Chapter 21: AEDs, Anticonvulsants Flashcards
What does it mean when it is said that siezures have a bimodal distribution?
More common in early childhood and in the elderly.
What is a seizure?
Sudden, excessive, and synchronous discharges of neurons.
What can seizures result in?
- Transient loss of consiousness
- Abnormal movements
- Atypical or odd behavior
- Distorted perception
What are the the two types of seizures?
- Partial (Affects a localized area of the brain initially)
- Generalized (Involves both hemispheres from the start; No Aura/Warning Signs)
What are the main differences between partial and generalized seizures in regards to treatment?
Partial - All AEDs are effective except ethosuximide.
Generalized - AED options are more limited.
What are the types of Partial seizures.
Simple Partial: Sensory changes or auras without loss of awareness.
Complex Partial: Impaired awareness, often involving the temporal lobe.
Secondarily Generalized: Starts as a focal seizure but spreads to involve both hemispheres.
What are the types of Generalized seizures?
Generalized Tonic-Clonic (GTC): Stiffening and jerking of muscles.
Tonic/Atonic: Sudden stiffening (tonic) or loss of muscle tone (atonic).
Absence: Brief episodes of staring or loss of awareness.
Myoclonic: Sudden, quick muscle jerks.
What are the Mechanisms of action to target with anti convulsants?
- Voltage-Gated Na Channels
- Potentiation of GABAergic mechanisms
- Blockade of Ca Channels
- Blockade of glutamate receptor channels (NMDA, AMPA)
- Opening of voltage-gated K channels
- Antagonism of Exocytosis.
What are the drugs that target Voltage gated Na channels?
- Phenytoin
- Carbamazepine
- Oxcarbazepine
- Lamotrigine
- Phenobarbital (Higher Doses)
- Valproic Acid (Higher Doses)
These drugs prolong the inactivation state of Na channels.
What are the pharmacokinetics of Phenytoin?
- Zero order kinetics (Drug metabolism gets saturated) - Watch dose
- p450 metabolism - beware of toxicity
- Enzyme Inducer
What are the pharmacokinetics of Carbamazepine/Oxcarbazepine?
- P450 Metabolism
- Enzyme Inducer (Less so for oxcarb)
- Induces its own metabolism
- Dose adjustment is required
- May lower other medication levels (oral contraceptives)
What are the pharmacokinetics of Lamotrigine?
- Metabolized by glucoronic acid conjugation.
- If combined with valproic acid (VPA), slowly increase VPA to avoid toxicity/side effects
- VPA ↓s metabolism (glucuronidation) resulting in 2-fold ↑ in lamotrigine half-life
- Levels ↓ significantly in pregnancy or with oral contraceptive as glucuronidation is induced by estrogen -> Increased dose required
What are the pharmacokinetics of Valproic Acid?
- Heavy protein binding → displaces other protein bound medications → toxicity (e.g. with phenytoin)
- Blocks liver metabolism → ↑ Lamotrigine, Phenobarbital levels
- VPA level is decreased by P450 inducers (e.g. phenytoin)
What are all the different ways to potentiate GABA to increase inhbition and the drugs involved in each?
Increase Duration of Cl- channel opening: Phenobarbital
Increase Frequency of Cl- channel opening: **Benzodiazepines
**
Felbamate, Topiramate, and Valproic Acid may have similar effect (not their main mechanism of action)
Blockade of GABA degradation by GABA transaminase (GABA-T) blockade:
Vigabatrin
** Valproic acid** at high concentrations
Blockade of GABA transporter (GAT-1) in neurons and glial cells:
Tiagabine
What are the different Benzodiazepines used to treat seizures and epilepsy?
Lorazepam and Midazolam -> Used in emergency situations intravenously. (Loraepam can be used sublingualy by patient at aura to avoid seizure generalization)
Diazepam - Rectal -> Used in children by parents at home to stop seizures.
Clobazam -> Used as adjunctive AED long term seizure treatment.
Benzodiazepine withdrawal may cause seizures in non epileptic persons.
What two drugs increae GABA in the ECF?
* Vigabatrin inhibits GABA transaminase
* Tiagabine inhibits GABA transporters
What are the drugs that block Ca channels?
Ethosuximide, Valproic Acid -> Block Low Threshold T-Type Ca channels in the thalamus, the pacemaker **for absence seizures. **
Gabapentin, Pregabalin -> *Block Pre-synaptic V-gated Ca channels. *
Explain the mechanism of how GABApentin and Pregabalin work.
- molecular structure similar to GABA but no direct activation of receptor
- Bind to α2δ subunit of presynaptic voltage dependent Ca2+ channel → ↓ Ca2+ entry → ↓ excitatory neurotransmitter Glutamate release
What drugs use glutumate antagonism to treat seizures?
Phenobarbital
Felbamate: NMDA blocker
Topiramate: AMPA blocker
Perampanel: AMPA blocker
What drugs increae K channel permeability?
Valproic Acid
Ezogabine
What drugs use exocytosis antagonism?
Levetiracetam
How does Levetiracetam work and what are the adverse effects?
Mechanism: Binding to SV2A synaptic vesicle protein →↓ stimulatory neurotransmitter release
Adverse Effects: Depression, Suicidal Ideas, Aggression.
Most anticonvulsants metabolized by hepatic enzymes;
Except?
- Gabapentin
- Pregabalin
- Vigabatrin
- Levetiracetam
These are excreted by the kidney.
What are 3 mechanisms of drug interactions with anticonvulsants?
By **blocking antiseizure drug metabolism **
By displacing the drugs from plasma proteins binding sites -> Increased Potency (Valproic Acid increases Phenytonin Levels)
Induction of antiseizure drug metabolism (e.g. by Rifamipin, or some antiseizure meds themselves)
- Carbamazepine (CBZ) induces its own metabolism, lowering its levels over time.
What are all the P450 inducers?
- Phenytoin
- Phenobarbital
- Carbamazepine
What are all the effects of P450 enzyme inducers?
- Decreased levels of other drugs:
Drugs metabolized by the P450 system (e.g., statins in elderly patients) may have reduced efficacy. - Decreased active Vitamin D levels:
Leads to lower calcium absorption, increasing the risk of osteoporosis. - Reduced efficacy of oral contraceptives:
May lead to contraceptive failure.
What does Valproic acid do to Lamotrigine?
It blocks liver metabolism leading to increase Lamotrigine Levels.
What things would make the ideal antiepileptic treatment?
