CNS: Antiepileptic drugs Flashcards
Seizures
clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons
Epilepsy
Chronic disorder characterized by spontaneous recurrent seizures
Convulsions
Involuntary, paroxysmal skeletal muscle contractions
Partial Seizure Simple
Limited motor or sensory signs, consciousness intact
Partial Seizure Complex
Consciousness Impaired
Secondary Generalized
Symptoms increase until resembling a generalized seizure
Generalized Seizures
Absence/Petit Mal
Sudden brief loss of consciousness
Generalized Seizures
Myoclonic Seizures
Sudden, brief, shocklike contractions of muscles
Generalized Seizures
Clonic seizures
Rhythmic, synchronized contractions throughout the body, loss of consciousness
Generalized Seizures
Tonic Seizures
Generalized, sustained muscle contractions throughout the body, loss of consciousness
Generalized Seizures
Tonic-Clonic/Grand Mal
Major convulsions of entire body, loss of consciousness
Generalized Seizures
Atonic seizures
Sudden loss of muscle tone in the head and the neck; consciousness may be maintained or loss briefly
Status Epilepticus
More than 30 minutes of continuous seizure activity Two or more sequential seizures spanning this period without full recovery between seizures Medical emergency Diazepam, lorazapam IV (fast, short acting) Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established
Rationale for Drug treatment
Antiepileptic drug Decreases the frequency and/or severity of seizures in people with epilepsy Treats the symptom of seizures not the underlying epileptic condition Goal – maximize quality of life by minimizing seizures and ADEs Effective in 60% of patients with epilepsy (seizure free), 20% experience drastic reduction in seizures
Pharmacokinetics/Dynamics
Good oral absorption and bioavailability Most metabolized in liver but excreted 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 efficacy
Classifications of AED: Classical
Phenytoin Phenobarbital Primidone Carbamazepime Ethosuximide Valproate (valproic acid)
Classification of AED: Newer
Lamotrigine Felbamate Topiramate Gabapentin/pregabalin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin
Side effects of AED
Sedation – especially with barbiturates
Cosmetic – phenytoin, steven johnson’s syndrome (rare)
Weight gain – valproic acid, gabapentin
Weight loss – topiramate
Reproductive function – valproic acid
Cognitive – topiramate
Behavioral – felbamate, leviteracetam
Allergic - many
Epilepsy-Basic Neurophysio: Causes of Hyperexcitabiltiy
excitatory post synaptic potentials (EPSPs)
inhibitory post synaptic potentials (IPSPs)
changes in voltage gated ion channels
alteration of local ion concentrations
Epilepsy-Glutamate
The brain’s major excitatory neurotransmitter Two groups of glutamate receptors Ionotropic—fast synaptic transmission Three subtypes – AMPA, kainate, NMDA Glutamate-gated cation channels Metabotropic—slow synaptic transmission G-protein coupled, regulation of second messengers (cAMP and phospholipase C) Modulation of synaptic activity Modulation of glutamate receptors Glycine, polyamine sites, zinc, redox site
Epilepsy GABA
Major inhibitory neurotransmitter in the CNS Two types of receptors GABAA—post-synaptic, specific recognition sites, linked to CI- channel
GABAB —presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to G-proteins to increase K+ current
Cellular Mechanisms of Seizure Generation
Excitation (too much) Ionic—inward Na+, Ca++ currents Neurotransmitter—glutamate, aspartate
Inhibition (too little) Ionic—inward CI-, outward K+ currents Neurotransmitter—GABA
Targets for AEDs
↑ inhibitory neurotransmitter system such as GABA ↓ excitatory neurotransmitter system – glutamate
Block voltage-gated inward positive currents – Na+ or Ca++ ↑ outward positive current – K+
Many AEDs have multiple MOAs
Dicarbamates Felbamate (Felbatol®)
- Indicated for treatment of partial seizures in adults and children generalized absence seizures (Lennox-Gastaut syndrome) in children Potent AED lacking sedative effect (unlike all other AEDs)
- ADEs GI issues Rare but fatal aplastic anemia => restricted for use only in extreme refractory epilepsy
Topiramate (Topamax®)
- Used for partial seizures, as an adjunct to tonic-clonic seizures (add-on or alternative to phenytoin)
- MOA Acts on AMPA receptors, blocking the glutamate binding site, but also blocks kainate receptors and Na+ channels, and enhances GABA currents
- ADEs Paresthesia – ‘pins and needles’ Fatigue Taste change Weight loss Difficulty concentrating
Benzodiazepenes
- Clonazepam (Klonopin®) Used for absence seizure (sometimes myoclonic)
- Most specific ADE among benzos – selective for GABAa 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 Cause ataxia Behavioral changes
BarbituratesPhenobarbital, Primidone (Mysoline®)
- Used for partial seizures, especially in neonates, first class of drugs
- MOA: ↑ inhibitory effects of GABA
- ADEs: Very strong sedation, cognitive impairment, behavioral changes, folate deficiency, vitamin K deficiency, skin problems Tolerance may arise, risk of dependence Primidone is metabolized to phenobarbital Induce CYP450 enzymes Seldom used due to side effects
Tiagabine (Gabitril®)
- Interferes with GABA reuptake Used for treatment of partial seizures
- ADEs: Decreased concentration Dizziness, somnolence, nervousness Chest pain, hypertenstion, edema, syncope, vasodilation Alopecia Speech disorder
Vigabatrin
- Irreversible inhibitor of GABA amino-transferase – enzyme responsible for the degradation of GABA => GABA released at synaptic site => enhances inhibitory effects U
- seful for treatment of partial seizures and tonic-clonic seizures as an alternative agent ADEs – sedation, dizziness, weight gain
Na+ Channels as AED Targets
- Neurons fire at high frequencies during seizures Action potential generation is dependent on Na+ channels
- Use-dependent or time-dependent Na+ channel blockers reudce high frequency firing without affecting physiological firing
AEDs That Act Primarily on Na+Channels
Phenytoin, Carbamazepine – Block voltage-dependent sodium channels at high firing frequencies—use dependent
Oxcarbazepine – Blocks voltage-dependent sodium channels at high firing frequencies – Also effects K+ channels
Zonisamide – Blocks voltage-dependent sodium channels and T-type calcium channels
Hydantoins, Phenytoin (Dilantin®), Fosphenytoin (Cerebyx®)
First-line for partial seizures Some use for tonic-clonic seizures
MOA: Blocks voltage-dependent sodium channel at high firing frequencies Highly protein bound Induces P450 enzyme system
ADEs: GI irritation, sedation, gingival hyperplasia, hirsutism, nystagmus, ataxia, dysarthria Fosphenytoin – prodrug for phenytoin (used as IM injection)
Iminostilbenes Carbamazapine (Tegretol®)
Tricyclic antidepressant used for partial seizures and some use in tonic-clonic seizures
MOA: Similar to phenytoin Induces P450 enzyme system => induces its own metabolism
ADEs: Sedating, agranulocytosis and aplastic anemia, leukopenia, hyponatremia, cardiac arrhythmias, CHF
Iminostilbenes Oxcarbazapine (Trileptal®)
Newer agent – related to carbamazapine Approved for monotherapy in partial seizures
MOA: Same as carbamazapine May also augment K+ channels Some CYP450 induction
ADEs: Sedating but less toxic than carbamazapine
Zonisamide (Zonergan®)
Used as add-on for partial and generalized seizures
MOA Blocks voltage-dependent sodium channels and T-type calcium channels
ADEs Serious skin rash Suicidal ideation Metabolic acidosis Anemia, leukopenia
Ca2+ Channels as Targets
General Ca2+ channel blockers have not proven to be effective AEDs. Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca2+ currents
Succinimides Ethosuximide (Zarontin®)
MOA Acts specifically on T-type channels in thalamus, and is very effective against absence seizures ADEs GI disturbances Less sedating Movement disorders Skin rashes
Gabapentin (Neurontin®), Pregabalin (Lyrica®)
Used in add-on therapy for partial and tonic-clonic seizures
MOA Act specifically on calcium channel subunits called α2δ1.
It is unclear how this action leads to their antiepileptic effects, but inhibition of neurotransmitter release may be one mechanism
ADEs Less sedating
K+ Channels
K+ channels have important inhibitory control over neuronal firing in CNS—repolarizes membrane to end action potentials K+ channel agonists would decrease hyperexcitability in brain So far, the only AED with known actions on K+ channels is valproate
Carboxylic Acids proate (Valproic Acid®)
First-line for generalized seizures, also used for partial seizures
MOA Acts on K+ channels to decrease hyperexcitability in the brain
Also blocks Na+ channels and enhances GABAergic transmission Highly protein bound Inhibits CYP450
ADEs CNS depressant GI disturbances Hair loss Weight gain Teratogenic Hepatotoxic
Regulation of Neurotransmitter Release
Several AED have actions that result in the regulation of neurotransmitter release from the presynaptic terminal, such as lamotrigine, in addition to their noted action on ion channels or receptors
Levetiracetam appears to have as its primary action the regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A
Levetiracetam (Keppra®)
Add-on therapy for partial seizures
MOA regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A
ADEs CNS depression
Lacosamide (Vimpat®)
Used for partial-onset seizures 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
ADEs N/V/D Diplopia Dose adjust in patients with mild or moderate hepatic impairment or severe renal impairment
Drug Interactions of AEDs
Many AEDs are notable inducers of cytochrome P450 enzymes and a few are inhibitors
Of the classic AEDs, phenytoin, carbamazipine, phenobarbital, and primidone are all strong inducers of cytochrome P450 enzymes
Valproate inhibits cytochrome P450 enzymes
Treatment Considerations of AEDs
Most AEDs undergo complete or nearly complete absorption when given orally
Fosphenytoin (prodrug) may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home
Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproate are available as IV preparations for emergency use
Most AEDs are metabolized in the liver (P450) by hydroxylation or conjugation. These metabolites are then excreted by the kidney.
Gabapentin undergoes no metabolism and is excreted unchanged by the kidney
Monotherapy is preferred: better patient compliance, less adverse effects Add-on therapy is often necessary to eliminate “break-through” or refractory seizures
Considerations in Rehabilitation
Thorough medical history is a must! Monitor patient progress – keeping dosages within therapeutic window Schedule sessions around the time of day when side effects such as H/A, dizziness, sedation, GI disturbance are mild Ataxia might impair patient’s ability to participate in various functional activities (if persistent – start coordination exercises) Interventions that might exacerbate skin conditions should be avoided Depending on the seizure triggers, some patients might do better in quieter environments at the time of day when chance of seizure is minimal
