Term 2 Pharm - Epilepsy Drugs Flashcards
Key Drugs for Epilepsy:
Phenobarbital Phenytoin Ethosuximide Benzodiazepines (lorazepam, etc.) Carbamazepine Valproate Gabapentin Lamotrigine Topiramate Levetiracetam
What Are Epileptic Seizures ?
“Occasional, sudden, excessive, rapid and local discharges of gray matter”
- Seizures require repetitive and synchronized firing of neurons.
How Do Neurons Work ?
The resting membrane potential of a neuron depends as first approximation the K+ conductance and is ~ -70mv.
Each neuron has many ion channels for K+, Na+, Ca++, Cl- and other ions.
Ion channels may be voltage-gated, or ligand-gated.
Opening of Ca++ and Na+ channels tends to produce depolarization.
Opening of K+ and Cl- channels tends to produce hyperpolarization.
Neurotransmitters released from presynaptic neurons act on the ligand-gated channels of postsynaptic neurons.
Describe Seizures at the Neuronal Level
- Excitatory synapses generate EPSPs by depolarization making action potentials more likely.
- Inhibitory synapses generate IPSPs by hyperpolarization, making action potentials less likely.
- If excitation substantially exceeds inhibition, repetitive action potentials result in seizures.
Tell me about GABA
GABA (gamma-amino butyric acid) Mediates Inhibition
- GABA binding to its receptor opens a chloride channel that hyperpolarizes the cell. This makes neuronal firing and seizures less likely.
- Some anti-epileptic drugs, benzodiazepines and barbiturates, are agonists at GABA receptors.
- Different receptor sub-types may mediate different functions.
Tell me about Glutamate
Glutamate Mediates Excitation
- Glutamate binding to its receptors opens Na+ and Ca++ channels that depolarize the cell, making neuronal firing and seizures more likely.
- Some anti-epileptic drugs block release of glutamate (lamotrigine), or are glutamate receptor antagonists (topiramate).
- There are many glutamate receptor sub-types.
Classification of Epilepsy and Seizures:
2 types: Generalized or Partial
General seizures
- initially bilateral
- widespread cerebral involvement
“In generalized epilepsy the whole brain is electrically irritable and generalized seizures involve the whole brain at onset.”
Partial seizure
- Focal/Localization related
“In focal epilepsy, one part of the brain is electrically irritable, and partial seizures begin from there and may spread diffusely (secondary generalization).”
Most drugs work for both types of seizures, but some are better for one kind and some for another. The reasons are unclear, and the facts are not explained by the apparent mechanisms of the drugs.
Mechanisms of Anti-epileptic Drugs
ALL anti-epileptic drugs are for treatment only. They do NOT cure epilepsy or prevent a seizure from occurring
- Block Na-dependent APs - this will decrease sustained high frequency neuronal firing.
(Drugs acting on Na+ channels include phenytoin, carbamazepine, valproate, topiramate and lamotrigine) - Calcium channel blockade = Reduce Ca uptake
(Ethosuximide blocks T-type Ca++ channels.
These are found in the thalamus… Good for petit mal seizures/Absence seizures) - GABA agonists = GABA binding to its receptor opens a chloride channel, entry of chloride hyperpolarizes the neuron and makes firing action potentials less likely.
(Barbiturates, benzodiazepines and topiramate are GABA agonists… Barbituates prolong the GABA-mediated Cl- channel openings, decreasing CNS excitability… Benzodiazepines increase the frequencey of GABA-mediated Cl- channel openings, decreasing CNS excitability) - Glutamate antagonists = Glutamate binding opens a Na+ and Ca++ channel.
Entry of Na+ and Ca++ depolarizes the neuron, and makes firing of action potentials more likely –> BLOCK this (Lamotrigine blocks glutamate release, Topiramate is a glutamate antagonist)
*Lamotrigine is an anti-epileptic via more than one mechanism (black Na channels AND blocks glutamate release)
Describe a petit mal/absence seizure
Absence (petit mal) seizures have a 3 Hz spike wave discharge which probably involves a cortico-thalamic loop.
Pharmacokinetic Principles: Absorption
“entry of drug into the blood”
- Timing varies widely by drug, formulation,patient characteristics
- Essentially complete for all AEDs (except gabapentin which has a saturable intestinal transporter at high doses)
- Generally slowed by food in stomach (CBZ may be exception)
- Usually takes several hours (important for rapid control of seizures, and for interpreting blood levels)
Steady State and Half-Life
- It takes 5 half-lives to reach steady state.
- With a particular dose one wants the steady state level to be in the therapeutic range.
- It the drug has a long half life, one needs a loading dose to reach the therapeutic range rapidly.
IMPORTANT for phenytoin and phenobarbital.
Therapeutic Index
T.I. = TD 5O% / ED 50%
One wants the ED50%, which is the dose or blood level at which 50% of users benefit, to be as low as possible; and the TD50%, which is the dose or blood levels at which 50% of users have toxic side-effects, to be as high as possible.
Most anti-epileptic drugs have fairly good therapeutic indices, but comparisons between drugs are difficult because of limited data and individual differences.
Pharmacokinetic Principles: Elimination
Elimination: removal of active drug from the blood by metabolism and excretion.
- Metabolism/biotransformation — generally hepatic; usually rate-limiting step.
- Excretion — mostly renal (active and inactive metabolites)
- Changes in metabolism over time (auto-induction with carbamazepine) or with polytherapy (enzyme induction or inhibition).
- Differences in individual metabolism.
The Cytochrome P-450 Isozyme System
The principle enzymes involved with AED metabolism include
CYP2C9, CYP2C19, CYP3A4
- The enzymes most involved with drug metabolism. Found in the liver.
- Nomenclature based upon homology of amino acid sequences.
- Enzymes have broad substrate specificity, and individual drugs may be substrates for several enzymes.
The Cytochrome P-450 Isozyme System
Inducers:
- phenobarbital
- ethosuximide
- phenytoin
- carbamazepine
- tobacco/cigarettes
