Antiseizure drug Pharmacology Dr. Pond Flashcards
What are the possible causes of seizures?
-disturbed levels of body water/electrolytes
-disturbed level of blood glucose
-altered blood gases
-raised body temperature
-altered sleep patterns
-hormonal changes
-Toxicity
excess excitation
lack of inhibition
Where in the brain are seizures thought to arise?
Cerebral cortex (outermost part of the brain)
partial seizures
generalized seizures
What is the difference between partial and generalized seizures?
-partial seizures: start a specific locus in the cerebral cortex
-generalized seizures: both hemispheres are involved in the onset
What differentiates a simple partial seizure from a complex partial seizure?
simple: consciousness is not impaired
complex: consciousness is impaired -> may have a simple partial-onset where patients are aware -> followed by loss of consciousness OR they are unconscious right away
Secondarily generalized seizures
-simple partial to generalized (start at on area and spread to both hemispheres)
-complex partial to generalized
-simple partial to complex partial to generalized
What is a synonym for secondarily generalized seizures?
tonic-clonic seizure?
What is the gyrus (bump) before the central sulcus called?
-precentral gyrus
-> Primary motor cortex Homunculus, frontal lobe
-> collateral control: left control right sight of the body
seizures in the left side of the motor cortex will affect the right sight of the body
Which structure is found behind the central sulcus?
Postcenter gyrus
-> Primary somatosensory cortex Homunculus
collateral: sensation on the right side of the body are received on the left side of the brain
seizures in this area can sometimes be perceived as a tingeling
In which lobe is the Primary somatosensory cortex Homunculus located?
Parietal lobe
How long does a simple partial seizure last?
20-60 seconds
consciousness is not impaired
What symptoms are expected when seizures occur in the motor cortex?
Tonic-clonic movements of the upper or lower limb
Other symptoms - seizure
Occipital lobe (eye): flashing lights
Temporal lobe (auditory): ringing, noises
Autonomic: sweating, flushing, pallor, or epigastric sensation
How long does a complex partial seizure last?
-30 seconds to 2 minutes
impairment of consciousness
Features of complex partial seizures
-blank stare
-funny face, grimaces
-chewing movements of the mouth
-bad or unusual smell before the seizure
-dysphasia (unable to speak)
-auditory hallucination
-visual hallucination
Symptoms of Generalized seizures: Absence
last less than 30 sec
-vacant stare
-eyes rolled upwards
-eyelids flutter
-cessation of activity
-lack of responses
-patients may be unaware that they are having a seizure and move on with what they have been doing before the seizure
How are muscles affected by seizures?
Myoclonic: sudden, shock-like contraction (<1sec)
-> often occur falling asleep or shortly after waking up
Tonic: muscle stiffening -> person falls to the ground
Clonic: repetitive muscle jerking and short post-ictal phase
Atonic: sudden loss of muscle tone, dropping of head or limb, possible fall to the ground
Characteristics Tonic-clonic seizure
Tonic phase: stiffening, epileptic cry, cyanosis, incontinence
Clonic phase: clonic jerks of limbs, body and head, salivary frothing (foam), eyes blinking, cyanosis
Post-ictal (time after the seizure): confusion, fatigue, drowsiness, hypotension, confusion, headache, nausea
Antiseizure drug MOA
-Sodium channel modulation (fast inactivation)
-Sodium channel modulation (slow inactivation)
-K+ channel opener
-Blockade of voltage-gated calcium channels
-> getting back to resting potential
What is the MOA of Levetiracetam/brivaracetam?
-Synaptic vesicle protein 2A modulation
hinder vesicle formation
What are MOAs that involve GABA?
-Prolongs chloride channel opening: GABA binds to Cl(-) channels -> inhibitory (IPSP): barbiturates and stiripentol
-Increased frequency of chloride channel opening: benzodiazepines, ganaxolone
-Inhibits GABA-transaminase
-Blocks synaptic GABA reuptake
-increases GABA: Valproate
-Glutamate antagonist (Glutamate is an excitatory NT -> blocking will have an inhibitory effect):
->AMPA/kainate: phenobarbital, lamotrigine, perampanel, topiramate
->NMDA: carbamazepine, valproate, felbamate, lamotrigine, oxcarbazepine,
eslicarbazepine
Which channels are affected by Phenytoin?
-blocking voltage-gated Na-channels (presynaptic - preventing action potential, postsynaptic)
-blocking Ca2+ channels -> prevent Glutamate (excitatory NT) release
Kinetic features of Phenytoin
-Elimination of phenytoin is dose-dependent (1st order), -> metabolism is saturable - changes to 0 order when accumulating
-Fosphenytoin: prodrug, more soluble, less alkaline -> less skin irritation
Phenytoin: Adverse Effects
-Drowsiness
-Involuntary movement of the eyes, double vision
-Loss of muscle coordination (ataxia)
-Gingival hyperplasia (20% of chronic therapy)
-Hirsutism
-Pregnancy risk !!!
-Stevens-Johnson Syndrome (SJS)/Toxic epidermal
necrolysis (TEN)
-> Immune-complex–mediated hypersensitivity complex
-Purple Glove Syndrome (IV) – must be
administered slowly
What is a common Phenytoin IV complication?
-Purple Glove Syndrome
Skin necrosis and gangrene may develop
Which channels are affected by Carbamazepine?
-Inactivation of Na+ channels
-High threshold Ca2+ channel blocker
-Inhibit NMDA receptors
-Autiinduction of its own metabolism (CYP 3A4), higher dose needed with continuous therapy
ADE/BBW of Carbamezapine
ADE:
-drowsiness, dizziness, double vision & ataxia (poor muscle control), rash, nausea/vomiting
-Pregnancy risk!!!
BBW:
-agranulocytosis (low number of neutrophils)
-aplastic anemia (number of blood-building stem cells goes down)
-SJS, TEN
Which channels are affected by Lamotrigine?
-Inactivation of Na+ channels
-Increase GABA neurotransmission
-Low threshold Ca2+ channel blocker
-Inhibits AMPA, kainate, and NMDA receptors (Glutamate receptors)
Adverse effects of Lamotrigine
-drowsiness, dizziness, blurred vision,
headache
-rashes, SJS !!!
-Most evidence for safe use in pregnancy
Which channels are affected by Valproate/Valproic acid?
-Inactivation of Na+ channels
-Low threshold Ca2+ blocker
-Increased GABA levels possibly through increasing synthesis and/or decreasing degradation of GABA
-Inhibit NMDA receptors (Glutamate receptor)
Adverse effects of Valproate
-drowsiness, dizziness, weight gain, hair loss,
polycystic ovarian syndrome, blurred vision, headache, tremor
-hepatotoxicity – hyperammonemia (drunken-like behavior), pancreatitis
Which channels are affected by Topiramate?
-Inactivation of Na+ channels
-Activates/enhances GABAA receptor currents
-inhibits AMPA/Kainate receptors
-carbonic anhydrase inhibitor
-high threshold Ca2+ channel blocker
ADE of Topiramate
-Drowsiness, dizziness, weight loss,
metabolic acidosis, paresthesia, impaired concentration,
schizophreniform disorder
Which antiseizures may be used in pregnant patients?
Lamotrigine
risk: Phenytoin, Carbamazepine, Valproate/Valproic acid (BBW), Primidone, Phenobarbital, Ethosuximide, Benzodiapenes
Which channels are affected by Zonisamide?
-Inactivation of Na+ channels
-high threshold Ca2+ channel blocker
-increased GABA neurotransmission
-carbonic anhydrase inhibitor (change pH -> anticonvulsant)
-Low threshold Ca2+ channel blocker
ADE of Zonisamide
-drowsiness, cognitive impairment,
rarely SJS and TENS, schizophreniform disorder
Which channels are affected by Rufinamide?
-Inactivation of Na+ channels
ADE:
-dizziness, drowsiness, headache, nausea, fatigue
-shortened QT interval (common) !!
Which channels are affected by Primidone?
-Metabolized into phenobarbital (and PEMA)
-Primidone itself: prolonged inactivation state of Na+ channel
-Phenobarbital: GABA(A)
modulator
ADE of Primidone
-half life 6-8 hours, but phenobarbital half-life is 4-5 days
-Pregnancy risk
-Adverse effects: dizziness, drowsiness, ataxia, nausea
MOA of Lacosamide
-newer drug
-Increased number of Na+ channels in the
SLOW inactivation state (occurs with prolonged neuronal activity)
-> long-term regulation of sodium channel availability
-Adverse effects: dizziness, headache, double vision,
nausea, fatigue (less drowsiness)
MOA of Ezogabine
-opening KCNQ channels (specific K channels) -> K moves out (inhibitory)
ADE of Ezogabine
-drowsiness, dizziness, fatigue
-urinary retention/symptoms
-prolonged QT interval
-retinal abnormalities
-skin discoloration
What are drugs that inhibit low threshold Ca channels (T-type)?
-ethosuximide
-also zonisamide, valproate, lamotrigine
useful in Absence seizure
Drugs inhibiting high threshold Ca2+ channels
-gabapentin, pregabalin
-lamotrigine, Levetiracetam
-carbamazepine, oxcarbazepine
-phenobarbital, phenytoin
-topiramate, zonisamide, felbamate
How do drugs enhance the activity of GABA?
GABA -> inhibtory
GABA recycle (conversion to Glutamate in glial cells)
-on GABA transporter: tigabine
-on GABA-T enzyme: vigabatrin, valproate
-on succinic dehydrogenase: valproate
-on GABA receptors (postsynaptic): barbiturates (phenobarbital, primidone), benzodiazepines
MOA of Benzodiapenes
Increase frequency of GABA(a) receptor channel opening -> increasing amplitude of IPSP
-pregnancy risk
-ADE: Sedation, tolerance, dependence, withdrawal
MOA Phenobarbital
-increase duration of GABAA receptor channel opening -> increasing duration of IPSP
-At high concentrations: prolongs inactivation state of Na+ channels
-high threshold Ca2+ channel blocker
-GABA receptor agonist
-AMPA antagonist (Glutamate, excitatory)
-long half-life: 4-5 days
MOA of Vigabatrin
-Irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme that degrades GABA
-ADE: permanent visual field defects !!
fatigue, dizziness, confusion, skin rash, weight gain
MOA Tiagabine
-inhibitor of GABA uptake (both neurons and glia)
Which receptors are involved in the MOA of Cannabidiol?
GPR55
-it antagonizes LPI -> so LPI (lipid
lysophosphatidyl-inositol (LPI) cant work on GPR55
-…
-Effects of food: Increased Cmax 5-fold; increased AUC 4-fold
-CYP and UGT inducer/inhibitor
Which receptors are involved in the MOA of Stiripentol?
-GABA(a) receptor -> allosteric modulator:
↑ duration of GABA IPSPs
-Prefers GABAA receptors with α3 subunits, highest in immature brain* (Dravet syndrome - epilepsy at a young age)
-used with Clobazam
-CYP inhibitor/inducer - may increase levels of clobazam and its metabolite (Ndesmethylclobazam)
Which receptors are involved in the MOA of Cenobamate?
-GABA(a) receptor
-> enhances GABA(a) receptor neurotransmission
-Inactivation of Na+ channels (persistent current blocked, not voltage-dependent channels), causes hyperpolarized state
Drugs acting on Glutamate receptors
-AMPA receptor antagonists: perampanel, topiramate, lamotrigine, phenobarbital
-NMDA receptor antagonists: felbamate,
carbamazepine, valproate, lamotrigine, oxcarbazepine
MOA of Perampanel
-Non-competitive AMPA receptor antagonist
-ADEs:
Aggression, hostility, irritability, anger & homicidal
ideation and threats
drowsiness, dizziness, fatigue, gait problems, some weight gain
MOA of Felbamate
-blocks use-dependent NMDA receptor
-Inactivation of Na+ channels
-inactivation of high threshold Ca2+ channel blocker
-ADE: Causes aplastic anemia* and severe hepatitis
