Anticonvulsant drugs Flashcards
Barbiturate drugs
Phenobarbital
Benzodiazepine drugs
lorazepam
Seizure
episode of neurologic dysfunction (abnormal neuronal firing) manifest by changes in motor control, sensory perception, behavior, and/or autonomic dysfunction
Epilepsy
recurrent spontaneous seizures arising from aberrant electrical activity in the brain
Occurrence of unprovoked seizures separated by 24 hours
Seizure types
Focal- seizure activity starts in one area of the brain
Generalised- seizure activity involves both hemispheres of the brain (absence, tonic clonic, myoclonic, clonic, tonic, atonic)
and Unknown (epileptic spasm, others)
Focal (Partial) Seizures
Aware (simple partial)
Impaired awareness (complex partial)
Secondarily generalized
Generalized
Tonic-clonic (grand mal)
Absence (petit mal)
Myoclonic
Atonic
Pathophysiology: Excessive excitation or disordered inhibition:
Small number of neurons fire abnormally
Membrane conductance and inhibitory currents break down
Excess excitability spreads
Locally (focal) or more widely (generalized)
Pathophysiology: Multiple mechanisms:
Altered ion channels
Receptor modification
Alteration in 2nd messaging
Changes in extracellular ion concentrations
Abnormal neurotransmitter uptake & metabolism
Shift in ratio/function of inhibitory circuits
Antiepileptic Drug (AED) Mechanisms of Action
Limit sustained, repetitive firing of neurons, mediated by promoting the inactivated state of voltage-gated Na+ channels
Enhanced γ-aminobutyric acid (GABA) mediated synaptic inhibition, mediated by presynaptic or postsynaptic actions
Inhibition of voltage-gated Ca2+ channels
drugs that enhance Na+ channel inactivation
carbamazepine, phenytoin, topiramate
lamotrigine, valproate, zonisamide
(anti-focal seizures)
drugs that enhance GABA synaptic transmission
vigabatrin, valproate, tiagabine (pre-synaptic)
benzodiazepines, barbiturates (post-synaptic)
drugs thatt reduce Ca2+ channel current
valproate, ethosuximide
anti-absence drugs
Basic Pharmacology of AEDs- Pharmacokinetics:
Absorption 80-100%
Most not highly protein bound
- Exception: phenytoin, tiagabine, valproic acid
Hepatic metabolism
Slow plasma clearance
Some have long t1/2 > 12 hours
Common Adverse Drug Reactions
Neurotoxic Effects: Sedation Dizziness Blurred or double vision Difficulty concentrating Ataxia
Phenytoin MOA, PK, uses, ADRs
MOA: * prolongs inactivated state of Na+ channel
– Decreases synaptic release of glutamate and enhances release of GABA
PK: * highly protein bound
- Dose-dependent elimination
- CYP2C9 and CYP2C19 metabolism
- Fosphenytoin (phosphate ester prodrug)
Focal seizures, generalized tonic-clonic
Unique ADRs: * gingival hyperplasia, hirsutism
– Cardiac effects: hypotension, bradycardia, arrhythmia
Carbamazepine
MOA: * prolongs inactivated state of Na+ channel
– Decrease presynaptic release of glutamate
PK: * potent CYP inducer
– Autoinduction t1/2 36 hours –> 8-12 hours after cont. therapy
Focal seizures, generalized tonic-clonic, trigeminal neuralgia, mania in bipolar disorder
Unique ADRs: * hyponatremia, blood dyscrasias (agranulocytosis), * leukopenia, SJS (Asian descent esp.)
Lamotrigine
MOA: * prolongs inactivated state of Na+ channel
– Also inhibits voltage-gated Ca2+ channels
Focal seizures, generalized tonic-clonic, bipolar disorder
Unique ADRs: *skin rash
Valproic Acid
MOA: * prolongs inactivated state of Na+ channel, may block NMDA receptor mediated excitation, may increase levels of GABA
PK: * highly protein bound
Absence seizures, myoclonic seizures, generalized tonic-clonic, focal seizures, status epilepticus, bipolar disorder, migraine prophylaxis
Unique ADRs: GI distress, * fine tremor, weight gain, hair loss
– Hepatotoxicity, thrombocytopenia
Topiramate
MOA: actions on * Na+ channels, * GABAA receptors, high-voltage * Ca2+ currents, may act on *glutamate/NMDA receptors
Focal, generalized tonic-clonic, Lennox-Gastaut, infantile spasms, absence seizures, migraine
Unique ADRs: *paresthesias, nervousness, *weight loss
Benzodiazepines and Barbiturates
Diazepam:
MOA: enhance * GABA-mediated Cl- influx and enhance the generation of inhibitory membrane potentials
PK: * extremely lipophilic
Status epilepticus, myoclonic, focal, generalized tonic-clonic seizures
Phenobarbital
MOA: * enhances GABA mediated current and can also decrease excitatory responses (glutamate release)
PK: * hepatic enzyme inducer
Focal seizures, generalized tonic-clonic
Gabapentin
MOA: bind α2δ subunit of voltage-gated N-type Ca2+ channels, *decrease Ca2+ entry, decrease synaptic release of glutamate
PK: * not metabolized
Focal seizures, generalized tonic-clonic, neuropathic pain, post-herpetic neuralgia
Unique ADRs: headache, tremor
Levetiracetam
MOA: binds * synaptic vesicular protein SV2A. Modifies synaptic release of glutamate and GABA.
Focal seizures, generalized tonic-clonic, myoclonic seizures
Unique ADRs: * serious mood and behavioral changes (less common)
Ethosuximide
MOA: reduces low threshold * Ca2+ (T-type) current
PK: long t1/2 40 hours
* Absence seizures
Unique ADRs: * gastric distress
General Treatment Approach
AEDs suppress seizures but do not cure
Accurate seizure diagnosis essential
Monotherapy preferred (50-70% can be maintained on single agent)
Increase dose gradually
Monitor treatment regularly
If further dose increase inadvisable, consider prescribing another drug as monotherapy
Compliance is essential
Focal seizures
drugs of choice
Carbamazepine –or– lamotrigine –or– levetiracetam –or– oxcarbazepine –or– valproate
Primary generalized tonic-clonic
drugs of choice
Carbamazepine –or– lamotrigine –or– oxcarbazepine –or– valproate
drugs of choice Absence
Ethosuximide –or– lamotrigine –or– valproate
drugs of choice Atypical absence, myoclonic, atonic
Levetiracetam –or– lamotrigine –or– valproate
AED Drug Interactions
Phenytoin
- Protein binding (sulfonamides)
- Metabolism
- —– Competes for metabolism CYP2C9 (warfarin) & 2C19
- —– Also results in enzyme induction (oral contraceptives)
Carbamazepine
- Enzyme induction (phenytoin, oral contraceptives)
Valproic acid
- Enzyme inhibition (carbamazepine)
Lamotrigine
- Oral contraceptives may decrease lamotrigine concentrations
AEDs and Pregnancy
Interactions with oral contraceptives
- Effectiveness of OCs reduced (likely due to induction of CYP3A4) by : carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide
Potential teratogenic effects
- Increased risk of congenital malformations: phenytoin, valproate, topiramate
Treatment of Status Epilepticus
A medical emergency – continuous seizures lasting at least 5 minutes or ≥ 2 seizures with incomplete recovery of consciousness, mortality 20%. Goal is rapid termination of behavioral and electrical seizure activity.
Steps: assessment –> initial therapy –> long-term control
IV benzodiazepines – enhance GABAA Cl- flux
- Lorazepam (Ativan) longer duration of action than diazepam
- Diazepam (Valium)
IV phenytoin or fosphenytoin – enhances inactivated state of voltage-dependent Na+ channels.
IV phenobarbital – enhances GABAA Cl- flux
Anesthesia
A 25 y/o male is referred to a neurologist after experiencing a motor vehicle accident in which there were no injuries. He has always had episodes of “zoning out”; but unfortunately, his most recent episode occurred while driving home from work. His neurologist will most likely recommend an agent with which mechanism of action to treat these episodes?
A. Binds an allosteric site on GABA receptor
B. Blocks voltage-gated Na+ channels
C. Enhances GABA-mediated Cl- influx
D. Modifies release of glutamate and GABA through action on SV2A protein
E. Reduces the low threshold Ca2+ (T-type) current
These are absence seizures.
Reduces the low threshold Ca2+ (T-type) current
A 16 y/o female with complex partial seizures is instructed to begin taking lamotrigine. Her neurologist recommends initiating low doses with dose increases every two weeks. It is important to titrate lamotrigine slowly, as it may cause dose-related:
A. gingival hyperplasia. B. leukopenia. C. paresthesias. D. skin rash. E. tremor.
D. skin rash.
A 15 y/o male with juvenile myoclonic epilepsy presents to his neurologist for follow-up. He has been receiving appropriate drug therapy, but is concerned about recent hair loss. Which drug is this patient most likely receiving?
A. Gabapentin B. Lamotrigine C. Levetiracetam D. Phenytoin E. Valproic acid
Valproic acid
A 60 y/o female has a history of complex partial seizures and a mechanical valve replacement. She has been receiving carbamazepine and warfarin (INR therapeutic) concomitantly for several years. She recently began experiencing an increased incidence of seizures; therefore, during a non-related hospital stay, her carbamazepine is switched to levetiracetam. 12 days later, she presents to the ED with an uncontrolled bloody nose, ecchymosis across her back and legs, and an INR = 10.4. What is the best explanation as to the cause of this drug-drug interaction?
A. CYP450 inducer added; increased warfarin metabolism
B. CYP450 inducer removed; decreased warfarin metabolism
C. CYP450 inhibitor added; decreased warfarin metabolism
D. CYP450 inhibitor removed; increased warfarin metabolism
CYP450 inducer removed; decreased warfarin metabolism
A 28 y/o female with a history of complex partial seizures presents to her PCP for follow-up. Her only medication is carbamazepine which she began six months ago; she has since been seizure free. At this routine visit, her provider discovers she is six weeks pregnant. What is the best strategy for antiepileptic drug therapy in this patient?
A. Continue carbamazepine
B. Continue carbamazepine and add diazepam
C. Convert carbamazepine to valproic acid
D. Immediately discontinue carbamazepine
E. Immediately discontinue carbamazepine and begin folic acid
Continue carbamazepine
