L11: Epilepsy and Anticonvulsants

Describe the two phases of gran mal seizures ?

1) Tonic phase = rigid contraction of muscles

2) Clonic phase = jerky contraction

Name the type of epilepsy where it does not propagate across the whole body ?

Jacksonian epilepsy (partial seizure)

- So doesn't produce body wide effects

What are the four different types of epilepsy?

- Generalized seizure (grand mal or tonic-clonic seizure)= initial sustained contracture of the musculature, often accompanied by defecation and cessation of respiration, followed by waves of violent synchronous contraction. Consciousness reappears after several minutes.

- Generalized seizure (petit mal or absence seizure) not associated with motor function but involves a loss of attention for periods of seconds.

-Partial seizures (Jacksonian epilepsy) cause muscle spasms in one digit, limb or on one side of the body, often spreading from one location to another.

- Status epilepticus is when a grand mal seizure continues or repeats for a period of 30 min or more. Life-threatening often always involves cessation of respiration

What is used to record epilepsy ?

Electroencephalogram (EEG)

How does an EEG work ?

1) Electrodes attached to the scalp

2) Each AP/ synaptic potential activates an inward current in the postsynaptic neurone

3)The summation of the tinny inward current

4) Electrodes pick up the summed changes in extracellular voltage

(caused by the activity of many axons and synapses)

What are the causes of epilepsy ?

- Brain injury = caused by a stroke or by traumatic injury (car accidents etc) can provide an epileptic focus which persists long after the injury has healed

-Infection (viral or bacterial) = can cause inflammation which provides an epileptic focus

- Tumours

- Autoimmune disease can also cause localized encephalitis which provides an epileptic focus

•Idiopathic

What is the most common cause of epilepsy ?

Idiopathic = no obvious pathology

What experimental tool has been very useful for developing and testing anti-epileptic drugs ?

Kindling

What is kindling ?

- An experimental model

- Uses repetitive electrical or chemical stimulation of a small region of the brain.

-Initially, the stimulation excites only a local brain area

- After several repetitions of stimulation the excitability spreads across the brain like the patterns observed during an epileptic seizure.

How do both of the anti-epileptic drugs act ?

By suppressing the excitability of neurones

What are the two main classes of anti-epileptic drugs ?

1) Act to enhance the activity of inhibitor ion channels gated by NT GABA ()

2) Act to voltage-dependent Na/Ca channels in user dependent manner

What is a user dependent manner in terms of anti-epileptic drugs ?

Preferentially target Na/Ca channels which are used frequently

- Avg axon in brain is not typically elicited with high-frequency

Name drugs that enhance opening of the GABAA receptor ?

Barbiturates

Benzodiazepines

Valproic acid

KBr

Name use-dependent Na and Ca channel blockers?

Phenytoin

Carbamazepine

Gabapentin

Why are GABA A receptors inhibitory?

GABA A = chloride channels

- Low conc of Cl- inside CNS neurone cell

- Opening of Cl- channels

- Influx of Cl-

- Inside of the cell becomes more negative => inhibitory effects

What is the predominant inhibitory neurotransmitter accounting for 30% of all synapses

GABA

(alpha amino butyric acid)

What are the three different GABA receptors ?

1) GABA A

2) GABA B

3) GABA C

What type of receptors are GABA b ?

GPCR

How to GABA b receptors work ?

- Gi inhibits cAMP => K+ conductance and stabilisation of membrane potential

(Predominantly presynaptic )(Agonist baclofen)

Name the GABA receptors that are also chloride channels ?

GABA A and C

- They have very different subunit composition to GABA A receptors

Why does diazepam only work in the presence of GABA?

We don't want an effect in the absence of inhibition

- As this would result in the inhibition of all cells in the brain => unconsciousness

State the different drugs that bind to the GABA A receptor ?

1) Ethanol

2) Benzodiazepine

3) Barbiturate

4) Neurosteroids (used as anaesthetics)

What are the different subunits in the GABA receptors?

5 subunits (aplha, beta, gamma, delta, rho ) which form a pentameric chloride channel

- All subunits bind GABA

What is the difference between the expression of alpha and beta subunits channel and alpha, beta, gamma

A+B => channel that binds GABA and benzodiazepines but with low affinity

A+B+G=> channel with pharmacological profile and similar affinity to native GABA A receptor

State the minimal channel subunits ?

2 alpha

2 beta

1 gamma

How is diversity increased in a minimal native channel ?

substitutions with delta and rho

State the isoforms of the subunits

6 alpha

4 beta

3 gamma

1 delta

1 rho

Why are there more than 100 potential channel permutations ?

The isoforms of the subunits provide a range of combinations

How do benzodiazepines work ?

They bind in the left between the alpha1 and gamma2 subunit

What do benzodiazepines promote ?

They do not directly open the channel but they create an increase in affinity of GABA (enhance binding)

What happens in the absence of GABA for benzodiazepines ?

There is no effect - so inhibition is not caused randomly

State the different cognitive effects of

Alpha 1(BZD site) => sedative effect

Alpha 2(BZ site)=> anxiolytic effects

Knocking out alpha 5(BZ site)=> cognitive function

Why may alpha subunits have distinct cognitive effects ?

Different alpha subunits in the GABA A receptors are expressed in distinct brain regions

State an alpha 1 selective drug that mostly have replaced benzodiazepines as sedatives?

Z drugs e.g zolpidem

What is the possible problem with long term benzodiazepine use ?

Addiction

State the side effect of benzodiazepines ?

alpha5 BZ site is probably responsible for the loss of cognitive function caused by benzodiazepines

What is the role of barbiturates?

Prolong the open time of the GABA A ion channel

What is the possible binding site of barbiturates ?

beta subunit

(site is not known for certain)

What happens at high concentrations of barbiturates ?

At high conc=> open the GABA A ion channel even in the absence of GABA

What are the two major problems with the use of barbiturates ?

1) Low therapeutic index combined with ability to act in the absence of GABA means that an overdose can be fatal (used in death row and to put dogs down)

2) Tolerance through up-regulation of P450 enzymes (important in breaking down drugs)in the liver (so constantly upping the dose)

State the other pharmacological sites on the GABA A receptor?

- Neurosteroid binding site (binding site of alphaxalone & propofol) => cause anaesthesia not used for epilepsy as they impair normal function

- Picrotoxin acts to block the CI- conductance pore => promotes seizures

- Ethanol enhances GABA action => explains the sedative effects of alcohol

- Bromide ions => enhances inhibition

Name the ions that were more permeable through the GABA A ion channel than chloride ions ?

Bromide ions

(used as sedative and first successful anti-epileptic)

- no longer in use because of toxicity in humans

State three common anti-epileptics acting at the GABA A receptor ?

- Diazepam (valium a benzodiazepine) is effective in enhancing the effects of endogenous GABA. Widely used as a sedative and anticonvulsant (i.e. anti-epileptic). (use less due to problem of addiction)

-Midazolam (benzodiazepine) is 2-3 times more potent than diazepam and is used as a sedative and anti-epileptic.

- •Phenobarbital (barbiturate) opens the GABA receptor, even in the absence of endogenous GABA. Effective anticonvulsant but overdose can be fatal (unlike benzodiazepines). Suicide risk - not often used in humans.

State two dependent blocker drugs ?

- Carbamazepine

- Phenytoin

How do use-dependent blockers of sodium channels work ?

- Bind only to inactivated Na channels => more often the channel opened the ore potently it is blocked

When are use-dependent blockers at their greatest potency ?

The more often the channel opens, the longer the channel is in the inactivated state => greater potency of the blocker

Name a uncommon monogenic epilepsy ?

Angelman syndrome ("happy puppet syndrome")

What is the nature of most idiopathic epilepsies ?

(Idiopathic = those with no obvious cause )

Polygenic in nature

What are the major signs associated with monogenic (single-gene) epilepsy ?

- Development delay

- Visible abnormalities

- Cognitive and motor impairment

Is monogenic epilepsy inherited ?

Sometime it is inherited

Most commonly a spontaneous mutations with no familial history

What is a common cause of GABA A mutation ?

Loss of inhibition => epilepsy

Ho does reduced recycling of GABA lead to epilepsy ?

Problems with the recycling of GABA (GABA T and SSADH mutations) => epilepsy

- May be because these mutations cause extensive CNS abnormalities

Name the class 1 drugs that enhance the activity of GABAerig systems ?

- Benzodiazepines (BDZs e.g. diazepam, clonazepam)

- Barbiturates (e.g. phenobarbital)

- Vigabatrin

- Tiagabine

(For tonic-clonic, partial, temporal lobe seizures:)

How are BDZs administered to patients ?

- intravenously or via anal suppository to treat status epilepticus but are usually too sedative for prophylactic use in other epilepsies

- given orally in patients who do not respond to other treatments

What it the mechanism of action of vigabatrin ?

inhibits GABA transaminase (decreases metabolism of GABA). Note: may provoke absence seizures.

What is the mechanism of action of tiagabine ?

Tiagabine inhibits GABA uptake (increases the concentration of GABA in the extracellular space). Note: may provoke absence seizures.

State the class 2 of therapeutic drugs for For tonic-clonic, partial, temporal lobe seizures - may provoke absences ?

Carbamazepine, phenytoin

State the mechanism of action of carbamazepine and phenytoin ?

These drugs reduce the likelihood of action potentials firing at high frequencies but have relatively little effect at low frequencies.

(Their binding (and hence blocking action) on the voltage-gated sodium channels is state-dependent (bind to and stabilize the inactivated state).)

What class of drug is Ethosuximide ?

Class 3

- drugs for treating absence seizures only

How is Ethosuximide thought to work ?

Thought to work by blocking T-type voltage-gated Ca2+ channels in thalamic neurons. These channels are important for the generation of rhythmic activity in the neurons. Not useful for tonic-clonic seizures

Name the class 4 drugs useful for both tonic-clonic and absence seizures ?

Lamotrigine:

- Use-dependent blocker of sodium channels

Sodium valproate:

Mechanism uncertain. Combines a weak blocking action on voltage-gated sodium channels with a weak inhibition of GABA transaminase. Associated with fetal abnormalities.

State the possible mechanism of action of gabapentin and pregabalin ?

Probably work by inhibiting Ca channel function and so reducing release of excitatory neurotransmitter

State the mechanism of action of retigabine (Ezogabine in USA) ?

Acts by enhacing opening of K+ channels of the KCNQ type. Anticonvulsant effect probably due to stabilization of the resting membrane potential of neurones.

State the mechanism of action of perampanel and felbamate: ?

(Perampanel = approved in EU and in USA for partial seizures in persons >12 yo)

Thought to act as antagonists of AMPA receptors (ionotropic glutamate receptors).

State the mechanism of action of Levetiracetam?

binds to a synaptic vesicle protein called SV2A so it may affect neurotransmission - briveracetam licenced for use in Europe and US from Jan-Feb 2016

Name the class 5 therapeutic drug treatments ?

- Gabapentin, pregabalin

- Regtigabine (Ezogabine in US)

- Perampanel,Felbamate

- Levetiracetam

- Topiramate, Zonisamide

What does loss of function mutations in Nav1.1 cause?

- cause Dravet syndrome ("severe myoclonic epilepsy of infancy")

- Na channel use-dependent blockers (e.g. carbamazepine, phenytoin) worsen the condition

Where are Na v1.1 channels mainly expressed

in inhibitory neurons

Where are Nav 1.2 and Nav1.6 channels mainly expressed ?

excitatory neurons

What do gain of function in NaV1.2 or NaV1.6 cause cause ?

Epileptic fits starting soon after birth

- Na channel use-dependent blockers are effective treatments

How are K channels an example of monogenic epilepsy ?

- different K channels - cause hyperpolarisation and so stabilise the neuronal membrane potential

- loss-of function K channel mutations can cause epilepsy

State the other causes of monogenic epilepsy ?

- Mutations in genes in the ubiquitin pathway cause Angelman syndrome

- These genes attach the small molecule ubiquitin to other proteins and so modify their function.

- The end result is enhanced neuronal excitation

What are the three causes of monogenic epilepsy ?

- Na channel mutations

- K channels mutations

- Mutations in genes in the ubiquitin pathway

What is the term for epilepsies with no obvious cause?

Idiopathic epilepsies

Describe monogenic epilepsy of GABA ?

- GABA A mutations in various subunits (a, b, g etc) => loss of inhibition =>epilepsy

- GABA B mutations (rare)

- GABA-T (GABA transaminase) and SSADH mutations cause epilepsy fits

Why does GABA T causing epilepsy fits seem contradictory ?

which seems contradictory as reduced recycling of GABA should increase GABA in the synaptic cleft. May be because these mutations cause extensive CNS abnormalities.