Unit 10: Antiepileptics/Anticonvulsants Flashcards
Drugs for epilepsy - phenobarbital - phenytoin - ethosuximide - carbamazepine - valproate
Seizure
Seizure: periods of self-sustained neural hyper-excitation
- during a seizure, the forebrain neurons cease their normal activities and begin to fire in massive, synchronized bursts
- blood flow to the brain is increased
- greater use of glucose and oxygen
- seizure ends when the inhibitory mechanism mechanisms of the brain regain control (after seconds/minutes)
Seizure Causes
Seizure Causes:
- high fever (esp in children), brain infection, meningitis
- head injury or trauma
- alcohol or benzodiazepine withdrawal
- drug intoxication—stimulants (cocaine, amphetamine), antidepressants (bupropion)
- stroke or cardiovascular event
- electroconvulsive therapy (ECT)
Epilepsy
Epilepsy (seizure disorder): a group of neurological disorders characterized by spontaneous, recurrent seizures
Note: seizures alone ≠ epilepsy
- every brain has a “seizure threshold”—every brain will generate a seizure if subjected to a high level of excitatory stimulation
- people with epilepsy have a low seizure threshold
Epilepsy Demographics
Epilepsy Demographics
WHO
- point prevalance: roughly 1% of the global population has epilepsy at any given time
- lifetime prevalence: about 4% of the population will have epilepsy at some point in life
- can co-occur with certain genetic syndromes, such as:
- Fragile-X syndrome
- Down’s syndrome
- Rett’s syndrome
- Angelman’s syndrom
WHAT
- neurological disorder characterized by spontaneous, recurrent seizures
WHEN
- onset can occur at any time
- in many patients, seizures begin in childhood, often before the age of 15
- children with epilepsy will sometimes “outgrow” seizures or have reduced frequency of seizures in adulthood
- recent increase of seizure onset after 65 (perhaps since people are living longer)
WHERE
- global
WHY
- genetics — account for 70% of the risk factors
- due to a mutation in a gene controlling neuron excitability
- structural/metabolic — remaining 30% of causal factors
- a clear structural (eg: scar; cancer; benign tumor; vascular malformation) or metabolic cause
Epilepsy Comorbidities
Epilepsy Comorbidities:
- cognitive—memory issues
- psychiatric—anxiety, depression, ADHD, psychosis
- other—asthma, migraine, stroke, ulcers
Types of Seizures
Types of Seizures
(A) Generalized—occur throughout the cortex
(B) Partial—occur in one location in the cortex
(C) Status epilepticus—a seizure lasting longer than 5 mins
(A)
Absence (petit mal)
- briefly unconscious, blank stare
- no memory of attack
- lasts less than 30 secs
- 3 per second spike and wave throughout whole brain
Tonic Clonic (grand mal)
- stiff muscles, unconscious (tonic phase), dramatic convulsions (clonic phase)
- no memory of attack
- lasts less than 5 mins
- constant spiking throughout brain
(B)
Simple Partial
- conscious, memory of attack, sensory/motor/emotional symptoms
- duration varies
- localized spiking in neocortical or limbic area of brain
Complex Partial (temporal lobe)
- conscious but non-responsive, automatisms (involuntary movement), no memory of attack
- duration varies
- localized then spreading spiking in one or both temporal lobes
(C)
Status epilepticus
- a generalized or partial seizure lasting longer than 5 minutes
- can be life-threatening—considered a medical emergency
- occurs in:
- seizure disorder
- brain injury (trauma, tumor, infection)
- intoxication
- alcohol/benzo withdrawal
- treatment: benzodiazepines, phenytoin, phenobarbital
Seizure Detection/Risks
Seizure Detection—occurs via electroencephalogram (EEG)
- the more that neurons fire, the higher the peaks and valleys
Risks—consequences if seizures go untreated:
- difficulty learning
- aspiration pneumonia—caused by inhaling food or saliva during seizure
- injury—from falls, bumps, self-inflicted bites, driving or operating machinery during seizure
- permanent brain damage
- excitotoxicity—cell death as a result of excessive neuron firing
- seizure worsening—can be fatal (eg: status epilepticus)
- suicide
Seizure Treatment
Seizure Treatment:
(1) Keto Diet
- many forms of childhood and adult epilepsies are improved by a ketogenic diet
- a diet low in carbs causes the body to metabolize fats into ketones (beta-hydroxybutyrate) which the brain uses as an alternative energy source
(2) Antiepileptics/Anticonvulsants
- act by promoting GABA signalling, OR,
- by reducing the function of voltage-gated ion channels
- common side effects:
- sleepiness
- memory impairment
- nausea/GI upset
- dependence/withdrawal
Ketogenic Diet for Epilepsy
Ketogenic Diet MOA
- ketone bodies
- medium chain triglycerides
- anti-inflammatory effects
- mitochondrial function improvements
- epigenetics
- gut microbiome
Anticonvulsants
Anticonvulsants
1) Phenobarbital
2) Phenytoin
3) Ethosuximide
4) Carbamazepine
5) Valporic acid
Anticonvulsants:
1) Phenobarbital
1) Phenobarbital
- 1st drug discovered for tonic-clonic and partial seizures
- oldest drug still in use
- cheap and safe, long half-life
- a barbiturate
Target: GABA receptors/channels
MOA: enhances GABA-A system—agonist of GABA (activates GABA, holding the channel open longer, allowing more chloride in)—increases the inhibitory effects
Side Effects
- sedation/sleepiness
- memory impairment
- GI upset
Anticonvulsants:
2) Phenytoin
2) Phenytoin (Dilantin)
- second drug for tonic-clonic and partial seizures
- second oldest drug still in use
- less sedating than phenobarbital—also has long half-life
Target: voltage-gated sodium channels
MOA: antagonist of voltage dependent sodium channels
- blocks the channels and reduces the number of action potentials that a neuron can fire
Side Effects
- headache
- nausea
- dizziness
- sleepiness
- acne
- gingival hyperplasia (overgrowth of gums)
- hirsutism (facial hair)
Anticonvulsants:
3) Ethosuximide
3) Ethosuximide (Zarontin)
- used for absence seizures
Target: T-type calcium channels (thalamus)
MOA: antagonist of voltage dependent T-type calcium channels
- these channels trigger the release of neurotransmitter when the action potential reaches the axon terminal
- blocks T-type calcium channels found in the thalamus—reduces the amount of glutamate released
Side Effects
- upset stomach
- diarrhea
- weight loss
- hiccups
Anticonvulsants:
4) Carbamazepine
4) Carbamazepine (Tegretol)
- a treatment for tonic-clonic and partial seizures
Target: voltage dependent sodium channels
MOA: antagonist of voltage dependent sodium channels
- carbamazepine blocks the channels and reduces the number of action potentials that a neuron can fire
- MOA similar to phenytoin, but with different side effects
Side Effects:
- dizziness
- nausea
- problems with coordination
- reduces number of white blood cells
Anticonvulsants:
5) Valproate
5) Valproate (Valproic acid) (Depakene)
- the first broad-spectrum drug—effective for absence, tonic-clonic, and partial seizures
Target: unknown
MOA: multiple and not fully understood
1) blocks voltage dependent sodium channels
- similar to phenytoin—reduces number of action potentials
2) epigenetics—opens up chromatin/DNA structure to allow more gene expression
- one gene expressed is for an enzyme that makes GABA
- more GABA = more inhibition of neuron firing
