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Pharmacology (Semester 6) > 4.1 Anti Epileptic Drugs > Flashcards

4.1 Anti Epileptic Drugs Flashcards

1
Q

Define epilepsy

A

Recurrent tendency to spontaneous intermittent abnormal electrical activity in brain leading to seizure

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2
Q

Seizures may be with or without loss of __________, and with or without __________

A Seizure in the motor cortex area will cause __________

A

consciousnes, convulsions, convulsions

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3
Q

What 2 things must we be aware of when prescribing Anti Epileptic Drugs (AEDs)

A

1) ADRs - Common, some serious
2) DDIs - Some positive combined with other AEDs but often negative PK interactions

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4
Q

Give a medico-social consequence of misdiagnosis of Epilepsy

A

ban on driving a car (+ other social ,financial, medical implications)

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5
Q

What causes Epilepsy? (4)

(NEIL)

A

Increase in Cerebral Neurone Excitability by :

  • Spread of Neuronal Hyperactivity
  • Increased Excitation
  • Decreased Inhibition
  • Loss of Homeostatic Control
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6
Q

What are the TWO main types of Epilepsy?

A

FOCAL seizures (partial) – affect one (unilateral) hemisphere

GENERALISED seizures – affect both (bilateral) hemispheres

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7
Q

What is Status Epilepticus and how does it differ from other seizures?

A

Most seizures are short lived (up to 5 mins) BUT Status Epilepticus is prolonged or repeated frequently WITHOUT recovery interval

Medical Emergency!

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8
Q

What are the major risks if Status Epilepticus is not treated?

A

1) varying degrees of brain dysfunction/damage ➞ by hypoxic encephalopathy
2) death ➞ sudden unexpected death in epilepsy (SUDEP)

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9
Q

Give 4 dangers of severe Epilepsy (not incl brain damage or SUDEP)

A
  1. Physical injury relating to fall /crash
  2. Hypoxia – respiratory muscles in spasm
  3. Cognitive impairment
  4. Serious psychiatric disease
  5. Significant adverse reactions to medication
  6. Stigma / Loss of livelihood / life changing event
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10
Q

What are the 2 main therapeutic targets for AEDs

A

1) Voltage Gated Sodium Channel Blockers
2) Enhancing GABA Mediated Inhibition

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11
Q

Explain the mechanism of VGSC hyperactivity in epilepsy

A

1) local loss of membrane potential homeostasis starts at focal point
2) small number of neurones form a generator site and heavily depolarise
3) hyperactivity spreads via synaptic transmission to other neurones

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12
Q

What is the purpose of VGSC blockers?

A

VGSC Blockers reduce probability of high abnormal spiking activity so neurons can only fire at a constant rate.

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13
Q

Explain the MoA of VGSC blockers

A

1) the VGSC blockers enters the chanel and gains access to binding site during depolarisation (when they are open).
2) the blocker stablises this channel as it enters its refractory peroid which prolongs its inactivation state.
3) by increasing the relative refractory period of the chanels it brings the firing rate back to normal.
4) once neurone membrane potential returns back to normal the VGSC Blocker detaches from binding site.

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14
Q

Give 2 common examples of a VGSC blocker

A

Carbamazepine and Phenytoin

(both prolong VGSC inactivation state)

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15
Q

Carbamazepine is well absorbed (75% protein bound) and exhibits _______ PK.

Its Initial t1/2 is _____ hrs BUT reduces to a t1/2 of _____hrs.

A

Linear, 30, 15,

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16
Q

Why does t1/2 of Carbamazapine reduce after repeated use?

A

Carbamazipine is a strong inducer of CYP450 (3A4).This particular isoform of CYPs is actually the one which metabolises carbamazipine itself, hence this drug activates its own phase 1 metabolism. The effect of this is a reduction in its t1/2 to 15hrs after repeated use.

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17
Q

How does the change in t/12 of carabamazipine over time affect the dosage we prescribe to our patients?

A

Initially start on lower dosage (100-200mg 1-2 per day)

With continued use dose must be increased in steps of around 100-200mg in 2 weeks (800mg-1.2g divided doses throughout day)

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18
Q

Give 2 epilepsy types treated with Carbamazepine

A

1) Generalised Tonic-Clonic
2) Partial - All

(Not Absence Seizures)

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19
Q

What are some common symptoms of ADRs experienced with carbamazipine?

A

Wide ranging Type As: affects on the CNS such as –

dizziness, drowsy, ataxia, motor disturbance, numbness & tingling

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20
Q

Give 4 other systemic ADRs that may be experienced with carbamazipine

A
  1. GI - upset vomiting
  2. CV – can cause variation in BP
  3. Hypersensitivity (Rashes)
  4. Hyponatraemia

Rarely: Severe bone marrow depression – neutropenia

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21
Q

What is a major contraindication for carbamazipine?

A

AV conduction problems

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22
Q

As carbamazipine is a CYP450 inducer, it can also increase metabolism of other drugs which decreases their effectivness

Give 4 examples

A

1) Phenytoin (AED) ➞ also effects its PK/binding due to ↑ conc of CBZ in plasma
2) Warfarin
3) Systemic Corticosteroids
4) Oral contraceptives

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23
Q

What is Stevens-Johnson syndrome (SJS)?

A

A rare but serious disorder of hypersensitivity caused by an ADR (unpredictable) or sometimes by an infection

It begins with flu-like symptoms, followed by a red or purple rash that spreads and forms blisters. It affects the skin, mucous membrane, genitals and eyes.

Medical emergency! requires treatment in ITU or burns unit

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24
Q

Give a drug class which interferes with the action of Carbamazepine (+ examples)

A

Antidepressants - SSRIs MAOIs TCAs and TCA

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25
Q

Give 2 things we must always do for drug monitoring of carbamazipine

A

1) Monitor dosing to effect and adjust dosing as t1/2 decreases
2) Always check BNF with any other drugs given

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26
Q

Phenytoin is well absorbed but 90% is bound in plasma, what is the implication of this on DDIs?

Give 2 examples

A

Competitive protein binding can increase levels of free phenytoin in plasma which exacerbates Non-Linear PKs

Valproate (AED) and NSAIDs displace bound phenytoin, increasing plasma levels of the free drug

Because Phenytoin shows non-linear kinetics and large intrasubject variability (for dose required to remain within theraputic window), small increases in plasma conc of free drug will have serious effects

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27
Q

Phenytoin is a CYP450 inducers, specifcally isoform ____

A

3A4

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28
Q

What is the effect of Phenytoin on CYPP450 and how does this differ from carbamazipine

A

Both induce the CYP3A4 but, phenytoin is metabolised by CYP2C9 and CYP2C19 and so does NOT increases its own metabolism

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29
Q

Why does Carbamazipine increase metabolism of Phenytoin?

A

because in additon to increasing its own metabolism by inducing CYP3A4 it also induces CYP2C9 which is a metaboliser of Phenytoin

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30
Q

Why can we not calculate t1/2 for phenytoin?

What does this mean for dosing?

A

Because at theraputic concs it shows NON-LINEAR kinetics and variable t1/2 = 6-24 hrs

There is also big differences with intra-subject variability and hence there is large variability in dose required to get to therapeutic levels

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31
Q

What are some common symptoms of ADRs experienced with phenytoin?

A

Very wide ranging Type A’s: effects on the CNS such as –

dizziness, ataxia, headache, nystagmus, nervousness

32
Q

Phenytoin is well absorbed but 90% is bound in plasma, what is the implication of this on DDIs?

Incl 2 drug examples

A

If phenytoin is given while patient is on valporate or NSAIDs, competitive protein binding by phenytoin will displace these drugs from their binding sites and increase levels of free drug in plasma

However, it is hard to determine what % of phenytoin actually displaces the already bound drug. ie if patient is given 2mg will the entire 2mg bind, 1mg or 0.25 mg? We dont know.

Due to Phenytoins non-linear kinetics and large intrasubject variability this signifcantly excerbates its non-linear pk

33
Q

Give 3 systemic ADRs that may be experienced with Phenytoin

A

1) Gingival Hyperplasia (20%)
2) Rashes - Hypersensitivity
3) + Stevens Johnson (2-5%)

34
Q

In additon to valporate and NSAIDs give another DDi with Phenytoin

A

Increases metabolism of the OCP (reducing its effectivness) due to induction of CYP3A4 enzyme

35
Q

What is Cimetidine and what is its effect on Phenytoin

A

Cimetidine is a histamine antagonist (anti-histamine)

Inhibits the metabolism of Phenytoin

36
Q

Give 2 things we must always do for drug monitoring of Phenytoin

A

1) check BNF for any other drugs given in combination
2) close monitoring of free concentration in plasma (can use salivary levels as indicator of free plasma)

37
Q

Give 2 types of Epilepsy that can be treated with Phenytoin

A

1) Generalised Tonic-Clonic
2) Partial - All

(Not Absence Seizures)

38
Q

What is the action of Lamotrigine?

A

VGSC blocker ➞ prolongs VGSC inactivation state AND has a seconday role in Ca2+ channel blocking + decreasing glutamate release

39
Q

Lamotrigine is well absorbed and shows a ________ PK

Its t1/2 is ____ hrs and only undergoes _______ metabolism meaning it does not have CYP450 _______.

A

Linear, 24, Phase II, induction

40
Q

What is the benefit of no CYP450 induction by Lamotrigine?

A

fewer DDIs

41
Q

Give 3 ADRs of Lamotrigine

A

1) CNS Dizziness, ataxia, somnolence (less marked thank others)
2) Nausea (some mild (10%) and serious (0.5%))
3) Skin rashes

42
Q

Give 3 DDIs of Lamotrigine and their effects

A

1) Adjunct therapy with other AEDs.
2) OCP reduce LTG plasma level
3) Valproate ↑ LTG in plasma (competitive binding)

43
Q

Give 3 types of Epilepsy treated with Lamotrigine

A

1) Partial Seizures
2) Generalised -Tonic-clonic
3) Absence Seizures

+ other subtypes

44
Q

What is the first line AED?

When is it not used as first line and why?

A

Lamotrigine

Not first line paediatric use as increased ADRs

45
Q

Which AED is most commonly prescribed during pregnancy?

A

Lamotrigine

46
Q

Give a common example of drug which enhances GABA mediated inhibition

A

γ-Aminobutyric acid

47
Q

What is the purpose of enhancing GABA mediated Inhibition for epilepsy?

A

It has a major role in post synaptic inhibition, 40% synapses in brain are GABA-ergic

Increasing GABA is natural anticonvulsant or excitatory ‘brake’

48
Q

Give the name of the 3 distinct pharmacological targets located on the GABA channel

A

1) binding with GABAA receptor by direct GABA agonists
2) binding to Benzodiazepine Site on GABA receptor to Enhance GABA action
3) binding to Barbiturate site on GABA receptor to enhance GABA action

49
Q

Give the general mechanism of GABA mediated inhibition enhancement

A

Increased Chloride current into neurone - increases threshold for action potential generation

Reduces likelihood of epileptic neuronal hyperactivity

Makes membrane potential more negative

50
Q

What is the role of Benzodiazepines?

A

Act at distinct receptor site on GABA Chloride channel. Increases Chloride current into neurone which increases threshold for action potential generation

51
Q

How do we enhance GABA mediated inhibition furthur

A

Binding of GABA or BZD enhance each others binding ➞ act as positive allosteric effectors

More bound to each site = more inhibition by GABA

52
Q

Benzodiazapines are well absorbed (90-100%) and are highly plasma bound 85-100%

They have a _______ PK and a t/2 which varies between ____ and ____ hrs

A

Linear, 15-45 hrs

53
Q

Give 4 ADRs of Benzodiazepines

A
  1. Sedation
  2. Tolerance with chronic use
  3. Confusion impaired co-ordination
  4. Aggression
  5. Dependence/Withdrawal with chronic use
  6. Abrupt withdrawal seizure trigger
  7. Respiratory and CNS Depression
54
Q

Give 2 DDIs with Benzodiazepines

A

1) Some adjunctive use
2) Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia.

55
Q

Give 2 types of epilepsy we can use Benzodiazepines to treat

Incl specific drug examples

A

1) Lorazepam / Diazepam - for Status Epilepticus
2) Clonazepam - for Absence seizures - short term use

56
Q

Why are benzodiazapines not first line AEDs?

A

Side effects limit first line use

57
Q

Give 3 pharmacological targets against GABA metabolism

A

1) Inhibition of GABA inactivation
2) Inhibition of GABA re-uptake
3) Increase rate of GABA synthesis

Targeting these sites enhance action of GABA (GABA ↑)

58
Q

What is the role of Valproate in enhancing GABA mediated Inhibition

A

There is evidence in vitro for mixed sites of action (pleiotropic)

Thought to be:

  • weak inhibition of GABA inactivation enzymes- GABA ↑
  • weak stimulus of GABA synthesising enzymes-GABA ↑
  • VGSC blocker + weak Ca2+ channel blocker - discharge ↓ (makes excitable neurones less likley to fire)
59
Q

Valporate is 100% absorbed then 90% plasma bound

It exhibits ______ PK and has a t1/2 of ___ hrs

A

Linear, 15

60
Q

Give 3 ADRs of Valproate

A

Generally less severe than with other AEDs but incl

1) teratogenic causing increased no. of birth defects
2) CNS sedation ataxia tremor - weight gain
3) Hepatic function - ↑ transaminases in 40% patients (can lead to hepatic failure- rare)

61
Q

Give 4 DDIs of Valproate and how

A

1) Adjunct therapy with other AEDs (both Valproate and adjunct PKs affected - check BNF)
2) antidepressants - SSRIs MAOIs TCAs & TCA inhibit action of Valproate
3) antipsychotics - antagonise Valproate by lowering convulsive threshold.
4) Aspirin - competitive binding in plasma

62
Q

What must we do when drug monitoring patients on Valporate?

Why may this be less/more impt for Valporate?

A

Close monitoring of free concentration in plasma (can use salivary levels as indicator)

Plasma Valproate is not closely associated with the efficacy of the drug however, must monitor for blood, metabolic and hepatic disorder

63
Q

Give 3 types of Epilepsy treated with Valporate?

A

1) Partial Seizures
2) Generalised Tonic-Clonic
3) Absence Seizures

64
Q

What is the use of Cannabis oil in epilepsy?

A

Used as adjuvant therapy

Contains cannabinoids, notably THC (psychoactive effects) and CBD (therapeutic effects)

  • The CBD is an agonists of cannabinoid receptors CB1 and CB2
  • CBD is cross-reactive with many GPCRs as agonist and antagonist
  • CBD increases plasma conc of Clobazam (benzodiazapine), by inhibition of CYP2C19
65
Q

What is meant by the ‘balance of risk’ for epilepsy during pregnancy?

A

potential for seizures damaging to mother and foetus VS potential risk of drug teratogenicity

66
Q

How does management of epilepsy during pregancy differ in mild vs severe disease?

A

Mild disease - consider stopping treatment

Severe disease or Status Epilepticus - in most cases preferable to continue treatment

67
Q

What is the effect of carbamazepine/phenytoin on contraception

A

Failure rate x 4

68
Q

Give 3 Dangers to the foetus during pregnancy if mother continues of AESs

A

1) Congenital malformations
2) Valproate a/w neural tube defects: spina bifida, craniofacial and digital abnormalities
3) Learning difficulties / mild neurological dysfunction

69
Q

Which AED is specifcally associated with neural tube defects?

A

Valproate

70
Q

If mother is required to stay on her AED during pregnancy, how would we manage this?

A

Multiple AEDs increase teratogenic risk, so use a single AED agent if possible at lowest dose ➞ Lamotrigine

71
Q

Give 2 dietary supplements a pregnant women on AED’s should take, and why

A

Folate supplement - to reduce risk of neural tube defects

Vit K supplements (10 mg/day) in last trimester - because AEDs are associated with Vit K deficiency in new born

72
Q

Give 2 consequences of Vit K deficiency in a newborn

A

coagulopathy and cerebral haemorrhage

73
Q

Status Epilepticus is a Medical Emergency. Risk increases with _______ of seizure.

Priorities are _______, _______, _______

_______ may result from high AED doses, which may require intubation and ventilation in ITU.

Do NOT forget to exclude ________.

A

Duration, Airway, Breathing, Circulation, Hypoventilation, Hypoglycaemia

74
Q

Give 3 ways benzodiazapines can be administered for status epilepticus

A

1) IV Lorazepam (0.1 mg/kg) - preferred due to longer half life
2) IV Diazepam (0.2 mg/kg) or Rectal Diazepam 10mg suppository
3) Buccal Midazolam 5-10 mg (Epistatus)

Administration depends on situation, use clinical judgement

75
Q

If Benzodiazapines do not work, we can use phenytoin.

Give the dosage, one benefit and what we MUST monitor when using this drug

A

Zero order kinetics, use 15-20 mg/kg

Benefit: rapidly reaches therapeutic levels IV

Cardiac monitoring! For arrhythmias + hypotension

76
Q

Give 3 other drugs that can be used in treatment of Status Epilepticus

A

Midazolam, Thiopentone, Propofol

77
Q

SUMMARY: give the most appropriate drug for the following

  1. Generalised and Absence seizures
  2. Pregnancy
  3. Focal seizures e.g Temporal Lobe
  4. Status Epilepticus
A

1) Valproate for Generalised and Absence seizures
2) Lamotrigine in pregnancy
3) Carbamazepine for Focal seizures e.g Temporal Lobe
4) Lorazepam for Status Epilepticus + start Phenytoin

Pharmacology (Semester 6) (17 decks)

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