Seizures
manifestation of an abnormal and excessive excitation and synchronization of cortical neurons
Epilepsy
chronic dx characterized by spontaneous recurrent seizures
Convulsions
involuntary, paroxysmal skeletal muscle contractions
Partial Seizures
- Simple= limited motor or sensory signs, consciousness intact
- Complex= consciousness impaired
- Secondary Generalized= symptoms increase until it resembles a generalized seizure
Generalized Seizures
- Absence (petit mal)= sudden, brief loss of consciousness
- Myoclonic sz= sudden brief “shocklike” contractions of muscles
- Clonic sz= rhythmic, synchronized contractions throughout the body, loss of consciousness
- Tonic sz= generalized, sustained ms contraction throughout the body, loss of consciousness
- Tonic-Clonic sz(grand mal)= major convulsions of entire body, loss of consciousness
- Atonic sz= sudden loss of ms tone in the head and neck; consciousness may be maintained or lost briefly
Status Epilepticus
- more than 30 minutes of continuous seizure activity
- 2 or more sequential seizures spanning this period w/o full recovery b/t seizures (on-going sz)
- medical emergency
- tx w/ short-acting benzos (diazepam & lorazepam)
- use rectal benzo gel for kids
Rationale for Anti-Epileptic drugs
- ↓ the frequency/ severity of sz in epilepsy pts
- treats sxs of sz not the underlying epileptic condition
- goal= maximize QOL by minimizing sz and ADLs
- effective in 60% of pts w/ epilepsy (sz free) 20% experience big sz reduction
PK & PD of Anti-Epileptic drugs test
- good oral absorption & bioavailability
- most metabolized in liver, but excretion is UNCHANGED in kidneys
- classic AEDs generally have more severe CNS sedation than newer drugs
- because of overlapping mechanisms of action; best drug can be chosen based on minimizing side effects in addition to efficiency
Classical Anti-Epileptic Drugs
- phenytoin
- phenobarbital
- carbamazepime
- primidone
- ethosuximide
- valoproate (valproic acid)
Newer Anti-Epileptic Drugs
- lamotrigine
- felbamate
- topiramate
- gabapentin/pregabalin
- tiagabine
- vigabatrin
- oxycarbazepine
- levetiracetam
- fosphenytoin
Side Effects of Anti-Epileptic Drugs
- sedation: especially w/ barbiturates
- cosmetic: phenytoin (hairy tongue, severe dermatologic effect)
- weight gain- valproic acid & gabapentin
- weight loss- topiramate
- reproductive fxn- valproic acid
- cognitive- topiramate
- behavioral- felbamate, leviteracetam
- allergic- many
Causes of Hyperexcitability in Epilepsy
- excitatory post synaptic potentials (EPSPs)
- inhibitory post synaptic potentials (IPSP)
- changes in voltage gated ions channels
- alteration of local ion concentrations
Major NTs in the brain (Epilepsy)
- glutamate
- GABA
- ACh
- DA
- serotonin
- histamine
Cellular Mechanism of Sz Generation
- Excitation (too much):
- ionic: inward Na⁺ & Ca⁺⁺ currents
- NT= glutamate, aspartate - Inhibition (too little)
- ionic: inward Cl⁻, outward K⁺ currents
- NT= GABA
Target for Anti-Epileptic Drugs
- ↑ inhibitory nt system such as GABA
- ↓ excitatory nt system- glutamate
- block voltage-gated inward (+) currents- Na⁺ & Ca⁺⁺
- ↑ outward (+) current- K⁺
- many AEDs have multiple MOAs
Dicarbamates- Felbamate (felbatol)
Indicated for tx of:
- partial sz in adults and children
- generalized absence szs (Lennox-Gastaut syndrome) in children
Potent AED, lacks sedative effect (unlike other AED)
MOA:
- antagonizes the glycine site on the NMDA receptor & blocks Na⁺ channels
- possibly blocks the excitatory effects of glutamate
Adverse Effects:
- GI issues
- rare but fatal aplastic anemia → restricted for use only in extreme refractory epilepsy
Topiramate (Topamax)
-used for partial sz, as an adjunct to tonic-clonic sz (add-on to phenytoin)
MOA: acts on AMPA receptors, blocks glutamate binding site, also blocks kainate receptors and Na⁺ channels and enhances GABA currents
Adverse Effects:
- paresthesia (pins & needles)
- fatigue
- taste change
- weight loss
- difficulty concentrating
Benzodiazepines
- Clonazepam (Klonopin)
- used for absence sz (sometimes myoclonic)
- most specific ADE among benzos- selective for GABA
- sedating, may lose effectiveness to development of tolerance - Diazepam (Valium) and Lorazepam (Ativan)
- used as first-line treatment for status epilepticus (delivered IV-fast acting)
- sedating
- causes ataxia
- behavioral changes - Phenobarbital, Primidone (Myosoline)
- used for partial sz, especially in neonates
- look at page
Tigabine (Gabitril)
- interferes w/ GABA re-uptake
- used to treat partial sz
- uncommonly used
ADEs:
- ↓ concentration
- dizziness, somnolence, nervousness
- chest pain, hypertension, edema, syncope, vasodilation
- alopecia
- speech disorder
Vigabatrin
- uncommonly used
- treats partial sz & tonic-clonic sz as an alternative agent
- irreversible inhibitor of GABA amino-transferase
- enzyme responsible for the degradation of GABA
- GABA released at synaptic site
- enhances inhibitory effects
ADEs:
- sedation
- dizziness
- wt gain
Na⁺ Channels as AED Targets
- neurons fire at high frequencies during seizures
- action potentials generation is dependent on Na⁺ channels
- use-dependent/ time-dependent Na⁺ channel blockers reduce high frequency firing w/o affecting physiological firing
AEDs that act primarily on Na⁺ channels
Phenytoin, Carbamazepine
- block voltage-dependent Na⁺ channels at high firing frequencies (use dependent)
Oxcarbazepine
- blocks voltage-dependent Na⁺ channels at high firing frequencies
- also effects K⁺ channels
Hydantoins:
Phenyoin (Dilantin)
Fosphenytoin (Cerebyx)
- first line for partial seizures
- some use for tonic-clonic seizures
- Fosphenytoin- prodrug for phenytoin (used as IM)
MOA:
- blocks voltage-dependent Na⁺ channel at high firing frequencies
- highly protein bound (have to monitor blood closely)
- induces P450 enzyme system
Adverse Effects
- GI irritation
- sedation
- gingival hyperplasia
- hirsutism
- nystagmus
- ataxia
- dysarthria
Iminostilbenes: Carbamazapine (Tegretol)
-tricyclic antidepressant used for partial sz & tonic-clonic sz
MOA:
-similar to phenytoin
induces P450 enzyme system → induces its own metabolism
Adverse Effects:
- Sedating
- agranulocytosis and aplastic anemia
- leukopenia
- hyponatremia
- cardiac arrhythmias
- CHF
Iminostilbenes: Oxcarbazapine (Trileptal)
- newer agent- related to carbamazapine
- approved for monotherapy in partial sz
MOA:
- same as carbamazapine
- may also agument K⁺ channels
- some CYP450 induction
Adverse Effects:
-sedating, but less toxic than carbamazapine
Zonisamide (Zonergan)
-used as add-on for partial and generalized sz
MOA:
-blocks voltage-dependent Na⁺ channels and T-type Ca⁺⁺ channels
Adverse Effects:
- Serious skin rash
- suicidal ideation
- metabolic acidosis
- anemia, leukopenia
Lamotrigine (Lamictal)
-add-on therapy or monotherapy for refractory partial sz
MOA:
- inhibits glutamate release and (perhaps) Ca⁺⁺ channels
- metabolism affected by valproate, carbamazapine, phenobarbital, phenytoin
Adverse Effects:
- less sedating than other AEDs
- severe dermatitis in children
Ca⁺⁺ Channels as Targets
- general Ca⁺⁺ channel blockers have not proven to be effective AEDs
- absence sz are caused by oscillations b/t thalamus & cx that are generated in thalamus by T-type (transient) Ca⁺⁺ currents
Succinimides:
Ethosuximide (Zarontin)
MOA:
- acts specifically on T-type channels in thalamus
- very effective against absence sz
Adverse Effects:
- GI disturbances
- less sedating
- mov’t disorders
- skin rashes
Gabapentin (neurotin)
Pregabalin (lyrica)
-used in add-on therapy for partial and tonic-clonic sz
MOA:
-acts specifically on Ca⁺⁺ channel subunits called
K⁺ channels as Targets
- K⁺ channels have important inhibitory control over neuronal firing firing in CNS- repolarizes membrane to end action potentials
- K⁺ channel agonists would ↓ hyperexcitability in the brain
- only AED with known actions on K⁺ channels is valproate
Carboxylic Acids:
Valproate (Valproic Acid)
-first-line for generalized sz, also used for partial sz
MOA:
- acts of K⁺ channels to ↓ hyperexcitability in the brain
- also blocks Na⁺ channels and enhances GABAergic transmission
- highly protein bound
- inhibits CYP450
Adverse Effects:
- CNS depressant
- GI disturbances
- hair loss
- weight gain
- teratogenic (ADE on fetus)
- heptotoxic
Regulation of NT release on Anti-Epileptics
- several AEDs have actions that result in the regulation of nt release from the pre-synaptic terminal
- ie. lamotrigine in addition to their noted action on ion channels
- levetiracetam appears to have as its primary action the regulation of nt release by binding to the synaptic vesicle protein SV2A
Levetiracetam (Keppra)
-add-on therapy for partial sz
MOA
-regulation of nt release by binding to the synaptic vesicle protein SV2A
Adverse Effects
-CNS depression
Lacosamide (Vimpat)
-used for partial onset sz as adjunctive therapy
MOA
- enhances the number of Na⁺ channels entering into the slow inactivated state
- regulates and reduces the long-term availability of Na⁺ channels
Adverse Effects
- N/V/D
- diplopia
- dose adjust in pts with mild/mod hepatic impairment or severe renal impairment
Anti-Epileptic Drug Interactions
- many AED are notable inducers of cytochrome P450 enzymes and a few are inhibitors
- *of the classics, phenytoin, carbamazipine, phenobarbital, and primidone are all strong inducers of cytochrome P450 enzymes**
- valproate inhibits cytochrome P450 enzymes
Treatment Considerations for Anti-Epileptic Drugs
- most AEDs undergo complete or nearly complete absorption when given orally
- fosphenytoin (prodrug) can be administered IM if IV can’t be established in cases of frequent repetitive sz
- diazepam (also as rectal gel) been shown to terminate repetitive sz and can be administered by family members at home
- phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproate are available as IV prep for emergency use
- AEDs metabolized in liver and excreted by kidneys
- add-on therapy is often necessary to eliminate “break-through” or refractory sz
Status Epilepticus
- more than 30 minutes of continuous sz activity
- 2 or more sequential szs spanning this period w/o full recovery b/t szs
- medical emergency
Treatment
- diazepam, lorazapam IV (fast, short acting)
- followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established
Considerations in Rehab for Anti-epileptics
- thorough medical hx!
- monitor pt progress-keeping dosages w/in therapeutic window
- schedule sessions around time of day when side effects (H/A, dizziness, sedation, GI disturbances) are mild
- ataxia might impair pt’s ability to participate in various fxnal activities (start coordination exercises)
- interventions that might exacerbate skin conditions should be avoided
- depending on the seizure triggers some pts might do better in a quieter environment at the time of day when chance of seizure is minimal