Anticonvulsants, Anxiolytics & Hypnotics

Question 1

What is epilepsy?

Answer 1

is the condition of recurrent, spontaneous seizures arising from abnormal, synchronous and sustained electrical activity in the brain. Too much excitation, excessive, uncontrolled activity.

Question 2

What is a seizure?

Answer 2

A SEIZURE is an episode of neurological dysfunction of abnormal firing of neurones manifesting as changes in motor control / sensory perception / behaviour / autonomic function.

Question 3

Pharmacological Treatment for epilepsy:

Answer 3

brain and therefore suppress seizure activity.

Treatment depends in part on the type of seizure(s) experienced by the patient, this will then determine an appropriate antiepileptic (also known as anticonvulsant) drug regimen, or further treatment could involve surgery to remove the focus of the seizure.

Question 4

Generalised tonic/clonic:

Answer 4

1st line:
Carbamazepine, Lamotrigine, Na Valproate, Oxcarbazepine

Adjunctive
Clobazam, Lamotrigine, Levetiracetam, Na Valproate, Topiramate

May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Phenytoin, Pregabalin

Question 5

Tonic or Atonic

Answer 5

1st line
Na Valproate

Adjunctive
Lamotrigine

May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin

Question 6

Absence seizure:

Answer 6

1st line
Ethosuximide, Lamotrigine, Na Valproate

Adjunctive
Ethosuximide, Lamotrigine, Na Valproate

May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin, Phenytoin

Question 7

Myoclonic

Answer 7

1st line:
Levetiracetam, Na Valproate, Topiramate

Adjunctive
Levetiracetam, Na Valproate, Topiramate

May worsen seizures:
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin, Phenytoin

Question 8

Focal (partial):

Answer 8

1st line:
Carbamazepine, Lamotrigine, Levetiracetam, Oxcarbazepine, Na Valproate

Adjunctive
Carbamazepine, Clobazam, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Na Valproate, Topiramate

Question 9

Excitatory / Inhibitory Balance in the CNS:

GABA and glutamate:

Answer 9

GABA enhancing drugs:

• (Valium, barbiturates) act as
• Anxiolytics
• Sedatives
• Anti-convulsants

Glutamate excites the brain
- Glutamate enhancing drugs can be convulsant
Glutamate blocking drugs can be anti-convulsant and prevent excitotoxicity (e.g. memantine in AD)

Question 10

Why are GABA and Glutamate Important neurotransmitters:

Answer 10

• Regulate and control many functions in the brain
• Potential for role in very wide range of neuroscience disease states
• Challenge is achieving benefit without side-effects
  We now know understand the requirements for safe and effective receptor modulation (positive/negative)

Question 11

Neuronal firing:

Answer 11

Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

The more excitatory potential it receives, it will push the membrane potential threshold to activate an action potential, Na+ comes in, membrane becomes more positive. It then reaches threshold
Cl- brings threshold down to inhibit AP. When something goes wrong, seizures can occuer

Question 12

Physiological protection against repetitive firing occurs via inhibition at two levels:

Answer 12

• The cellular level (e.g., Na+ channel inactivation)

- The network level (e.g., GABA-mediated inhibition)

Question 13

Currently available anticonvulsants fall into four main categories:

Answer 13

(1) drugs that inhibit Na+ channels
(2) drugs that inhibit calcium channels
(3) drugs that enhance GABA-mediated inhibition
(4) drugs that inhibit glutamate receptors

Question 14

drugs that inhibit Na+ channels

Answer 14

AEDs that target the sodium channels prevent the return of these channels to the active state by stabilizing them in the inactive state.

Question 15

drugs that inhibit Ca2+ channels

Answer 15

AEDs that inhibit these T-calcium channels are particularly useful for controlling absence seizures

High voltage activated channels – involved in neurotransmitter release

Question 16

drugs that enhance GABA-mediated inhibition

Answer 16

Synthesis: mediated by glutamic acid decarboxylase (GAD)

Storage: GABA is packaged into presynaptic vesicles by a transporter (VGAT)

Release: In response to an action potential and the presynaptic elevation of intracellular Ca2+, GABA is released into the synaptic cleft by fusion of GABA-containing vesicles with the presynaptic membrane

Reuptake: Neurons and glia take up GABA via specific GABA transporters (GATs). Four GATs have been identified, GAT-1, GAT-2, GAT-3 and GAT-4, each with a characteristic distribution in the CNS

Breakdown: Within cells, the widely distributed mitochondrial enzyme GABA-transaminase (GABA-T) metabolises GABA

GABA receptor agonists GABA reuptake inhibitors – blocking uptake of GABA, less excitationn GABA transaminase inhibitors – prevents breakdown

Question 17

drugs that drugs that inhibit glutamate receptors:

Answer 17

• The AMPA and the Kainate sites open a channel through the receptor, allowing sodium and small amounts of calcium to enter
• The NMDA site opens a channel that allows large amounts of calcium to enter along with the sodium ions. This channel is blocked by magnesium in the resting state.
• The metabotropic site is regulated by complex reactions and its response is mediated by second messengers.

Question 18

Synergistic Interplay Between AMPA and NMDA Receptors at Excitatory Synapses:

Answer 18

Activation of AMPA receptors causes depolarisation which relieves the Mg2+ block, and thereby activates, NMDA receptors

Question 19

Caution: NMDA receptor antagonists have a limited use because:

Answer 19

they produce psychosis and hallucinations. In addition to these adverse effects, learning and memory may be impaired by blocking these receptors

Question 20

Anxiety:

Answer 20

Anxiety is a NORMAL component of everyday life. It is a normal response to a stressful or threatening situation. It becomes a disorder when it is inappropriate or disrupts an individual’s social life

Anxiety disordersare a group of mental disorders characterized by excessive feelings of anxiety and fear

Examples of Anxiety & Related Disorders include:
Generalised Anxiety Disorder (GAD), Social Phobia / Social Anxiety, Panic Attacks / Panic Disorders, Post-Traumatic Stress Disorder, Obsessive Compulsive Spectrum Disorders

Question 21

Anxiety pharmacological treatment:

Answer 21

• No major therapeutic advance since benzodiazepines introduced in early 1960s
• Current first-line treatments are repositioned antidepressants (SSRIs and SNRIs)
• Subsequent pharmacological treatments include benzodiazepines e.g. diazepam (“Valium”)
  Fast-acting but sedation occurs in 50% patients
• Benzodiazepine use increased by 110% between 1965 and 1970
• Between 1973 and 1975 annual number of prescriptions for benzodiazepines exceeded 80 million
• In the mid-1970s 10-20% of adults in Western countries regularly consumed benzodiazepines
• Peak of valium sales was 1978 with 2.3 billion pills
• Marketed as anxiolytics (minor tranquillizers) and hypnotics (sleeping pills)
• Anxiolytic and hypnotic benzodiazepines only differ in pharmacokinetics and marketing

Question 22

Benzodiazepines – Mechanism of Action

Answer 22

GABAA receptor

Typically made up of two α and two β subunits among the five subunits, though the particular subunit composition often varies widely among brain regions and species

The receptor complex possesses sites of action for a number of clinically important drugs (Benzodiazepines)

These are known as GABA modulators because they increase or decrease the effect of GABA (Note: some have no effect in the absence of GABA)

Question 23

Benzodiazepines, GABAAR and Targeting the Anxiolytic Subtypes of GABAAR:

Answer 23

Benzodiazepines (BZs), e.g. diazepam, are anxiolytic but also cause sedation
They are positive allosteric modulators (PAMs) at 4 subtypes of GABAARs (α1, α2, α3 & α5)

GABAARs have different neuroanatomical distributions and therefore different functions