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Psych/Neuro EXAM 3
Psych/Neuro EXAM 3 Nieto Anticonvulsants
51
Pharmacology
Graduate
09/09/2011

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Term
ideal anticonvulsant
Definition
completely suppress seizures at doses that do not cause sedation or other CNS side effects

well tolerated and effective against various types of seizures

onset of action should be rapid after parenteral and long durations after oral for prevention of recurrent seizures
Term
general structures of anticonvulsants
Definition
[image]

anticonvulsants have this COMMON STRUCTURE

nitrogen with 2 carbonyls = ureide group

the X group will ALWAYS close the ureide group into the ring

hydantoins, oxazolidinediones, and succinimides are 5 member rings; all are bioisoteric replacements of each other
Term
MOAs of anticonvulsants
Definition
stabilization and prolongation of the inactive stage of the ion channels (hydantoins, carbamazepine, lamotrigine)

effects on GABA concentration:
benzodiazepines, barbiturates - enhancing of GABA on the GABA-A chloride channel
tiagabine decreases GABA reuptake
gabapentin decreases GABA metabolism

Ca signaling

NMDA antagonists
Term
hydantoins
[image]
water solubility?
pKa?
sodium salt?
Definition
[image]

water solubility: at physiological pH it will be unionized = more lipophilic

pKa: weak acid, 8.3

administration of this drug is problematic.
formulated as a Na salt to make it ionized (better for parenteral solution)
the solution has to have a pH 2 lotP units above the pKa (the solution has to be pH = 10.5 or more)
the solution is very basic and if it sits in the bottle for a while it will precipitate (pH will decrease over time due to contact with CO2)

even if it does not precipitate, the basic solution injected into a pH of 7.4 will precipitate
have to be careful about how much you infect into the patient to avoid precipitation
Term
pharmacokinetics of phenytoin
[image]
Definition
saturable metabolism: a small increase in phenytoin dose will cause a large increase in phenytoin plasma levels

pharmacokinetics are age-dependent

INDUCES CYP
INDUCES GLUCURONIDASES
Term
metabolism of phenytoin
[image]
Definition
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60-75% excreted as HPPH
Term
common metabolism of hydantoins
Definition
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Term
pharmacokinetics of fosphenytoin
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Definition
prodrug of phenytoin

parenteral use

as a replacement for parenteral phenytoin

[image]
Term
pharmacokinetics of ethotoin
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Definition
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hydantoin

less toxic but less effective and more sedative than phenytoin

saturable and non-linear metabolism
Term
pharamcokinetics of mephenytoin
[image]
Definition
more sedative than phenytoin

more toxic

N-desmethyl metabolite contributes to efficacy and toxicity

[image]
Term
hydantoins SAR
Definition
hydantoin ring system not necessary in Na channel binding
what is needed is the ureide group

prodrugs:
phosphenytoin
N-benzoylcarbonyl-amino acid
piperazine

prodrugs are formed at this N position
Term
iminostilbenes
Definition
[image]
Term
pharmacokinetics of carbamazepine
[image]
Definition
high effectiveness and low incidence of side effects

INDUCER of liver enzymes (AUTOINDUCER)
INDUCER OF GLUCUNORYLTRANSFERASE

t1/2 = 12-17 hours
t1/2 of epoxide metabolite = 5-8 hours

epoxide carbamazepine is active and more toxic than CBZ
Term
major metabolism of carbamazepine
[image]
Definition
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Term
pharmacokinetics of oxcarbazepine
[image]
Definition
less active than carbamazepine

less toxic

INDUCES CYP3A4
INDUCES GLUCURONYLTRANSFERASES
INHIBITS CYP2C19
Term
metabolism of oxcarbazepine
[image]
Definition
[image]

epoxidation:
will occur on the phenyl rings, not on the bridge (blocked by the carbonyl)

hydroxylation:
on phenyl rings

reduction:
of the carbonyl
of the amide

oxidation:
epoxidation of the phenyl rings

glucuronidation

may be less toxic than CBZ b/c there is not an epoxide formed on the bridge
Term
SAR of iminosilbenes
Definition
all emphasize blocking of the formation of an epoxide (circled)

[image]
Term
general properties of barbiturates
Definition
[image]

primidone is an exception b/c it does not have an ureide structure

all barbiturates are acids; the pKa will be lower than the hydantoins

lipophility:
if unionized, they will be less lipophilic than the hydantoins (although not hydrophilic)

most have sedative-hypotic activity, few have antiseizure
Term
barbiturate chemistry
Definition
barbiturates have a pKa = 5

[image]

at a pH < 7 the molecule will be ionized; the charge (-) will be resonanced around the molecule

if the charge in on the N, loses an H
if the charge in on the O, loses the double bond
Term
barbiturate SAR
Definition
[image]

POSITION 5:

DISUBSTITUTION IS ALWAYS NEEDED AT POSITION 5

position 5 has the most liberty to change; it is where the physicochemical properties are changed

carbon number related to the lipophilicity; increased lipophilicity = faster onset of action

polar groups on the side chain can modulate lipophilicity

branching, cyclic, aromatic, and halogens = increased lipophilicity

POSITION 1 AND 3:

substitution on one imide result in increased lipophilicity

ALWAYS have to have one UNSUBSTITUTED amine

ethyl groups or larger = anticonvulsants

substitution on both: completely lose the acid/base properties (which is needed for activity)

OXYGEN REPLACEMENT:

replaced with S (thiopental) increases lipophilicity

increase in lipophilicity = rapid onset and short duration (anesthetics)
Term
pharamcokinetics of barbiturates
Definition
ABSORPTION:
phenobarbital pKa = 7.4
AT PHYSIOLOGICAL PH, THE IONIZATION WILL BE 50/50!
if you go 2 log units above it will be 100% ionized
if you go 2 log units below it will be 100% unionized

DISTRIBUTION:
40-60% protein bound (phenobarbital)
plasma t1/2 = 2-6 days

METABOLISM:
same as hydantoins

EXCRETION:
25-50% excreted unchanged (phenobarbital)
50-75% metabolites
Term
pharmacokinetics of phenobarbital
[image]
Definition
SUBSTRATE OF CYP ENZYMES
INDUCER OF CYP ENZYMES
Term
pharmacokinetics of primidone
[image]
Definition
INDUCES CYP ENZYMES

oxidized in vivo to phenobarbital
primidone is a prodrug of phenobarbital

[image]
Term
pharmacokinetics of mephobarbital
[image]
Definition
SUBTRATE, INHIBITOR, AND INDUCER OF CYP ENZYMES
Term
examples of benzodiazepines (most commonly used anti-convulsants)
Definition
[image]
Term
pharmacokinetic properties of clorazepate dipotassium
[image]
Definition
prodrug of N-desmethyl diazepam (the MOST anti-convulsant activity)

[image]
Term
pharamcokinetics of diazepam
[image]
Definition
converted to N-desmethyl diazepam (t1/2 = 71 hours)
[image]

high lipid solubility

95% bound to plasma proteins

t1/2 = 46 hours
Term
diazepam metabolism
[image]
Definition
[image]
Term
pharmacokinetics of clonazepam
[image]
Definition
well absorbed

95-98% bound to plasma proteins

one of the most potent
Term
clonazepam metabolism
Definition
[image]
Term
example oxazolidinedions and succinimides
Definition
[image]

oxazolidinediones:
dimethadione
trimethadione

succinimides:
ethosuximide
methsuximide
phensuximide
Term
pharmacokinetics of trimethadione
[image]
Definition
prodrug of dimethadione (N-dealkylation)
[image]
Term
metabolism of ethosuximide
[image]
Definition
[image]
Term
pharmacokinetic properties of methsuximide
[image]
Definition
N-desmethyl metabolite is more active
[image]

t1/2 = 2.6-4h (methsuximide); 25h (N-desmethylmetabolite)

more toxic than ethosuximide
Term
valproic acid analogs
Definition
[image]
Term
pharmacokinetics of valproic acid
[image]
Definition
pKa = 4.7 = low absorption
ionized at physiological pH
[image]

90% bound to proteins

30-50% excreted as glucuronide conjugate in the urine

uses amino acid transporters to become absorbed and to cross the BBB
Term
metabolism of valproic acid
[image]
Definition
[image]

the only TOXIC metabolite of valproic acid is the 4-ene-VPZ
Term
valproic acid SAR
Definition
[image]

prodrugs that will increase the lipophilicity (increase absorption by decreasing possible ionization)

phosphatidyl choline analogs: designed to use the transporters better
Term
pharmacokinetics of felbamate
[image]
Definition
NMDA antagonist

SUBSTRATE, INHIBITOR, AND INDUCER OF CYP ENZYMES
Term
felbamate metabolism
[image]
Definition
[image]
Term
pharmacokinetics of levetiracetam
[image]
Definition
rapid and complete absorption

linear pharmacokinetics and minimally protein bound

esterase hydrolyzed
[image]

DOES NOT INTERACT WITH CYP ENZYMES!!!
metabolized by esterases to a carboxylic acid
Term
pharmacokinetics of topiramate
[image]
Definition
derivative of D-fructose

only 20% metabolized by CYP

minimal protein binding

INDUCER AND INHIBITOR OF CYP

SAFE FOR PEOPLE WITH SULFA ALLERGIES
3 Os makes a sulfamate, not a sulfonamide
[image]
Term
pharmacokinetics of zonisamide
[image]
Definition
non-linear pharmackinetics

moderate protein binding

DO NOT USE IN PATIENTS WITH A SULFONAMIDE ALLERGY!
Term
metabolism of zonisamide
[image]
Definition
[image]

acetylation
ring opening
Term
pharmacokinetics of gabapentin
[image]
Definition
GABA mimetic analog

absorption:
60% (low doses)
less at higher doses

NOT METABOLIZED (>90% excreted unchanged)

designed as a lipid soluble GABA analog

biochemical studies showed:
gabapentin is not a Na channel blocker as phenytoin or carbamazepine -> act at a different site
gabapentin increases GABA accumulation in discrete regions in a time course that parallels the anticonvulsants effect
Term
pharmacokinetics of pregabalin (3-isobutyl-GABA)
[image]
Definition
the S isomer displaces gabapentin binding and has anticonvulsant activity

blocks the production of glutamic acid

pregabalin inhibits the transformation of alpha-ketoglutaric acid into glutamic acid by interacting with the transaminase

glutamic acid is part of the cascade to make GABA

[image]
Term
pharmacokinetics of lamotrigine
[image]
Definition
triazine derivative

metabolized by glucuronidation

disturbances in folate metabolism may be related to phenytoin, phenobarbital, and primidone therapeutic effect

folic acid and other folates showed convulsant effect

lamotrigine is a potent anticonvulsant (Na channel blocker) and has weak antifolate activity

lamotrigine provides broader seizure protection than phenytoin and carbamazepine
Term
pharmacokinetics of tiagabine
[image]
Definition
nipecotic acid derivative

metabolized by CYP3A4

oral bioavailability: 90-95%

t1/2 = 5-8 hours
Term
metabolism of tiagabine
[image]
Definition
[image]
Term
pharmacokinetics of lacosamide
[image]
Definition
NO DRUG INTERACTIONS DUE TO CYP ENZYMES OR PROTEIN BINDING

well absorbed (amphiphilic)
Term
pharmacokinetics of rufinamide
[image]
Definition
orally active, relatively well absorbed (with food), not extensively bound to plasma proteins

steady state is reached within 2 days, consistent with its ELIMINATION T1/2 OF 6-10 HOURS

NOT A SUBSTRATE OF CYP ENZYMES
WEAK INDUCER OF CYP ENZYMES
EXTENSIVELY METABOLIZED VIA HYDROLYSIS BY CARBOXYLESTERASES TO A PHARMACOLOGICALLY INACTIVE CARBOXYLIC ACID DERIVATIVE, WHICH IS EXCRETED IN THE URINE
[image]

pharmacokinetics are not affected by impaired renal function
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