Epileptic Drugs Flashcards
HLA-B 1502
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
HLA-A 3101
strongly associated with carbamazepine-induced drug reaction with eosinophilia and systemic symptoms
known as “DRESS”
Seen in European and Asian patients
aromatic AED’s
carbamazepine oxcarbazepine eslicarbazepine phenytoin lamotrigine phenobarbital
these drugs are known to have pharmacogenomic interactions.
what AED’s are known inducers of CYPs, UGTs and P-glycoprotein?
phenobarbital
primidone
phenytoin
carbamazepine
which AEDs are specifically weak to moderate inducers of CYP3A4?
oxcarbazepine
eslicarcazepine
which AED is an inhibitor of CYPs and UGTs?
Valproate
What are the voltage-gated Na+ channel Inhibitors?
Phenytoin
Fosphenytoin
Lamotrigine
Carbamazepine
What’s the absorption, distribution, metabolism and excretion of phenytoin?
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
what patients require dose adjustments for phenytoin therapy?
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)
MOA of Phenytoin
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
Uses of phenytoin
Focal seizures
Generalized Tonic-Clonic Seizures
Status epilepticus
Prevention and treatment of seizures during or following neurosurgery
what are the adverse effects of phenytoin?
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
side effects for Phenytoin - PHENTOINS
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
What are phenytoins effects in pregnancy?
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
how does phenytoin affects the thyroid function diagnostic test?
it can make it seem like serum levels are high because phenytoin bind TBG and displaces thyroxin
how is carbamazepine different from oxcarbazepine and eslicarbazepine?
carbamazepine is metabolized by and a strong inducer of CYP3A4
Oxcarbazepine and eslicarbazepine are weaker inducers. These are also renally excreted
Eslicarbazepine Inhibits CYP2C19
what is the MOA of carbamazepine?
it prolonged the inactive state of VG Na+ channels by binding allosterically.
this blocks sustained firing and decreases propagation of synaptic impulses
what are the therapeutic uses of carbamazepine and it’s related drugs?
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.
what are the cautions or adverse effects of carbamazepine?
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
lamotrigine
given orally with 98% bioavailability
hepatic glucuronidation which is renally excreted
what are the important drug and disease interactions of Lamotrigine?
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
what are the MOA of Lamotrigine?
VG Na+ channel blocker with potential additional actions. Block is dependent on the use of the channel
What are the therapeutic uses of lamotrigine?
Broad spectrum - partial seizures, primary generalized seizures and generalized seizures of Lennox-Gestaut syndrome
nonseizure - bipolar disorder 1
what are the adverse effects of lamotrigine?
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
lamotrigine: pregnancy effects and drug interactions
pregnancy effects in humans are not fully known yet
Phenytoin,
carbamazepine, and
phenobarbital induce
metabolism of lamotrigine
Valproic acid inhibits
lamotrigine’s metabolism
Valproic Acid - pharmacokinetic properties
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
Valproate MOA
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)
Therapeutic Uses of Valproate
Generalized tonic-clonic seizures
focal seizures
absence seizures
status epilepticus
non-seizure applications include Acute Mania, migraine prophylaxis and diabetic neuropathy
Valproate Adverse effects
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
teratogenic effects of valproate
neural tube defects
craniofacial defects
cardiovascular malformation
drug interactions of Valproate
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
Topiramate - MOA
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
Topiramate - therapeutic uses
focal seizures
primary generalized tonic-clonic seizures
lennox-gastaut syndrome
non-seizure applicants include prophylaxis of migraine and cluster headaches, neuropathy and weight loss
Topiramate - common adverse effects
Somnolence, fatigue, dizziness, cognitive slowing,
paresthesias, nervousness, and confusion
Weight loss
Topiramate - Adverse effects due to the inhibition of carbonic anhydrase
oligohydrosis leading to hypothermia
increased risk of kidney stone formation
metabolic acidosis (by decreasing serum bicarbonate)
acute myopia with secondary angle-closure glaucoma
topiramate - pregnancy and drug interaction
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
Felbamate - MOA
blocks NMDA glutamate receptor - the block depends on the use of the receptor
potentiation of GABA mediated inhibition
felbamate - therapeutic uses
should really be the last line - refractory uses because of the serious side effects
focal seizures
Lennox-Gestaut syndrome
Informed consent must be obtained
Felbamate - adverse effects, contraindications and common side effects
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
Gabapentin - PK and MOA
gabapenoids - gabapentin and pregabalin
Drug is taken in by L-type amino transporters
The MOA is by blocking the alpha2gamma subunit of VG Ca+
Ganapentin - therapeutic uses
adjunct for treatment of focal seizures
neuropathic pain and many other off-label uses
adverse effects of gabapentin
minor - sedation, dizziness, weight gain and peripheral edema
no human known adverse pregnancy effects - put on pregnancy registry
Levetiracetam - MOA and PK
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
Levetiracetam - Therapeutic uses
adjunct therapy for
focal seizures
seizures Primary generalized tonic-clonic
myoclonic seizures
Levetiracetam - adverse effects
fatigue and irritability
weakness and dizziness
psychotic symptoms
there is low potential for metabolic drug interactions
ethosuximide - PK and Therapeutic Uses
Given orally
metabolized by CYP3A4 but excreted renally
long half life - 50h in adults and 30h in children
used for Absence seizures
ethosuximide - MOA
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
ethosuximide - Adverse Effects
nausea and vomiting
somnolence, sleep disturbance and hyperactivity
phenobarbital - PK and MOA
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)
phenobarbital - Therapeutic uses
focal seizures
generalized tonic-clonic seizures
status epileptics
phenobarbital - adverse effects
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
Benzodiazepine
diazepam
lorazepam
clonazepam
Benzodiazepine - MOA
binds to allosteric site on alpha and beta subunits of GABA receptor causing increased frequency of opening of Cl- channels
diazepam
benzo with rapid onset and short action
action is short because of a rapid redistribution
clonazepam
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
nonseizure uses of Benzo’s
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
Adverse Effects of Benzos
Oral/Rectal - sedation, depression, incoordination and behavioral disturbances
parenteral - Acute hypertension, muscle weakness, respiratory depression and cardiac arrest
Benzo - pregnant patient
teratogenic
floppy baby syndrome with withdrawl symptoms
