Seizures (and a bit on anesthesia) Flashcards
Seizures
self-sustaining and self-limiting episodes of synchronized neural hyperactivity that can be detected by EEG
What causes seizures
- brain trauma (head injury)
- brain tumours
- stroke, cardiovascular events
- brain infection, meningitis, fever
- medications (antidepressants, cocaine, amphetamine)
- alcohol withdrawal
- hormone fluctuations
- hereditary forms of epilepsy
idiopathic epilepsy
idiopathic meaning unknown origin
- doctors now send DNA for testing to identify certain genes
EEG only detects
cortical activity (and in the gyri better than the sulci)
Thalamus is thought to mediate
really synchronized, slow-wave brain waves
Generalized seizures (absence and tonic clonic)
- absence (petit mal): briefly unconscious, blank stare, no memory of the attack, lasts less than 30 seconds, 3 per second spike and wave throughout the whole brain.
- tonic clonic (grand mal): unconscious, dramatic convulsions, no memory of attack, lasts less than 5 minutes, constant spiking throughout the whole brain
status epilepticus
grand mal seizing for over five minutes
Partial seizures (simple, complex)
- simple partial seizure: conscious (a lot of cortex still working), has memory of the attack, sensory/motor/emotion symptoms, duration varies, localized spiking in neocortical or limbic area of brain
- complex partial (temporal lobe): conscious but non-responsive, automatisms, no memory of attack, duration varies, localized then SPREADING spiking in one of both temporal lobes
Adverse consequences to not managing epilepsy
- difficulty learning
- breathing in food or saliva into lungs during seizure which can cause aspiration pneumonia (pulmonary pneumonias from lung infections)
- injury from falls, bumps, self-inflicted bites, driving or operating machinery during a seizure
- permanent brain damage (neurons irreplaceable)
- death from seizures
- death from suicide
epilepsy on a cellular level: calcium influx
Epilepsy is an imbalance of excitation
- results in seizure, head trauma, ischemic cell death
glutamate signalling results in:
- membrane depolarization > opening of voltage-gated calcium channels > influx of calcium
- NMDARs opening > influx of calcium
- Some GPCRs are linked to Gq > calcium release from store site
OVERALL, increase in intracellular calcium which leads to activation of Ca++ dependent enzymes and eventually, cell death
ion channels can be (choose your own adventure)
- excitatory or inhibitory
- ligand- or voltage-gated
therapeutic targets to reduce neuronal excitability
NT ion channels (ligand-gated)
- GABA (inhib)
- Glutamate and Acetylcholine (excitatory)
- not only regulated bu the levels or activity of the receptors, but also by the production, packaging, release, and clearance of NTs (so can target all those diff processes)
Voltage-gated ion channels
- sodium ion channels - propagation of the action potential
- potassium ion channels - repolarization/hyperpolarization of the membrane
- calcium channels - trigger the release of NTs
Four mechanisms of action for different anti-seizure medications
- Modulate voltage-dependent sodium channels (make them less active)
- facilitate GABA A channels and GABAergic transmission
- Negatively modulate voltage-gated calcium channels (calcium channel in thalamus thought to be important in absence seizures
- broad spectrum drugs with multiple targets
some epilepsy drugs that modulate voltage dependent sodium channels
- phenytoin
- carbamazapine
- felbamate
- lamotrigine
- valproate
Epilepsy drugs that facilitate GABA a channels and GABAergic transmission
Agonists or positive allosteric modulator of GABA A
- agonist: topiramate
- Positive allosteric modulators: barbiturates and benzodiazedines
- block reuptake or metabolism of GABA: tiagabine, vigabatrin
- increase GABA synthesis: gabapentin, pregabalin
Epilepsy drugs that negatively modulate voltage gated calcium channels?
- ethosuximide - inhibits VGCC in thalamus (T-type calcium channels)
- gabapentin - blocks VGCC
- lamotrigine
Broad-spectrum target drugs for epilepsy
lamotrigine, zonisamide, topiramate, valproate
Tiagabine
prevents reuptake of GABA into neuron
Vigabatrin
blocks degradation of GABA
Topiramate, phenobarbital, diazepam, lorazepam, clonazepam all have what in common?
act on the GABA A channel and promote its activation
Gabapentin and pregabalin
both increase synthesis of GABA
Epilepsy drugs that act at glutamate synapses
block VCSCs: phenytoin, carbamazepine, lamotrigine, felbamate
block VGCC: ethosuximide, lamotrigine, gabapentin
block post-synaptic AMPARs: phenobarbital, topiramate, lamotrigine
What receptors do glutamate activate?
- AMPARs (Na+ channe;s)
- NMDARs (Na+/Ca2+ channels)
- metabotropic receptors (mGluRs)
What medication is used to treat absence seizures?
ethosuximide
- inhibits VGCC in the thalamus, T-type
- recall that the thalamus is thought to regulate the slow-wave synchronized sleep seen in sleep
Contraindication of epilepsy meds
alcohol use
phenytoin:
drug interactions
Can decrease the effectiveness of:
- oral contraceptives
- anticoagulants
- carbamazepine
- steroidal anti-inflammatory drugs
Potent inducer of cytochrome P450 enzymes so increases the metabolism of these drugs - can be an issue for drugs with a narrow therapeutic window
phenytoin pharmacokinetics can also be affected by multiple drugs - can be displaced from serum albumin
phenobarbital:
drug interactions
Can decrease the effectiveness of:
- oral contraceptives
- anticoagulants
- carbamazepine
- and steroidal anti-inflammatory drugs
inducer of CYP 450 enzymes - increases metabolism of above drugs
Valproate:
drug interactions
- valproate increases serum levels of phenytoin
- valproate and aspirin or warfarin can cause reduced clotting and spontaneous bleeding
Common adverse effects of anti-seizure meds
- somnolence: decreased activity of neurons in the reticular formation
- GI upset: actions on autonomic nervous systems (depressed activity of cholinergic neurons innervating GI tract (parasympathetic nervous system)
- cognitive impairment, memory problems: depressed activity of cortical neurons
- physical dependence/withdrawal problems - CNS adapts to depressive actions of the anticonvulsant (if patient discontinues too rapidly, seizures may result)
Purpose of anesthesia (3)
- immobility
- spinal reflexes will cause twitching and large muscle jerks in response to cut
- immobility / loss of reflexes is easy to measure and monitor for proper level of anesthesia - amnesia
- want to prevent explicit memory of surgery
- also prevent implicit memory (info collected from sensory systems that does not reach conscious awareness - tested this with priming experiments) - unconsciousness
- prevent personal awareness. knock em out.
Where does anesthesia act?
- immobilizing properties - neural inhibition at the spinal cord
- amnesic properties - hippocampus, amygdala, prefrontal cortex, sensory and motor cortex
- rendering patient unconscious - cortex, thalamus, reticular formation
Anesthetics: administration
- anesthetics can be inhaled or injected IV
- inhaled anesthetics are easier to reverse and adjust dose
- usually combo of IV and inhaled anesthetics is used
Anesthetic drugs: injected and inhaled
injected:
- propofol, thiopental, diazepam, lorazepam, ketamine
inhaled:
- sevoflurane, desflurane, isoflurane (GABA agonists)
- halothane
- nitrous oxide
