Anticonvulsants Medchem Flashcards Preview

Pharmacy School 2016-17 > Anticonvulsants Medchem > Flashcards

Flashcards in Anticonvulsants Medchem Deck (30):
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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

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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

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PhenylEthylMalonamide (PEMA)

 

Anticonvulsant Properties

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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.

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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

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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)

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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

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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

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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

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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)

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L-glutamine

 

Glutamic Acid Decarboxylase (GAD) takes it to GABA - Valproate activates GAD

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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

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Succinate Semialdehyde (SSA)

 

Converted to Siccinate by SSA-DH (using NAD as a cofactor and getting NADH)


Valproate inhibits SSA-DH

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Succinate

 

Used in TCA cycle

15

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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

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Gabapentin enacarbil (Horizant)

For pain associated with shingles; NOT FOR EPILEPSY

Lipophilic prodrug of Gabapentin

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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

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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

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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

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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

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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

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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

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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

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Lacosamide (Vimpat)

D-serine like group

T1/2 = 12-13 hours

40% excreted unchanged

O-demethylation through 2C19 (experiences minor effects from P450 inducers)

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Levetiracetam (Keppra)

SV2A protein modulation

T1/2 = 6-8 hours

Great choice for adjunctive therapy since no P450 metabolism or glucoronidation

66% excreted unchanged

Most remaining hydrolyzed to inactive acid

No blood/liver/skin toxicities

No P450 or UGT induction/inhibition

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Brivaracetam (Briviact)

More lipophilic analog of Keppra (more potent SC2A ligand)

40% excreted unchanged; 2C19 hydroxylation on propyl side chains as well as amide hydrolysis

T1/2 = 9 hours

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Rufinamide (Banzel)

Modulates Na channels

Extensively metabolized: Hydrolysis to acid metabolite (inactive) followed by glucuronidation

T1/2 = 8-12 hours

Weak 3A4 inducer and Weak 2E1 inhibitor

Some drug interaction despite no major P450 routes

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Ezogabine

K+ channel activator

Metabolism: Glucuronidation, N-acetylation

T1/2 = 6-10 hours

No major P450 metabolism

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Perampanel

T1/2 - 105 hours

AMPA receptor

Major metabolism - 3A4 metabolism

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Cannabidiol