1 Applied Pharmacokinetics of Antiepileptic Drugs (AEDs) B. Gitanjali Gitanjali-21:

2 Absorption Aqueous solubility - Poor aqueous solubility Impairs absorption from GIT – carbamazepine Erratic absorption from parenteral (SC, IM) sites - phenytoin Poor oral bioavailability – phenytoin Slows time to attain peak plasma levels – carbamazepine May cause physical drug interactions during IV infusions Gitanjali-25:

3 Absorption Lipid solubility – Good lipid solubility Enhances absorption across membranes Quicker absorption Crosses BBB easily – reaches good levels in CSF Excreted in breast milk, can cross placenta Gitanjali-26:

4 General relationship between Substrate concentration and reaction Rate for any enzyme catalysed reaction Rate Substrate concentration Graph becomes flatter as the enzyme becomes saturated with substrate. Gitanjali-27:

5 Specific case of... Drug elimination Elimin’n rate Drug concentration Gitanjali-28:

6 For most drugs Drug concentration Elimination rate Highest concentrations actually seen in real therapeutic use. Too little to saturate the enzyme. Almost no curvature. Gitanjali-29:

7 For most drugs [Expansion of the relevant part of the graph] Drug concentration Elimination rate Graph would start to curve if we went to much higher concentrations and began to saturate the enzyme. Gitanjali-30:

8 Exceptions... Drugs where concentrations seen therapeutically are high enough to saturate the eliminating enzymes. Phenytoin - The only case of real clinical significance Salicylates Ethanol Theophylline may approach saturation but, in practice, it can be treated as following linear kinetics. Gitanjali-31:

9 Rate of eliminat’n Blood drug conc Linear kinetics (most drugs) Non-linear kinetics (e.g. phenytoin) Gitanjali-32:

10 Dosage adjustment For most drugs, changes in dosage produce proportionate changes in blood concentrations. e.g. if you increase dose size by 25%, blood levels will also increase by 25%. For non-linear drugs (primarily phenytoin), an increase in dose size will cause a disproportionate increase in blood levels. A 25% increase in dose size might lead to a doubling in blood levels. So beware !!!! Gitanjali-33:

11 Pharmacokinetics of Carbamazepine Limited aqueous solubility Absorption- slow, erratic, peaks at 4-8 hrs, after large dose peaks after 24 hrs. t½=15-20 hrs after single dose t½=10-20 hrs during long term therapy t½= 9-10 hrs during therapy with phenytoin or phenobarbitone Gitanjali-34:

12 Carbamazepine…cont Metabolised in liver to an active metabolite – 10, 11 epoxide Enhances its own metabolism Gitanjali-35:

13 Drug interactions- points to consider Complex – refer to textbooks when possible May enhance toxicity without a corresponding increase in antiepileptic effect. Highly variable and unpredictable Gitanjali-36:

14 Drug interactions- points to consider Usually caused by hepatic enzyme induction or hepatic enzyme inhibition Interactions due to displacement from protein binding sites not significant. TDM advisable with combination therapy Gitanjali-37:

15 Interactions with carbamazepine Carbamazepine often lowers plasma concentrations of: phenytoin (it may also raise phenytoin concentration) valproate Gitanjali-35:

16 Interactions with phenobarbitone or primidone Often lowers plasma concentrations of phenytoin (it may also raise phenytoin concentration) valproate carbamazepine clonazepam ethosuximide (sometimes) Gitanjali-36:

17 Interactions with phenytoin Often lowers plasma concentrations of valproate carbamazepine clonazepam Ethosuximide and primidone (sometimes) Often raises plasma concentrations of Phenobarbitone Gitanjali-37:

18 Interactions with valproate Often raises plasma concentrations of An active metabolite of carbamazepine lamotrigine phenobarbitone, primidone Phenytoin (but may lower it too) Sometimes raises plasma concentrations of ethosuximide Gitanjali-38:

19 Gitanjali-49: