Anticonvulsants, Anxiolytics & Hypnotics Flashcards
What is epilepsy?
is the condition of recurrent, spontaneous seizures arising from abnormal, synchronous and sustained electrical activity in the brain. Too much excitation, excessive, uncontrolled activity.
What is a seizure?
A SEIZURE is an episode of neurological dysfunction of abnormal firing of neurones manifesting as changes in motor control / sensory perception / behaviour / autonomic function.
Pharmacological Treatment for epilepsy:
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.
Generalised tonic/clonic:
1st line:
Carbamazepine, Lamotrigine, Na Valproate, Oxcarbazepine
Adjunctive
Clobazam, Lamotrigine, Levetiracetam, Na Valproate, Topiramate
May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Phenytoin, Pregabalin
Tonic or Atonic
1st line
Na Valproate
Adjunctive
Lamotrigine
May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin
Absence seizure:
1st line
Ethosuximide, Lamotrigine, Na Valproate
Adjunctive
Ethosuximide, Lamotrigine, Na Valproate
May worsen seizures
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin, Phenytoin
Myoclonic
1st line:
Levetiracetam, Na Valproate, Topiramate
Adjunctive
Levetiracetam, Na Valproate, Topiramate
May worsen seizures:
Carbamazepine, Gabapentin, Oxcarbazepine, Pregabalin, Phenytoin
Focal (partial):
1st line:
Carbamazepine, Lamotrigine, Levetiracetam, Oxcarbazepine, Na Valproate
Adjunctive
Carbamazepine, Clobazam, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Na Valproate, Topiramate
Excitatory / Inhibitory Balance in the CNS:
GABA and glutamate:
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)
Why are GABA and Glutamate Important neurotransmitters:
- 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)
Neuronal firing:
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
Physiological protection against repetitive firing occurs via inhibition at two levels:
- The cellular level (e.g., Na+ channel inactivation)
- The network level (e.g., GABA-mediated inhibition)
Currently available anticonvulsants fall into four main categories:
(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
drugs that inhibit Na+ channels
AEDs that target the sodium channels prevent the return of these channels to the active state by stabilizing them in the inactive state.
drugs that inhibit Ca2+ channels
AEDs that inhibit these T-calcium channels are particularly useful for controlling absence seizures
High voltage activated channels – involved in neurotransmitter release
drugs that enhance GABA-mediated inhibition
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
drugs that drugs that inhibit glutamate receptors:
- 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.
Synergistic Interplay Between AMPA and NMDA Receptors at Excitatory Synapses:
Activation of AMPA receptors causes depolarisation which relieves the Mg2+ block, and thereby activates, NMDA receptors
Caution: NMDA receptor antagonists have a limited use because:
they produce psychosis and hallucinations. In addition to these adverse effects, learning and memory may be impaired by blocking these receptors
Anxiety:
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
Anxiety pharmacological treatment:
- 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
Benzodiazepines – Mechanism of Action
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)
Benzodiazepines, GABAAR and Targeting the Anxiolytic Subtypes of GABAAR:
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
