Anticonvulsants Flashcards
What are the two broad categories of SZR
- Generalized: conceptualized as originating at some point within and rapidly engaging bilaterally distributed neural networks
- Focal (or partial):
Involve only a portion of the brain, typically part of one lobe of one hemisphere
Can be associated with impairment of consciousness or awareness (previously called complex partial seizure) or no impairment of consciousness (previously called simple partial seizures)
Can evolve over seconds into a tonic-clonic convulsion, also referred to as a secondarily generalized seizure
What are the 5 phases tonic-clonic SZR
five phases of a primary tonic-clonic seizure:
(1) flexion
(2) extension
(3) tremor
(4) clonic
(5) postictal
What does tonic mean
Flexion or extension
What does clonic mean
Clonic: rhythmic, repetitive, jerking muscle movements
What does myoclonic mean
Myoclonic: brief, lightning-like jerking movements of the entire body or the upper and occasionally lower extremities
What is an atomic SZR
Characterized by a loss of muscle tone
Often described as drop attacks in which a patient loses tone and falls to the ground
What is an absence SZR
Typical seizures are brief and abrupt, last 10-30 seconds, and occur in clusters
Usually results in a short loss of consciousness, or the patient may stare, be motionless, or have a distant expression on his or her face
Define epilepsy
Epilepsy: condition characterized by 2 or more epileptic seizures that are unprovoked and have no identified cause
Define epileptic SZR
Epileptic Seizure: clinical manifestation presumed to result from abnormal and excessive discharge of a set of neurons in the brain that results in abnormal movements or perceptions
Define SZR
Seizure: a paroxysmal disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness
What is primary and secondary epilepsy
Primary Epilepsy: no specific anatomic cause
-Drug treatment (MAY) be for life
Secondary Epilepsy: reversible disturbances responsible for seizures
- Tumors
- trauma
- hypoglycemia
- alcohol withdrawal
Drug treatment is used until the primary cause of the seizure can be corrected
What is the non pharm approach to SZR/ epilepsy
Dietary Modifications: some data supports a low-carbohydrate, high fat diet (ketogenic diet)
Vagus Nerve Stimulator for difficult to manage partial seizures
Implanted stimulator delivers stimuli on a regular basis and patients can use “on demand” stimulation
Alternative Treatments: biofeedback, mega vitamins, and melatonin
Surgery
Driving Restrictions:
All states have restriction, refer to state restrictions
Some states require mandatory physician reporting to the state department of transportation
Since Lifelong SZR therapy in no longer the standard, when can therapy be withdrawn
May attempt withdrawal from therapy if:
- Seizure free for 2-5 years
- Single seizure type
- Normal neurological exam and IQ
- Normal electroencephalogram (EEG) with medication treatment
Withdraw medications slowly and one at a time if on poly-therapy
What is the MOA of anticonvulsants
anticonvulsants work by blocking the initiation or preventing the spread of electrical discharge by several mechanisms
- Enhancement of GABAnergic transmission
- Diminution of excitatory transmission (i.e. Glutamate)
- Modification of ionic conductance (i.e. Calcium, Sodium)
What are the two narrow spectrum anticonvulsants used to treat absence SZR
Ethosuximide
Valproate (alternative)
What is the MOA of phenytoin
Sodium Channel blocker
Can you used phenytoin in absence SZR
NO !
is phenytoin a 1st line Tx for SZR
NO!
Can you use phenytoin in pregnancy
No
What are the ADE of phenytoin
Non-dose-related adverse effects:
- Sexual dysfunction
- Hirsutism (excessive hair growth)
- gingival hyperplasia (40-90%)
- Long term use causes coarsening of facial features
Dose-related adverse effects:
- Nystagmus (rapid eye movement)
- ataxia
- drowsiness
- cognitive impairment
High Dose Indicators:
- Blurred or double vision
- Thick tongue
- Dizziness
Less common: N/V, anemia, drowsiness, hyperglycemia and anti-arrhythmic activity
how does phynetoin affect the mouth
Gingival hyperplasia
What are the DDI for phenytoin
Multiple enzyme activity
Anticoagulants increase phenytoin concentration
Contraceptives, reduces efficacy of contraceptives
What is a common clinical error of phenytoin
Common clinical error is to increase the dosage directly from 300mg/day to 400mg/day
- toxicity frequently occurs
A decrease in protein (e.g. hypoalbuminemia) results in an increase in free drug concentration and same total drug concentration.
How does protein effect phenytoin
A decrease in protein (e.g. hypoalbuminemia) results in an increase in free drug concentration and same total drug concentration.
NEEDS CLOSE DRUG MONITORING
is phenytoin a 1st or zero order kinetic drug
Zero order, drug concentration changes with respect to time at a constant rate;
What is the MOA of fosphenytoin
prodrug for phenytoin; fast sodium channel blocker
What is the clincal use of fosphenytoin and what advantage does it have to phenytoin
Clinical Use:
- Status epilepticus
- Parenteral formulation for loading or maintenance dosing in place of phenytoin
Advantages over phenytoin:
- Preferred when parenteral administration is needed (reduced extravasation, faster load)
- Infusion can be up to 150mg of phenytoin equivalents per minute
- Can be mixed in NS or D5W
1mg of phenytoin is equal to __ of fosphenytoin
1.5 mg
What is the MOA of Carbamazepine
Sodium Channel Blocker
What is the clinical use of Cabamazepine
Clinical Use:
-Only available orally
- Primary generalized tonic-clonic, simple or complex partial
- Newer anticonvulsants are beginning to displace it from this role
Other uses: trigeminal neuralgia and bipolar disease
What is the enzyme interaction of Carbamazepine
CYP3A4 inducer and auto inducer (self induction) for up to 1 month
What are the ADE of carbamazepine
Many adverse effects related to intermediate metabolite
RASH
WT GAIN
SIADH
Hypo NA Bone Marrow suppression SJS Necrosis Osteomalacia
Because of its ADE profile what must be monitored with carbamazepine
LFTs and CBC status at baseline then for 2-3 months and then every 1-2 years
Concern of aplastic anemia and agranulocytosis that can occur within the first 4 months
Can carbamazepine be used in pregnancy
NO
What are the DDI of Carbamazepine
Drug Interactions: CYP 3A4 substrates
Lamotrigine may also increase carbamazepine epoxide levels
Concomitant use of valproic acid can inhibit epoxide hydrolase and cause carbamazepine epoxide accumulation
Contraceptives: reduces efficacy of estrogen-containing contraceptives, oral progestin-only contraceptives, and the etonogestrel implant
What genetic testing must be done for carbamazepine
Patients with HLA-B1502 and/or HLA-A3101 allele are at increased risk of hypersensitivity syndrome, aka Stevens Johnson Syndrome
Asians
What is the MOA of oxcarbamazepine
Sodium channel blocker
What is the clin use of Oxcarbazepine
Generalized tonic-clonic
Other uses: trigeminal neuralgia and bipolar disease
Reserve for patients who do not tolerate carbamazepine due to drug interactions or adverse effects
Which drug should be chosen by providers
Carbamazepine or phenytoin
Carbamazepine is first choice of many providers
- Less sedating
- Not associated with hirsutism (excess hair growth), acne, gingival hyperplasia
- Phenytoin has reputation for causing functional impairment and learning problems
What is the MOA of primidone and Phenobarbital
Increases GABA mediated chloride influx
What is the clincal use of Phenobarbital
Generalized tonic-clonic seizures, simple or partial seizures
Refractory status epilepticus; tried for virtually every seizure type, especially when attacks are difficult to control
Can phenobarbital be used in pregnancy
D, not advised
What are the DDI of phenobarbital
Drug-interactions:
- CYP Interactions
- Ethanol: additive CNS and respiratory depression
- Contraceptives: reduces efficacy of estrogen-containing contraceptives, oral progestin-only contraceptives, and the etonogestrel implant
What is the MOA of Primidone
Increases GABA mediated chloride influx (inhibitory neurons)
Metabolized to phenobarbital and phenylethylmalonamide
What is primidone Metz to
Metabolized to phenobarbital and phenylethylmalonamide
What is the clin use of primidone
Alternate choice in generalized tonic-clonic seizures and used for essential tremor
May be used with carbamazepine and phenytoin
What are the BXD commonly use to treat SZR
Most Commonly Used Drugs:
Diazepam (Valium)*
Lorazepam (Ativan)*
Clonazepam (Klonopin)
What is the MOA of Gabapentin
Inhibition of α2δ subunit of voltage-dependent calcium channels
An analog of GABA, but does not directly impact GABA receptor
What is the Clin Use of Gabapentin
Partial onset seizures
Neuropathic pain and post herpetic neuralgia pain
Spasmolytic
Diabetic neuropathy (off-label)
What are the ADE of Gabapentin
Drowsiness, fatigue, dizziness, headache, weight gain, and tremor during initiation
Excreted renally, may need adjustments
What is the MOA of Pregabalin
Inhibition of α2δ subunit of voltage-dependent calcium channels.
GABA derivative similar to gabapentin that binds pre-synaptically to the alpha-2-delta subunit of the voltage-gated calcium channel and blocks influx of calcium in hyper excited neurons
What is the clin use of Pregabalin
Partial-onset seizure (adjunct)
Non-epileptic: neuropathic pain associated with diabetic neuropathy, restless leg syndrome, post-herpetic neuralgia, fibromyalgia, pain due to spinal cord injury, social phobia
What are the ADE of pregablin
Adverse effects:
Sexual dysfunction, dizziness, weight gain, edema, angioedema, creatine kinase elevations
Insomnia, nausea, headache, diarrhea reported after abrupt discontinuation
What is the DOC in an absent SZR
Ethosuximide
What monitoring must accompany ethosuximide
CBC due to neutropenia and leukopenia
What is the MOA of Valporic Acid
Blocks T-type calcium currents
Blocks sodium channels
Increases GABA production
Decreases GABA degradation
What is the clinical use for Valporic Acid
Generalized non-convulsive seizures
2nd line agent in absence seizures to ethosuximide when the patient has concomitant generalized tonic-clonic attacks
Non-epileptic indications:
Manic episodes associated with bipolar disorder
Migraine prophylaxis
What effect does valproic acid have with lamotrigine
Increases lamotrigine levels and risk of serious rash
Requires lamotrigine dose reduction
What effect does Valporic acid have on carbamazepine
Exacerbates carbamazepine epoxide accumulation
Effect of Valporic acid with ethosuximide
Inhibits the metabolism of ethosuximide
What are the ADE of valproic ACid
Common:
alopecia, N/V, interferes with platelet aggregation, pancreatitis, sedation, weight gain (average of 2 kg after one year), rash
Serious:
Thrombocytopenia
Multi-organ hypersensitivity
Black box warning for hepatic failure fatalities
Monitor LFTs
Very Rare (<0.002% and most are in children under 10)
Can Valporic acid be used in pregnancy
Pregnancy Category: D
X for migraine prophylaxis
Substantial increase in the incidence of spina bifida
What drug can be used in valproic acid OD
Naloxone may reverse CNS depressant effects, theoretically it can have a convulsant effect
What is the MOA of lamotrigine
Decreases glutamate and aspartate release
Delays repetitive firing of neurons
Blocks fast sodium channels
What is the clincal use of Lamotrigine
Generalized tonic-clonic seizures
Lenox-Gastaut: specific pediatric onset epilepsy
Non-epileptic: maintenance treatment of bipolar I mood disorder
What are the ADE of lamotrigine s
SJS!
Slowly ti trate this drug!
VALPROIC ACID INCREASES RISK
What is the MOA of Topiramate
Fast sodium channel blocker
Enhances GABA activity
Antagonizes AMPA/kainase activity
Weak carbonic anhydrase inhibitor
What is the Clin use of Topiramte
Clinical Use:
Primary generalized tonic-clonic seizures, simple or complex partial with or without generalization
Absence seizure (adjunct)
Lenox-Gastaut
Non-epileptic: migraine prophylaxis
Pregnancy Category: D
What are the ADE of Topiramate
memory impairment
Met. Acidosis
Encephalopathy
What DDI does Topiramate have
Contraceptives
How are febrile SZR tx
Treat fever with acetaminophen (Tylenol) and treat status epilepticus if required
Prolonged febrile seizures may be treated with phenobarbital or diazepam
What are the emergency meds for epilicticus
Lorazepam, Diazepam, midazolam
What are the urgent medications for Status epilepsy
Fosphenytoin
Phenytoin
Phenobarbital
Off Label:
Valproic Acid
Levetiracetam (Keppra)
Lacosamide
What medications can be used in refractory status epilepsy
Pentobarbital (must be on ventilator)
Propofol (must be on Vent)
Midazolam
What are the effects of geriatric SZrs on medications
Seizure medications with renal elimination must be adjusted according to the CrCl value
Carbamazepine: decreased clearance
Phenytoin: decreased protein binding if hypoalbuminemic or in renal failure
Valproic acid: decreased protein binding
Diazepam: increased half-life
Lamotrigine: decreased clearance
What are the DOC for eclampsia
Mag,. Sulfate
What drug prevents neural tube defects
Folic acid supplementation
WHich drugs absolutely should be avoided in pregnancy
Avoid or limit the dose of the following agents:
Phenytoin: Risk of cleft palate, Risk of poor cognitive functions
Carbamazepine: risk of posterior cleft palate
Benzodiazepines
Phenobarbital:
Risk of cardiac malformations
Risk of poor cognitive functions
Valproic acid: risk of major congenital malformation
Topiramate: risk of major congenital malformation
Which drugs have they highest and lowest risk of sexual dysfunction
Highest incidence of sexual dysfunction: carbamazepine, phenobarbital, phenytoin, pregabalin, topiramate, and zonisamide
Improved sexual functioning: lamotrigine and oxcarbazepine
Which drugs have most effect on bone suppression and increase fx
Risk is increased with carbamazepine, clonazepam, phenobarbital, phenytoin, and valproic acid
