Applied Pharmacokinetics of Antiepileptic Drugs (AEDs) B. Gitanjali

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

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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
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Specific case of ...Drug elimination
Eliminn rate
Drug concentration
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For most drugs
Elimination rate
Highest concentrations actually seen in real
therapeutic use. Too little to saturate the
enzyme. Almost no curvature.
Drug concentration
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For most drugsExpansion 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
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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.

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Non-linear kinetics (e.g. phenytoin)
Linear kinetics (most drugs)
Rate of eliminatn
Rate of eliminatn
Blood drug conc
Blood drug conc
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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 !!!!
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Pharmacokinetics of Carbamazepine

• Limited aqueous solubility
• Absorption- slow, erratic, peaks at 4-8 hrs,
  after large dose peaks after 24 hrs.
• t½15-20 hrs after single dose
• t½10-20 hrs during long term therapy
• t½ 9-10 hrs during therapy with phenytoin or
  phenobarbitone

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Carbamazepinecont

• Metabolised in liver to an active metabolite
  10, 11 epoxide
• Enhances its own metabolism

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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

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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

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Interactions with carbamazepine

• Carbamazepine often lowers plasma concentrations
  of
• phenytoin (it may also raise phenytoin
  concentration)
• valproate

Gitanjali-35
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Interactions with phenobarbitone or primidone

• Often lowers plasma concentrations of
• phenytoin (it may also raise phenytoin
  concentration)
• valproate
• carbamazepine
• clonazepam
• ethosuximide (sometimes)

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Interactions with phenytoin

• Often lowers plasma concentrations of
• valproate
• carbamazepine
• clonazepam
• Ethosuximide and primidone (sometimes)
• Often raises plasma concentrations of
• Phenobarbitone

Gitanjali-37
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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

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Thank you
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