Anticonvulsants Medchem Flashcards
Phenobarbital (Luminal)
1912 - approved as first anticonvulsant (initially intended as a tranquilizer)
Acts at GABAa receptor
SE: Sedation
Metabolized via para-hydroxylation by 2C9/2C19
T1/2 = 2-6 days
Potent inducer of P450s and soem UGTs
Primidone (Mysoline)
Oxidized to phenobarbital or metabolized to phenylethylmalonamide (PEMA) - all 3 molecules have anticonvulsant properties
Less sedating overall than phenobarbital
Still induces P450s and UGTs
PhenylEthylMalonamide (PEMA)
Anticonvulsant Properties
Phenytoin (Dilantin) - Hydtantoins
Discovered its usefulness from electroshock seizure tests in 1938
Blocks Na channels
Less sedating than phenobarbital
Metabolized by 2C9 and 2C19 to arene oxide metabolite and/or p-hydroxylated metabolite (inactive); GSH will take arene oxide to glutathione and mercaptopuric acid metabolites
Potential for major skin reactions due to arene oxide intermediate
Like phenobarbital and primidone, induces P450s and UGTs.
Fosphenytoin Sodium
Water soluble prodrug of phentoion for IM/IV injections
Metabolism: Phosphate cleaved by phosphatases yielding phenytoin, phosphate and formaldehyde
Conversion T1/2 = 15 minutes
Ethosuximide (Zarontin) - Succinimide
Can be first choice in ansence seizure suncomplicated by other seizure types
R groups are small alkyl groups as opposed to aromatic rings, giving it effectiveness against absense seizures?
Works by blocking Ca2+ channels
Metabolized by hydroxylation on ethyl sidechain (3A4/2E1)
Toxicities include rare anemias, hepatotoxicity, reduced kidney function (limited use; blood and liver tests required)
Valproic Acid (Depakene) or Divalproex Sodium (Depakote)
Discovered in 1963
Metabolism: Direct glucuronidation to inactive state; double bond formation by b-oxidation giving active 2-ene metabolite
T1/2 reduced when taking other AEDs (phenobarbital, phenytoin)
Valproate can inhibit 2C9, some UGTs and epoxide hydrolase
Potential hepatotoxicity - liver function monitoring required
Rare pancreatitis and can cause fetal malformations
Carbamazepine (Tegretol)
Blocks Na+ channels
Black box warnings: aplastic anemia (agranulocytosis), serious skin reactions (SJS; particularly in Asians with HLA-B 15:02 allele)
Clinical monitoring required; rare liver toxicity
Metabolism: CBZ metabolized to CBZ 10,11 epoxide by 3A4 and then to CBZ 10,11 diol by epoxide hydrolase; epoxide can become an alkylated protein (toxic) or CBZ can undergo metabolism to an iminoquinone which can then be alkylated to form another toxic compound
Oxcarbazepine (Trileptal) - CBZ analog that doesn’t form toxic epoxide
Reduced (T1/2 = 12 hours) to monohydroxy metabolite (T1/2 9-11 hours)
Licarbazepine = monohydroxy metabolite = main metabolite
Eslicarbazepine acetate (Aptiom)
Prodrug that undergoes rapid ester hydrolysis to form eslicarbazepine (the S-enantiomer of Licarbazepine)
Both oxcarbazepine and licarbazepine induce 3A4 (however, less than CBZ); they both inhibit 2C19
Both also lack major blood toxicity of CBZ but can cause some skin reactions (less common though)
L-glutamine
Glutamic Acid Decarboxylase (GAD) takes it to GABA - Valproate activates GAD
GABA
GABA-AT takes to Succinate Semialdehyde (SSA) sing 2-oxogluterate as a cofactor (yielding L-Glu in the process)
Valproate and Vigabatrin both inhibit GABA-AT
Succinate Semialdehyde (SSA)
Converted to Siccinate by SSA-DH (using NAD as a cofactor and getting NADH)
Valproate inhibits SSA-DH
Succinate
Used in TCA cycle
Gabapentin (Neurontin)
Originally designed as more lipophilic GABA (doesn’t act at GABA receptors though)
Acts at specific calcium channels (a2d)
T1/2 = 5-7 hous
Great for adjunctive therapy because…Not appreciably metabolized, doesn’t induce/inhibit hepatic enzymes, doesn’t alter PK of other AEDs and is not altered much itself, lacks blood/liver toxicities
Gabapentin enacarbil (Horizant)
For pain associated with shingles; NOT FOR EPILEPSY
Lipophilic prodrug of Gabapentin
Pregabalin (Lyrica)
Acts at same Ca2+ channels as gabapentin (a2d)
T1/2 = 6 hours
Less than 2% metabolism and has similar qualities to Gabapentin for adjunctive therapy
Schedule 5 due to some euphoria
Vigabatrin (Sabril)
Vinyl group
Irreversible inhibitor of GABA-AT
Not significantly metabolized (T1/2 = 7.5 hours)
Induced CYP2C9
Used as a racemate but only S is active
Used in adjunctive therapy for refractive complex partial seizures not controlled with other drugs
BLACK BOX - CAN CAUSE PERMANENT VISION LOSS
Felbamate
Used only in patients resistant to other therapies due to liver toxicity
Black Box: Aplastic anemia, hepatic failure (requires clinical monitoring)
Can be dosed up to 3600mg/day
Minor route of felbamate metabolism involves carbamate hydrolysis, oxidation and elimination of carbamic acid…giving Atropaldehyde (a good Michael acceptor, or electrophile, that can alkylate biomolecules)
Atropaldehyde can also react with GSH, detoxifiying it
Lamotrigine (Lamictal)
Metabolism (Major): Glucuronidation is main route (T1/2 = 24-35 hours; reduced to about 15 hours when administered with phenobarbital, phenytoin or CBZ)
Metabolism (Minor): via P450 to reactive arrene oxide matbolite, followed by glutathione conjugation
Black Box: Serious skin rashes possible
Topiramate (Topamax)
Sugar core and sulfamate group
70% excreted unchanged with the remaining 30% undergoing other pathways
T1/2 = 20-30 hours but pheyntoin and CBZ can decrease this
Weak CYP3A4 inducer and 2C19 inhibitor
1.5% of patients will develop kidney stones due to beleived carbonic anhydrase inhibition
Zonisamide (Zonegran)
Sulfonamide group (adds to possible carbonic anhydrase inhibition - kidney stones in 4%)
Sulfonamide group also causes potential for Sulfa allergies (but not sulfamate of Topiramate)
T1/2 = 63 hours
Metabolism: 3A4 reduction; N-acetylation of sulfonamide
Tiagabine (Gabitril)
Blocks GAT-1 GABA transporter
Characterized by 2 thiophene-like structures
Bulkiness provides steric blockade of transporter
Metabolism: 3A4 to 5-oxo-metabolite
Lacosamide (Vimpat)
D-serine like group
T1/2 = 12-13 hours
40% excreted unchanged
O-demethylation through 2C19 (experiences minor effects from P450 inducers)
