Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacology > Antiepileptic drugs > Flashcards

Antiepileptic drugs Flashcards

1
Q

Epilepsy/Epilepsies

A
  • Prevalence of epilepsy: 0.5 - 1 %
  • Mostly chronic disease, that comes along with epileptic seizures
    -> Abnormal electric discharge in cerebrum, takes usually seconds to minutes (exception: Status epileptics)
  • Disorder of: consciousness, vegetative system, motor system, thinking, memory, sensibility, perception, emotion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Epileptic seizures -> FOCAL (synchronous discharge in one hemisphere, often induced by acquired damage)

A
  1. simple focal seizures (consciousness preserved), 4 %
    -> e.g. convulsions of the left hand with expansion to the left arm
  2. Komplex focal seizures (consciousness impaired), 16 %
    -> e.g. incoherently opening and closing of the shirt and smacking; no postiktal memory of the seizure (amnesia)
  3. Secondarily generalized seizures tonic-clonic seizures with focal start (consciousness lost during generalization), 33 %
    -> e.g. olfactory hallucinations, a simple focal start of the seizure which can be remembered, then initial scream, fall, tonic and clonic convulsion, amnesia for the generalized phase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Epileptic seizures -> PRIMARY GENERALIZED (synchronous discharge of neurons in both hemispheres)

A
  1. Absence seizures (consciousness lost for a short time), 1 %
    -> e.g. complete mental absence for 20 s with fixed gaze and “writing break” during a dictation in school; no exact postictal memory
  2. Myoclonic seizures (loss of consciousness not perceived due to short duration), 1 %
    -> e.g. symmetric clonic jerks of the arms including drop of toothbrush in the morning; no exact postictal memory
  3. Generalized tonic and/or clonic seizures (loss of consciousness), 33 %
    -> e.g. sudden fall to the floor without preceding aura, tonic and clonic convulsion phase, tongue biting, short postictal sleep, amnesia
  4. Atonic seizures (loss of consciousness not perceived due to short duration), 1 %
    -> e.g. sudden sinking or falling to the floor due to generalized loss of muscle tone; no exact postictal memory
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Epilepsy syndroms

A

GENERALIZED
- West Syndrome
- Lennox Gastaut Syndrome
- childhood absence epilepsy
- Juvenile myoclonic epilepsie
- Juvenile absence epilepsy

FOCAL
- Rolando epilepsy
- nocturnal frontal lobe epilepsy
- familial temporal lobe epilepsy
- symptomatic focal epilepsy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Epileptogenesis

A
  • brain tumor
  • Enzephalitis
  • stroke
  • contusion

-> all of these lead to latency and focal epilepsy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Classification of epileptic seizures

A

For therapy, the differentiation between two groups of epilepsies is important:
GENERALIZED epilepsy
- predominance of genetic component
- seizures involve from the start the whole brain i.e. both hemispheres at the same time
FOCAL (= partial) epilepsy
* Often symptomatic, less frequently genetically caused
* Seizures develop in a circumscribed area of the brain. They can, however, move on to a secondary generalized seizure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What’s treated with anti epileptic drugs (AEDs)?

A

EPILEPTIC SEIZURE
-> sudden change of brain’s electric activity. Often only once
-> Therapeutic options: usually too short for therapeutic intervention (exception: status epilepticus)
EPILEPTOGENESIS
-> development of epilepsy
-> therapeutic options: up to now none
EPILEPSY
-> propensity to unprovoked epileptic seizures
-> therapeutic options: prophylaxis of further seizures

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Status epilepticus

A

Definition: prolonged epileptic seizure
> 5 minutes of tonic-clonic seizures OR > 20 minutes of non-convulsive seizures

Prognosis: Status will not stop spontaneously, potentially life-threatening condition → here, as an exception, treatment of the individual seizure

Treatment:
* Initially with benzodiazepines
* If status persists, other antiepileptic drugs are given i.v.
* If status persists further, patient is anesthetized

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Epilepsy - pathophysiology

A
  • Dysbalance between inhibitory and excitatory influences
  • Electric instability of single neurons

Cellular correlates
- paroxysmal depolarization: Ca2+ influx, AMPA/NMDA receptor activation
- high frequent action potentials: Na+-influx
- after hyperpolarisation: K+ efflux, GABA receptor activation

Cellular phenomena also occur between seizures

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Epilepsy - Pathophysiology

A

SURROUND INHIBITION
Spreading of excitation is usually prevented by inhibitory, mainly GABAergic interneurons in the surrounding of epileptic active cells

BREAKDOWN OF SURROUND INHIBITION
-> Activation of surrounding neurons
-> Highly synchroneous activity of neuronal assemblies
-> Epilepsy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Treatment of epilepsy

A
  • Recognition and Prevention of seizure triggers (self-control)
  • Drug therapy (most frequent type of treatment)
  • Surgical resection of the seizure focus :
  • resection of seizure focus
  • disconnection
  • Vagus-Nerve-Stimulation: Implantation of a pacemaker influencing the vagus nerve
  • Deep brain stimulation: Implantation of a pacemaker influencing anterior thalamic nucleus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

History of anti epileptic drugs

A

1874 Potassium bromide was discovered by Sir Charles Lock, personal physician of the British queen, as effective against epilepsy
1912 The neurologist Alfred Hauptmann introduces Phenobarbital which was used before as sleep-inducing drug as anti epileptic drug
1938 Phenytoin is the first less sedating substance on the market
1950ies Development of Benzodiazepines by L.H. Sternbach, used since the 1960s in the anticonvulsive therapy
1960ies Discovery of anti epileptic properties of valproic acid, which is still today a substance of first choice
-> Development of Carbamazepine. With these two substances still many people with epilepsy in Europe are treated.
1980ies many further substances are introduced into antiepileptic therapy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Classification according to mechanism of action
-> GABA-erg

A

Activation of receptors
Blockade of degradation
Blockade of uptake
- Benzodiazepine
- Phenobarbital
- Primidone
- Valproic acid
- Felbamate
- Topiramate
- Vigabatrin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Classification according to mechanism of action
-> Na+-channel blocker

A

Blockade
- Phenytoin
- Carbamazepine
- Oxcarbazepine
- Esclicarbazepine
- Lacosamid
- Zonisamid
- Lamotrigin
- Topiramate
- Valproic acid
- Felbamat

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Classification according to mechanism of action
-> Glutamate inhibitors

A

Blockade
- Felbamate
- Topiramate
- Perampanel

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Classification according to mechanism of action
-> Ca2+ channel blocker -> T-Ca2+-channel

A

Blockade
- Ethosuximid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Classification according to mechanism of action
-> Ca2+-channel-blocker -> alpha2-gamma-ligands

A

Blockade
- Gabapentin
- Pregabalin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Classification according to mechanism of action
-> Vesicle protein ligands -> SV2A

A

Blockade
- Levetiracetam

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Desired effects of anti convulsive drugs

A
  • Enhancement of inhibitory transmission
  • Inhibition of excitation spreading
  • Inhibition of excitatory transmission
20
Q

Neurotransmitters: amino acids

A

The CNS contains a high concentration of excitatory and inhibitory amino acids: glutamate (Glu, glutamic acid), aspartate (Asp, aspartic acid), gamma- Aminobutyric acid (GABA) and Glycine.

21
Q

Transformation of glutamate to GABA

A

GABA
- most frequent inhibitory transmitter in the CNS
- mainly transmitter of inhibitory interneurons
- almost all neurons are sensitive to GABA

SYNTHESIS from glutamate by glutamate decarboxylase (GAD)

INACTIVATION by GABA transaminase (GABA-T) to succinc semialdehyde (SSA)

22
Q

GABAergic systems
-> gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter

A

GABAergic are
- many short interneurons in cortex, bulbs olfactoris, hippocampus, cerebellum, retina
- neurons of the extrapyramidal basal ganglia (neocortex-striatum-globus pallidus/s. nigra-thalamus-neocortex)

23
Q

Synaptic transmission through GABA

A

alpha- Ketoglutarate -> Transaminasen -> Glutamate -> Glutaminase -> Glutamat-Decarboxylase -> GABA -> GABA-Transaminase -> Glutamate -> Succinatsemialdehyd-Dehydrogenase -> Succinate -> Citrat-cyclus -> alpha ketoglutarat

Glutamate -> Glutamin-Synthetase -> Glutamine

24
Q

Glutamatergic systems
-> Glutamate and aspartate are the most important excitatory neurotransmitters

A

Glutamatergic are (beside others)
* Pathway from neocortex to striatum
* Pathway from bulbus olfactoris to olfactory Cortex
* cortical projections to hippocampus
* Pyramidal cells of hippocampus
* Climbing fibers
* Granule cells of the cerebellum

25
Q

Enhancement of inhibitory transmission

A
  • modulation of inhibitory receptors
  • modulation of inhibitory neurotransmitters’ activity (synthesis, reuptake, degradation)
26
Q

GABAA-receptor

A

GABAA receptor: ligand-gated ion channel, ionotrope receptor
GABAB receptor: G protein coupled, metabotrope receptor

19 subunits of the GABAA receptor are known:
alpha (6 types: alpha1-alpha6)
beta (3 types: beta1-beta3)
gamma (3 types: gamma1-gamma3)
delta, epsilon, pi, theta, rho (3 types: 1-3)
-> Most GABAA-receptors are made 1 gamma, 2 beta and 2 alpha subunits

Binding sites of the endogenous ligand GABA and benzodiazepines (BZD) differ! -> “allosteric” binding
Benzodiazepines bind to interface between alpha and gamma subunit
Barbiturates bind to beta subunit

27
Q

Allosteric enhancement of effects of GABA

A
  • Increase of the opening probability of the Cl- channel -> Benzodiazepines
  • increase of the opening duration of the Cl- channel -> Barbiturates
  • alpha1-subunit mediates the anti-epileptic effect
28
Q

Baribiturates

A

Phenobarbital was the first organic anti epileptic drug (Hauptmann, 1912)
- in developing countries, it is today still the most frequently used antiepileptic drug
-> characteristic side-effect of barbiturates: Sedation

Phenobarbital (Lepinal, Luminal)
Primidon (Liskantin)

29
Q

Benzodiazepines

A

1965: Approval of diazepam (Valium ®), initially introduced as sedative and anxiolytic
Other Benzodiazepines used as antiepileptics: Lorazepam, Clonazepam, Clobazam
Charakteristic side-effect of benzodiazepines:
-> Sedation
-> Tolerance
-> withdrawal seizures if withdrawn after long use

Diazepam (Valium)

30
Q

GABA-Analogs - partially GABAergic

A

Valproic acid (=Valproate): inhibits GABA-transaminase -> reduces GABA degradation

Vigabatrin: inhibits GABA-transaminase -> reduces GABA degradation

Gabapentin: inhibition of a Ca2+ channel (alpha2delta ligand; N type)
In vitro: increased activity of GAD -> enhances GABA-synthesis?

Many AEDs have more than one mechanism of action, in some cases not all of them have been fully understood yet

31
Q

General notes: Mechanisms of action

A
  • “Old” antiepileptic drugs (1st generation): often provided clinically and/or in animal models effective without exact knowledge of mechanism of action

1975: start of the anticonvulsant drug development program. > 28,000 new chemical entities have since been screened, mainly in rodent models

“New” antiepileptic drugs: mechanisms of action were described during earlier development stages, new targets were discovered

Modern research: development of antiepileptic drugs more strongly oriented on structure-specific effects

32
Q

Animal models in AED research

A

Epilepsy: genetical approach or chemically/electrically induced epileptogenesis
Epileptic seizures: chemically/electrically induced seizures

33
Q

Animal models in AED research
-> Electrical and chemical kindling

A

(Electrical) kindling: repeated electrical stimulation (usually amygdala, hippocampus) leads over time to:
* Lowered convulsion threshold
* Aggravation of clinical symptoms
* generalization
* Occurence of spontaneous seizures
→ early phase: model for complex-focal seizures
→ later: secondarily generalized, complex-focal seizures

Chemical kindling:
Pilocarpin: Agonist of cholinergic muscarinergic receptors
Kainate: Agonist of ionotropic glutamate receptors (kainate type)

seizure → status epilepticus → latency → spontaneous seizures

34
Q

Animal models in AED research
-> Example: Effects of Topiramat on kainite-kindling induced cell death

A

Methods
* Topiramat/Vehicle i.p; 1h later: Kainate (KA)/Vehicle i.c.v.
* EEG, Videomonitoring
* 24h after KA: brain extraction, Cresyl Violet & TUNEL staining
* 3h after KA: brain extraction, Immunohistochemistry (Hippocampus) and Western blots (CA3 region Hippocampus): p-Erk, p-P38 MAPK, p-Jnk, active-caspase-3

Topimarat (TPM) appears to act neuroprotective by:
1. reduction of seizures = reduction of primary damage
2. Impact on seizure-induced apoptosis (via pERK) = reduction of secondary damage

35
Q

Na+ channel blocker

A

PHENYTOIN
- antikonvulsive action discovered 1938
- less sedative compared to barbiturates
- only against focal epilepsy

CARBAMAZEPINE
- introduced 1963
- one of the most commonly used AEDs today
- only against focal epilepsy

LAMOTRIGINE
- introduced 1993
- drug of choice for focal and generalized epilepsy

36
Q

Na+ channels in the brain

A

Voltage gated Na+ channel can be in 3 different states
1. Resting (closed)
-> Depolarisation
2. Open
-> prolonged depolarization
3. Inactivated (closed)

AEDs promote the inactivated state of Na+ channels - inactivated state is stabilized -> amplitude and duration of action potentials is not changed.

AEDs lead to reduction of repetitive action potentials.

37
Q

Ionotropic glutamate receptors
-> AMPA receptor

A
  • 4 subunits
  • depending on composition, more or less permeable for Ca2+ ions
38
Q

Ionotropic glutamate receptors
-> NMDA receptor

A
  • 4 subunits
  • most commonly 2 x NR1 and a combination of different subtypes of NR2 (e.g. NR2A and NR2B)
  • depending on subunit composition, many additional binding sites (e.g. Zn, Glycin, Polyamines)
39
Q

Glutamate-receptor antagonism
-> Topiramate

A
  • introduced 1995
  • AMPA receptor blocker
  • also effect on Na+ channels and agonist of GABAA receptors
  • against focal and generalized epilepsy
40
Q

Glutamate-receptor antagonism
-> Felbamate

A
  • Antagonism at glycin binding site of NMDA receptor
  • Also weak gabaergic effect
  • Potentially severe side effects, only used in severe refractory epilepsy
41
Q

Voltage-dependent Ca2+ channels in the brain

A

Consist of several subunits, termed α1, α2δ, β1-4, and γ
5 Types of channels, broadly divided into their modes of gating:
high-voltage activated: L-, P/Q- and N-type
intermediate-voltage activated: R-type
low-voltage activated: T-type

42
Q

Ca2+ channel blocker
-> Gabapentin

A
  • Introduced 1993
  • α2δ-ligand (α2δ = subunit of N-type Ca2+-channel)
  • Against focal epilepsy
43
Q

Ca2+ channel blocker
-> Ethosuximide

A
  • Blocker of T-type Ca2+-channel
  • Against absences, not effective against tonic-clonic seizures
44
Q

Vesicle protein ligands
-> Levetiracetam

A
  • Introduced 2000
  • Ligand of the synaptic vesicle protein SV2A
  • Against focal and generalized epilepsy

Exact mechanism is not clear yet, as exact function of SV2A are still not proven. Interestingly in healthy brain/neurons, neither electrophysiological properties nor transmitter release is affected by Levetiracetam.

45
Q

Overview of mechanisms of action of AEDs

A
  • Allosteric agonism at GABAA receptor
  • Inhibition of GABA transaminase
  • Activation of GABA decarboxylase
  • Na+ channel blockade
  • Glutamatergic antagonism (i.e. at AMPA or NMDA receptor)
  • Ca2+ channel blockade (N-type or T-type)
  • Binding to vesicle protein SV2A
46
Q

Why so many different drugs with different mechanisms for epilepsy?

A

Epilepsy is a heterogenous disease – heterogenous pathophysiological mechanisms, heterogenous symptoms (i.e., focal vs. generalized; absence seizures,… )
-> some drugs are only effective against specific forms of epilepsy (e.g. ethosuximide for absences)

Side-effects/Drug interactions: Some AEDs can have severe side effects, in some cases especially for specific subgroups of patients (e.g. pregnant women, patients with additional diseases)

-> Bsp: Gingiva-hyperplasia after phenytoin treatment, Spina bifida in a newborn after mother was treated with valproate

Induction of cytochrome P450 enzymes (2C, 3A4) and UGT by carbamazepine, phenytoin, phenobarbital, primidon -> enhanced clearance of other medication

Inhibition of 2C9 and UGT by valproate -> reduced clearance of some other AEDs

1/3 of patients are pharmacoresistant, i.e. they still experience seizures despite of AED treatment

47
Q

Summary Epilepsy

A
  • Epilepsy is a very heterogenous disease; broad division into focal & generalized seizures (however, underlying pathologies are much more complex)
  • AEDs can have several mechanisms of action, i.e. can interfere with inhibitory or excitatory transmission in the brain
  • Typical mechanisms of action may involve
    • GABAergic effects
    • Glutamatergic effects
    • Na+ or Ca+ channel blockade
    • Binding to vesicle proteins
  • Many AEDs have more than one mechanism of action
  • More research into underlying neurobiology & pathophysiology is necessary, especially to find better treatment options for pharmacoresistent patients and maybe even to prevent epileptogenesis

Pharmacology (22 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions