Anticonvulsant drugs Flashcards by Briana Tillman

Barbiturate drugs

Phenobarbital

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Benzodiazepine drugs

lorazepam

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Seizure

episode of neurologic dysfunction (abnormal neuronal firing) manifest by changes in motor control, sensory perception, behavior, and/or autonomic dysfunction

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Epilepsy

recurrent spontaneous seizures arising from aberrant electrical activity in the brain

Occurrence of unprovoked seizures separated by 24 hours

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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)

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Focal (Partial) Seizures

Aware (simple partial)
Impaired awareness (complex partial)
Secondarily generalized

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Generalized

Tonic-clonic (grand mal)
Absence (petit mal)
Myoclonic
Atonic

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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)

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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

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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

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drugs that enhance Na+ channel inactivation

carbamazepine, phenytoin, topiramate

lamotrigine, valproate, zonisamide

(anti-focal seizures)

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drugs that enhance GABA synaptic transmission

vigabatrin, valproate, tiagabine (pre-synaptic)

benzodiazepines, barbiturates (post-synaptic)

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drugs thatt reduce Ca2+ channel current

valproate, ethosuximide

anti-absence drugs

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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

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Common Adverse Drug Reactions

Neurotoxic Effects:
Sedation
Dizziness
Blurred or double vision
Difficulty concentrating
Ataxia

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Phenytoin MOA, PK, uses, ADRs

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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

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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

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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

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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

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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

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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

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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

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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

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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

Anticonvulsant drugs Flashcards

(37 cards)