- AS YOU CAN TELL, HERE WE HAVE A LIST OF ANTIEPILEPTIC DRUGS ON THE LEFT SIDE. IN THE MIDDLE COLUMN, WE HAVE THE HALF-LIFE--THAT'S WHAT IT MEANS--THE HALF-LIFE FOR A PARTICULAR MEDICATION TO BE REMOVED FROM THE BODY, AND WE HAVE A NEXT COLUMN WHICH IS THE TIME TO STEADY STATE. IN GENERAL, MEDICATIONS MAY TAKE ABOUT 3 TO 5 HALF-LIVES IN ORDER TO BE ABLE TO REACH STEADY STATE. SO THE REASON WHY WE NEED TO LEARN ABOUT THE HALF-LIFE-- WHICH, BY THE WAY, IS IN THE SERUM COMPARTMENT OR IN THE PLASMA COMPARTMENT IS TO LEARN ABOUT HOW TO DOSE PROPERLY MEDICATIONS AS WELL AS HOW LONG WILL IT TAKE FOR THIS MEDICATION TO ACHIEVE THE STEADY STATE. NOW, YOU CAN OPIATE TO DO THAT BY LOADING SOMEBODY WITH INTRAVENOUS MEDICATIONS, BUT NOT EVERY SINGLE OF THESE MEDICATIONS IS AVAILABLE IN THAT FORMULATION. NOW, IN THE NEXT SLIDE, WHAT WE HAVE FROM THIS TABLE, 65-4, IS WHETHER THERE ARE MEDICATIONS THAT ARE PARTICULARLY IMPORTANT IN TERMS OF METABOLITES BEING OF CLINICAL IMPORTANCE FOR EFFICACY OR TOXICITY. THE TWO METABOLITES THAT ARE OF IMPORTANCE ARE FOR THE CARBAMAZEPINE DRUGS, SUCH AS CARBAMAZEPINE ITSELF OR OXCARBAZEPINE, WHICH ARE METABOLIZED IN A SLIGHTLY DIFFERENT WAY, BUT BOTH MEDICATIONS ARE BOTH METABOLITES OF CLINICAL IMPORTANCE. PROTEIN BINDING IS ANOTHER PROPERTY OF MEDICATION'S PHARMACOKINETIC PROPERTY, AND, AS YOU CAN TELL, THERE'S A LOT OF VIABILITY IN SOME PARTICULAR MEDICATIONS. FOR EXAMPLE, YOU CAN SEE THAT PROTEIN BINDING IS 90% FOR PHENYTOIN, PRIMIDONE BEING 80%, TIAGABINE 95%, VALPROIC ACID ALSO IN THE 90%, AND CARBAMAZEPINE CAN BE, ON AVERAGES, ABOUT 75%, BUT, DEPENDING ON THE POPULATION AND THE CONCENTRATION OF PROTEINS, IT'S BETWEEN 40% AND 90% OF A TOTAL DOSE IS IN THIS FORM. NOW, THE TOTAL DOSE THAT-- I'M SORRY. THE TOTAL SERUM CONCENTRATION IS NOT ENTIRELY ACTIVE. PROTEIN BINDING CAN BE CONSIDERED AS AN EXTRA CLOSET OR SPONGE WHERE YOU HAVE EXTRA COMPONENTS OF THE MEDICINE THAT ARE READILY AVAILABLE BUT AT THE SAME TIME NOT AVAILABLE FOR CROSSING THE BLOOD-BRAIN BARRIER, WHICH IS TYPICALLY WHERE WE ARE GONNA BE LOOKING FOR AN EFFECT OF AN ANTIEPILEPTIC DRUG. NOW, THERE ARE SEVERAL PRINCIPLES THAT I WANT TO JUST BRIEFLY OUTLINE, AND THOSE ARE THAT, AGAIN, IT TAKES 5 HALF-LIVES TO GET TO 95% STEADY STATE. IF YOU ARE IV LOADING WITH A MEDICATION, CURRENTLY WE HAVE IV FORMULATIONS FOR THE FOLLOWING MEDICATIONS. WE HAVE FOR LACOSAMIDE, FOR LEVETIRACETAM, FOR PHENOBARBITAL, FOR PHENYTOIN, AND FOR VALPROIC ACID. THOSE ARE THE 5 MEDICINES OUT OF THE LIST OF MEDICINES THAT I GAVE YOU IN THE TABLE THAT HAVE IV FORMULATIONS. NOW, WHEN YOU LOAD SOMEBODY WITH THIS MEDICATION, THE IDEA IS THAT YOU ARE GONNA GET TO STEADY STATE FASTER, EITHER BECAUSE YOU NEED TO BREAK A STATUS EPILEPTICUS OR YOU NEED TO BREAK OR REPLACE A PARTICULAR DOSING FOR A FORMULATION OF ONE OF THESE MEDICATIONS THAT IS NOT ABLE TO BE GIVEN ORALLY IN A PATIENT THAT HE HAS BEEN CHRONICALLY ON THESE MEDICINES AND IT'S IN THE SURGERY ROOM. NOW, SERUM CONCENTRATIONS CAN BE MEASURED, ESSENTIALLY, ONCE THE DISTRIBUTION OF THESE MEDICATIONS OCCUR, AND SO IF THEY ARE BEING LOADED IV, YOU CAN MEASURE THE SERUM CONCENTRATION AS QUICK AS HALF AN HOUR TO A COUPLE OF HOURS ON THE OTHER ARM, PERHAPS, OR IN ANOTHER SITE BECAUSE YOU WANT TO ELIMINATE THE POSSIBILITY THAT SOME OF THE MEDICATION WAS LEFT IN THE CATHETER. NOW, THE CONCENTRATIONS THAT YOU ARE AIMING, TYPICALLY, THAT WE USE ARE TROUGH LEVELS. PEAK CONCENTRATIONS ARE, GENERALLY SPEAKING, CONSIDERABLY HIGHER, AND, THEREFORE, IF YOU ARE, FOR EXAMPLE, AIMING FOR A PHENYTOIN LEVEL OF 20 OR 22 MICROGRAMS PER ML, YOU MIGHT BE LOOKING TO PROVIDE THE MAINTENANCE DRUG JUST LIKE WHEN TROUGH LEVELS ARE OBTAINED WITHIN A FEW HOURS OR ONE HOUR OR TWO. OFTEN WHEN AN INDIVIDUAL GETS LOADED IN THE EMERGENCY ROOM WITH, FOR EXAMPLE, PHENYTOIN, THEY MAY BE GIVEN THE NEXT ORAL FORMULATION, MAINTENANCE ORAL FORMULATION, PERHAPS LATER THAT AFTERNOON OR NEXT DAY, AND BY THAT TIME, NOW THE DRUG CONCENTRATION HAS FURTHER DROPPED TO LEVELS THAT ARE SUBTHERAPEUTIC, AND SO THIS IS AN IMPORTANT COMPONENT TO CONSIDER. NOW, FROM THE STANDPOINT OF PROTEIN BINDING, IT IS ALSO IMPORTANT TO UNDERSTAND THAT ORAL DOSING, FOR EXAMPLE, WITH A MEAL OR HIGH-PROTEIN SUPPLEMENT, WILL DELAY ABSORPTION, AND IN SOME CONDITIONS WHERE YOU HAVE A FAST GASTROINTESTINAL TRANSIT, YOU MAY HAVE A CIRCUMSTANCE WHERE YOU MAY SEQUESTER OR [INDISTINCT] A PARTICULAR DOSING OF A MEDICATION. NOW, IN THE STANDPOINT OF IV FORMULATION, NOT EVERY MEDICATION HAS THE SAME AFFINITY TO SERUM PROTEINS. FOR EXAMPLE, IV VALPROATE HAS A HIGHER AFFINITY THAN PHENYTOIN-- VALPROATE HAS HIGHER AFFINITY THAN PHENYTOIN TO PROTEINS. THEREFORE, WHEN YOU HAVE SOMEBODY WHO'S CHRONICALLY ON PHENYTOIN AND YOU LOAD THIS PERSON WITH IV VALPROATE, YOU'RE GONNA HAVE A DISPLACEMENT OF PHENYTOIN FROM THE BINDING POOL TO THE UNBINDED, MEANING THE FREE LEVEL, AND TRANSIENTLY YOU ARE GONNA CREATE A TOXICITY LEVEL FOR THE UNBINDED LEVEL, AND PATIENTS MAY FEEL THAT THEY ARE HAVING TOXICITY, AND YOU MIGHT ATTRIBUTE THIS TO THE VALPROATE, AND CERTAINLY THAT'S THE CAUSE OF THIS FACTOR, BUT THE ACTUAL REASON WHY THESE PATIENTS DEVELOP THIS TOXICITY IS BY A TRANSIENT INCREASE IN THE FREE PHENYTOIN LEVEL, WHICH WILL BE CLEAR WITHIN A FEW HOURS BY METABOLISM OR [INDISTINCT]. NOW, TO UNDERSTAND AND PREDICT DRUG INTERACTIONS, ONE NEEDS TO UNDERSTAND THE ALPHABET SOUP OF HEPATIC ENZYMES, AND HEPATIC ENZYMES ARE, BY DESIGN, THE ENZYMES THAT CATALYZE THE BREAKING DOWN OF PARTICULAR MEDICATIONS FOR THEIR CLEARANCE AS WELL AS FOR DESTRUCTION AND INACTIVATION. AS YOU CAN TELL LOOKING AT THE LIST OF MEDICATIONS, FIRST WE NEED TO SEE THAT SOME MEDICINES DO NOT UNDERGO HEPATIC ELIMINATION. THOSE MEDICINES ARE GABAPENTIN, LEVETIRACETAM, VIGABATRIN, AND PREGABALIN. THOSE MEDICATIONS, AS YOU MAY BE ACQUAINTED FROM CLINICAL PRACTICE, DO NOT HAVE OFTEN MANY SIDE EFFECTS--I'M SORRY, NOT SIDE EFFECTS, DRUG INTERACTIONS--AND THE REASON FOR THAT IS BECAUSE ONE OF THE MAJOR SOURCES OF DRUG INTERACTIONS IS METABOLISM, INDUCTION, ET CETERA. NOW, THESE WHAT IS LISTED HERE IS THE SOURCE FOR THESE PARTICULAR MEDICATIONS WHO METABOLIZE THESE MEDICINES. FOR EXAMPLE, IF WE LOOK AT PHENYTOIN, WHAT WE ARE GONNA SEE IS THAT WE SEE 2C9. WELL, THERE ARE POLYMORPHISMS OF MANY OF THESE MEDICINES, BUT THE GREAT MAJORITY OF INDIVIDUALS ARE GONNA METABOLIZE PRIMARILY BY 2C9. NOW, YOU MAY KNOW THAT PHENYTOIN IS ONE OF THOSE NONLINEAR GENERICS IN THE SENSE THAT A PARTICULAR DOSE INCREASE HAS A PARTICULAR RELATIONSHIP TO SERUM CONCENTRATION, AND THERE IS A POINT THAT IT'S GOING UP, AND STARTING FROM THAT POINT, IT BECOMES EXPONENTIAL. WELL, THAT POINT IS THE SEPARATION OR THESE TWO ISOENZYMES, THE 2C9. ONCE IT'S COMPLETELY FILLED IN TERMS OF BEING UTILIZED AT THE MAXIMUM CAPACITY, THEN THE 2C19 TAKES OVER AND BREAKS DOWN THE MEDICATION, BUT THE EFFICIENCY RATE OF BREAKING DOWN THIS MEDICINE IS DRAMATICALLY DIFFERENT. NOW, SOME OTHER MEDICINES THAT HAVE A LOT OF DRUG INTERACTIONS, SUCH AS FELBAMATE, AS YOU CAN TELL, IT'S BEEN METABOLIZED BY 3A4 BUT ALSO BY 2E1 AND SEVERAL OTHER ISOENZYMES. CARBAMAZEPINE IS ALSO METABOLIZED IN A MULTITUDE OF ISOENZYMES. NOW, IF WE LOOK AT THE NEXT TABLE THAT HAS THE EFFECTS ON HEPATIC ENZYMES OF ANTIEPILEPTIC DRUGS, WHAT WE SEE IS THAT THERE ARE SOME MEDICINES THAT IN PARTICULAR INDUCE THE METABOLISM OF SOME PARTICULAR ISOENZYMES. INDUCTION MEANS THAT THE EFFICIENCY FOR THESE PARTICULAR ISOENZYMES INCREASES OVER TIME, AND, FOR EXAMPLE, PHENOBARBITAL, PHENYTOIN, CARBAMAZEPINE, FELBAMATE, ALL OF THOSE MEDICATIONS ARE INDUCERS OF 3A4. ABOUT 60% OR SO OF THE MEDICATIONS THAT WE USE IN CLINICAL PRACTICE ARE METABOLIZED BY THAT PARTICULAR ISOENZYME. THAT IS ONE OF THE REASONS WHY THESE MEDICATIONS HAVE CONSIDERABLE EFFECTS ON OTHER MEDICINES. NOW, ANTIEPILEPTIC DRUGS NOT ONLY INDUCE SOME MEDICINES, BUT THEY CAN INHIBIT SOME PARTICULAR MEDICATIONS. FOR EXAMPLE, VALPROATE INHIBITS THE METABOLISM OF 2C9, AND TOPIRAMATE ALSO INHIBITS THE METABOLISM OF 2C19. THAT IS ONE OF THE REASONS WHY PHENYTOIN LEVELS, FOR EXAMPLE, MAY INCREASE WHEN TAKEN CONCOMITANTLY WITH TOPIRAMATE OR VALPROATE. SO AS A MAIN PRINCIPLE, KNOWING THIS ALPHABET SOUP, YOU ARE ABLE TO PREDICT THE INTERACTIONS BETWEEN PARTICULAR MEDICATIONS. THE EXAMPLE THAT I CHOSE IS, PHENYTOIN IS PRIMARILY METABOLIZED BY 2C9 AND 2C19, AND CARBAMAZEPINE INDUCES ALL OF THESE 2C9 HEPATIC ISOENZYMES. THE EFFECT OF ADDING CARBAMAZEPINE TO A CHRONIC PHENYTOIN WILL RESULT IN A REDUCTION OF THE PHENYTOIN LEVEL DUE TO AN INCREASE EFFICIENCY OF 2C9 AND 2C19. OF NOTE AGAIN IS THAT SOME MEDICINES ALSO HAVE NO MAJOR EFFECT ON HEPATIC ENZYMES, IN PARTICULAR ETHOSUXIMIDE, GABAPENTIN, LACOSAMIDE, LEVETIRACETAM, PREGABALIN, TIAGABINE, AND ZONISAMIDE UNDER MOST CONCENTRATIONS. NOW, MEDICATIONS THAT INDUCE 3A4 INCLUDE CARBAMAZEPINE, FELBAMATE, OXCARBAZEPINE, PHENOBARBITAL, AND PHENYTOIN. TO SOME EXTENT, SOME MEDICATIONS, LIKE TOPIRAMATE AND LAMOTRIGINE, MAY INDUCE 3A4 IN A DOSE-DEPENDENT MANNER, AND THAT MAY ACCOUNT WHY, FOR EXAMPLE, ORAL CONTRACEPTIVES, WHICH ARE METABOLIZED BY 3A4, DIMINISH THEIR EFFECTIVENESS WHEN A CONCOMITANT ENZYME INDUCER IS PRESENT. NOW, COMMON MEDICATIONS THAT ARE METABOLIZED BY 3A4 INCLUDE SEVERAL -AZOLAMS--LIKE ALPRAZOLAM, TRIAZOLAM, AND MIDAZOLAM--AMITRIPTYLINE, CALCIUM CHANNEL BLOCKERS, CARBAMAZEPINE, CORTICOSTEROIDS, DIGOXIN, CYCLOSPORIN--THIS IS ACTUALLY AN IMPORTANT ASPECT FOR TRANSPLANT PATIENTS--METHADONE, PROTEASE INHIBITOR, WHICH ARE VERY IMPORTANT BECAUSE THAT'S WHAT KEEPS THE SERUM COUNT LOW FOR THE HIV PARTICLES, AND, THEREFORE, USING A CONCOMITANT ENZYME-INDUCING MEDICATION OF 3A4 AND AN HIV MEDICATION MIGHT NOT BE IN THE BEST INTERESTS OF PARTICULAR PATIENTS. SOME OTHER DRUG INTERACTIONS-- SUCH AS STATINS: SIMVASTATIN, ATORVASTATIN, AND SEVERAL OTHER STATINS--ARE METABOLIZED BY 3A4. CHOLESTEROL ITSELF IS METABOLIZED BY 3A4, TOO, AND, THEREFORE, THE USE OF AN ENZYME-INDUCER ANTICONVULSANT IN THE PRESENCE OF A CHRONIC STATIN, AGAIN, MIGHT NOT BE BEST FOR A PARTICULAR PATIENT. ANOTHER INTERACTION IS THE EFFECT ON VITAMIN D, AND THIS MIGHT ACCOUNT FOR THE EXCESSIVE PRESENCE OF OSTEOPENIA AND OSTEOPOROSIS IN PATIENTS TAKING CHRONIC AEDs FOR EPILEPSY, WHICH MIGHT RESULT IN AN INCREASED AMOUNT OR NUMBER OF FRACTURES. SIMILARLY, SOME CHEMOTHERAPY DRUGS ARE METABOLIZED BY 3A4, AND SOME OTHER MEDICATIONS--SUCH AS LEVETIRACETAM OR MEDICATIONS THAT DO NOT INDUCE DRAMATICALLY 3A4, LIKE LAMOTRIGINE--MIGHT BE PREFERRED IN THOSE PARTICULAR SCENARIOS. LET'S SHIFT GEARS AND TALK A LITTLE BIT ABOUT SYNERGISM AND ANTAGONISM OF COMBINATIONS OF MEDICATIONS, OF ANTIEPILEPTIC MEDICATIONS. SYNERGISM IS ESSENTIALLY THE IDEA THAT YOU GET MORE THAN YOU PUT ON, AND SO THE IDEA HERE IS 1+1=3. YOU GET MORE OF AN EFFECT THAN WHAT YOU ACTUALLY PUT INTO THE EQUATION. AN EXAMPLE OF THAT MIGHT BE VERY APPLICABLE IS, THE PRESENCE OF TWO SEDATIVE DRUGS, WHEN COMBINED, MAY BE WORSE IN TERMS OF SEDATION IN A PARTICULAR SET OF CIRCUMSTANCES. ANTAGONISM MAY BE A CIRCUMSTANCE WHERE SUBTRACTION IS NOT JUST ENOUGH. YOU MIGHT, FOR EXAMPLE, OBVIATE, OR ALLOW, A HIGHER DOSE OF A PARTICULAR MEDICATION WHEN YOU HAVE A DRUG THAT HAS AN ANTAGONISTIC EFFECT TO THAT EFFECT, AND THAT COULD BE, AGAIN, YOU KNOW, SEIZURES, SEIZURE FREQUENCY. IF YOU WERE THINKING ABOUT, FOR EXAMPLE, ADDING CLOZAPINE, WHICH IS AN ANTIPSYCHOTIC THAT MAY INCREASE THE LIKELIHOOD OF SEIZURES, TO A MEDICINE TO A MEDICINE THAT IS AN ANTICONVULSANT, BUT WHAT WE'RE LOOKING HERE IN TERMS OF COMBINING ANTIEPILEPTIC DRUGS IS, WE ARE LOOKING FOR SYNERGISM OF EFFICACY AND ANTAGONISM OF SIDE EFFECTS. SO THAT'S THE IDEA OF COMBINATION. NOW, THIS, UNFORTUNATELY, HAS NOT BEEN STUDIED SYSTEMATICALLY IN CLINICAL TRIALS. POST-HOC ANALYSIS, MEANING AFTER THE STUDY WAS DONE, WE HAVE BEEN ABLE TO FIND, ESSENTIALLY, TWO STUDIES THAT THEY HAVE LOOKED AT THE POTENTIAL COMBINATION OF MEDICATIONS. THIS PARTICULAR STUDY DESIGN IS VERY COMPLICATED. THIS IS PART OF THE LAMOTRIGINE 105 STUDY THAT WAS SPONSORED BY THE MANUFACTURER OF LAMOTRIGINE, GLAXOWELLCOME, AND THIS WAS A STUDY THAT WAS PUBLISHED IN 1997 BY MARTIN BRODIE. THE IDEA HERE WAS A CONVERSION TO MONOTHERAPY. SO THEY TOOK PATIENTS WITH SEIZURES WHO WERE BEING NOT ADEQUATELY CONTROLLED WITH A SINGLE MEDICATION--PHENYTOIN, CARBAMAZEPINE, OR VALPROATE. THEY STARTED ADDING ON LAMOTRIGINE, THAT THEN THEY WITHDREW THE MEDICATION, AND THE WITHDRAWAL PERIOD IS THE ONE THAT MATTERS IN THIS PARTICULAR COMPONENT, AND SO THE WITHDRAWAL PERIOD IN THIS PARTICULAR SCENARIO SEEMS TO FAVOR THE LOWER GRAPH, AND THE LOWER GRAPH IS THE COMBINATION OF LAMOTRIGINE AND VALPROATE. NOW, YOU MAY ASK, "WELL, WE KNOW THAT WE HAVE A PHARMACOKINETIC INTERACTION BETWEEN VALPROATE AND LAMOTRIGINE," AND WHEN YOU LOOK AT THE NEXT TABLE AND LOOK AT THE WITHDRAWAL LEVELS AND YOU LOOK AT LAMOTRIGINE LEVELS, THE LEVELS WERE DEFINITELY HIGHER DURING THE ADD-ON COMPONENT AS COMPARED TO CARBAMAZEPINE AND PHENYTOIN, BUT THE LEVELS ACTUALLY OF LAMOTRIGINE WERE LOWER COMPARED TO THE OTHER TWO GROUPS. UNFORTUNATELY, ALTHOUGH THIS MAY BE STATISTICALLY SIGNIFICANT, IT'S NOT A PROSPECTIVE RANDOMIZED CONTROL TRIAL WHERE THE PRIMARY END POINT IS SPECIFICALLY TO ASSESS THE COMBINATION OF MEDICATIONS. THIS IS ONE EXAMPLE THAT SUGGESTS THAT THERE ARE WAYS OF UNDERSTANDING WHERE A PARTICULAR COMBINATION OF MEDICATION MIGHT BE SUPERIOR TO OTHER PARTICULAR COMBINATIONS. NOW, THE FOLLOWING GRAPH, ESSENTIALLY, ARE LOOKING AT HOW DID YOU STUDY THESE SCIENTIFICALLY, AND THIS WAS A STUDY IN EXPERIMENTAL ANIMALS. ON ONE HAND, YOU CAN PUT THESE IN TWO AXES. YOU CAN PUT ONE MEDICATION IN ONE AXIS AND THE OTHER MEDICINE IN THE OTHER AXIS. IF, FOR EXAMPLE, YOU WERE ABLE TO ACHIEVE THE SAME EFFECT, WHATEVER IT IS--A SEDATION, FALLING OFF BECAUSE OF MODERATE IMPAIRMENT, OR DIMINISHMENT OF THE ED50 FOR MAXIMUM ELECTROSHOCK IN A PARTICULAR PRESENCE OF A MEDICATION, ET CETERA. SO WHATEVER YOUR MEASURE IS, YOU CAN PLOT. IT 50% OF ONE MEDICINE AND 50% OF THE OTHER MEDICINE ARE EQUIVALENT TO THIS, YOU MIGHT END UP AND ACHIEVE THE SAME AMOUNT THAN THE 100% OF A PARTICULAR DRUG. YOU END UP WITH THIS PARTICULAR GRAPH WHERE THE TWO MEDICATIONS, MEANING 50% OF DRUG "Y" AND 50% OF DRUG "X," ADD UP, AND YOU CAN ESSENTIALLY PLOT THIS STRAIGHT LINE. IF YOU HAVE SYNERGISM, ESSENTIALLY IT MEANS THAT IN ORDER TO ACHIEVE THAT EFFECT, MEANING IT'S A 50% MAXIMUM ELECTROSHOCK LEVEL, YOU ARE ABLE TO DO THAT WITH ESSENTIALLY 30 CENTS ON THE DOLLAR, 30 CENTS, 30%. FOR EXAMPLE, IN DRUG "X" AND 30% OF DRUG "Y" WAS TOGETHER SUFFICIENT IN ORDER TO ACHIEVE THAT SYNERGISM. IN CONTRAST, ANTAGONISM IS EXACTLY THE OPPOSITE, IN A SENSE IS, I'M ABLE TO TOLERATE A HIGHER DOSE OF A PARTICULAR MEDICINE WITHOUT FALLING ASLEEP IN THE PRESENCE OF HIGHER DOSE OF A PARTICULAR OTHER MEDICATION, AND IN THIS PARTICULAR SCENARIO, EITHER MEDICATION AT 50% WILL HAVE BEEN A DOUBLE HELPING. SO IT'S CONSIDERABLY PULLED TO THE RIGHT. IN THIS SENSE, WILL NOT GIVE US ANY PARTICULAR COMBINATION. NOW, IF YOU MOVE INTO THE PARTICULAR GRAPH WHERE I HAVE THE PLASMA CONCENTRATIONS OF PHENOBARBITAL ON THE LEFT SIDE AND IN THE X-Y AXIS I HAVE THE PHENYTOIN CONCENTRATION--THIS IS FROM THE WORK OF MASUDA-- ESSENTIALLY, EACH OF THESE DOTS REFLECTS A RAT THAT WAS TAKING THE COMBINATION OF PHENYTOIN AND PHENOBARBITAL. THE CLOSED CIRCLES WERE RATS THAT WERE SHOCKED AND DID NOT HAVE A SEIZURE, WHILE IN CONTRAST, THE OPEN CIRCLES ARE RATS THAT WERE SHOCKED AND DEVELOPED A CONVULSION. AS YOU CAN TELL, THE GRAPH INDICATES THAT THE COMBINATION OF THE TWO MEDICATIONS, PHENYTOIN AND PHENOBARBITAL, TOGETHER MIGHT BE SYNERGISTIC. THE PROBLEM IS THAT THE COMBINATION OF THESE TWO MEDICATIONS IS ALSO SYNERGISTIC FOR SIDE EFFECTS AND PERHAPS ON A STRONGER LEVEL. NOW, THIS IS WORK FROM CZUCZWAR AND BOROWICZ IN 2002, AND CZUCZWAR IN PARTICULAR HAS DONE A SERIES OF EXPERIMENTAL COMBINATIONS OF SEVERAL COMMONLY USED ANTICONVULSANTS, AND WHAT HE HAS FOUND IS THAT SOME PARTICULAR MEDICATIONS COMBINED IN A SYNERGISTIC MANNER FOR EFFICACY--IN THIS CASE, DRUG CONCENTRATIONS OR DOSING OF TOPIRAMATE AND LAMOTRIGINE IN A ONE-TO-ONE BASIS--WAS ABLE TO ACHIEVE THE SAME EFFECT AT A LOWER CONCENTRATION THAN EXPECTED IN A STATISTICALLY SIGNIFICANT MANNER. IN COMPARISON, THERE WAS ALSO ANTAGONISM OF NEUROTOXICITY. IN THIS PARTICULAR CASE, THE PRESENCE OF LAMOTRIGINE WAS ABLE TO ALLOW RATS PERFORM A BATTERY OF MORE COGNITIVE TESTS THAT DEMONSTRATED THAT IT WAS A LITTLE BIT ADVANTAGEOUS TO COMBINE THE TWO MEDICATIONS AND HAD DIMINISHMENT IN TERMS OF TOXICITY. NOW, CLINICALLY, I HAVE SEEN THIS IN AN ANECDOTAL BASIS. UNFORTUNATELY, WE DON'T HAVE RANDOMIZED STUDIES OF PARTICULAR COMBINATIONS. THE NEXT PHASE OF THE PRESENTATION DISCUSSES COMMON SIDE EFFECTS AND IDIOSYNCRATIC REACTIONS OF AEDs. WHAT I HAVE WRITTEN HERE IN THESE TABLES--AGAIN, TAKEN FROM THE SAME CHAPTER IN THE PHARMACOTHERAPY TEXTBOOK OF DIPIRO--IS, I DESCRIBE THE SIDE EFFECTS BY CONCENTRATION DEPENDENT--MEANING AS YOU KEEP INCREASING THE DOSE, YOU GET MORE OF THAT SIDE EFFECT-- IDIOSYNCRATIC, MEANING THAT PARTICULAR SIDE EFFECTS MAY BE VERY PARTICULAR TO PARTICULAR INDIVIDUALS WITH GENOTYPE AND PHENOTYPE; AND SOME ISSUES THAT ARE CHRONIC SIDE EFFECTS OF MEDICATIONS, AND, UNFORTUNATELY, THE MEDICATIONS IN GENERAL, THE CONCENTRATION-DEPENDENT SIDE EFFECTS TEND TO BE VERY MUCH SIMILAR ACROSS THE BOARD. WHY? BECAUSE OUR MEDICINES ARE NEUROACTIVE MEDICATIONS AND, THEREFORE, IN A DOSE-DEPENDENT MANNER, THEY TEND TO STOP SEIZURES OR SLOW DOWN THE BRAIN, AND, UNFORTUNATELY, THAT RESULTS IN A DOSE-DEPENDENT INCREASE IN SOME PARTICULAR SIDE EFFECTS, SUCH AS FATIGUE AND SOMNOLENCE, UNSTEADINESS, ET CETERA. NOW, THE IDIOSYNCRATIC EFFECTS THAT ARE IMPORTANT HAVE TO DO WITH THE ISSUE OF RASH. THERE ARE SOME MEDICINES--LIKE CARBAMAZEPINE, IN PARTICULAR-- SOME POLYMORPHISMS IN THE ASIAN POPULATIONS HAVE BEEN ASSOCIATED WITH THE PRESENCE OR HAVING AN INCREASED RISK OF RASH. IN PARTICULAR, IN THE CASE OF LAMOTRIGINE, THE DOSE ESCALATION OF LAMOTRIGINE HAS ALSO BEEN ASSOCIATED WITH AN INCREASED LIKELIHOOD OF RASH. THAT HAS NOT BEEN STUDIED, BY THE WAY, ON CARBAMAZEPINE, BUT IT'S POSSIBLE THAT THAT ASSOCIATION EXISTS. NOW, MEDICATIONS THAT ARE UNLIKELY TO PROVIDE YOU WITH A RASH, FOR EXAMPLE, WOULD BE LEVETIRACETAM, GABAPENTIN, AS WELL AS RUFINAMIDE IS ANOTHER OF THE MEDICINES AND VALPROIC ACID. NOW, CO-MORBIDITIES. ESSENTIALLY, I HAVE A SINGLE SLIDE, AND THAT IS, YOU KNOW, CO-MORBIDITIES, IN PARTICULAR IN OUR VA POPULATION, ARE ASSOCIATED WITH THE PRESENCE OF CO-MEDICATIONS, AND THEREFORE, IF YOU HEAR THAT PERSON HAS A PARTICULAR CONDITION, CHECK FOR THIS PARTICULAR DRUG INTERACTIONS. SO LOOKING FOR ENZYME-INDUCING DRUG INTERACTIONS IS VERY IMPORTANT IN PEOPLE WHO HAVE CHRONIC TREATMENT FOR CHOLESTEROL, FOR HIV, FOR CHEMOTHERAPY, FOR CALCIUM CHANNEL DRUGS, ET CETERA. NOW, SOME CHRONIC EFFECTS, SUCH AS INCREASED WEIGHT OR WEIGHT GAIN, THAT HAPPENS WITH GABAPENTIN AND VALPROATE MIGHT TELL US THAT PERHAPS THESE ARE MEDICATIONS THAT MAY NOT BE BEST IN AN OBESE DIABETIC PATIENT. DESPITE THAT, VALPROATE AND PARTICULARLY GABAPENTIN MIGHT BE VERY HELPFUL TO CREATE SOME OF THE NEUROPATHIC EFFECTS OF PAIN OF PERIPHERAL NEUROPATHY IN DIABETES, BUT THIS IS SOMETHING THAT YOU NEED TO CONSIDER. NOW, IN CONCLUSION, WHAT I HAVE DONE TODAY IS TRY TO PROVIDE YOU A FRAMEWORK TO IDENTIFY DRUG INTERACTIONS BASED ON TWO PRINCIPLES--THE ALPHABET SOUP OF HEPATIC ENZYMES AS WELL AS THE IDEA THAT SOME PARTICULAR PROTEIN BINDING EFFECTS MIGHT BE OF IMPORTANCE FOR DRUG INTERACTIONS. I ALSO HAVE DISCUSSED THE UNFORTUNATELY LACK OF EVIDENCE FOR COMBINING AEDs IN A MORE EFFECTIVE MANNER. HOWEVER, I HAVE GIVEN YOU SOME IDEAS AS TO HOW TO COMBINE DRUGS, PERHAPS, SYNERGISTICALLY FOR EFFICACY WHILE YOU'RE LOOKING FOR ANTAGONISMS OR DRUGS THAT COUNTERACT EACH OTHER IN TERMS OF SIDE EFFECTS. ALSO, IT IS IMPORTANT TO EDUCATE PATIENTS ABOUT COMMON SIDE EFFECTS AND IDENTIFICATION OF EARLY IDIOSYNCRATIC REACTIONS WHEN WE START MEDICATIONS AND LASTLY HOW TO PREDICT COMMON EFFECTS OF ANTIEPILEPTIC DRUGS ON CO-MORBIDITIES, AND WITH THIS SLIDE, I CONCLUDE THE LECTURE COMPONENT OF THE TALK, AND I WILL BE HAPPY TO TAKE ANY QUESTIONS IF THERE ARE ANY. THANK YOU. PHIL? HELLO? - HELLO? - OK. I GUESS-- - YES. THE LINES ARE OPEN. - I EXPECT A TEXT. I'M LOOKING NOW. - DOES ANYBODY HAVE ANY QUESTIONS? - YES. I HAVE A QUESTION. - OK. - AM I OPEN FOR RIGHT NOW? - YES. YOU ARE. EVERYBODY IS OPEN. - RIGHT. ALL RIGHT. VERY GOOD. I'M A NEW NEUROLOGY PROVIDER UP HERE IN SAGINAW, MICHIGAN, AND I NOTICED YOU MENTIONED THAT THERE WAS NO DEFINITE PROOF OF SYNERGY WITH MEDICATION. OTHERWISE, PEOPLE WOULD BE USING THEM COMMONLY, BUT HOW ABOUT THE STRATEGY OF USING, PERHAPS, EFFECTIVE MEDICATION THAT PRODUCES A LOT OF SIDE EFFECTS, REDUCING ITS DOSE, AND THEN USING AN INJUNCTIVE THERAPY SUCH THAT I CAN ACHIEVE GOOD SEIZURE CONTROL WITHOUT HAVING TO PUSH THE FIRST DRUG TO THE MAXIMUM DOSE? - OK. SO THE MANTRA THAT HAPPENED BACK IN THE SEVENTIES AND MID EIGHTIES WAS TO PUSH A GIVEN MEDICINE TO NO SEIZURES OR UP TO MAXIMUM TOLERATED DOSE. SO THAT HAS BEEN THE MANTRA BASED ON THE IDEA, PARTICULARLY, OF THE OLDER ANTICONVULSANTS. THERE WERE A SERIES OF SMALL CASE COHORT STUDIES OF COMBINING PHENYTOIN AND PHENOBARBITAL TOGETHER. AS I DISCUSSED BRIEFLY WITH THE DATA IN EXPERIMENTAL ANIMALS, THERE IS EVIDENCE THAT COMBINING THE TWO MEDICATIONS MAY ACHIEVE A HIGHER BENEFIT, AND SO THE IDEA WAS THEN TO, RATHER THAN USING LOWER CONCENTRATIONS OF BOTH MEDICINES BECAUSE OF THE CONCOMITANT-- WHEN YOU START ADDING PHENOBARBITAL BECAUSE OF THE INDUCTION, YOU'RE GONNA LOWER YOUR PHENYTOIN LEVELS, AND SO YOU MIGHT ACTUALLY END UP ACHIEVING LOWER CONCENTRATIONS FROM THIS PHARMACOKINETIC COMBINATION. NOW, IT HASN'T BEEN STUDIED WITH THE NEWER ANTICONVULSANTS, MEANING THE MEDICATIONS THAT CAME ALONG SINCE 1993, WHICH IS TIAGABINE, FELBAMATE, GABAPENTIN, LAMOTRIGINE, ET CETERA. NOW, IN GENERAL, WHAT YOU INDICATED IS EXACTLY WHAT WE DO IN PRACTICE. YOU KEEP INCREASING ONE FIRST DOSE, ONE FIRST MEDICATION, AND THEN YOU ACHIEVE TOXICITY. THE PATIENT, AS YOU SEE, IS HAVING SEIZURES. SO YOU MIGHT BE ABLE TO BACK OFF ONE OR TWO, YOU KNOW, STEPS IN THAT TITRATION SCALE THAT, YOU KNOW, IS THERE AND THEN START ADDING A SECOND MEDICATION AS ADJUNCTIVE THERAPY. HOWEVER, IF YOU ARE GONNA USE THE SECOND MEDICATION, THE TWO THINGS THAT YOU NEED TO LOOK INTO IS, NUMBER ONE IS, YOU DON'T WANT TO HAVE AN INDUCTION OF THAT MEDICATION, MEANING LOWERING THE DOSE OF THAT MEDICINE, OF THE FIRST MEDICINE, AND NUMBER TWO IS, YOU WANT TO USE, PERHAPS, YOU KNOW, SOME OF THE NEWER MEDICATIONS. SO, FOR EXAMPLE, IF YOU START TALKING ABOUT PHENYTOIN AND ADDING TO PHENYTOIN LAMOTRIGINE, THAT'S A COMBINATION THAT WE OFTEN DO. NOW, THE MEDICATION LEVETIRACETAM IS ANOTHER COMBINATION. NOW, PEOPLE HAVE BUY MEDICINES BASED ON MECHANISM OF ACTION. UNFORTUNATELY, WE DO NOT HAVE ANY DATA TO SUPPORT THE IDEA THAT COMBINING MEDICATIONS BASED ON MECHANISMS OF ACTION IS SUPERIOR THAN STACKING MORE MEDICINES WITH THE SAME MECHANISM. - EMPIRICALLY-- - IT'S EMPIRICAL, UNFORTUNATELY. - AND WE'LL DO THAT. WE'LL SAY, "YOU DON'T HAVE ENOUGH CONTROL ON A SODIUM "CHANNEL BLOCKER, AND, THEREFORE, I'M GOING TO USE ANOTHER MEDICATION THAT HAS A DIFFERENT EFFECT." - IN GENERAL, THAT'S WHAT WE DO, BUT WE, UNFORTUNATELY, DON'T HAVE CLASS- ONE EVIDENCE TO SUPPORT THAT PARTICULAR, YOU KNOW, CONCEPT. THAT'S WHAT WE DO CLINICALLY. - I WISH YOU HAD THAT MAGIC CHART WHERE YOU COULD SAY, "IF USING DRUG "A," THEN DRUG "B" IS YOUR BEST ADJUNCT"... - EXACTLY. - BUT WE DON'T HAVE THAT, SO-- ALL RIGHT. WELL, THANK YOU. - I HAVE A QUESTION. - SURE. - SUSAN FROM CINCINNATI VA. I'M AN RN. DO YOU EVEN HAVE ANY OTHER STUFF ABOUT COMBINATIONS OF THE NEWER DRUGS TOGETHER THAT YOU-- I KNOW THERE'S NO EMPIRICAL EVIDENCE, BUT IN YOUR EXPERTISE, WOULD YOU SAY THAT SOME OF THESE HAVE WORKED WELL TOGETHER BESIDES THE PHENYTOIN? LET'S SAY YOU'RE NOT ON THE PHENYTOIN. - OK. SO DEFINITELY, YOU KNOW, IN PARTICULAR FOR INDIVIDUALS WHO ARE COMING WITH-- I MEAN, I LOOK AT CO-MORBIDITIES A LOT, AND, YOU KNOW, HOW DO WE CHOOSE MEDICATIONS? WE CHOSE MEDICATIONS WHICH WE SAY BECAUSE OF EFFICACY, BUT RANDOMIZED STUDIES PRETTY MUCH HAVE SAID THAT THE EFFICACY OF ALL THESE MEDICINES IS EQUAL, OK, IN MONOTHERAPY OR IN ADJUNCTIVE THERAPY. NOW, COMBINATIONS THAT I LIKE TO USE, FOR EXAMPLE, I LIKE TO USE IN INDIVIDUALS WHO HAVE HAD HEAD INJURIES, I USE LAMOTRIGINE QUITE OFTEN. NOW, LET'S SAY THAT LAMOTRIGINE HAS BEEN USED AND THAT PARTICULAR INDIVIDUAL STARTS DEVELOPING HEADACHES. A HIGH CONCENTRATION OF LAMOTRIGINE IS A MEDICINE THAT IS ASSOCIATED WITH HEADACHES. I MAY USE A MEDICATION LIKE TOPIRAMATE OR LIKE LEVETIRACETAM, AND SO I MAY LOWER-- - [INDISTINCT] - PARDON? I MAY ADD THAT MEDICATION TO THAT PARTICULAR COMBINATION. SO MEDICATIONS LIKE LAMOTRIGINE, LEVETIRACETAM, THE L-DRUGS, DO MIX WELL. IF THE PROBLEM IS I HAVE SOMEBODY WHO OFTEN SHOW UP IN MEDICATION IN THE EMERGENCY ROOM, I MAY BE FORCED TO USE A MEDICINE LIKE VALPROATE OR PHENYTOIN BECAUSE THEY ARE AVAILABLE IN IV FORMULATIONS. UNFORTUNATELY IN EMERGENCY ROOMS, IT'S ALMOST LIKE A KNEE JERK REACTION, AND OFTEN I GET PATIENTS WHO I HAVE BEEN WITHDRAWING FROM PHENYTOIN AND THEY ARE BACK ON PHENYTOIN, BUT IN GENERAL, MANY OF OUR NEWER MEDICATIONS HAVE BETTER SIDE EFFECT PROFILES. NOW KEEP IN MIND THAT WE--AS AN INSTITUTION, THE VA--COMPLETED THE VA COOPERATIVE STUDY OF TREATMENT OF SEIZURES IN THE ELDERLY, AND LAMOTRIGINE WAS CONSIDERED THE BETTER MEDICATION TO START ON PEOPLE WHO ARE OVER THE AGE OF 60. WHY? BECAUSE IT HAS LESS DRUG INTERACTIONS. IT WAS BETTER TOLERATED. NOT SO MUCH BECAUSE IT HAD BETTER EFFECTIVENESS. IN FACT, CARBAMAZEPINE HAS EQUAL EFFECTIVENESS. - THANK YOU. THAT'S GREAT. - YOU'RE WELCOME. OTHER QUESTIONS? WELL, THANK YOU FOR PARTICIPATING. PLEASE REMEMBER, WE HAVE A NATIONAL NETWORK OF EPILEPSY CENTERS ACROSS THE STATES, AND WE ARE ABLE TO SEE THE DIFFERENT CENTERS ACROSS THE NATION, SOME OF THE REFRACTORY EPILEPSY PATIENTS WITH GUSTO. - WHERE ARE THOSE CENTERS? - CENTERS ARE PRESENT ACROSS THE UNITED STATES. WE HAVE 16 CENTERS. SO IF YOU-- RYAN, ARE YOU THERE? - I AM. YES. - CAN YOU PROVIDE THE WEB SITE? - IF YOU GO TO WWW.EPILEPSY.VA.GOV, IT WILL HAVE A LIST OF THE EPILEPSY CENTERS. - OH, OK. VERY GOOD. - AND IT HAS THE MECHANISM ON HOW TO REFER PATIENTS. - ALL RIGHT. I'M SURE I'LL RUN INTO A FEW OF THEM. - BUT, I MEAN, THEY ARE DISTRIBUTED ACROSS THE UNITED STATES WITH MANY OF THE POLYTRAUMA CENTERS HAVING ASSOCIATION WITH ONE OF THESE PLACES. OK. WELL, THANK YOU VERY MUCH FOR YOUR ATTENTION, AND HOPEFULLY, WE WILL DISCUSS PARTICULAR PATIENTS IN THE FUTURE.