Pharm 31 Flashcards
seizure definition
- Abnormal, excessive brain electrical discharges
- A single seizure does not indicate a diagnosis of epilepsy
- There may be a non-epileptic identifiable cause
epilepsy definition
- Involves idiopathic, recurrent, transient disturbances of brain function
- May manifest as:
- Episodic impairment or loss of consciousness
- Abnormal motor phenomena
- Psychic or sensory disturbances
- Perturbation of ANS
types of seizures
focal and generalized
Simple focal seizures
consciousness is not impaired
complex focal seizures
alteration in consciousness
generalized seizures
- involve entire brain
- always involve a LOC
- described by clinical manifestations
drugs with established therapeutic ranges (4)
- phenytoin
- valproic acid
- carbamazepine
- phenobarbital
Main pharmacokinetic features that can be problematic for phenytoin
Saturable (non-linear) metabolism
broad spectrum hepatic enzyme inducer (loss of hormonal contraceptive efficacy)
Main pharmacokinetic features that can be problematic for valproic acid
Hepatic enzyme inhibitor, especially “UGT”
Main pharmacokinetic features that can be problematic for carbamazepine
Broad spectrum hepatic enzyme inducer (loss of hormonal contraceptive efficacy)
induces its own metabolism
Main pharmacokinetic features that can be problematic for phenobarbital
Broad spectrum hepatic enzyme inducer (loss of hormonal contraceptive efficacy)
very long half-life
Drugs that can induce congenital abnormalities if taken during pregnancy and cause osteoporosis (4)
- phenytoin
- valproic acid
- carbamazepine
- phenobarbital
Drugs that require renal monitoring due to >50% renal excretion
- acetazolamide
- gabapentin
- pregablin
- topiramate
autoinducer drugs (2)
carbamazepine
lamotrigine
common MOA of antiseizure drugs: modulate ion channels. How does this occur?
- prolonging inactivated state of Na+ channel or enhancing inactivation of the Na+ channel.
- Modulate/block voltage gated Ca2+ channels
- Activation or opening of Cl- channels (hyperpolarizes)
- alteration of neuronal bicarb flux
common MOA of antiseizure drugs: some work via neutrotransmitters and/or neurotransmitter receptors. How does this occur?
- pharmacologic enhancement of GABA neurotransmission
2. inhibited glutamate neurotransmission
MOA ion channel blockade of phenytoin and fosphenytoin
block Na+ channel
MOA ion channel blockade of gabapentin and pregabalin
block Ca2+ channels
MOA ion channel blockade of carbamazepine
block Na+ channels
MOA ion channel blockade of lamotrigine
block Na+ channels
MOA ion channel blockade of ethosuximide
block Ca2+ channels
MOA of barbiturates and phenobarbital
Positive allosteric effector of GABA-A
MOA of benzodiasepines and clonazepam
Positive allosteric effector of GABA-A
Benzodiasepines effect on GABA-A receptors
bind GABA receptors and increase the likelihood of GABA-linked-chloride channel opening
do not directly activate GABA receptors
Barbiturates effect on GABA-A receptors
at low to moderate doses prolong the time of opening of the Cl- channel
Z drugs (zolpidem, zaleplon, eszopiclone) effect on GABA-A receptors
agonists of GABA receptors and sepcific to GABA-A receptors with alpha-1 subunit
ethosuximide MOA
blocks T-type Ca2+ channels
ethosuximide use
highly effective (first line) for absence seizures ('petit mal')
ONLY for absence seizuresethosuximide ADE
GI
CNS
idiosyncratic reactions of HA, hiccups, blood dyscrasias, lupus-like, behavioral disturbances, and parkinsonism
hypersensitivity reactions
phenytoin MOA
blockade of sodium channels and inhibits rapidly repetitive action potentials
binds preferentially to inactivated state of Na+ channel and prolongs the duration of the closed state
phenytoin metabolism
metabolized b 2C9 and 2C19
cyp enzyme broad inducer
phenytoin administration: oral
prevents seizures
phenytoin administration: IV
for status epilepticus and must be administered slowly: 1 gram at least 20 minutes to infuse
fosphenytoin administration: IV
1 gram phenytonin equivalent dose may be administered over only seven minutes
PRODRUG: thus takes just as long to start working
fast phenytoin IV administration ADE
- purple glove syndrome
- ataxia, confusion, dizziness
- dysrhytmia, hypotension, bradycardia
4 BZDs most useful as antiseizure drugs
- Clonazepam
- Lorazepam
- Diazepam
- Clobazam
daily benzo for seizure prevention
clonazepam
carbamazepine MOA
Na+ Channel Blocker – similar to phenytoin
Some effects similar to tricyclic antidepressants…
NE and serotonin re-uptake inhibition
carbamazepine metabolism
Self inducer (CYP3A4)
Full enzyme induction takes 3-6 weeks on a fixed dose regimen
1/2 life reduces by more than half after autoinduction period of a few weeks (about 40 days)
carbamazepine black box warning
aplastic anemia, agranulocytosis, hyponatremia
carbamazepine ADE
thrombocytopenia, leukopenia, hyponatremia
antiseizure drug requiring genetic testing
oxcarbazepine and carbamazepine requires HLA-B*1502 to be checked –> esp. asian populations due to life threatening rash risk
lamotrigine MOA
produces a voltage- and use-dependent inactivation of sodium channels
lamotrigine use
Focal (partial) seizures (monotherapy or adjunct)
Generalized seizures (adjunct)
Including the difficult-to-treat Lennox-Gastaut syndrome
lamotrigine ADE
- lamictal rash (serious, can be fatal, rash) –> to reduce this risk, slow and low dosing titrated up over four weeks
- CNS effects of dizziness, HA, diplopia, somnolence
valproate use
effective against many seizure types: generalized seizures: absence, myoclonic, and generalized tonic-clonic seizures
Valproate is also used for partial (focal) seizures, bipolar disorder, and migraine prophylaxis. “Broad spectrum”
valproate MOA
blocks high-frequency repetitive firing of neurons via Na+ channel blockade
Blockade of the NMDA receptor as well as increased [GABA] in the brain may also contribute to its mechanism of action.
gabapentin MOA
Prevents presynaptic calcium entry, which then…
Reduces presynaptic NT release; = reduced glutamate release from glutaminergic neurons.
gabapentin use
adjunct treatment of partial seizures and post-herpetic neuralgia
pregabalin use
- Partial epilepsy
- Diabetic peripheral neuropathy
- Post-herpetic neuralgia
- Fibromyalgia
pregabalin ADE
Common: dizziness, blurred vision
Can cause some euphoria
Schedule-V controlled substance
levetiracetam use
adjunctive therapy of partial seizures, with some potential advantages:
Not extensively metabolized and does not interact with other drugs via cytochrome P450 pathways
Relatively well tolerated compared to other agents
The starting dose can be an effective dose
acetazolamide use
altitude sickness, as a diuretic, or to reduce intraocular pressure, but also has anti-seizure effects.
Acetazolamide is generally used as adjunct therapy for seizure disorders.
Acetazolamide may produce its antiseizure effects by causing a mild brain acidosis or by altered bicarbonate flux.
acetazolamide MOA
a carbonic anhydrase inhibitor
Bicarbonate moving out of neurons via GABA-receptor ion channels is a depolarizing effect, which is reduced by carbonic anhydrase inhibitors
acetazolamide ADE
Metabolic acidosis.
Headache, hearing dysfunction, tinnitus, paresthesias.
GI disturbances: nausea and vomiting, appetite loss, taste alteration, polyuria.
Drowsiness or confusion
zonisamide MOA
Na+ channel blockade
Also a mild carbonic anhydrase inhibitor, but CA inhibition is milder than seen with acetazolamide
zonisamide use
Increasing use across the lifespan children (liquids), pregnancy and older adults
zonisamide ADE
may cause metabolic acidosis (CA)
The FDA recommends monitoring serum bicarbonate before starting treatment, and during treatment with zonisamide, even in the absence of symptoms
topiramate MOA
Na+ channels blockade
topiramate use
Partial or primarily generalized tonic-clonic seizures
Monotherapy for ages 10+
Adjunctive therapy for patients aged 2+; including seizures associated with Lennox-Gastaut syndrome
Migraine prophylaxis.
To promote weight loss (in combo with phentermine)
Several additional intriguing uses are off-label
topiramate metabolism
Selective inducer of CYP3A4
Primarily cleared by the kidneys, so not a “self-inducer”
Increases the rate of metabolism of drugs metabolized by CYP3A4 (there are many!) – including hormonal contraceptives
topiramate ADE with D/C
difficulty with memory
paresthesias
psychomotor slowing
FDA approval for post-herpetic neuralgia:
gapapentin and pregabalin
FDA approval for diabetic peripheral neuropathy:
pregabalin
FDA approval for fibromyalgia pain:
pregabalin
FDA approval for trigeminal neuralgia:
carbamazepine (Tegretol®)
Identify three antiseizure drugs FDA approved for bipolar disorder
Valproic acid, carbamazepine, and lamotrigine are mood stabilizers that can be used in bipolar disorder
Drugs initiated during acute mania
Lithium, +/- valproic acid +/- atypical antipsychotic drug
Drugs used long term for PREVENTING mania and cycling
Lithium, +/- valproic acid +/- atypical antipsychotic drug, lamotrigine
Migraine Prevention: FDA approved uses for topiramate
- epilepsy
- migraine prophylaxis
- weight loss
topiramate migraine use ADE
- paresthesia
- memory difficulty
- language problems
increasing dose pass recommended daily dose of 100mg/day can result in even more and severe ADE
valproate for migraine prevention indications
Mania associated with bipolar disorder
Migraine prophylaxis
valproate of migraine use MC ADE
weight gain nausea somnolence tremor dizziness hair loss
valproate of migraine use pregnancy use
contraindicated in pregnancy:
- Highest risk of AEDs for major congenital malformations.
- Lower IQ is also seen in children of women who used valproate during pregnancy.
try to avoid these drugs in pregnancy (4) due to major malformations of the fetus (esp. male fetuses)
valproate
phenobarbital
topiramate
phenytoin
drugs that are considered safer during pregnancy
lamotrigine
levetiracetam
gabapentin
zonisamide
