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Clinical Pharmacology and Therapeutics > AEDs > Flashcards

AEDs Flashcards

1
Q

What is epilepsy?

A

An episodic discharge of abnormal high frequency electrical activity in the brain, leading to seizures

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2
Q

How is epilepsy diagnosed?

A

Evidence of recurrent seizures unprovoked by other identifiable causes

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3
Q

What is the prevalence of epilepsy?

A

0.5-1 in 100

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4
Q

How should epilepsy be viewed?

A

As a symptom of an underlying neurological disorder (not a single disease entity)

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5
Q

What % of patients have success with epilepsy treatment?

A

75%

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6
Q

How many sudden deaths per year are caused by chronic epilepsy?

A

500

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7
Q

What are the 4 mechanisms of epilepsy?

A
  • Increased excitatory activity
  • Decreased inhibitory activity
  • Loss of homeostatic control
  • Spread of neuronal hyperactivity
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8
Q

What are the 2 major classes of seizure?

A

Partial/Focal

Generalised

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9
Q

How can partial seizures be divided?

A

Simple or complex

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10
Q

What is status epilepticus?

A

Seizure prolonged beyond 5 minutes or a series of seizures without a recovery interval

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11
Q

Why is status epilepticus a medical emergency?

A

If it is untreated it can lead to brain damage or death (SUDEP)

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12
Q

What are some of the physical dangers of severe epilepsy?

A

Physical injury secondary to seizure (fall, car crash)
Danger to others (see above)
Hypoxia
SUDEP
Varying degrees of brain damage or cognitive impairment

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13
Q

What are some of the dangers of treating epilepsy?

A

ADRs

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14
Q

What are some of the psychosocial dangers of epilepsy?

A

Stigma
Loss of livelihood
Loss of driving liscence
Psychiatric disease

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15
Q

What % of epilepsy cases are primary/idiopathic?

A

65-70%

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16
Q

What can cause secondary epilepsy?

A

Other disease affecting the brain
Vascular disease
Tumours

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17
Q

What % of epilepsy in the elderly is secondary?

A

60%

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18
Q

What sensory stimuli can precipitate a seizure?

A

Flashing lights
Strobes
Other periodic sensory timuli

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19
Q

What brain diseases can precipitate a seizure?

A 
Brain injury
Haemorhhage
Drugs
Alcohol
Structural abnormality/lesion
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20
Q

What metabolic disturbances can precipitate a seizure?

A

Hypoglycaemia
Hypocalcaemia
Hyponatraemia

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21
Q

What infections can precipitate a seizure?

A

TB
HIV
Cerebral malaria
Meningitis

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22
Q

How can some therapeutic agents precipitate a seizure?

A

By lowering the fit threshold

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23
Q

What therapeutic agents/drugs can precipitate a seizure?

A

Polypharmacy
Recreational drug abuse
Alcohol
Missing doses of medication

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24
Q

What are the main therapeutic targets for AEDs?

A
  • Voltage gated sodium channels (blocking)

- GABA mediated inhibition (enhancing)

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25
Q

When are VGSCs active?

A

Only when the neurone is activated

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26
Q

How do VGSC blockers work?

A

They bind to the activated/depolarised gate to prevent further propagation of action potentials

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27
Q

What do VGSC blockers reduce?

A

The probability of high abnormal spiking activity

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28
Q

What happens to the VGSC blockers when the membrane potential is back to normal?

A

It detaches from the site

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29
Q

Name 3 VGSC bloclers

A
  • Carbamezepine
  • Phenytoin
  • Lamotrigine
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30
Q

What is the indication for carbamezepine according to NICE/BNF?

A

-Focal and secondary generalised tonic-clonic seizures,
Primary generalised tonic-clonic seizures

  • Trigeminal neuralgia
  • Prophylaxis of bipolar disorder unresponsive to lithium
  • Adjunct in acute alcohol withdrawal
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31
Q

Tell me about the pharmacology of carbamezepine

A

Well absorbed
75% bound to protein in the blood
Linear pharmacokinetics

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32
Q

What is the half life of carbamezepine?

A

30 hours

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33
Q

What dose should carbamezepine for epilepsy be started at in an adult?

A

100-200mg 1-2 times a day

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34
Q

What is funny about carbamezepines metabolism?

A

It induces CYP450 but is also metabolised by it, so it affects its own phase one metabolism, how crrraaaazy is that?!?!

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35
Q

What can happen with use of carbamezepine?

A

Half life reduces to 15 hours

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36
Q

What CNS side effects can carbamezepine have?

A 
Dizziness
Drowsiness
Ataxia
Motor disturbance
Numbness
Tingling
Headache
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37
Q

What GI side effects can carbamezepine have?

A

GI upset

Vomiting

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38
Q

What CVS side effects can carbamezepine have?

A

Variations in BP

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39
Q

What other (not CVS, CNS or GI) side effects can carbamezepine have?

A

Rashes
Hyponatraemia
Rarely - severe bone marrow suppression

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40
Q

When is carbamezepine contraindicated?

A
  • AV node conduction problems
  • Hx of bone marrow suppression
  • Acute porphyrias
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41
Q

Is carbamezepine safe in pregnancy?

A

It increases the risk of neural tube defects

Doses should be adjusted to plasma levels

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42
Q

Which drugs are decreased in efficacy due to carbamezepine inducing CYP450?

A

Phenytoin
Warfarin
Systemic corticosteroids
Oral contraceptives

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43
Q

What other DDIs happen with carbamezepine and phenytoin?

A

Phenytoin binds to plasma proteins and displaces carbamezepine so CBZ plasma concentration increases (so probs has some other side effects because of that)

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44
Q

How should carbamezepine be monitored?

A

Dose to effect, and adjust dosing as t1/2 decreases

First check plasma conc after 1-2 weeks of use

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45
Q

What is the indication for phenytoin according to NICE/BNF?

A

Tonic-clonic seizures , Focal seizures (adults and children)

Prevention and treatment of seizures during or following neurosurgery or severe head injury in adults and children

Status epilepticus

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46
Q

Tell me about the pharmacology of phenytoin

A

Well absorbed
90% bound to plasma protein
CYP450 inducer (not metabolised by cyp450)

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47
Q

What can cause plasma concentrations of phenytoin to increase?

A

Competition from other protein bound drugs for binding sites

48
Q

Why are therapeutic levels of phenytoin hard to manage?

A

Phenytoin has linear kinetics at subtherapeutic levels, but non-linear at therapeutic levels

49
Q

What is the half life of phenytoin?

A

UNPREDICTABLE!!!

6-24 hours

50
Q

Why is it necessary to titrate the levels of phenytoin?

A

To achieve a balance between efficacy and side effects, and keeping it within the therapeutic window

51
Q

What CNS side effects can be experienced with phenytoin?

A 
Dizziness
Ataxia
Headaches
Nystagmus
Nervousness
52
Q

What ADR do 20% of phenytoin users experience?

A

Gingival hyperplasia

53
Q

What ADR do 2-5% of phenytoin users experience?

A

Rashes (hypersensitivity and Stevens Johnson)

54
Q

What dose should phenytoin for epilepsy be started at in an adult?

A

3-4mg/kg daily initially

55
Q

Which other drugs does phenytoin compete for binding sites with in the plasma?

A

Valproate
NSAIDs
Salicylates (including aspirin)

56
Q

Which drug is decreased in efficacy with phenytoin, and why?

A

Oral contraceptive as it is metabolised by CYP450

57
Q

What does cimetidine do to phenytoin?

A

Increases plasma concentration (no effect on plasma protein binding), probably by inhibiting its metabolism

58
Q

How should phenytoin use be monitored?

A

Free concentration in plasma

59
Q

What can e used as an indication of free concentration of phenytoin in plasma?

A

Salivary levels of phenytoin

60
Q

When is phenytoin contrainidcated?

A

Acute porphyrias
2nd or 3rd degree heart block
Sino-atrial block
Sinus bradycardia

61
Q

When should phenytoin be stopped immediately?

A

If there is hepatotoxicity

62
Q

What can happen in phenytoin toxicity? (symptoms)

A 
Nystagmus
Diplopia
Slurred speech
Ataxia
Confusion
Hyperglycaemia
63
Q

What is the indication for lamotrigine according to NICE/BNF?

A

Focal seizures
Primary and secondary generalised tonic-clonic seizures
Bipolar Disorder

64
Q

Tell me about the pharmacology of lamotrigine

A

Well absorbed
Linear PK
Not a CYP450 inducer

65
Q

What is the half life of lamotrigine?

A

24 hours

66
Q

Why does lamotrgine have fewer DDIs than other VGSC blockers?

A

It is NOT a CYP450 inducer

67
Q

Why else is lamotrigine a good VGSC blocker?

A

It has less marked ADRs

68
Q

What CNS side effects does lamotrigine cause?

A

Dizziness
Ataxia
Somnolence

69
Q

What other side effects can lamotrigine cause?

A 
Mild Nausea (10%)
Serious nausea (0-5%)
Skin rashes (especially in children)
70
Q

When is it especially important to monitor drug levels with lamotrigine?

A

When used in combination therapy with other AEDs

71
Q

What can decrease the levels of lamotrigine in theblood?

A

Oral contraceptives

72
Q

How do valproate and lamotrigine interact?

A

Valproate increases LTG in blood due to competative binding

73
Q

What are the potential benefits of lamotrigine over other AEDs?

A

Potentially safer in pregnancy than other VGSC blockers

74
Q

What are the 2 ways of enhancing GABA mediated inhibition?

A

Decreasing GABA metabolism

Binding with GABAa receptors

75
Q

Which agents bind with GABA a receptors?

A

Valproate

Benzodiazepines

76
Q

Which agent decreases GABA metabolism?

A

Valproate

77
Q

What % of synapses in the brain are GABA-ergic?

A

40%

78
Q

What is the major role of GABA in the brain?

A

Post-synaptic inhibition

79
Q

What does this mean increased levels of GABA do?

A

Act as a natural anticonvulsant and as an excitatory brake

80
Q

Where do benzodiazepines and barbiturates work?

A

At different sites (subnits) on the GABA receptor

81
Q

What is the structure of a GABA receptor?

A

Cl- channel running between 5 subunits, each with different associated bidning sites

82
Q

How does binding with a GABA a receptor work as an AED mechanism?

A

The binding of the drug causes an increased Cl- current through the channel into the neurone so the threshold for an action potential is increased and the resting membrane potential becomes more negative

83
Q

What are the mechanisms of decreased GABA metabolism?

A
  • Inhibit reuptake
  • Inhibit inactivation
  • Increase synthesis
84
Q

Why is valproate considered a “dirty” drug?

A

It is pleotropic i.e. it acts at multiple sites

85
Q

Describe the many actions of valproate (breifly)

A

Weak inhibition of GABA inactivation
Weak stimulus of GABA roduction
VGSC blocker
Weak Ca2+ channel blocker

86
Q

Tell me about the pharmacology of valproate

A

100% absorbed
90% bound to plasma
Linear PK

87
Q

What is the half life of valproate?

A

15 hours

88
Q

What is good aboiut valprate for the patient?

A

The ADRs are generally less severe than with other AEDs

89
Q

What CNS side effects can valproate have?

A

drowsiness
ataxia
tremor

90
Q

What other side effects can valproate have?

A

Weight gain

Deranged hepatic function (eg increased transaminase)

91
Q

What inhibits valproate?

A

Antidepressants! SSRIs, MAOI, TCAs,

92
Q

How do antipsychotics antagonise valproate?

A

By lowering the convulsive threshold

93
Q

How do aspirin and valproate interact?

A

Compete for binding sites so plasma valproate increases

94
Q

What is the indication for valproate according to NICE/BNF?

A

All forms of epilepsy

95
Q

What is the starting dose for an adult for valproate?

A

600mg daily (divided into 1 or 2 doses)

96
Q

What is the deal with pregnancy and valproate?

A

Valproate is contraindicated in pregnancy as it is teratogenic
Pregnancy should be excluded before starting valproate
An effective contraceptive must be given with valproate in women with child-bearing potential

97
Q

What is the deal with pregnancy and valproate?

A

Valproate is contraindicated in pregnancy as it is teratogenic
Pregnancy should be excluded before starting valproate
An effective contraceptive must be given with valproate in women with child-bearing potential

98
Q

Name some benzodiazepines

A

Valium
Lorazepam
Diazepam
Clonazepam

99
Q

When do benzos act?

A

At a distinct site on the GABA chlorine channel

100
Q

What effect do GABA and BZDs have on each other?

A

They enhance the effect of the other

101
Q

Tell me about the pharmacology of benzodiazepines

A

Well absorbed (90-100%)
Highly plasma bound (85-100%)
Linear PK

102
Q

What is the half life of benzodiazepines?

A

~15-45 hours

103
Q

When are benzos used, and why?

A

Usually only in status epilepticus as they have a wide range of ADRs. Not usually first line for epilepsy.

104
Q

What are some of the ADRs of benzodiazepines?

A 
Sedation
Tolerance in chronic use
Confusion
Impaired coordination
Aggression
Trigger seizures if withdrawn abruptly
Respiratory and CNS depression
105
Q

How is a benzo overdose treated?

A

IV flumazenil

106
Q

What is the problem with flumazenil?

A

It may precipitate a seizure or arrhythmia

107
Q

What is the optimal aim when prescribing AEDs?

A

Monotherapy!

108
Q

With this in mind, how should epilepsy drugs be started?

A

Systematically, one at a time, replacing those which are ineffective

109
Q

What should drug choice be based on?

A

The individual patient and the seizures they have had

110
Q

What should be done in pregnancy with epilepsy?

A

Balance the risk of epilepsy vs the risk to the pregnancy (AED teratogenicity)

111
Q

What is the failure rate of OCP when combined with AED?

A

4x higher than normal as metabolism increased (up to 4-8% failure rate). Dose dependant, up to 10%.

112
Q

What effect can many AEDs have on the foetus?

A

Facial and digital hypoplasia

General congenital malformation

113
Q

Which AED is a) the worst in pregnancy, and b) the safest?

A

a) Valproate

b) Lamotrigine

114
Q

What can help reduce the risk of neural tube defects with AEDs?

A

Taking a folate suppliment, ideally prior to conception

115
Q

What other suppliment should be given to the mother on AEDs, when, and why?

A

Vitamin K
Third Trimester
Prevents newborn deficiency which leads to coagulopathy and haemorrhage

116
Q

What are the drugs usually given for status epilepticus in order of priority?

A
  1. Benzos (usually lorazepam) - fast acting with good control
  2. Phenytoin - reaches therapeutic levels quickly IV but cardiac monitoring (zero order kinetics)
  3. Midazolam/Pentobarbital/Propofol

Clinical Pharmacology and Therapeutics (26 decks)

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