Anti-Epileptics Flashcards
What are seizures?
- self sustaining and self timing episodes of synchronized neural hyperactivity that can be detected by EEG
What causes seizures or epilepsy?
- brain trauma - enough neurons die which can lead to excitotoxicity
- brain tumours
- stroke, CV events –> brain starved of O2 –> cell death –> release of glutamate
- brain infection, meningitis, fever - body makes antibody receptors against the brain
- medications
- alcohol withdrawal
- hormone fluctuations
- idiopathic epilepsy: hereditary but the cause is unknown
How does the EEG pattern differ between a normal pattern, absence seizure and tonic clonic?
normal
- no synchrony between neurons firing
- sum of neurons is low amplitude
absence seizure
- typical spike and wave pattern but there is synchrony between neurons so there is a larger sum
- all electrodes along cortex picking up seizures
tonic clonic
- a lot of neural activity and no synchrony, very high constant spiking through whole cortex
Absence seizures
- general
- briefly unconciosu, blank stare, no memory of attack
- less than 30 seconds
- 3 per second spike and wave throughpout whole brain
tonic clonic seizures
- general
- unconscious, dramatic convulsions, no memory of attack
- lasts less than 5 minutes (more then 5 is status elepticus)
- constant spiking throughout whole cortex
Simple partial seizure
- conscious (cortex still working), memory of attack, sensory/motor/emotion symptoms representative of where it is
- duration varies
- localized spiking in neocotical or limbic area of brain
Complex partial seizure
- conscious but unresponsive, automastisms, no memory of attack
- begins locoalized but spreads over time - can become tonic clonic with no intervention
- duration varies
- localized then spreading spiking in one or both temporal lobes
What are the adverse outcomes of not managing epilepsy?
- difficulty learning
- breathing in food and saliva into lungs during seizure which causes aspiration pneumonia
- injury from falls, biting and driving during seizure
- permanent brain damage
- death from seizure
- death from suicide from depression associated with epilepsy
Describe the mechanism by which seizures cause cell death through glutamate
seizures cause the release of glutamate which acts on
- NMDA receptors: opens receptor operated Ca channels
- AMPA: upon membrane depolarization, AMPA can be triggered to open voltage gated Ca channels even though they usually doesn’t let Ca through
- metabotropic receptors: GPCRs release Ca from endoplasmic reticulum
this increases Ca inside the cell which activates Ca dependent enzymes which results in
- lipid peroxidation
- proteolysis
- free radical formation
- DNA damage
- damage to mitochondria –> impairs respiration
this results in cell death
What are the classes of glutamate receptors
- AMPA
- NMDA
- metabotropic receptors
How does activation differ in epilepsy?
- in normal balance IPSPs and EPSPs are regulated
- usually want to promote inhibition or decrease inhibition
- can act on sodium potassium ion channel to promote excitation and promote hyperpolarization
What are the NT ion channel therapeutic targets?
GABA - inhibitory
Glutamate and acetylcholine - excitattory
- can regulate the synaptic enzymes
- regulated by levels of activity of neuron, production, packing, release and clearance of NTs
Voltage gated ion channels as therapeutic targets to reduce neuron excitability
- sodium ion channels: role in propagation of AP, blocking Na channels blocks electrical activation
- K ion channels: repolarization/hyperpolarization of membrane along the neuron and at terminal
- Ca channels: trigger NT release,
- Cl channels: can block them so resting potential is lower so it will not be excited as easily
4 possible MOA for different anti-seizure medication
- modulate voltage dependent sodium channels to make them less active –> less able to propagate AP which decrease excitability
- modulate GABAa or GABAergic transmission –> increase GABA which is inhibitory which makes the cell less excitable
- negative modulate voltage gated calcium channels –> role in NT release so if you negatively modulate it the cell will be less excitable, calcium channels in the thalamus are very important in absence seizures
- broad spectrum drugs with multiple targets
What drugs modulate voltage dependent sodium channels at the glutamate synapse?
Block VGNaC, presynaptic
- phenytoin (very prescribed)
- carbamazepine
- lamotrigine
- felbamate
- valproate –> acts through multiple targets and acts epigenetically to regulate gene expression
What drugs facilliate GABAa and GABAergic transmission?
agonist: topiramate (promote GABAa activation, post synaptic)
PAM: barbiturates –> phenylbarbitol, benzodiazepines –> diazepam, clonazapam, lorazopam (promote GABAa activation, post synaptic)
Prevents GABA reuptake: tiagabine (blocks GAT-1, presynaptic)
Blocks degradation of GABA: vigabatrin (antagonist of GABA-T enzyme that degrades GABA, presynaptic)
Increases GABA synthesis: gabapentin, pregobalin
What drugs negatively modulate voltage gated calcium channels - inhibit/block and which Ca channels at glutamate synapse?
Block VGCC, presynaptic
- ethosuximide: inhibits VGCC in the thalamus –> T type Ca channel –> first line treatment for absence seizures
- gabapentin: blocks VGCCs
- lamotrigine
Which drugs block post synaptic AMPA receptors at the glutamate synapse?
phenobarbital, topiramate, lamotrigine
What broad spectrum drugs with multiple targets can be used as anti seizure medication?
- lamotrigine*
- carbamazepine*
- zonisamide
- topiramate
- valproate
*drugs used to treat bipolar disorder (antipsychotics) –> this may mean that the genes that predispose someone to BP also put them at risk of epilepsy
Which drugs are used for the different kinds of seizures?
Partial
- simple complex and tonic-clonic seizures
- phenytoin, carbamazepine, gabapentin
Generalized
- tonic clonic, myoclonic, atonic, absence
- only absence is treated with ETHOSUXIMIDE
- all treated with valproic acid
all seizures are then treated with
- lamotrigine, felbamate, topiramate
Drug interactions of phenytoin, phenobarbital and valproate
- alcohol is contra indication for all
phenytoin
- decreases effectiveness of oral contraceptives, anticoagulants, carbamazepine, steroidal anti inflammatory drugs because it increases their metabolism
- potential inducer of CYPs
- pharmacokinetics affected by drugs that displace it from serum albumin including antiseizure drugs –> this would make it have a stronger effect bc it is more bioavailable
phenobarbital
- same drug interactions as phenytoin (not phamacokinetics)
- inducer of CYPs
valproate
- increases serum levels of phenytoin
- valproate and aspirin/warfarin cause reduce clotting and spontaneous blleding
- inhibitor of CYPs
Common adverse effects of anti seizure medication
- somnolescence - decreased acitvty of neurons in reticular formation
- GI upset: actions on ANS - depressed activity of cholinergc neurons activating GI tract
- cognitive impairment and memory problems: depressed activity of cortical neurons
- physical dependence/withdrawal: CNS adapts to depressive actions of drugs, abrupt discontinuation can cause seizures
What does anesthesia represent?
- immobility to the point of no reflexive movements
- amnesia
- consciosuness
How is immobility acheived in anesthesia
- spinal reflexes cause twitching and muscle jerks in response to cut –> use muscle relaxants
- immobility and loss of reflexes is easy to measure and monitor for proper level of anesthesia
- neural inhibition of spinal cord
How is amnesia acheived in anesthesia?
- want to prevent explicit memory of surgery and implicit memory (collected from sensory systems that doesn’t reach consciousness - not remebered byt recorded)
- reduce firing in hippocampus, amygdala, prefrontal cortex, sensory and motor cortex
How is consciousness changed in anesthesia?
- personal awarness is mediated by cortex, thalamus and reticular formation
- anesthetics prevents a person from remebering at an unconcsious level
A) To achieve surgical anesthesia a drug must:
B) is this acheivable?
- render patient unconsious
- immobilie patient to suppress reflex movements and relax skeletal muscles
- have amnestic properties
B) no one drug can do all these things
How are anesthetics administered? What drugs are used? What do they act on?
- inhaled or injected, usually a combination is used
- low dose of injected is used and then topped off with inhaled
- inhaled are easier to reverse and adjust dose
injected
- propofol (rapidly metabolized so reverse of OD is easy), thiopental, diazepam, lorazepam –> GABA agonists
- ketamine –> blocks NMDA receptor –> dissociative anesthetic
inhaled
- sevoflurane, desflurane, isoflurane, helothane –> GABA agonists
- nitrous oxide
What is a common anesthetic regimen?
- BNZ prior to surgery to reduce anxiety and it is a muscle relaxant and sedative –> diazepam, lorazepam
- propofol IV to induce anesthesia - rapidly metabolized by liver and can be continuous infused
- inhaled anesthetic to maintain surgical plane of anesthesia –> sevoflurane
- opioid to provide analgesia (too much can cause stiff chest, contribute to tolerance, and lessen effectiveness of post op opioids)
