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Pharmacology > Epileptic Drugs > Flashcards

Epileptic Drugs Flashcards

1
Q

HLA-B 1502

A

predisposed people for interaction with aromatic AED’s

can be fatal, you see skin reactions known as Stevens-Johnson Syndrome or toxic epidermal necrolysis

more common in Asians

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2
Q

HLA-A 3101

A

strongly associated with carbamazepine-induced drug reaction with eosinophilia and systemic symptoms

known as “DRESS”

Seen in European and Asian patients

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3
Q

aromatic AED’s

A 
carbamazepine
oxcarbazepine
eslicarbazepine
phenytoin
lamotrigine
phenobarbital

these drugs are known to have pharmacogenomic interactions.

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4
Q

what AED’s are known inducers of CYPs, UGTs and P-glycoprotein?

A

phenobarbital
primidone
phenytoin
carbamazepine

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5
Q

which AEDs are specifically weak to moderate inducers of CYP3A4?

A

oxcarbazepine

eslicarcazepine

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6
Q

which AED is an inhibitor of CYPs and UGTs?

A

Valproate

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7
Q

What are the voltage-gated Na+ channel Inhibitors?

A

Phenytoin
Fosphenytoin
Lamotrigine
Carbamazepine

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8
Q

What’s the absorption, distribution, metabolism and excretion of phenytoin?

A

Given Oral, IV, IM

IM route is not recommended, IV route is painful

distributes to the brain, liver, muscle and fat.

Hepatic metabolism - CYP2C9 & 19, CYP3A4 with glucuronide metabolites

Zero order kinetics - this mean the half life of the drug depends on the plasma concentration

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9
Q

what patients require dose adjustments for phenytoin therapy?

A

patients with renal failure require lower maintenance doses - but not loading doses

patients with hypoalbuminemia may require lower dosing because it can decrease protein binding (freeing up drug)

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10
Q

MOA of Phenytoin

A

prolongs the inactivated (refractory) state of VG Na+ channel

this blocks the high-frequency repetitive firing of action potentials and decreases the propagation of synaptic impulses

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11
Q

Uses of phenytoin

A

Focal seizures

Generalized Tonic-Clonic Seizures

Status epilepticus

Prevention and treatment of seizures during or following neurosurgery

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12
Q

what are the adverse effects of phenytoin?

A

nausea, nystagmus, diplopia, dizziness, cognitive impairment, ataxia, tremor and sedation

peripheral neuropathy, atrophy of the cerebellum

Vitamin D and folic acid deficiency

Gingival hyperplasia, hirsuitism and coarsening of facial features

serious toxicities - skin, rash, Steven Johnson Syndrome, and toxic epidermal necrolysis, hepatitis and agranulocytosis

IV-related: hypotension, bradycardia, dysrhythmia, extravasation, purple glove syndrome

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13
Q

side effects for Phenytoin - PHENTOINS

A

P - P-450 P-Glycoprotein interactions
H - Hirsutism
E - Enlarged gums
N - Nystagmus
Y - Yellowing of skin
T - teratogenicity
O - Osteomalacia
I - interfers with folic acid absorption causing anemia
N - Neuropathies: vertigo, ataxia and headache
S - skin coarsening, skin reactions, purple glove syndrome

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14
Q

What are phenytoins effects in pregnancy?

A

increased risk of congenital malformations:

skull and facial abnormalities

microcephaly

mental retardation

underdeveloped nails of fingers and toes

Hypoprothrombinemia and hemorrhage have occurred in the
newborns - supplementation with Folic Acid and Vitamin K

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15
Q

how does phenytoin affects the thyroid function diagnostic test?

A

it can make it seem like serum levels are high because phenytoin bind TBG and displaces thyroxin

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16
Q

how is carbamazepine different from oxcarbazepine and eslicarbazepine?

A

carbamazepine is metabolized by and a strong inducer of CYP3A4

Oxcarbazepine and eslicarbazepine are weaker inducers. These are also renally excreted

Eslicarbazepine Inhibits CYP2C19

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17
Q

what is the MOA of carbamazepine?

A

it prolonged the inactive state of VG Na+ channels by binding allosterically.

this blocks sustained firing and decreases propagation of synaptic impulses

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18
Q

what are the therapeutic uses of carbamazepine and it’s related drugs?

A

focal seizures

focal seizure that evolves to generalized seizures

the non-seizure applications include Trigeminal Neuralgia and Acute Mania

Oxcarbazepine and Eslicarbamazepine are used solely for focal seizures.

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19
Q

what are the cautions or adverse effects of carbamazepine?

A

acute side effects - dizziness, sedation (high dose), ataxia, nystagmus and nausea

HLA-B1502 (Asians) and HLA-A 3101 patients have severe hypersensitivity skin reactions - SJS, TENS, hepatotoxicity (DRESS)

Syndrome of inappropriate ADH - unregulated water reabsorption causing hyponatremia and water intoxication.

tertatogenic effects — Increased risk of spina bifida, craniofacial defects, cardiovascular malformations, and hypospadias

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20
Q

lamotrigine

A

given orally with 98% bioavailability

hepatic glucuronidation which is renally excreted

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21
Q

what are the important drug and disease interactions of Lamotrigine?

A

Valproate - half life is more than doubled

Halflife is reduced in patients taking strong broad spectrum inducers - carbamazepine, phenytoin, phenobarbital and primidone

half-life is increased in patients with hepatic insufficiency

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22
Q

what are the MOA of Lamotrigine?

A

VG Na+ channel blocker with potential additional actions. Block is dependent on the use of the channel

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23
Q

What are the therapeutic uses of lamotrigine?

A

Broad spectrum - partial seizures, primary generalized seizures and generalized seizures of Lennox-Gestaut syndrome

nonseizure - bipolar disorder 1

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24
Q

what are the adverse effects of lamotrigine?

A

nausea, dizziness, tremor, diplopia, ataxia, anxiety and insomnia

Can worsen migraine headaches

series reactions are SJS, TEN and DRESS with HLA-B 1502 being the most at risk

Reduce risk by slow titration.

Even slower titration when administered with Valproate

25
Q

lamotrigine: pregnancy effects and drug interactions

A

pregnancy effects in humans are not fully known yet

Phenytoin,
carbamazepine, and
phenobarbital induce
metabolism of lamotrigine

Valproic acid inhibits
lamotrigine’s metabolism

26
Q

Valproic Acid - pharmacokinetic properties

A

Valproate is taken orally or given by IV

Oddball AED because of High Protein Binding

hepatic metabolism including CYP, glucuronide conjugation and mitochondrial Beta-oxidation

on the short side half life that increased in patients with liver disease

Valproic acid inhibits CYP2C9 and induces CYP2A6

27
Q

Valproate MOA

A

VG Na+ channel block

reduces VG T-type Ca+ channel currents

-this limits sustained repetitive neuronal firing

increases synaptic GABA:
stimulating the synthesis
inhibiting it’s degradation
inhibiting the transporter that would remove it from the synaptic cleft (GAT-1)

28
Q

Therapeutic Uses of Valproate

A

Generalized tonic-clonic seizures

focal seizures

absence seizures

status epilepticus

non-seizure applications include Acute Mania, migraine prophylaxis and diabetic neuropathy

29
Q

Valproate Adverse effects

A

common ones are nausea, vomiting, abdominal pain and heartburn - gradual titration of the drug helps with these

sedation, dizziness, ataxia and cognitive impairment

weight gain, hair loss and tremor

hepatotoxicity

thromcocytopenia and reduced platelet function

hyperammonemia

acute pancreatitis - rare

increases prevalence of polycystic ovary syndrome

30
Q

teratogenic effects of valproate

A

neural tube defects
craniofacial defects
cardiovascular malformation

31
Q

drug interactions of Valproate

A

displaces plasma protein binding

valproate will increase levels of Lamotrigine when these are given in unison it’s important to do an extra slow titration of the Lamotrigine

32
Q

Topiramate - MOA

A

Blockage of VG Na+ channels

Depresses the excitatory action of
AMPA

Binds GABA-receptor and enhances inhibitory effect of GABA

inhibits carbonic anhydrase - causes the inability to sweat and hyperthermia

33
Q

Topiramate - therapeutic uses

A

focal seizures

primary generalized tonic-clonic seizures

lennox-gastaut syndrome

non-seizure applicants include prophylaxis of migraine and cluster headaches, neuropathy and weight loss

34
Q

Topiramate - common adverse effects

A

Somnolence, fatigue, dizziness, cognitive slowing,
paresthesias, nervousness, and confusion

Weight loss

35
Q

Topiramate - Adverse effects due to the inhibition of carbonic anhydrase

A

oligohydrosis leading to hypothermia

increased risk of kidney stone formation

metabolic acidosis (by decreasing serum bicarbonate)

acute myopia with secondary angle-closure glaucoma

36
Q

topiramate - pregnancy and drug interaction

A

May cause fetal harm: oral clefts; hypospadias; other
congenital anomalies

use of valproate and topiramate together can cause hyperammonemia which could eventually lead to encephalopathy

other CNS depressants may enhance it’s effets

37
Q

Felbamate - MOA

A

blocks NMDA glutamate receptor - the block depends on the use of the receptor

potentiation of GABA mediated inhibition

38
Q

felbamate - therapeutic uses

A

should really be the last line - refractory uses because of the serious side effects

focal seizures
Lennox-Gestaut syndrome

Informed consent must be obtained

39
Q

Felbamate - adverse effects, contraindications and common side effects

A

adverse effects are very serious - aplastic anemia and serious hepatitis

contraindiced in patients with blood disorders or liver disease

common side effects are nausea, vomiting, headache, dizziness, somnolence, and
insomnia

40
Q

Gabapentin - PK and MOA

A

gabapenoids - gabapentin and pregabalin

Drug is taken in by L-type amino transporters

The MOA is by blocking the alpha2gamma subunit of VG Ca+

41
Q

Ganapentin - therapeutic uses

A

adjunct for treatment of focal seizures

neuropathic pain and many other off-label uses

42
Q

adverse effects of gabapentin

A

minor - sedation, dizziness, weight gain and peripheral edema

no human known adverse pregnancy effects - put on pregnancy registry

43
Q

Levetiracetam - MOA and PK

A

Drug binding to SV2A appears to reduce the synaptic release of glutamate and GABA

given IV with 100% bioavail and excreted renally - 2x daily dosing

44
Q

Levetiracetam - Therapeutic uses

A

adjunct therapy for

focal seizures

seizures Primary generalized tonic-clonic

myoclonic seizures

45
Q

Levetiracetam - adverse effects

A

fatigue and irritability

weakness and dizziness

psychotic symptoms

there is low potential for metabolic drug interactions

46
Q

ethosuximide - PK and Therapeutic Uses

A

Given orally

metabolized by CYP3A4 but excreted renally

long half life - 50h in adults and 30h in children

used for Absence seizures

47
Q

ethosuximide - MOA

A

reduces low threshold Ca2+ channel currents in thalamic neurons

supresses spike and wave EEG pattern seen in absence seizures and raises the threshold for seizure event

48
Q

ethosuximide - Adverse Effects

A

nausea and vomiting

somnolence, sleep disturbance and hyperactivity

49
Q

phenobarbital - PK and MOA

A

PK - Oral and IV with 50% protein binding.

Metabolized by CYP2C9 and some renal excretion

Very long half life - 1.5 to 5 days

MOA - bind allosteric sites of alpha and beta subunits of GABA - receptor prolonging the duration of Cl- channel closure leading to a higher influx of Cl- causing a decreased in excitability (hyper-polarization)

50
Q

phenobarbital - Therapeutic uses

A

focal seizures

generalized tonic-clonic seizures

status epileptics

51
Q

phenobarbital - adverse effects

A

sedation, depression of mood, cognitive impairment, hyperactivity, agitation and porphyria (in susceptible pops)

Rash, hepatotoxicity and bone marrow toxicity

can cause respiratory depression when used with Benzos

hypotension

fetal risks

52
Q

Benzodiazepine

A

diazepam
lorazepam
clonazepam

53
Q

Benzodiazepine - MOA

A

binds to allosteric site on alpha and beta subunits of GABA receptor causing increased frequency of opening of Cl- channels

54
Q

diazepam

A

benzo with rapid onset and short action

action is short because of a rapid redistribution

55
Q

clonazepam

A

oral with slower onset but longer anti-seizure activity

metabolized by CYP3A4

can be used alone with adjunct for Lennox-Gastaut syndrome, petit mal variant. Akinetic and myoclonic seizures

56
Q

nonseizure uses of Benzo’s

A

Anxiety; panic disorder; alcohol withdrawal; muscle relaxant (esp diazepam); sedative-hypnotic; preop sedation, anxiolysis, and amnesia; induction of anesthesia (balanced anesthesia); sedation for mechanically ventilated patients

57
Q

Adverse Effects of Benzos

A

Oral/Rectal - sedation, depression, incoordination and behavioral disturbances

parenteral - Acute hypertension, muscle weakness, respiratory depression and cardiac arrest

58
Q

Benzo - pregnant patient

A

teratogenic

floppy baby syndrome with withdrawl symptoms

Pharmacology (23 decks)

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