Exam 2 Drugs: Anti-seizures (26)

Question 1

Phenytoin

Answer 1

• cyclic ureides, di-phenyl-substituted hydantoin
• mech: blocks high freq firing of neurons through action on voltage-gated Na channels (prolongs inactivation state). Also decreases synaptic release of glutamate and enhances synaptic release of GABA
• alters Na, K, and Ca conductance, alters membrane potentials, alters [ ] of AA, NE, ACh, and y-aminobutyric acid
• blockage of Na channels is fast inactivation which delays by milliseconds and uses a hinged-lid mechanism
• clinical app: generalized tonic-clonic seizures, partial seizures (all three types)
• 90% bound to plasma proteins: can be displaced by phenylbutazone and sulfonamides (can cause increase in free drug)
• can have decrease in protein binding from hypoalbuminemia or renal disease (decrease in total plasma [ ] but not free [ ] )
• has affinity for thyroid binding globulin so can interfere with some test of thyroid function
• no active metabolites
• dose-dependent elimination, t1/2= 12-36 hrs (low dose 24 hrs)
• metabolized by CYP2C9/10 and 2C19
• levels increased by Cimetidine, disulfiram, felbamate, and isoniazid
• levels decreased by carbamazepine and phenobarbital
• increases metabolism of carbamazepine, lamotrigine, levodopa, oral contraceptives, quinidine and warfarin
• phenytoin can exacerbate absence seizures
• at high doses, saturates the P450 system and small change in dose can have large change in plasma [ ] (increases risk of adverse)
• adverse: nystagmus and loss of smooth extra-ocular pursuit movements, diplopia, ataxia (both require dose adjustment), gingival hyperplasia, hirsutism, facial coursening
• can have abnormalities of Vit D metabolism leading to osteomalacia
• agranulocytosis has been reported in combo with fever and rash but very rare
• contra: hydantoin hypersensitivity
• induces Cyp 2C/3A & UGTs

Question 2

Fosphenytoin

Answer 2

• cyclic ureide
• more soluble prodrug of phenytoin
• parenteral IV, IM formulation
• rapidly converted to phenytoin in plasma

Question 3

Phenobarbital

Answer 3

• cyclic ureide
• derivative of barbituric acid, has a phenyl ring
• one of the oldest currently available anti-seizure drugs
• mech: suppress high-frequency repetitive firing through action on Na+ channels, block L- and N-type Ca channels, enhances phasic GABAa receptor responses (binds to allosteric site, prolongs openings of Cl- channels), decrease excitatory response and enhance inhibitory transmission
• may selectively suppress abnormal neurons
• nearly complete absorption, not significantly bound to plasma proteins, peak [ ] .5-4 hours, no active metabolites
• t1/2 = 75-125 hours
• clinical app: partial seizures (esp. w/ secondary tonic-clonic) and generalized tonic-clonic seizures. Also tried when attacks difficult to treat
• may worsen general seizures of other types (absence)
• Induces P450s that increase metabolism of valproate, carbamazapine, felbamate, phenytoin, and lamotrigine
• levels can be increase by valproate or phenytoin
• adverse: sedation, cognitive issues. ataxia hyperactivity
• not really a first line agent because of sedative effects
• contra: porphyria, severe liver dysfunction, resp. disease
• induces CYP 2C/3A, induces UGT, metabolized by 2C9/19, not inhibited by UGTs and not metabolized by them

Question 4

Primidone

Answer 4

• cyclic ureide
• derivative of barbituric acid
• metabolized to phenobarbital and phenylethylmalonamide (PEMA)
• all 3 compounds anti-convulsants
• mech: similar to phenytoin
• well absorbed orally, not highly bound to plasma proteins
• peak [ ] 2-6 hours, t1/2= 10-25 hours
• clinical app: generalized tonic-clonic seizures, partial seizures
• may be more effective than phenobarbital
• has anticonvulsant action independent of its metabolites
• PEMA effect relatively weak
• adverse: sedation, cognition issues, ataxia, hyperactivity
• interactions similar to phenobarbitol

Question 5

Ethosuximide

Answer 5

• cyclic ureide
• introduced as “pure petit mal” drug
• 3 anti-seizure succimmides have been marketed in US
• mech: reduces T-type low threshold Ca currents which provide pacemaker current in thalamic neurons (these generate rhythmic cortical discharge of absence attack)
• clinical app: absence seizures, very narrow spectrum of clinical activity
• well absorbed orally, peak [ ] 3-7 hours
• not protein bound, completely metabolized to inactive compounds
• t1/2= 40 hours
• reduces low-threshold T-type currents in a voltage dependent manner w/o alternating voltage dependence or recovery kinetics of the sodium channel
• 1st line therapy for uncomplicated absence seizures
• clearance decreased by valproate
• adverse: (almost exclusively dose-related) GI irritation, lethargy, headache, dizziness, hypereactivity
• temporary dosage reduction may allow adaption
• doesn’t enduce or inhibit CYPs or UGTs

Question 6

Carbamazepine

Answer 6

• tricyclic
• closely related to imipramine
• many similarities to phenytoin
• mech: block high-freq firing of neurons through action on VG Na channels. Decrease synaptic release of glutamate and acts PRE-synaptically to decrease transmissions.
• also interacts with adenosine receptors but significance unknown
• clinical app: generalized tonic-clonic seizures, partial seizures, bipolar disorder, very effective in trigeminal neuralgia
• older patients may tolerate dose poorly –> ataxia and unsteadyness
• only in oral form, well absorbed
• effective in adults and children
• extended release preps available
• peak levels 6-8 hours
• can exacerbate absence seizures
• toxicity: (dose related) diplopia and ataxia, nausea, hyponatremia, water intoxication, aplastic anemia, agranulocytosis, leukopenia, rash
• many interactions with other drugs b/c of CYPs
• contra :MAO-Is
• induces CYP2A9/3A, UGTs
• metabolized by 1A2/2C8, no UGTs
• linear metabolism makes it a more attractive choice for patients with potential drug interactions than phenytoin

Question 7

Oxcarbazepine

Answer 7

• Tricyclic
• closely related to carbamazepine
• clinical app: generalized tonic-clonic, partial
• less potent than carbamazepine
• fewer hypersensitivity reactions
• induces hepatic enzymes to lesser extent –> minimizes drug interactions
• hyponatremia more common than with carbamazepine
• shorter t1/2, active metabolite longer duration
• contra: MAO-Is
• induces CYP3A4 and UGTs
• inhibits CYP2C19 and weakly UGTs
• metabolized by UGTs, not CYPS

Question 8

Eslicarbazepine

Answer 8

• tricyclic
• mech: stabilizes inactivated state of VG Na channels, inhibits T-type Ca channels
• does not modulate GABA or glycine
• used in combo with other medications to control partial seizures
• oral dose daily
• mild to moderate hepatic impairment okay, renal impairment need dose adjustment
• FDA warning on suicidal behavior

Question 9

Diazepam

Answer 9

• Benzodiazepine
• mech: potentiates GABAa responses
• clinical app: status epilepticus, anxiety, alcohol withdrawal
• IV or rectal gel very effective
• occasionally given orally long-term, but develop tolerance rapidly
• peak [ ] 1 hour
• highly protein-bound
• extensively metabolized
• minimal drug interactions
• levels decreased by carbamazepine or phenobarbital
• contra: glaucoma
• typically only used to acutely ablate seizures
• 4th drug of choice in treating absence seizures after ethosuximide, valproate, lamotrigine

Question 10

Clonazepam

Answer 10

• Benzodiazepine
• mech: potentiates GABAa responses
• clinical app: absence seizures, myoclonic seizures
• has been tried in infantile spasms
• long acting, well absorbed
• peak [ ] 1 hour, highly protein bound, extensively metabolized
• sedation prominent esp @ initiation of therapy
• small starting dose
• contra: glaucoma
• minimal drug interactions

Question 11

Clobazam

Answer 11

• Benzodiazepine
• mech: potentiates GABAa responses
• add-on therapy for Lennox-Gastaut Syndrome (new), absence seizures, myoclonic seizures, infantile syndrome
• orphan-drug designation
• well absorbed orally
• minimal interactions
• contra: glaucoma
• approved age 2+
• may cause delayed psychomotor development and behavioral disorders
• schedule IV drug, can cause abuse & dependence
• adverse: somnolence, sedation, fever
• may increase suicidal thoughts, need to monitor

Question 12

Gabapentin

Answer 12

• GABA derivative
• mech: decreases excitatory transmission (decrease glutamate release) by acting on VG Ca channels PRESYNAPTICALLY (alpha2delta subunit)
• clinical app: generalized tonic-clonic seizures, all types partial seizures, diabetic peripheral neuropathy, post-therpic neuralgia, prophylaxis of migraine
• bioavailability 50%, decreases with increased dosage
• not bound to plasma proteins
• not metabolized
• t1/2 6-8 hours
• minimal drug interaction
• increases [GABA] in neurons and glial cells in vitro main antiseizure effect through inhib of Ca channels
• not very effective for most patients
• adverse: somnolence, dizziness, ataxia, and tremor

Question 13

Pregabalin

Answer 13

• GABA derivative
• mech: decreases excitatory transmission (decrease glutamate release) by acting on VG Ca channels PRESYNAPTICALLY (alpha2delta subunit)
• clinical app: (adjunct to) partial seizures, diabetic peripheral neuropathy, fibromyalgia, post-therpic neuralgia
• only available orally, well absorbed
• not bound to plasma proteins
• not metabolized
• t1/2 6-7 hours
• minimal drug interactions
• structurally similar to gabapentin but more potent
• used for treatment of partial seizures in those with hepatic dysfunction

Question 14

Vigabatrin

Answer 14

• GABA derivative
• mech: irreversible inhibits GABA-transaminase (aminotransferase)
• indirectly enhances GABA activity via inhibitor of GABA metabolism
• marketed as a racemate (S+ enantiomer is active)
• clinical app: complex partial seizures, infantile spasms
• 70% bioavailable, not bound to plasma proteins
• not metabolized
• t1/2= 6-8 hours (pharmacodynamic activity more prolonged)
• minimal drug interactions
• toxicity: drowsiness, dizziness, agitation, psychosis, weight gain, visual field loss (long-term therapy)
• visual acuity testing every 3 months
• contra: pre-existing mental illness
• may inhibit vesicular GABA transporter
• sustained increase of the [ ] extracellular GABA
• can lead to some desensitization of synaptic GABAa receptors
• causes prolonged inactivation of nonsynaptic GABAa receptors
• decrease in brain glutamine synthesis