Applied Pharmacokinetics of Antiepileptic Drugs (AEDs) B. Gitanjali

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 Graph becomes flatter as the enzyme becomes saturated with substrate. Rate Substrate concentration Gitanjali-27:

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

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

7. For most drugs[Expansion of the relevant part of the graph] Graph would start to curve if we went to much higher concentrations and began to saturate the enzyme. Elimination rate Drug concentration 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. Non-linear kinetics (e.g. phenytoin) Linear kinetics (most drugs) Rate of eliminat’n Rate of eliminat’n Blood drug conc Blood drug conc 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. Thank you Gitanjali-49: