Term
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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 |
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Term
| general structures of anticonvulsants |
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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 |
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Term
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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 |
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Term
hydantoins
[image]
water solubility?
pKa?
sodium salt? |
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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 |
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Term
pharmacokinetics of phenytoin
[image] |
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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 |
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Term
metabolism of phenytoin
[image] |
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Definition
[image]
60-75% excreted as HPPH |
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Term
| common metabolism of hydantoins |
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Definition
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Term
pharmacokinetics of fosphenytoin
[image] |
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Definition
prodrug of phenytoin
parenteral use
as a replacement for parenteral phenytoin
[image] |
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Term
pharmacokinetics of ethotoin
[image] |
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Definition
[image]
hydantoin
less toxic but less effective and more sedative than phenytoin
saturable and non-linear metabolism |
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Term
pharamcokinetics of mephenytoin
[image] |
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Definition
more sedative than phenytoin
more toxic
N-desmethyl metabolite contributes to efficacy and toxicity
[image] |
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Term
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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 |
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Term
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Definition
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Term
pharmacokinetics of carbamazepine
[image] |
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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 |
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Term
major metabolism of carbamazepine
[image] |
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Definition
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Term
pharmacokinetics of oxcarbazepine
[image] |
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Definition
less active than carbamazepine
less toxic
INDUCES CYP3A4
INDUCES GLUCURONYLTRANSFERASES
INHIBITS CYP2C19 |
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Term
metabolism of oxcarbazepine
[image] |
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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 |
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Term
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Definition
all emphasize blocking of the formation of an epoxide (circled)
[image] |
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Term
| general properties of barbiturates |
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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 |
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Term
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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 |
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Term
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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) |
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Term
| pharamcokinetics of barbiturates |
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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 |
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Term
pharmacokinetics of phenobarbital
[image] |
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Definition
SUBSTRATE OF CYP ENZYMES
INDUCER OF CYP ENZYMES |
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Term
pharmacokinetics of primidone
[image] |
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Definition
INDUCES CYP ENZYMES
oxidized in vivo to phenobarbital
primidone is a prodrug of phenobarbital
[image] |
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Term
pharmacokinetics of mephobarbital
[image] |
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Definition
| SUBTRATE, INHIBITOR, AND INDUCER OF CYP ENZYMES |
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Term
| examples of benzodiazepines (most commonly used anti-convulsants) |
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Definition
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Term
pharmacokinetic properties of clorazepate dipotassium
[image] |
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Definition
prodrug of N-desmethyl diazepam (the MOST anti-convulsant activity)
[image] |
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Term
pharamcokinetics of diazepam
[image] |
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Definition
converted to N-desmethyl diazepam (t1/2 = 71 hours)
[image]
high lipid solubility
95% bound to plasma proteins
t1/2 = 46 hours |
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Term
diazepam metabolism
[image] |
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Definition
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Term
pharmacokinetics of clonazepam
[image] |
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Definition
well absorbed
95-98% bound to plasma proteins
one of the most potent |
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Term
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Definition
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Term
| example oxazolidinedions and succinimides |
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Definition
[image]
oxazolidinediones:
dimethadione
trimethadione
succinimides:
ethosuximide
methsuximide
phensuximide |
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Term
pharmacokinetics of trimethadione
[image] |
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Definition
prodrug of dimethadione (N-dealkylation)
[image] |
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Term
metabolism of ethosuximide
[image] |
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Definition
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Term
pharmacokinetic properties of methsuximide
[image] |
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Definition
N-desmethyl metabolite is more active
[image]
t1/2 = 2.6-4h (methsuximide); 25h (N-desmethylmetabolite)
more toxic than ethosuximide |
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Term
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Definition
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Term
pharmacokinetics of valproic acid
[image] |
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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 |
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Term
metabolism of valproic acid
[image] |
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Definition
[image]
the only TOXIC metabolite of valproic acid is the 4-ene-VPZ |
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Term
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Definition
[image]
prodrugs that will increase the lipophilicity (increase absorption by decreasing possible ionization)
phosphatidyl choline analogs: designed to use the transporters better |
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Term
pharmacokinetics of felbamate
[image] |
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Definition
NMDA antagonist
SUBSTRATE, INHIBITOR, AND INDUCER OF CYP ENZYMES |
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Term
felbamate metabolism
[image] |
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Definition
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Term
pharmacokinetics of levetiracetam
[image] |
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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 |
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Term
pharmacokinetics of topiramate
[image] |
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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] |
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Term
pharmacokinetics of zonisamide
[image] |
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Definition
non-linear pharmackinetics
moderate protein binding
DO NOT USE IN PATIENTS WITH A SULFONAMIDE ALLERGY! |
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Term
metabolism of zonisamide
[image] |
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Definition
[image]
acetylation
ring opening |
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Term
pharmacokinetics of gabapentin
[image] |
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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 |
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Term
pharmacokinetics of pregabalin (3-isobutyl-GABA)
[image] |
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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] |
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Term
pharmacokinetics of lamotrigine
[image] |
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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 |
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Term
pharmacokinetics of tiagabine
[image] |
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Definition
nipecotic acid derivative
metabolized by CYP3A4
oral bioavailability: 90-95%
t1/2 = 5-8 hours |
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Term
metabolism of tiagabine
[image] |
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Definition
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Term
pharmacokinetics of lacosamide
[image] |
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Definition
NO DRUG INTERACTIONS DUE TO CYP ENZYMES OR PROTEIN BINDING
well absorbed (amphiphilic) |
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Term
pharmacokinetics of rufinamide
[image] |
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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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