1. Anticonvulsants & Anxiolytics
Rishi Gandhewar 
24/03/19

2. Overview Anticonvulsants SBAs Anxiolytics ARQ & SAQ Feedback
Ask them what they want to focus on etc. Any general questions
Focus bit more on Anxiolytics (Anticonvulsants is Sohag)

3. LOs: Anti-Convulsants
Seizures: recognise the different seizure types
Anti-convulsants: recognise that anti-convulsant therapy is determined by the seizure type coupled with pharmacodynamics/pharmacokinetic properties of specific anti-convulsant drugs
What do they want you to know…
What the different types of seizures are
Which drug which seizure & WHY

4. What is a seizure?
“sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex”
Massive Jolt in Brain Activity caused by neurons being activated altogether
Diagnosis:
EEG
MRI

5. Seizure Types - Definitions
Seizure types & Symptoms
Tonic-clonic seizures: loss of consciousness  muscle stiffening  jerking/twitching  deep sleep  wakes up
Absence seizures: brief staring episodes with behavioural arrest
Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control
Myoclonic seizures: sudden, brief muscle contractions
Status epilepticus: > 5 min of continuous seizure activity

6. Seizure Types - Framework
Jacksonian Seizure begins as a partial seizure and spreads to become a generalised seizure

7. Neuron Types
Glutaminergic
GABAergic

8. Glutamate Inhibition

9. Glutamate Inhibition

10. Pharmacology – Na Channel Blockers
Carbamazepine
Pharmacodynamics
Stabilises inactive state of Na+ channel  reducing neuronal activity
Pharmacokinetics
Enzyme inducer
Onset of activity within 1 hour
16-30 hour half-life
Indications
Tonic-clonic seizures; partial seizures
NB: potential severe side-effects (SJS & TEN) in individuals with HLA-B*1502 allele
Lamotrigine
Inactivates Na+ channels  reducing glutamate neuronal activity
24-34 hour half-life
Tonic-clonic seizures; absence seizures

11. Pharmacology – Na Channel Blockers
Carbamazepine
Stabilises inactive state
Inducer
Give w/in 1 hour
Indications
Tonic-clonic seizures; partial seizures
NB: potential severe side-effects (SJS & TEN) in individuals with HLA- B*1502 allele
Lamotrigine
Inactivates Na+ channels
Tonic-clonic seizures; absence seizures

12. Pharmacology – VG-CCB Ethosuximide
T-type Ca2+ channel antagonist  reduces activity in relay thalamic neurones
Pharmacokinetics
Long half-life (50 hours)
Indications
Absence seizures

13. Pharmacology – VG-CCB Ethosuximide
T-type Ca2+ channel antagonist (Relay Thalamic Ns)
Indications
Absence seizures

14. Pharmacology – Glutamate Exocytosis & Receptors
Levetiracetam
Pharmacodynamics
Binds to synaptic vesicle associated protein (SV2A)  preventing glutamate release
Pharmacokinetics
Fast-onset (1 hour); half-life (10 hours)
Indications
Myoclonic seizures
Topiramate
Inhibits NMDA & kainate receptors
Also affects VGSCs & GABA receptors
Fast-onset (1 hour); long half-life (20 hours)

15. Pharmacology – Glutamate Exocytosis & Receptors
Levetiracetam
Binds SV2A
W/in 1hr
Indications
Myoclonic seizures
Topiramate
Inhibits NMDA & kainate receptors

16. Glutamate Inhibition - Overview

17. GABA Enhancement Neurotransmission
GABA can be released tonically & also following neuronal stimulation
GABA activates inhibitory post-synaptic GABAA receptors
GABAA receptors are chloride (Cl-) channels  membrane hyperpolarisation
GABA is taken up by GAT & metabolised by GABA transaminase (GABA-T)

18. GABA Enhancement GABA Tonic & Stimulated release Inhibitory
GABAA rec = Cl- channels  hyperpolarisation
Reuptake – GAT
Metabolism – GABA-T

19. Pharmacology – GABA Diazepam Sodium Valproate Pharmacodynamics
GABA receptor, PAM  increases GABA-mediated inhibition
Pharmacokinetics
Rectal gel - Fast-onset (within 15 min); half-life (2 hours)
Indications
Status epilepticus
Sodium Valproate
Inhibits GABA transaminase  increases GABA-mediated inhibition
Fast onset (1h); half-life (12h)
Indicated for ALL forms of epilepsy

20. Pharmacology – GABA Diazepam Sodium Valproate
GABA- PAM (positive allosteric modulator) enhances GABA effect
Rectal gel - 15 min onset
Indications
Status epilepticus
Sodium Valproate
Inhibits GABA-T
Fast onset (1h)
Indicated for ALL forms of epilepsy

21. Which Drug, When?

22. Which Drug, When?

23. Which Drug, When?

24. SBA 1
A patient complains about their body going ‘tight and then loose’ and this lasts for a couple of minutes but they remain conscious.
What type of seizure is this person having?
a) Tonic-Clonic
b) Complex Partial
c) Myoclonic
d) Tonic-Atonic
e) Status Epilleticus

25. SBA 1
A patient complains about their body going ‘tight and then loose’ and this lasts for a couple of minutes but they remain conscious.
What type of seizure is this person having?
a) Tonic-Clonic
b) Complex Partial
c) Myoclonic
d) Tonic-Atonic
e) Status Epilleticus

26. SBA 2
A patient seen in A&E is suffering a seizure- including fitting and jerking lasting 10 minutes
Which medication is most appropriate
a) Topiramate
b) Ethosuximide
c) Valproate
d) Carbamazepine
e) Diazepam
[Test yourself by trying to remember what types of seizures the other drugs are used to treat]

27. SBA 2
A patient seen in A&E is suffering a seizure- including fitting and jerking lasting 10 minutes
Which medication is most appropriate
a) Topiramate
b) Ethosuximide
c) Valproate
d) Carbamazepine
e) Diazepam
[Test yourself by trying to remember what types of seizures the other drugs are used to treat]

28. Anxiolytics - LOs
GABA: identify the processes (e.g. receptors, transporters & enzymes) involved in GABAergic central neurotransmission
Drugs targeting GABA: list the principal clinical uses and adverse effects of drugs acting on the GABAergic system and explain how pharmacokinetic differences determine clinical use

29. What is the difference between anxiolytics & sedatives/hypnotics?
Anxiolytic = Anxiety ( mental/physical activity)
Sedatives = mental/physical activity ( consciousness)
Hypnotics = Induce Sleep zzzZZZZ

30. Anxiolytics vs Sedatives & Hypnotics
Anxiolytics are LONG-acting
diluted action, lasting the whole day
Diazepam, Oxazepam (1/2 life- 8h)
Sedative & Hypnotics are SHORT-acting
concentrated action, quick onset
Oxazepam, Temazepam (1/2 life- 28h)
BOTH enhance GABA transmission, which reduces excitation  Calmness
Way to remember is: Anxiolytics has more letters than Sedatives or Hypnotics

31. GABA Most important INHIB. NT in the brain
Short Interneurons + some longer (nigrostriatal tract)
Pre-/Post-synaptic
Functions: Motor, Extrapyramidal, Emotional, Endocrine

32. GABA agonists should… HAVE WIDE MARGIN OF SAFETY
NOT DEPRESS RESPIRATION
PRODUCE NATURAL SLEEP (HYPNOTICS)
NOT INTERACT WITH OTHER DRUGS
NOT PRODUCE ‘HANGOVERS’
NOT PRODUCE DEPENDENCE

33. GABA agonists should…
Safety/ Pre-Effect: Wide margin, not interact with other drugs
Effect: Not depress Respiration & should produce Natural Sleep (hypnotics)
Post-Effect: Hangovers, Dependence

34. Neurochemistry 
GABA-T
GABA-T
POSTSYNAPTIC CELL

35. GABA Storage & Release: Stored at GABAergic vesicles (AP  Exocytosis)
Inactivation: Rapid Re-uptake at Pre-synaptic Membranes & Glial Cells (via GAT)
Reuptake is dependent on Na+/ATP therefore saturable
Metabolism:

36. GABA receptors! GABA-A GABA-B Type 1 (Pentameric Ionotropic)
Type 2 (Gi)
Cl- influx  Hyper-polarised
Decrease cAMP
Inhibitory Post Synaptic Potential (IPSP)
Decreased Ca2+ conductance  decreased exocytosis
Agonist – GABA, Muscimol
Antagonist- Bicuculline
Agonist – Baclofen
Antagonist - Saclofen
Hyper-polarisation means the membrane is more stable and therefore requires more stimulation for an AP to propagate

37. GABA-A complex

38. GABA in the GABA-A complex
Activation of the GABA receptor:
Directly opens the Cl- channel
Links to BDZ receptor via GM
Potentiates the BDZ receptor
(BARB rec NOT involved)

39. BDZ in the GABA-A receptor
Activation of the BDZ receptor:
Potentiates the GABA receptor
Links to GABA receptor via GM
Can open the Cl- channel at high concentrations
(BARB rec NOT involved)

40. BARB in the GABA-A receptor
Activation of the BARB receptor:
Potentiates the GABA receptor
Potentiates the BDZ receptor
Can open the Cl- channel at high concentrations
(GM NOT involved)

41. Benzodiazepines & Barbiturates
How do they work?
PAMs! (Positive Allosteric Modulators)
This means they enhance the normal activity of GABA rather than opening the Chlorine Channel Directly

42. Benzodiazepines & Barbiturates
What is the difference between the two?
BDZ
BARBs
Increase frequency Cl- channel opens
Increase duration Cl- channel remains open
Anxiolytics, Anti-spastic
Surgical Anaesthesia, Sedative/Hypnotic
1st choice drug – SAFE
NOT 1st choice drug – Unwanted side effects
Non-inducer
Inducer
Oxazepam (8h), Diazepam (32h)
Amobarbital, Phenobarbitone

43. Other drugs to be aware of…
Sedatives/Hynotics:
Zopiclone
Anxiolytics:
SSRIs
Anticonvulsants (Valproate, Tiagabine)
Antipsychotics (Olanzapine, Quetiapine)
Beta-blockers (Propranolol)
Buspirone (Serotonin receptor agonist)

44. ARQ 1 A: BDZs always open the Cl- channel directly
R: BDZs enhance the effect of GABA
a) TT – assertion explains reason
b) TT – assertion does not explain reason
c) TF
d) FF
e) FT

45. ARQ 1 A: BDZs always open the Cl- channel directly
R: BDZs enhance the effect of GABA
a) TT – assertion explains reason
b) TT – assertion does not explain reason
c) TF
d) FF
e) FT

46. SAQ 1
List 6 ideal features of GABA agonists for clinical use.

47. SAQ 1
List 6 ideal features of GABA agonists for clinical use. (Pre-effect) 1. Wide margin of safety 2. Does not interact with other drugs (Effect) 3. Does not depress respiration 4. Induces normal sleep (Post-Effect) 5. No hangover 6. No dependence

48. FEEDBACK (please)
bit.ly/muslimmedics