carbamazipine-1.pptx2.pdf

CARBAMAZEPINE 1 OBJECTIVES • • • • • • To study the Pharmacokinetics of Carbamazepine: Vd, t ½, Clearance, Bioavailability etc.. To understand the Key parameters. To learn about therapeutic and toxic plasma concentrations of the drug. To study about CYP 3A4 inducers and CYP 3A4 inhibitors. To...

CARBAMAZEPINE 1 OBJECTIVES • • • • • • To study the Pharmacokinetics of Carbamazepine: Vd, t ½, Clearance, Bioavailability etc.. To understand the Key parameters. To learn about therapeutic and toxic plasma concentrations of the drug. To study about CYP 3A4 inducers and CYP 3A4 inhibitors. To know about Autoinduction. To study about the sampling behaviour of the drug. 2 •Anticonvulsant compound. •Treatment of seizures. •Many dosage forms •oral suspensions, •chewable tablets, •oral immediate release tablets •extended release tablets •extended release capsules. Loading… •Effective dose for seizure disorders : •15 to 25 mg/kg/day. 3 •Metabolized by P450 isozymeCYP3A4. •Formation of carbamazepine-10,11-epoxide : •Having some anticonvulsant activity. •Ratio of carbamazepine-10,11-epoxide to carbamazipine higher in infants and preschool children than in adults. 4 •Less than 2% carbamazepine excreted unchanged in urine. •Bound to plasma albumin and α1 –acid glycoprotein to a significant extent. Loading… •Free fraction : Approximately 0.2 to 0.3, •Alteration in serum protein concentration may affect therapeutic range. 5 Key parameters: Therapeutic plasma concentration 4-12 mg/L. Bioavailability factor (F) 80% Chemical form (S) (administered as active form) 1.0 Volume of distribution(V)(based on oral administered data) 1.4L/kg . 6 • Clearance(cl) • Monotherapy 0.064L/kg/hr • Polytherapy 0.1L/kg/hr • Children (Monotherapy) 0.11L/kg/hr • α (freefraction) 0.2-0.3 7 • T1/2 • Adult monotherapy 15 hr • Adult polytherapy 10 hr • Polytherapy –a patient receiving other enzyme inducing anticonvulsant. 8 THERAPEUTIC AND TOXIC PLASMA CONCENTRATIONS Therapeutic plasma concentration 4-12 mg/L. Symptoms of toxicity : Plasma concentration exceeds 9 mg/L. Many clinicians prefer to use a therapeutic range of approximately 4-8 mg/L. 9 Carbamazepine drug interaction CYP 3A4 inhibitors ♦ Inhibit carbamazepine metabolism ♦ Increase plasma carbamazepine levels; cimetidine, diltiazem, erythromycin, clarithromycin, fluoxetine, loratadine, verapamil, valproate. . 10 • CYP 3A4 inducers • Induce rate of metabolism • Decrease plasma carbamazepine levels : • cisplatin, doxorubicin, felbamate, Loading… phenobarbital, phenytoin, primidone, • Rifampicin,Theophylline. 11 ADVERSE DRUG REACTIONS CNS: Blurred vision Drowsiness, Ataxia, Nystagmus, Skin rashes, Syndrome of inappropriate antidiuretic hormone(SIADH) and Hyponatremia. 12 • Dermatological and hematological side effects. • Mild leukopenia-10% of patients. • Teratogenic. 13 BIOAVAILABILITY: Lipid soluble compound Slowly and variably absorbed from GIT Bioavailability factor (F) : approximately 0.8 when administered as oral tablet, chewable tablet or suspension. Controlled release product : well absorbed , Bioavailability 89% of the suspension. 14 • Slowly absorbed, • Changes in gastrointestinal function could decrease bioavailability • Result in variable plasma concentration • Estimated to be greater than 75%. • Effects of gender and race not been systematically studied. 15 ♦Volume of distribution : ♦ Approximatly 1.4L/kg. ♦Wide range of reported values (0.8-1.9L/kg), ♦ Variability due to in plasma binding. ♦ Primarily bound to albumin and α1- acid glycoprotein ♦ Has free fraction of approximately 0.2 to 0.3. 16 CLEARANCE (CL) ♦ Exclusively by metabolic route, ♦ Less than 2% of an oral dose being excreted unchanged in urine. ♦ Clearance values difficult to estimate because bioavailability uncertain. 17 ♦ Average clearance value : Approximately 0.064 L/kg/hr in adult patients who have received the drug chronically. ♦ Higher in children : 0.11 L/kg/hr. In patients who are taking other enzyme inducing antiepileptic drugs concurrently, clearance increased to 0.1L/kg/hr. ♦ Increase in clearance : Auto induction of its metabolic enzymes. 18 ♦ Carbamazipine principle example of drug that displays autoinduction ♦ Potent inducer of drug metabolizing enzymes ♦ Important to initiate patients with relatively low dose to avoid side effects early in the therapy. ♦ Maintenance dose increased at 1-week to 2week intervals. ♦ Autoinduction of metabolism commonly causes changes in steady-state carbamazepine levels ♦ Less than proportional to an increase in the maintenance dose. 19 ♦ Cross-induction (i.e. enhanced metabolism) of other anti convulsants. Whenever added to anticonvulsant regimen or other agents are added ♦ Additional plasma level monitoring ♦ Ensures maintenance regimen optimal for therapeutic control. 20 HALF-LIFE(T1/2) • • • • Children metabolize more rapidly than adults Reported steady-state half-lives of 4-12 hours. Adult patients receiving carbamazepine monotherapy,-half life :15 hrs. Adult patients receiving other enzyme inducing antiepileptic drugs (eg.phenytoin,phenobarbital), half-life :10 hrs. 21 TIME TO SAMPLE • • • • • • Within first few weeks useful Most sensible time : Early morning before the first dose is administered, or Later in the day before the next dose. Such samples reflect trough conc. Comparable from day to day. 22 Limitations ♦ Autoinduction, ♦ Many drug interactions, toxicities and teratogenicity. Oxcarbazepine (Trileptal) ♦ Chemically similar to carbamazepine ♦ Improved safety profile. ♦ Alternative for Carbamazepine. 23 CONCLUSION • • • • Many patients, develop symptoms of toxicity when plasma concentration exceeds 9 mg/L. Carbamazepine, is primarily bound to albumin and α1- acid glycoprotein and has a free fraction of approximatly 0.2 to 0.3. Children metabolize carbamazepine more rapidly than adults Adult patients receiving other enzyme inducing antiepileptic drugs (eg.phenytoin,phenobarbital), half-life of approximately10 hrs. 24 • • • • Increase in clearance associated with chronic therapy is due to auto induction of its metabolic enzymes. Carbamazipine is the principle example of drug that displays autoinduction Potent inducer of drug metabolizing enzymes Oxcarbazepine is an alternative for Carbamazepine. 25 1. N.S., a 36 year old, 60 kg woman, is to be given carbamazepine as an anticonvulsant agent. Calculate a daily dose that will produce an average steady-state plasma concentration of approximatly 6 mg/L. Bioavailability : 0.8 Average clearance value: 0.064L/kg/hr S= 1.0 26 2. After 2 months, N.S.’s carbamazepine dose had been increased to 300 mg twice a day. With this regimen, she had some reduction in seizure frequency: however seizure control was still considered unsatisfactory. The steady state carbamazepine level at this time was reported to be 4 mg/L. What are possible explanations for this observed plasma level? What dose would be required to achieve a new steady state carbamazepine level of 6 mg/L. 27 LEARNING OUTCOMES • • • At the end of the chapter the student will be able to 1. Calculate daily doses of cabamazepine depending on parameters available 2. Understand various Pharmacokinetic parameters of Carbamazepine 28