Anti-Epileptic Drugs Flashcards
1
Q
What is epilepsy?
A
Episodic discharge of abnormal high frequency electrical activity in the brain, leading to seizures
2
Q
What does diagnosis of epilepsy require?
A
Evidence of recurrent seizures, unprovoked by other indentifiable causes
3
Q
In what % of epilepsy cases are therapeutics effective?
A
About 75%
4
Q
What causes epilepsy?
A
- Increased excitatory activity
- Decreased inhibitory activity
- Loss of homeostatic control
- Spread of neuronal hyperactivity
5
Q
What are the main types of seizures?
A
- Partial seizures
- Generalised seizures
6
Q
What are the types of partial seizures?
A
- Simple
- Complex
7
Q
Do you maintain consciousness in simple partial seizures?
A
Yes
8
Q
Do you maintain consciousness in complex partial seizures?
A
Consciousness is impaired - sufferer may be aware, but loose part of sensory impression
9
Q
What happens if a partial seizure spreads throughout the cortex?
A
You get secondary generalised seizures
10
Q
What changes in the brain occur in partial seizures?
A
- Loss of local excitatory/inhibitory homeostasis
- Increased discharges in focal cortical area
11
Q
What do the symptoms of partial seizures reflect?
A
The area affected
12
Q
What symptoms might you get from partial seizures?
A
- Involuntary motor disturbane
- Behavioural change
- Impending focal spread, accompanied by ‘aura’, e.g. unusual smell or taste, deja vu
13
Q
What happens in generalised seizures?
A
Seizures are generated centrally, and spread throughout both hemispheres with loss of consciousness
14
Q
What % of generalised seizures are tonic-clonic seizures?
A
60%
15
Q
What % of generalised seizures are absense seizures?
A
5%
16
Q
How long do most seizures last?
A
Up to 5 minutes
17
Q
What is status epilepticus?
A
When seizures are prolonged beyond 5 minutes, or experienced as a series of seizures without recovery interval
18
Q
What kind of epilepsy can status epilepticus occur in?
A
Any
19
Q
What should a prolonged seizure be treated as?
A
A medical emergency
20
Q
What can untreated status epilepticus lead to?
A
Brain damage and death
21
Q
What are the potential dangers in severe epilepsy?
A
- Physical injury relating to fall/crash
- Hypoxia
- Sudden death
- Varying degrees of brain dysfunction/damage
- Congnitive impairment
- Serious psychiatric disease
- Significant adverse reactions to medications
- Stigma/loss of livelihood
22
Q
What are the categories of aetiology of epilepsy?
A
- Primary
- Secondary
23
Q
What is primary epilepsy?
A
When there is no identifiable cause
24
Q
What % of epilepsies are primary?
A
65-70%
25
What can cause secondary epilepsy?
Medical conditions affecting the brain, *e.g. vascular disease and tumours*
26
What % of epilepsies are secondary?
30-35%
27
What are the categories of precipitants of epilepsy?
* Sensory stimuli
* Brain disease/trauma
* Metabolic disturbances
* Infections
* Therapeutics
28
What sensory stimuli might precipitate epilepsy?
Flashing lights/strobes, or other periodic sensory stimuli
29
What can cause brain disease/trauma precipitating epilepsy?
* Brain injury
* Stroke/haemorrhage
* Drugs/alcohol
* Structural abnormality/lesion
30
What metabolic disturbances can precipitate epilepsy?
* Hypoglycaemia
* Hypocalcaemia
* Hyponatraemia
31
How can therapeutics act as precipitants for epilepsy?
* Some drugs can lower the fit threshold
* Polypharmacy involving anti-epileptic drugs can cause lower levels of the drug
32
What are the therapeutic targets for AEDs?
* Voltage gated sodium channel blockers
* Enhancing GABA mediated inhibition
33
What is the mechanism of action of VGSC blockers?
Bind to the 4th domain of the voltage gated sodium channels and hold them in the inactivated state to temporarily prevent further action potential propagation
34
In what channel state and at what membrane potential can VGSC blockers bind?
Inactivated channel in a heavily depolarised membrane
35
In epilepsy how is membrane potential homeostasis lost?
1. Starts at a focal point with a small number of neurones unable to control membrane potential
2. The neurones in this area heavily depolarise
3. Hyperactivity spreads via synaptic transmission to other neurones
36
What effect do VGSC blockers have on the VGSCs?
Prolongs inactivation state to bring the firing rate back to normal
37
What happens once the membrane potential is restored to normal?
The VGSC blocker detaches from the binding site
38
Give 3 VGSC blockers
* Carbamazepine
* Phenytoin
* Lamotragine
39
What percentage of carbamazepine is bound to proteins in the plasma?
75%
40
What is the initial dose half-life of carbamazepine?
30 hours
41
What is the half-life of carbamazepine on repeated use?
15 hours
42
Why does the half-life of carbamazepine decrease on repeated use?
It is a very strong inducer of the CYP450 system and so increases its own Phase 1 metabolism
43
What CNS ADR’s can carbamazepine produce?
* Dizziness
* Drowsiness
* Ataxia
* Motor disturbance
* Numbness
* Tingling
44
What GI ADR’s can carbamazepine produce?
Vomiting
45
How can carbamazepine affect BP?
Can cause it to vary
46
What heart condition is a contraindication for carbamazepine use?
AV conduction problems
47
What non-CNS/GI/CVS ADR’s can carbamazepine have?
* Rashes
* Hyponatraemia
48
What is a rare but serious ADR of carbamazepine?
Severe bone marrow depression leading to neutropenia
49
What is the problem with carbamazepine being a CYP450 inducer?
It can interact with many other drugs
50
What drugs can carbamazepine affect the efficacy of?
* Phenytoin
* Warfarin
* Systemic corticosteroids
* Oral contraceptives
51
What other interaction can carbamazepine have with phenytoin?
Phenytoin can increase the plasma concentration of carbamazepine by decreaseing its protein binding
52
What group of drugs can interfere with the action of carbamazepine?
Antidepressants - SSRI's, TCA's and MAOI's
53
What types of epilepsy are treated with carbamazepine?
* Generalised tonic-clonic
* Partial seizures
54
What percentage of phneytoin is bound to plasma protiens?
90%
55
What is the problem with the high protein binding of phenytoin?
It can be involved in protein binding DDI's
56
What characteristic (other than protein binding) also makes phenytoin prone to DDI's?
It is a CYP450 inducer
57
What CYP450 enzyme is phenytoin an inducer of?
CYP3A4
58
What PK profile does phenytoin have?
Non-linear at therapeutic levels
59
What is the result of phenytoin following non-linear PK at therapeutic levels?
It has a very variable half-life (6-24 hours)
60
What are the CNS ADR's of phenytoin?
* Dizziness
* Ataxia
* Headache
* Nystagmus
* Nervousness
61
What are the non-CNS ADR's of phenytoin?
* Ginigval hyperplasia (20%)
* Rashes
* Hypersensitivity
* Stevens Johnson
62
What are the DDI's of Phenytoin?
* Competitive binding with Valproate
* NSAIDs increase plasma levels
* Decreases effectiveness of oral contraception
* Metbaolism is decreased by cimetidine
63
What must be done when prescribing Carbamazepine/Phenytoin?
Check BNF for interactions with all other prescribed medications
64
What monitoring is required with Phenyotin use?
Monitoring of free plasma concentration using salivary levels as an inidcator
65
What types of epilepsy are treated with Phenytoin?
* Generalised tonic-clonic
* Partial Seizures
66
Other than blocking VGSC what other mechanisms is Lamotrigine thought to have?
* Calcium channel blocker
* Decrease glutamate release
67
What is the half-life of Lamotrigine?
24 hours
68
How is Lamotrigine metabolised?
Enters directly into Phase 2 metabolism
69
Does Lamotrigine cause CYP450 related DDI's?
No!
70
What are the ADR's of Lamotrigine?
* Dizziness
* Ataxia
* Somnolence
* Nausea
* Mild - serious skin rashes
71
What are the DDI's of Lamotrigine?
* Oral contraceptives reduce plasma levels
* Valproate can increase plasma levels by competitive binding
72
What types of epilepsy are treated with Lamotrigine?
* Partial seizures
* Generalised seizures including Absence Seizures
73
What are the advantages of Lamotrigine?
* Increasingly first line
* Appears safer in pregnancy
74
Other than blockade of VGSC, how else can anti-epileptic drugs exert their acation?
By enhancing GABA mediated inhibition
75
What is the role of GABA?
It is a major inhibitory neurotransmitter
76
How may of the brains synapses are GABA-ergic?
40%
77
What is GABA's physiological role in relation to seizures?
It is the natural anticonvulsant that applies the 'brake' to excitation
78
By targetting what methods can GABA mediated inhibition be increased?
* Acting as a GABA agonist
* Inhibiting GABA inactivation
* Inhibiting GABA re-uptake
* Increasing the rate of GABA synthesis
79
Which GABA binding sites can increase GABA action (i.e. act as an agonist)?
* Benzodiazepine site
* Barbiturate site
80
Generally speaking, how does enhancement of GABA mediated inhibition have an anti-epileptic effect?
* GABA causes opening of Cl- channel which increases influx into the neurone
* This increases the negativity of the membrane potential and increases the threshold for action potential generation.
81
