applied pharmacokinetics of antiepileptic drugs aeds b gitanjali n.
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Applied Pharmacokinetics of Antiepileptic Drugs (AEDs) B. Gitanjali. Gitanjali-21:. Absorption. Aqueous solubility - Poor aqueous solubility Impairs absorption from GIT – carbamazepine Erratic absorption from parenteral (SC, IM) sites - phenytoin Poor oral bioavailability – phenytoin

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absorption
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:

absorption1
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:

slide4
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:

specific case of drug elimination
Specific case of ...Drug elimination

Elimin’n

rate

Drug concentration

Gitanjali-28:

for most drugs
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:

for most drugs expansion of the relevant part of the graph
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:

exceptions
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:

slide9

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:

dosage adjustment
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:

pharmacokinetics of carbamazepine
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:

carbamazepine cont
Carbamazepine…cont
  • Metabolised in liver to an active metabolite – 10, 11 epoxide
  • Enhances its own metabolism

Gitanjali-35:

drug interactions points to consider
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:

drug interactions points to consider1
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:

interactions with carbamazepine
Interactions with carbamazepine

Carbamazepine often lowers plasma concentrations of:

  • phenytoin (it may also raise phenytoin concentration)
  • valproate

Gitanjali-35:

interactions with phenobarbitone or primidone
Interactions with phenobarbitone or primidone

Often lowers plasma concentrations of

  • phenytoin (it may also raise phenytoin concentration)
  • valproate
  • carbamazepine
  • clonazepam
  • ethosuximide (sometimes)

Gitanjali-36:

interactions with phenytoin
Interactions with phenytoin

Often lowers plasma concentrations of

  • valproate
  • carbamazepine
  • clonazepam
  • Ethosuximide and primidone (sometimes)

Often raises plasma concentrations of

  • Phenobarbitone

Gitanjali-37:

interactions with valproate
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:

slide19

Thank you

Gitanjali-49: