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Applied Pharmacokinetics of Antiepileptic Drugs

(AEDs)

B. Gitanjali

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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

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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

Rate

Substrate concentration

Graph becomes flatter as the enzyme becomes saturated with substrate.

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Specific case of ...Drug elimination

Elimin’nrate

Drug concentrationGitanjali-28:

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For most drugs

Drug concentration

Eliminationrate

Highest concentrations actually seen in real therapeutic use. Too little to saturate the enzyme. Almost no curvature.

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For most drugs[Expansion of the relevant part of the graph]

Drug concentration

Eliminationrate

Graph would start to curve if we went to much higher concentrations and began to saturate the enzyme.

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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• EthanolTheophylline may approach saturation but, in practice, it can be treated as following linear kinetics.

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Rate of eliminat’n

Rate of eliminat’n

Blood drug conc Blood drug conc

Linear kinetics(most drugs)

Non-linearkinetics

(e.g. phenytoin)

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Dosage adjustmentFor 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.

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

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Carbamazepine…cont

• 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

therapyGitanjali-37:

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Interactions with carbamazepineCarbamazepine often lowers plasma concentrations of:

• phenytoin (it may also raise phenytoin concentration)

• valproate

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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• PhenobarbitoneGitanjali-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

• ethosuximideGitanjali-38:

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