CNS I Pharm - Antiepileptics Flashcards
Status Epilepticus
Life-threatening condition defined as either 30 minutes of continuous seizure or repeated seizures without regaining consciousness in between
Aura
Feeling or experience right before a seizure begins –> aura is indicative of a FOCUS OF SEIZURE ACTIVITY –> thus, it only occurs with PARTIAL seizures
Partial/Focal Seizure
Begins from a SINGULAR FOCUS
Can be SIMPLE (no impairment of consciousness) or COMPLEX (impairment of consciousness)
Symptoms depend entirely on the focus from which the seizure begins – motor, sensory, autonomic or psychiatric symptoms
EEG – Focal stimulation (sharp peak) and subsequent inhibition (drop after) of the surrounding neurons
Partial seizures can spread and become generalized
Generalized Seizure
No local onset - can occur secondary to a focal sometimes
ABSENCE Seizure
ABSENCE –> present with a LOSS OF ATTENTION and a JERKING OF THE EYELIDS/FACIAL MUSCLES
MYOCLONIC Seizure
Present with sudden, brief jerking of a SINGLE foot or arm, typically
ATONIC
Complete loss of muscle tone and often sudden collapse
TONIC, CLONIC, TONIC-CLONIC
Stiff (tonic), Jerky (clonic) or both (tonic-clonic) –> these are what we think of when we think of “classic” seizures
Tonic Clonic = GRAND MAL
Monotherapy vs. Polytherapy
MONO is what we want –> most patients remain seizure free from one drug
Polytherapy has minimal benefits and many more risks; BUT if it is necessary, use DIFFERENT CLASSES
General facts about Sodium Channel Blockers in Epilepsy
These drugs are NOT complete blockers of the sodium channel
They are also USAGE dependent –> high neuronal activity is required for the drugs to become active; when active, they reduce the sustained high frequency repetitive firing of APs
PHENYTOIN
Widely used sodium channel blocker
APPROVED FOR –> PARTIAL; GENERALIZED TONIC CLONIC; and STATUS EPILEPTICUS
Poor bioavailability, soluble, CYP450 metabolism (polymorphisms possible too)
Several Drug Interactions (Decreased levels with other AEDs - Carbamazepine, Phenobarbital)
Side Effects of Phenytoin
Neurological effects – ataxia, nystagmus, diplopia, SEDATION, coma
Cerebellar syndrome
Allergic rxns
Connective tissue problems
CARBAMAZEPINE
Blocks sodium channels to reduce sustained high frequency firing of APs
Also works on ACh and NMDA receptors
PARTIAL and GENERALIZED
Slow absorption, limited solubility
AUTOINDUCER of its own CYP enzyme –> more drug will cause less of an effect after using it for a while
Neuro side effects, headaches, dizziness, tics, movement disorders, allergy
Several Drug Interactions; Decreased levels with other AEDs (Phenytoin, Phenobarbital)
LACOSAMIDE
Selective enhances the SLOW INACTIVATION OF SODIUM CHANNELS (makes them more inactive)
Approved as an ADJUNCT ONLY FOR PARTIAL SEIZURES (so, not on its own)
Few drug interactions
Dizziness, ataxia, QT prolongation but not arrhythmic
ETHOSUXIMIDE
CALCIUM CHANNEL BLOCKER (only one for epilepsy)
Works on T-Type calcium channels in the thalamus, reducing low-threshold calcium currents – keeps neurons in “oscillatory” firing mode rather than “tonic”
ABSENCE SEIZURES ONLY (drug of choice)
Side Effects include dizziness, lethargy, headache, GI distress, rash, BM suppression
Mechanism of action for BENZODIAZEPINES
Thalamocortical relay neurons are acted upon by ETHOSUXIMIDE
There are GABAergic neurons projecting from the reticular nucleus of the thalamus to these relay neurons –> if these were ACTIVE, there would be a hyper polarization and an INCREASE in the low threshold calcium current - this would potentiate tonic firing and increase absence seizures
BENZOS work on GABAergic INTERNEURONS that act on those GABAergic neurons –> ENHANCE the interneurons (so they make the inhibition stronger) and they will keep those other GABA neurons from firing and there will be no tonic firing (alpha 3)
CLONAZEPAM
Second line for generalized ABSENCE and MYOCLONIC
LORAZEPAM
FIRST LINE FOR STATUS EPILEPTICUS
Benzos do what, in a nutshell?
Essentially increase the frequency of opening of the GABA receptors (encourage inhibition) – Makes sense since the brain is hyperexcitable
Side effects of benzos?
RESPIRATORY DEPRESSION, sedation, drowsiness, ataxia;
Paradoxical INCREASE in seizure frequency, tolerance after long term use
Withdrawal effects possible
Interactions with Carbamezapine, Phenobarbital (the benzos get lowered when on these other drugs - inducers)
PHENOBARBITAL
Acts on GABA receptors to INCREASE AVERAGE OPEN TIME (rather than frequency of opening)
PARTIAL, GENERALIZED TONIC-CLONIC, STATUS EPILEPTICUS
Also for WITHDRAWAL states
Very long half life
Side effects – Dizziness, Ataxia, Vertigo
INCREASED by Valpro and Phenytoin
TIGABINE
Increases GABA throughout the neuropil by BLOCKING GABA REUPTAKE!
Approved for PARTIAL SEIZURES
Side effects – confusion, sedation, dizziness
Levels DECREASED by carbamazepine, phenytoin, phenobarbital
VIGABATRIN
Acts intracellularly to INHIBIT GABA TRANSAMINASE (degradative pathway for GABA)
Increases GABA pool for release
PARTIAL and INFANTILE SPASMS
Loss in visual functioning, sedation fatigue
What are common side effects of all these drugs?
WELL, they increase GABA or potentiate its effect, so it just makes sense that SEDATION, CONFUSION, LACK OF COORDINATION, etc are all effects. CNS depression!
LEVITERACETAM
Binds to a specific protein in the presynaptic terminal which MEDIATES UPTAKE OF NT INTO VESICLES – not really sure how it works
PARTIAL SEIZURES, MYOCLONIC, TONIC CLONIC
Metabolized in the KIDNEYS rather than the LIVER –> avoids a lot of side effects and drug interactions!
Brief periods of psychosis, hyperactivity and aggression are possible
VALPROIC ACID
Uses all the mechanisms – BLOCKS NA CHANNELS, BLOCKS CALCIUM CHANNELS, INCREASES GABA by INHIBITING DEGRADATIVE PATHWAY
PARTIAL SEIZURES, GENERALIZED, ABSENCE, MYOCLONIC
Dose dependent protein binding, absorbed completely and rapidly
Side effects – Sedation, ataxia, tremor, hair loss, weight gain, cognitive slowing
Biggest Side Effect of Valproic Acid?
TERATOGENIC IN 1% OF CASES!
Efficacy of Anticonvulsants
1/3 of patients DO NOT respond to anticonvulsants!
Absence seizures
Generalized seizures; looks like sleeping/daydreaming with eyelid twitches (3/sec)
Can be elicited 80% of the time in the office by asking the child to hyperventilate for 3 minutes…weird
TREATMENT of a child ONLY with ABSENCE? –> ETHOSUXIMIDE!!!!!! Calcium channel blocker
Two best drugs for compliance?
CARBAMAZEPINE and PHENYTOIN (Na Channel Blockers!)
More on Status Epilepticus
Prolonged and frequent seizures with sufficiently brief intervals that produce an ENDURING EPILEPTIC CONDITION
Seizures lasting longer than 30 min or more OR repeated seizures w/o a return to consciousness in between
Causes? Pre-existing epilepsy not well controlled, acute neurological insults, electrolyte imbalances, drugs, alcohol, idiopathic
Higher in young and elderly (like seizures in general and epilepsy)
SIGNIFICANT morbidity and mortality!
Treating Status Epilepticus
Benzos!!!! LORAZEPAM first line!!!!! Don’t give them too fast or there will be RESP DEPRESSION
Can then add on PHENYTOIN –> monitor EKG and BP closely; can extravasate into tissues and cause PURPLE GLOVE SYNDROME which is where the fingers/hands turn dark red/purple; can be very dangerous and loss of limbs can result
Third drug to add is PHENOBARBITAL –> can cause resp depression and arrhythmias
What is unique about Phenytoin’s metabolism?
Enzymes can get saturated at HIGH DOSES (non-linear kinetics) –> once this happens there is an EXPONENTIAL INCREASE in the level of drug in the blood when more is added!
Half life can be really high (no real half life) – it is dependent on dose…
Which drug is teratogenic?
VALPROIC ACID silly!
