PDA III - Exam 2: Anticonvulsants and Circuits RW

What is epilepsy defined as?

CNS disease characterized by recurrent seizures

Chronic, periodic, and unpredictable seizure conditions

May or may not involve convulsions

What are seizures?

Abnormal (excessive) neuronal activity

Either due to excessive excitation or deficient inhibition

Usually self-limiting (run out of energy)

What are the 3 main descriptors of seizure activity?

Disordered

Synchronous

Rhytmic

What are the two main classifications of seizures?

Generalized

Focal

What are generalized seizures?

Affect both hemispheres

Cause loss of consciousness

How do generalized seizures affect both hemispheres?

Seizure focus (start) is in the thalamus

Thalamus connects the two hemispheres

Spreads to both sides

What are the types of generalized seizures?

Tonic-clonic (Grand Mal)

Absence (Petit Mal)

Myoclonic

Atonic

What are characteristics of Tonic-clonic (Grand Mal) seizures?

Generalized seizure

Max involvement of both hemispheres

Starts with rigid phase (tonic)

Followed by jerking of limbs (clonic)

Each phase lasting <1min

Ends with post-ictal state

What is described by the "post-ictal state" of Tonic-clonic (Grand Mal) seizures?

Last phase of seizure

Lasts 15-30 mins

Pt. is either asleep or confused/disoriented

Pt. has no recollection of seizure

What are characteristics of Absence (Petit Mal) seizures?

Generalized seizure

Mainly occurs in childhood

(dx. often missed, assume child is distracted)

Abrupt interruption in consciousness

Pt. has blank stare straight ahead

Sometimes may see lip smacking or rapid blinking

Lasts 15-20 seconds

Can happen >100x/day

What are characteristics of Myoclonic seizures?

Generalized seizure

Brief (about 1 second)

Occurs very quickly

Rapid jerking of the arms

Often mistaken for nervousness/clumsiness

What are characteristics of Atonic seizures?

Generalized seizure

Sudden loss of muscle tone

Pt. appears to pass out

May require pt. to wear a helmet (due to fall risk)

What are focal (partial) seizures?

Only involve 1 hemisphere

Seizure focus is only 1 area of the brain

Spread limited to the hemisphere it started in

(can progress to generalized)

What do focal (partial) seizures normally indicate?

Often due to presence of a brain lesion

Lesion due to injury, stroke, tumor, etc.

What are types of focal (partial) seizures?

w/o altered mental awareness

w/ altered mental awareness

w/ secondary generalization

What are characteristics of focal seizures without altered mental awareness?

Confined to area of brain that serves basic function

(ex. motor or sensation)

No loss of consciousness (preserved)

Symptoms depend on location

Can spread ipsilaterally (on same side)

What symptoms would be present if a focal seizures without altered mental awareness affected an area serving motor control?

Motor involvement usually confined to clonic (jerking)

Of one arm or leg

What symptoms would be present if a focal seizures without altered mental awareness affected an area serving sensation?

Sensory involvement includes:

Smelling/tasting something foul

Visual disturbances

Numbness in arm or leg

What are characteristics of focal seizures with altered mental awareness?

Seizure involves brain region that serves a complex fxn

(hippocampus, frontal lobe)

Consciousness is impaired

Usually preceded by an aura

What symptoms are seen during focal seizures with altered mental awareness, due to impaired consciousness?

Pt. has coordinated, involuntary movements

But, is unable to communicate or understand

What is the main difference between focal seizures w/ or w/o altered mental awareness?

W/ altered mental awareness causes loss of consciousness,

W/O does not

What complex functions can be affected by focal seizures with altered mental awareness?

Language, memory, and emotions

What are characteristics of focal seizures with secondary generalization?

Seizure starts of as focal

Evolves into a tonic-clonic (Grand Mal) seizure

How do focal seizures with secondary generalization spread into the 2nd hemisphere?

Start in only 1 hemisphere

Seizure activity reaches the Thalamus

Thalamus connects the hemispheres

Seizure spreads to the second hemisphere

What are the 3 steps of focal seizures?

Initiation

Synchronization

Spread

What is described by the initiation step of focal seizures?

Initiation of inc. electrical activity at the cellular level

What is described by the synchronization step of focal seizures?

Synchronization of electrical activity of surrounding neurons

What is described by the spread step of focal seizures?

Spread of electrical activity to adjacent regions

If spreads to the second hemisphere it becomes generalized

What is the theory of why focal seizure develop?

Many focal seizure most likely result from a failure of surround inhibition

What are possible causes of failure of sorround inhibition?

Infections, tumors, genetic variation

What is sorround inhibition?

Mech. in the brain to prevent synchronicity in surrounding areas

Preventing over-excitation, and therefore preventing seizures

Where is surround inhibition occuring?

Cerebral cortex

What is described by the inhibitory surround?

Area that is inhibited when cortical pyramidal neurons are activated

Inhibition prevents spread of over-excitation

What are cortical pyramidal neurons, as part of surround inhibition?

Glutamatergic neurons

Excitatory function

Located in the cerebral cortex

Part of surround inhibition circuit

Neurons A, B and D on the diagram

What are interneurons, as part of surround inhibition?

Mainly GABAergic

Inhibitory function

Located in the cerebral cortex

Part of surround inhibition circuit

Neurons C on the diagram

What is the first step in surround inhibition?

Some brain function excites cortical pyramidal neuron A

Once the cortical pyramidal neuron A is excited, what is the next step in surround inhibition?

Excited neuron A fires and AP

AP cause release of Glu

Glu causes excitation of connected neurons

What neurons are excited by the cortical pyramidal neuron A during surround inhibition?

A excites B and C

B is a cortical pyramidal neuron (excitatory)

C is a GABAergic interneuron (inhibitory)

When the GABAergic interneuron, C, is excited by the cortical pyramidal neuron, A, what is the resulting effect?

Prevents neurons connected to C from becoming excited

Stopping "synchronization" with connected neurons

D is not excited despite being connected to A, because it is also connected to C

("excitation leading to inhibition")

Summary of surround inhibition for reference:

How is signal transmission characterized while awake?

During awake phase neuron is in transmission mode

Signals transmitted as single spikes

Small, desynchronized, low voltage waves

How is signal transmission characterized while in slow wave sleep?

During slow wave sleep there is a burst mode

Large waves in a rhythm

Results in oscillations that cancel out stimuli

What do absence seizure EEG readings mimic?

Absence seizures produce "sleep like" waves

Large waves of electrical activity for 15-20 secs

Preventing stimuli from having an effect

What is the mechanism of Absence seizures?

Thalamocortical-Cortical symphony

Leading to oscillatory, synchronized, pattern of excitation

What is the Thalamocortical-Cortical symphony?

Oscillations of activity between the thalamus and cortex

What is the first step in the Thalamocortical-Cortical symphony?

Hyperpolarization of relay neurons

What are the thalamocortical-cortical relay neurons?

Glutamatergic (excitatory) neurons

Cell body in thalamus

Axon in cortexv

Once relay neurons are hyperpolarized, what is the next step in the Thalamocortical-Cortical symphony?

Hyperpolarization opens T-type Ca channels

Causing burst of activity of T-type Ca channels

(Ca influx)

What are T-type Ca channels?

Voltage-gated Ca channels

Opened by hyperpolarization

What occurs as a result of T-type channel activity, in the Thalamocortical-Cortical symphony?

Ca influx causes depolarization, leading to an AP

Results in synchronous depolarization in the cortex

(seen as spike and wave pattern on ECG)

What occurs as a result of synchronous depolarization in the cortex, in the Thalamocortical-Cortical symphony?

Excitatory input from the cortex

(Glu neurons located in the cortex)

Activates thalamic neurons

What are thalamic neurons?

GABAergic (inhibitory) neurons

Located in thalamus

Release GABA back to the cortex onto relay (thalamocortical) neurons

After thalamic (GABA) neurons are activated, what is the next step in the Thalamocortical-Cortical symphony?

GABAergic thalamic neurons release GABA onto relay (thalamocortical neurons)

Cause hyperpolarization of relay neurons

After relay (thalamocortical) neurons are hyperpolarized, what happens in the Thalamocortical-Cortical symphony?

Cycle is reinitiated

T-type Ca channels on thalamocortical neurons are excited by hyperpolarization

Hyperpolarization of T-type Ca channels causes another depolarization, leading to continuation of the cycle

Why is GABA, the major inhibitory NT, able to cause excitation in the Thalamocortical-Cortical symphony?

Causes hyperpolarization of T-type Ca channels

But, T-type Ca channels are excited by this hyperpolarization

Leading to further excitation downstream

What is the major therapeutic target for Absence seizures?

T-type Ca channels

Why is blocking T-type Ca channels helpful in absence seizures?

Blocking ability to be hyperpolarized (activated)

Therefore, won't depolarize and stimulate cortical neurons

"Breaking" the cycle

What drugs are used for absence seizures?

Ethosuximide (only used in absence seizures)

Valproic acid (Valproate)

Lamotrigine

Clonazepam

What drug is 1st line for absence seizures?

Ethosuximide

Only used in absence seizures

What drug is 2nd line for absence seizures?

Valproic acid (valproate)

What drug is 3rd line for absence seizures?

Lamotrigine

What drug is 4th line for absence seizures?

Clonazepam

What is the therapeutic problem in seizures drugs try to adress?

Excessive neuronal activity

Either due to too much excitation or too little inhibition

What are the proposed solutions to the excess neuronal activity therapeutic problem in seizures?

Dec. excitatory transmission in the brain

OR

Inc. inhibitory transmission in the brain

What are the 5 MOA's of anticonvulsants?

Prolong inactive conformation of voltage-gated Na channels

Inc. GABA activity

Block T-type Ca channels (only for absence)

Enhance K channels, inc. inhibition

(no drug examples)

Inhibit Glu activity

How does prolonging the inactive conformation of voltage-gated Na channels treat seizures?

Limits repetitive firing of neurons

Decreasing excitatory transmission

(inhibition of AP propagation)

What anticonvulsants work by prolonging the inactive conformation of voltage-gated Na channels?

Carbamazepine

Phenytoin

Topiramate

Lamotrigine

Valproic acid (Valproate)

Zonisamide

What is the MOA of Carbamazepine?

Na channel blocker

Binds and stabilizes fast voltage-gated Na channels

High affinity for refractory (inactive) conformation

Prolongs inactive conformation

Inhibiting propagation of APs

Leading to dec. AP freq.

What is the MOA of Phenytoin?

Na channel blocker

Binds and stabilizes fast voltage-gated Na channels

High affinity for refractory (inactive) conformation

Prolongs inactive conformation

Inhibiting propagation of APs

Leading to dec. AP freq.

What is the MOA of Topiramate?

Na channel blocker

Binds and stabilizes fast voltage-gated Na channels

High affinity for refractory (inactive) conformation

Prolongs inactive conformation

Inhibiting propagation of APs

Leading to dec. AP freq.

What is the MOA of Lamotrigine?

Na channel blocker

Binds and stabilizes fast voltage-gated Na channels

High affinity for refractory (inactive) conformation

Prolongs inactive conformation

Inhibiting propagation of APs

Leading to dec. AP freq.

What is the MOA of Zonisamide?

Na channel blocker

Binds and stabilizes fast voltage-gated Na channels

High affinity for refractory (inactive) conformation

Prolongs inactive conformation

Inhibiting propagation of APs

Leading to dec. AP freq.

How does increasing GABA activity treat seizures?

Inc. inhibitory tone

Prevents excessive excitation

A cause of excessive neuronal activity (seizures)

What anticonvulsants work by increasing GABA activity?

Barbiturates

Benzodiazepines

Vigabatrin

Valproic acid (valproate)

Tigabine

What is the MOA of Vigabatrin?

Inhibits GABA-T

Dec. GABA metabolism

Inc. GABA conc.

Inc. inhibitory tone

(GABA-T = GABA transferase)

What is the MOA of Tigabine?

Blocks GAT-1

Inhibits GABA reuptake

Inc. GABA conc.

Inc. inhibitory tone

(GAT-1 = GABA transporter, neg. regulator of GABA - performs reuptake)

What is the MOA of Benzodiazepines and Barbiturates?

Potentiate effects of GABA at GABA-A

Inc. effect of GABA

Inc. inhibitory tone

How does blocking T-type Ca channels treat seizures?

Only for absence seizures

T-type Ca channels present in the thalamocortical network

Prevents reinitiation of oscillation cycle

What anticonvulsants work by blocking T-type Ca channels?

Valproic acid (Valproate)

Ethosuximide

What is the MOA of Ethosuximide?

Blocks T-type Ca channels

Prevents from being opened by hyperpolarization, and causing subsequent depolarization

Used for absence seizures

What is the MOA of Valproic acid (Valproate)?

Prolongs inactive conformation of voltage-gated Na channels

Inhibits GABA-T and SSADH --> dec. metabolism of GABA)

(inc. GABA activity)

Blocks T-type Ca channels

Why can Clonazepam, a benzo, be used in Absence seizures?

GABA neurons express their own GABA-A

GABA-A can be inhibited by Benzo's

Clonazepam is selective for GABA-A present on GABAergic interneurons

What type of GABA-A is Clonazepam selective for?

Selective for GABA-A present on GABAergic interneurons

(ones involved in absence seizures)

What is the effect of Clonazepam in Absence seizures?

Acts at GABAergic interneuron

Potentiates effects of GABA at GABA-A

Leading to inc. inhibition

Causes interruption of hyperpolarization cycle that is present in Absence seizures

How does inhibiting Glu activity treat seizures?

Block Glu activity to reduce excitatory transmission

Prevents excessive excitation

What anticonvulsants work by blocking Glu activity?

Felbamate

Gabapentin

What is the MOA of Felbamate?

NMDA receptor antagonist

Inhibits Glu excitation by antagonizing it's receptor

Prevents AP transmission

What is the MOA of Gabapentin?

Inhibits voltage-gated Ca channels

Prevents Ca entry, which prevents NT release

Prevents excitation and spreading cause by NT

What is status epilepticus (SE) defined as?

1 continuous, unremitting seizure lasting >30 mins

OR

Recurrent seizures, w/o regaining consciousness between, lasting >30 mins

(brain in persistent seizure state; life threatening medical emergency

What is the treatment for status epilepticus (SE)?

IV diazepam or lorazepam

Why are IV Diazepam/Lorazepam used for status epilepticus (SE)?

Penetrate BBB quickly

Effective at stopping SE

What is the downside of using IV Diazepam/Lorazepam for status epilepticus (SE)?

Have short DOA when given by IV

(due to redistribution)

Seizures may recur

How is seizure recurrence prevented in status epilepticus (SE) treatment?

Give loading dose of a longer acting drug

SUch as phenytoin, phenobarbital, or carbamazepine

How are anticonvulsants metabolized?

Most are CYP450 substrates

Some may also inhibit or induce CYP enzymes

(D/I concerns)

How does enzyme induction occur?

Drug induces gene expression

Inc. gene expression eventually inc. conc. of enzyme

(takes time to accum. enzyme)

Inc. enzyme conc. leads to inc. metabolism of it's substrates

When do effects enzyme induction manifest?

Inc. enzyme activity 2-4 weeks after continuous dosing

Doesn't follow drugs kinetics

Need to wait to adjust dose

Can an inducer be spaced out from it's interacting drug to negate the interaction?

No, the issue is the enzyme has accum.

Enzyme accum. will still be present even if inducing drug isn't

When do effects enzyme induction disappear?

Inx. activity continues after drug discontinuation

(≥2-4 weeks)

Need time for accum. enzyme to be cleared

Doesn't follow drugs kinetics

How does enzyme inhibition occur?

Drug binds to and inhibits the metabolizing enzyme

When do effects enzyme inhibition manifest?

Dec. enzyme activity whenever the drug is present

Follows the drugs kinetics