiknya dikontrol antara hubungan konsetrasi dengan efek samping. Karena karbamazepin memiliki efek antidiuretik dengan menurunkan jumlah hormon antidiuretik, pada beberapa pasien dapat mengalami hyponatremia selama terapi kronik dan sebaiknya konsentrasi sodium plasmanya diukur secara berkala. Efek buruk hematologi dibagi menjadi dua jenis :LeukopeniaThrombocytopenia, leukopenia (cenderung turun jumlah sel darah putihnya 2 g/d), and some NSAID)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/mLstupor or coma : concentrations >175 g/mLCLINICAL MONITORING PARAMETERSThe 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.

BASIC CLINICAL PHARMACOKINETIC PARAMETERSValproic acid is primarily eliminated by hepatic metabolism (>95%).Hepatic metabolism is via glucuronidation, -oxidation, and -hydroxylation.Over 10 metabolites have been identified for valproic acid, and the 4-en-valproic acid metabolite may be associated with the drugs propensity to cause hepatotoxicity.About 15% of a valproic acid dose is recovered in the urine as unchanged drug.Valproic acid is eliminated almost completely by hepatic metabolism, and it is a low hepatic extraction ratio drug.hepatic clearance rate is described by the classic relationship :ClH = [LBF (fBClint)] / (LBF + fBClint)LBF : liver blood flowfB : the unbound fraction of drug in the bloodClint : intrinsic ability of the enzyme system to metabolize the drugSince valproic acid has a low hepatic extraction ratio, this expression for hepatic clearance simplifies ClH = fBClintclearance of valproic acid is not a constant as it is with linear pharmacokinetics, but is concentration or dose dependent.the clearance rate (Cl) increases because more unbound drug is available to hepatic enzymes for metabolism

This is the reason total steady-state concentrations increase disproportionately after a valproic acid dosage increase.

F : valproic acid bioavailabilityD : valproic acid dose : the dosage intervalClH : hepatic clearanceHowever, since unbound steady-state concentrations are only influenced by intrinsic clearance, unbound concentrations increase in a proportional amount to dose

Valproic acid volume of distribution (V = 0.15 0.2 L/kg) is also affected by concentration-dependent plasma protein binding and is determined by the physiologic volume of blood (VB) and tissues (VT)the unbound fraction of drug in the blood (fB) and tissues (fT)

As valproic acid concentrations, unbound fraction of drug in the bloodwhich causes an in the volume of distribution for the drug

t1/2 is related to clearance and volume of distribution using the same equation as for linear pharmacokineticst1/2 = (0.693 V) / Cl

On average, valproic acid half-life is 1218 hours in adult patients with total concentrations within the therapeutic range.Valproic acid is available as three different entities (all of them are prescribed as valproic acid equivalents)valproic acidsodium valproate (the sodium salt of valproic acid)divalproex sodium (a stable coordination compound consisting of a 1:1 ratio of valproic acid and sodium valproate)

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)The typical maintenance dose for valproic acid is 15 mg/kg/d resulting in 1000 mg or 500 mg twice daily for most adult patients.because age and coadministration of other antiepileptic drugs that are enzyme inducers, affect valproic acid pharmacokinetics, many clinicians recommend the administration7.5 mg/kg/d for adults or 10 mg/kg/d for children under 12 years of age receiving monotherapy15 mg/kg/d for adults or 20 mg/kg/d for children under 12 years of age receiving other drugs that are enzyme inducersEFFECTS OF DISEASE STATES AND CONDITIONSON PHARMACOKINETICS AND DOSINGFor valproic acid, oral clearance :(Cl/F) is 712 mL/h/kg and half-life is 1218 hours for adultsIn children 612 years old, oral clearance and half-life equal 1020 mL/h/kg and 68 hoursClearance rates can be higher and half-lives shorter in patients receiving other hepatic drugmetabolizing enzyme inducersFor adults receiving other antiepileptic drugs that are enzyme inducers, valproic acid clearanceadults is 1518 mL/h/kg and half-lives range from 4 to 12 hoursChildren is 2030 mL/h/kg and half-life is 46 hValproic acid volume of distribution (V/F) is 0.150.2 L/kgValproic 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 hoursthe 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 distributionAn index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system to the patientLiver DysfunctionElderly 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.Other Disease and ConditionsDRUG INTERACTIONSValproic acid is a potent inhibitor of hepatic drug metabolizing enzyme systems and glucuronidationantiepileptic drugs that have their clearance rates and Css by valproic acid-related enzyme inhibition (clonazepam, carbamazepine, phenytoin, primidone, lamotrigine, and ethosuximide)Valproic acid therapy also the clearance and Css of other drugs (zidovudine, amitriptyline, and nortriptyline)Phenytoin, lamotrigine, rifampin, and carbamazepine can valproic acid clr and valproic acid steady-state serum concentrationsCimetidine, chlorpromazine, and felbamate are examples of drugs that valproic acid clearance and valproic acid steady-state 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 seizuresINITIAL DOSAGE DETERMINATION METHODSPharmacokinetic dosing methodCLEARANCE ESTIMATEVOLUME OF DISTRIBUTION ESTIMATEHALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATESELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONSLiterature-Based Recommended DosingUSE OF VALPROIC ACID SERUM CONCENTRATIONS TO ALTER DOSESPseudolinear Pharmacokinetics MethodPharmacokinetic Parameter MethodBAYESIAN PHARMACOKINETIC COMPUTER PROGRAMSDOSING STRATEGIES

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

ReferencesBauer, Larry A.2008. Applied Clinical Pharmacokinetics Second Edition. Washington : MacGrawHill Medical

Bauer, Larry A. 2006. Clinical Pharmacokinetics Handbook. Washington : MacGrawHill Medical

Thanks For Your Attention