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Semester 5 - Farmocology > Session 11 - Epilepsy > Flashcards

Session 11 - Epilepsy Flashcards

1
Q

What is epilepsy?

A

Epilepsy is an episodic discharge of abnormal high frequency electric activity in the brain leading to seizure.

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2
Q

What does an epilepsy diagnosis require?

A

evidence of recurrent seizures unprovoked by any other identifiable causes.

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3
Q

Describe four things that happen in epilepsy on a neuronal level

A
  • Increased excitatory activity
  • Decreased inhibitory activity
  • Loss of homeostatic control
  • Spread of neuronal hyperactivity
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4
Q

What are two overarching categories of epilepsy

A

Partial seizures

Generalized seizures

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5
Q

Give two sub-types of partial seizures - What is the distinguishing feature between the two?

A

Simple (concious)

Complex (unconscious)

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6
Q

What four things occur in a partial seizure?

A

o Increased discharged in focal cortical area
 Symptoms reflect affected area
 Involuntary motor disturbance
 Behavioural change
 Impending focal spread accompanied by Aura, e.g. unusual smell or taste, déjà vu, jamais vu

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7
Q

What is jamais vu?

A

Sense of seeing a situation for the first time, despite it happening many times before

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8
Q

What is a generalized seizure?

A
  • Generated centrally and spreads through both hemispheres

- Loss of consciousness

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9
Q

What are two types of generalised seizure?

A

Tonic-clonic seizure
- Grand mal
Absence seizure
- petit mal

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10
Q

What occurs in a tonic-clonic seizure?

A

Initial rigidity (tonic) and shaking (clonic)

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11
Q

What occurs in an absence seizure

A

Loss of expression, stare blankly, patient not aware of them

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12
Q

What is status epilepticus?

A

Seizure that lasts >5 minutes.

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13
Q

What is the mortality rate in status epilepticus?

A

20%

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14
Q

What must be excluded in any suspected fit?

A

Hypoglycaemia

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15
Q

What two drugs do you give in status epilepticus

A

Benzodiazepines

Phenytoin

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16
Q

What is primary epilepsy

A

No identifiable cause - 60-65%

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17
Q

What is secondary epilepsy?

A

Medical conditions affecting the brain 30%

  • Vascular disease
  • Tumour
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18
Q

What is most common cause of epilepsy in the elderly?

A

Secondary epilepsy

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19
Q

Give four categories of stimuli which could trigger epileptic fit

A 
Sensory stimuli 
Brain disease/trauma
Metabolic disturbances
Infections 
Therapeutics
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20
Q

Give a sensory stimuli that can cause epileptic fit

A

Flashing lights/strobes

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21
Q

Give four brain diseases/trauma which can cause epilepsy

A

Brain injury
Stroke/Haemorrhage
Drugs/alcohol
Structural abnormality

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22
Q

Give three metabolic disturbances which can cause epilepsy

A

o Hypoglycaemia
o Hypocalcaemia
o Hyponatraemia

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23
Q

What kind of infection causes epilepsy

A

Febrile convulsions

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24
Q

What therapeutics can cause epilepsy?

A

Anti-epilectic drugs and polypharmacy

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25
Q

Give four dangers in severe epilepsy

A 
o	Physical injury relating to fall/crash
o	Hypoxia
o	SUDEP – Sudden death in Epilepsy
o	Varying degrees of brain dysfunction/damage
o	Cognitive impairment
o	Serious psychiatric disease
o	Significant adverse reactions to medication
o	Stigma/Loss of livelihood
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26
Q

How do anti-epileptic drugs generally work, generally?

A

By inhibiting the rapid, repetitive neuronal firing that characterises seizures

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27
Q

How do anti-epileptics work specifically?

A

o Inhibition of channels involved in neuronal excitability
 Voltage gated Sodium channels
 Inhibition of Calcium Channel Function (not examined)
o Enhancement of inhibitory activity
 GABA-mediated inhibition

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28
Q

How to sodium channel blockers work?

A

By binding to sodium channels and keeping them in an inactivated state.
Self regulating, as detach from binding site.

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29
Q

How does GABA mediated inhibition work?

A

an increase in Chloride current into the neurone, increasing the threshold for action potential generation

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30
Q

What are three main pharmacological targets of GABA enhancers?

A

o Direct GABA agonists
o Benzodiazepine Site – Enhance GABA action
o Barbiturate Site – Enhance GABA action

31
Q

Name five anti-epileptic drugs

A 
Phenytoin
Carbamezapine (will be examined!) 
Lamotrigine
Sodium Valproate
Benzodiazepine
32
Q

What is first line treatments for seizures?

A

Sodium Valproate and Lamotrigine, then carbamezapine (unless tonic, atonic or myoclonic)

33
Q

What is first line in partial seizure?

A

Carbamezapine

34
Q

What is the indication for phenytoin?

A

All forms of epilepsy except absence

35
Q

What is the mechanism of phenytoin?

A

 Prolongs VGSC inactivation state

 Stops the spread of excitation from focus

36
Q

Give some phenytoin ADRs

A

 CNS effects – dizziness, ataxia, headache, Nystagmus, nervousness
 Gingival Hyperplasia (20%)
 Rashes – Hypersensitivity (Stevens-Johnson Syndrome 2-5%)

37
Q

Give some phenytoin DDIs

A

 CYP450 Inducer
 Many drug interactions, e.g. Warfarin, OCP
 Cimetidine  Phenytoin 
 Well absorbed, 90% Protein Bound
 Competitive binding, e.g. with Valproate, NSAIDs
 Can exacerbate non-linear PKs

38
Q

What precaution must be taken with phenytoin admin?

A

 Phenytoin displays Non-Linear Pharmacokinetics at Therapeutic concentrations (linear at sub-therapeutic levels). This means close monitoring of free plasma levels is required – saliva often used.

39
Q

How is carbamezapine administered?

A

Oral/rectal

40
Q

What are the indications of carbamexzapine

A

Second line for most except for absence seizures, tonic, atonic and myoclonic seizures (may make worse)

41
Q

What is a contraindication for carbamezapine

A

 AV conduction problems

42
Q

What is the mechanim of action of carbamezapine?

A

 Prolongs VGSC inactivation state

43
Q

What are some CNS ADRs of carbamezapine?

A

Dizziness, drowsiness, ataxia, motor disturbances, numbness, tingling

44
Q

Give three ADRs of carbamezapine other than CNS

A

Gi -Vomiting
CVS - BP variations
Hyponatremia

45
Q

Give three DDIs for carbamezapine

A

 CYP450 Enzyme Inducer
 Many drug interactions, e.g. Warfarin, OCP
 Protein bound
 Another protein binding drug can raise Carbamazepine conc.
 Antidepressants (SSRIs, MAOIs, TCAs and TCA) interfere with Carbamazepine’s action

46
Q

What are some therapeutic notes for carbamezapine?

A

 Well absorbed, 75% protein bound
 Linear Pharmacokinetics
 Initial t½ is ~30hrs, but is a strong inducer of CYP450s and therefore affects its own Phase I metabolism. In repeated use t½ falls to ~15hrs
 Drug monitoring required to adjust dosing due to falling t½

47
Q

What are some indications for lamotrigine?

A

 All forms of epilepsy
 Partial seizures
 Generalized tonic-clonic and absence seizures (unlike phenytoin and carbamezapine)

48
Q

What are some contraindications for lamotrigine?

A

 Hepatic impairment

 Not first line use in paediatric patients due to ADRs

49
Q

What is lamotrigines mechanism of action

A

Prolongs VGSC inactivation state

50
Q

What are some ADRs for lamotrigine (3)

A

 Less marked CNS dizziness, ataxia, somnolence (drowsiness)
 Nausea
 Some mild (10%) and serious (0.5%) skin rashes, which limits child use

51
Q

Give some DDIs for lamotrigine

A

 Adjunct therapy with other anti-epileptic drugs
 Oral Contraceptives reduce Lamotrigine plasma levels
 Valproate increases Lamotrigine plasma levels (protein binding)

52
Q

In what situation can you use lamotrigine when you can’t use other AEDs?

A

Pregnancy

53
Q

Give three significatn therapeutic notes for lamotrigine

A

 Increasingly first line anti-epileptic drug
 Well absorbed, linear PK = 24hrs
 No CYP450 induction

54
Q

What is the mechanism of action of sodium valproate? (3)

A

 Weak inhibition of GABA inactivation enzymes   GABAA
 Weak stimulus of GABA synthesising enzymes   GABA A
 Weak VGSC blocker and Weak Ca2+ channel blocker   Discharge

55
Q

Give give ADRs for Sodium valproate

A

 Generally less severe than with other AEDs
 CNS sedation – Ataxia, tremor
 Weight gain
 Hepatic Dysfunction – Transaminases increased in 40% of patients
 Rarely hepatic failure

56
Q

In light of this, what is a major contraindication for sodium valproate?

A

Acute Liver Disease/Hepatic dysfunction

57
Q

Give four DDIs with Sod Val

A

 Adjust therapy with other AEDs
 Care needed with adjunct therapy, as both Valproate and adjunct PKs are affected. E.g. displaces Lamotrigine and Phenytoin, raising their free plasma concentrations
 Antidepressants (SSRIs, MAOIs, TCAs and TCA) inhibit Valproate
 Antipsychotics antagonise Valproate, by lowering convulsive threshold
 Aspirin displaces Valproate from plasma proteins, raising its free conc

58
Q

Give three indications for benzodiazepines

A

 Diazepam / Lorazepam – Status Epilepticus
 Clonazepam – Absence seizures, short term use
 Anxiety

59
Q

What is a CI for benzos

A

 Respiratory depression

60
Q

Give mechs of action of Benzos

A

 Act at a distinct receptor site on GABA Chloride channel
 Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors
 Increases Chloride current into the neurone, increasing threshold for action potential generation

61
Q

Give three ADRs for Benzos

A 
	Sedation
	Tolerance with chronic use
	Dependence/Withdrawal with chronic use
	Confusion, impaired co-ordination
	Aggression
	Abrupt withdrawal – seizure trigger
	Respiratory and CNS depression
62
Q

What is a DDI for Benzos?

A

 Highly protein bound (85-100%)

 Some adjunct use

63
Q

How can benzos overdose be reversed?

A

 Overdose reversed by IV Flumazenil

 Use may precipitate seizure/arrhythmia

64
Q

What is a basic prescribing rule for AEDs?

A

Monotherapy is the aim

Systematic use of one drug and replacement if necessary

65
Q

What is the conundrum in pregnany epileptics?

A

Will stopping treatment harm mother and baby more than continuing?

66
Q

What are the risks of AEDs with pregnancy

A

Neural tube defects
Face and digital hyoplasia
Vit K deficiency (coagulopathy and cerebral haemorrhage)

67
Q

What can mothers take to avoid birth defects?

A

Folate supplements

68
Q

What should be avoided and what should be used as AED in preg?

A

Sodium valproate should be avoided - neural tube defect

Lamotrigine should be used - 2% defect rate

69
Q

What is the defet rate with most AEDs?

A

8%

70
Q

What is failure rate of contraceptives with Carbamezapine/phenytoin?

A

5-10%

71
Q

What is baseline failure rate of contraceptives?

A

1-2%

72
Q

Outline phenytoin drug monitoring

A

o Sub-Therapeutic Levels
 Linear Kinetics
o Therapeutic Levels
 Non-Linear Kinetics
 Saturated enzymes
 Plasma t½ increases as dose is increased
 Steady State Concentration in Plasma (achieved with a daily dose) varies disproportionately with the dose (see image).
The therapeutic range of Phenytoin is quite narrow, 40-100μmol. Drug monitoring of the plasma levels of Phenytoin is required, as due to its pharmacokinetic properties this therapeutic range can be exceeded quite rapidly, causing adverse effects (see above).

73
Q

What is status epilepticus?

A

o Medical emergency
o Adult mortality ~20%
o Risk increases with the length of Status Epilepticus

74
Q

How do you manage status epilepticus?

A

o ABC approach
o Exclude hypoglycaemia
o Hypoventilation may result with high AED doses
o ITU for paralysis and ventilation if AEDs are failing

AEDs in Status Epilepticus
o Benzodiazepines
 Lorazepam (0.1mg/kg)
 Preferred to Diazepam due to longer t½
 Given intravenously (rectal if IV access difficult)
o Phenytoin
 Zero Order (Non-Linear) kinetics (15-20mg/kg)
 Rapidly reaches therapeutic levels IC
 Cardiac monitoring – Arrhythmias and hypotension

Semester 5 - Farmocology (27 decks)

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