1. Carbamazepine (Tegretol) Carbamazepine is one of the older drugs used for the treatment of epilepsy. It has a long history of effectiveness & safety. It is structurally similar to the tricyclic anti depressant agents. It has been the drug of choice for the treatment of trigeminal neuralgia & is used in treatment of generalised as well as complex partial seizures. It is most frequently prescribed for those patients who have failed to respond to other anti convulsant therapy or for those who have developed significant side effects from other anti convulsant agents.

2. Preparation, Dosage & Drug levels: Tegretol is prepaired as 200mg oral tablets,100mg chewable tablets & 100mg/5ml suspension. The usual dose of tegretol is 200mg given 3times daily. Like many drugs that to be taken continuously, It takes from 7 to 14 days to build up the blood level. The range of therapeutic serum concentration for carbamazepine is 4 to to 12 mg/L.

3. Toxic Side Effects: Many patients will develop symptoms of toxicity when plasma concentration exceed 9mg/L. Therefore, many clinicians prefer to use a therapeutic range of 4 to 8 mg/L. These side effects are : - Dizziness: a feeling that the room is spinning around. - Drunken sensation : a feeling of clumsiness,a staggering gait or feeling of slowest movement. - Light headedness :feeling like you might faint. - Double vision : inability to focus well. - Slurred speech: feeling of thick or swollen tongue,inability to control it while speaking. -.

4. Confusion : inability to think clearly. - Memory lapses : difficulty remembering the sorts of things you usually remember. Common side effects: Tegretol can damage your liver. If this occurs the whites of your eyes may turn yellow (jaundice), you may have diarrhea. Tegretol can damage your bone marrow where white blood cells are produced

5. Metabolism: Tegretol is metabolised by the liver. Therefore, the amount of tegretol that you need to take depends on how fast your liver metabolizes it.Anything that adversely affects liver function such as hepatitis or alcohol abuse will affect its ability to metabolise.

6. Key parameters : 4 - 12 mg/LTherapeutic plasma conc. 80 %Bioavailability 1Salt form (S) 1.4 L/kg Volume of distribution Conc. DependentClearance (CL) Conc. DependentHalf Life (t ½)

7. Uses: Tegretol is most effective when used to treat generalised tonic-clonic seizures.These are the type of seizures during which you lose consciousness & your arms or legs may stiffen or jerk. During complex partial seizures you will lose consciousness aware -ness of your surroundings,but you may appear awake to those around you.people who witness a partial complex seizures often describe the afflicted person as confused or staring.Tegretol is not very effective in treating other types of seizures.

8. Bioavailability(F): Carbamazepine is a lipid soluble compound which is slowly absorbed from the G.I.T. Peak plasma conc. Occur approximately 6hrs(range :2 to 24 hrs) after oral ingestion. Although the bioavailability of carbamazepine has not been directly determined,it is estimated to be greater than 70% & may approch 100%. Since carbamazepine is so slowly absorbed, changes in gastrointestinal function, especially those associated with rapid transit, could decrease its bioavailability & result in variable plasma conc. Of carbamazepine.

9. Volume of distribution (vd): The volume of distribution of carbamazepine is approximately 1.4 L/Kg. Carbamazepine, a neutral compound that is primarily bound to albumin & α1-acid glycoprotein, has a free fraction (alpha) of approximately 0.2 to 0.3.

10. Clearance (Cl): Carbamazepine is eliminated almost by the metabolic route,with less than 2% of an oral dose being excreted unchanged in the urine. Clearance values are difficult to estimate because bioavailability is uncertain. Nevertheless,the average clearance value appears to be approximately 0.064 L/Kg in patients who have received the drug chronically. In patients who are taking other enzyme inducing antiepileptic drugs,the clearance is increased to approximately 0.1 L/Kg/hr. Single dose studies suggest a clearance value which is one half to one third of the value observed in patients on chronic therapy.The increase in clearance associated with chronic therapy is apparently due to auto- induction of its metabolic enzymes. Auto-induction of metabolism commonly cause changes in steady-state carbamazepine levels which are less than proportional to an increase in the maintenance dose.

11. Half life (t1/2): Single dose studies predict a carbamazepine half life of approximately 30 to 35 hrs,steady state data suggest a half life of approximately 15 hrs in patients receiving carbamazepine monotherapy & approximately 10hrs in patients receiving other enzyme inducing anti epileptic drugs.

12. Time of sampling: Obtaining carbamazepine plasma samples within the first few weeks of therapy may be useful to establish a relationship between carbamazepine concentration & a patients clinical response. Once steady state has been achieved, the time of sampling within a dosing interval is arbitrary given the long half life & relatively short dosing interval for carbamazepine.Nevertheless,it is reasonable to obtain carbamazepine plasma samples at a consistent time within the dosing interval.

13. Question#1: N.S.,a 36 year old, 60 Kg female is to be given carba- mazepine as an anticonvulsant agent. Calculate a daily dose that will produce an avearage steady state plasma conc. Of approximately 6 mg/L. F=0.8, cl=3.84l/hr (0.064l/kg x 60kg),S=1 Maintenance dose = (cl)(cpss ave)(t) (s) (f) = (3.84l/hr)(6mg/l)(24hr/1day) (1) (0.8) = 691.2 mg/day this dose (approximately700mg/day)is that which would be required to achieve the steady state level of 6mg/l after auto induction of car- bamazepine metabolism had taken place.for this reason,N.S. should be started on a lower daily dose initially & increased at one to two week intervals based upon her clinical response.the usual initial daily dose for adult patients is 200 to 400mg with increases of approximately 200mg every 7 to 14 days.

14. Question#2: After 2 months,N.S.’s carbamazepine dose had been increased to 300mg BID.On 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 4mg/L. what are possible explanations for this observed plasma level? What dose would be required to achieve a new steady-state carbamazepine level of 6mg/L? Cl= 3.84L/hr, the anticipated carbamazepine level in N.S.for a dose of 600mg/day would be approximately 5mg/L. Cpss ave= (s)(f)(dose/t) Cl = (1)(0.8)(300mg/12hr) 3.84L/hr = 5.2 mg/L the observed level of 4 mg/L is within the predicted range, considering the fact that both bioavailability & clearance values derived from average literature values may not be applicable to N.S. At this point,it would be difficult to establish whether a slightly lower than expected bioavailability or a higher than average clearance was responsible for the observed level of 4mg/L.

15. Because of carbamazepine’s relatively slow absorption characteristics & long half life, it is propable that the measured concentration of 4 mg/L represents an average value.At steady state, the average plasma concentration should be proportional to the daily dose. Therefore,to increase the plasma conc. From 4 to 6 mg/L,one would simply increase the carbamazepine dose by 50%(from 600 to 900 mg/day).An alternate approach might be to calculate the apparent carbamazepine clearance for N.S.using an assumed bioavailability of 0.8 Cl = (s)(f)(dose/t) cpss ave = (1)(0.8)(600 mg/24hr) 4 mg/l = 5 L/hr this clearance value could then be used to calculate the maintenance dose as illustrated in question 1.However this time the clearance value which has been derived from the patient’s specific data would be used rather than an average value from the literature. Maintenance dose = (cl)(cpss ave)(t) (s)(f) = (5L/hr)(6mg/L)(24hr/day) (1)(0.8) = 900 mg/L if N.S.were receiving other anticonvulsant agents,it would be appropriate to monitor their conc. As well,since carbamazepine could induce their metabolism,thereby reducing their steady state conc.