Transcript Pharmacokinetics of the commonly used AEDs

Applied Pharmacokinetics
of Antiepileptic Drugs
(AEDs)
B. Gitanjali
1
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
• Slows time to attain peak plasma levels –
carbamazepine
• May cause physical drug interactions during
IV infusions
2
Gitanjali-25:
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
3
Gitanjali-26:
General relationship between Substrate
concentration and reaction Rate for any enzyme
catalysed reaction
Rate
Graph becomes
flatter as the enzyme
becomes saturated
with substrate.
Substrate concentration
Gitanjali-27:
4
Specific case of ...
Drug elimination
Elimin’n
rate
Drug concentration
Gitanjali-28:
5
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:
6
For most drugs
[Expansion of the relevant part of the graph]
Elimination
rate
Graph would start to curve
if we went to much higher
concentrations and began
to saturate the enzyme.
Drug concentration
Gitanjali-30:
7
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.
8
Gitanjali-31:
Non-linear
kinetics
(e.g. phenytoin)
Linear kinetics
(most drugs)
Rate of
eliminat’n
Rate of
eliminat’n
Blood drug conc
Blood drug conc
9
Gitanjali-32:
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 !!!!
10
Gitanjali-33:
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
11
Gitanjali-34:
Carbamazepine…cont
• Metabolised in liver to an active
metabolite – 10, 11 epoxide
• Enhances its own metabolism
12
Gitanjali-35:
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:
13
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
14
Gitanjali-37:
Interactions with carbamazepine
Carbamazepine often lowers
plasma concentrations of:
• phenytoin (it may also raise phenytoin
concentration)
• valproate
15
Gitanjali-35:
Interactions with phenobarbitone
or primidone
Often lowers plasma concentrations of
• phenytoin (it may also raise phenytoin
concentration)
• valproate
• carbamazepine
• clonazepam
• ethosuximide (sometimes)
16
Gitanjali-36:
Interactions with phenytoin
Often lowers plasma concentrations of
• valproate
• carbamazepine
• clonazepam
• Ethosuximide and primidone (sometimes)
Often raises plasma concentrations of
• Phenobarbitone
17
Gitanjali-37:
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
18
Gitanjali-38:
19
Gitanjali-49: