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3153 Seizure & Epilepsy > Adverse effects of ASMs > Flashcards

Adverse effects of ASMs Flashcards

1
Q

[Dose/Plasma concentration-related adverse effects]

4 broad classes of dose-related ADRs

A
  • CNS
  • GI
  • Psychiatric
  • Cognition

Dose related ADRs are usually the main limiting factor in epilepsy treatment

Severity and frequency of these ADRs vary amongst ASMs

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2
Q

[Dose/Plasma concentration-related adverse effects]

CNS side effects include:

A
  • Somnolence
  • Fatigue
  • Dizziness
  • Visual disturbances (double/blurred vision)
  • Nystagmus (vision condition, uncontrolled eye movement)
  • Ataxia (poor muscle control, clumsy movement)
  • Mental changes
  • Coma
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3
Q

[Dose/Plasma concentration-related adverse effects]

GI side effects include:

Which drugs more a/w these SEs?

A
  • Nausea
  • Vomiting

Carbamazepine
Valproate

Phenytoin

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4
Q

[Dose/Plasma concentration-related adverse effects]

Psychiatric side effects include:

Which drugs more a/w these SEs?

A
  • Behavioural disturbances (irritability, aggression, mood changes)

Levetiracetam

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5
Q

[Dose/Plasma concentration-related adverse effects]

Cognition side effects include:

Which drugs more a/w these SEs?

A
  • Speech fluency
  • Psychomotor slowing
  • Memory

Topiramate

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6
Q

[Dose/Plasma concentration-related adverse effects]

Hyponatremia is a possible dose-related ADR of which drug?

A

Carbamazepine

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7
Q

[Dose/Plasma concentration-related adverse effects]

When are dose-related ADRs most prominent?

A
  • Higher ASM concentrations
  • More frequent and occur at lower plasma conc. in pt receiving ASM combi therapy (due to additive neurologic effects)
  • Mostly occur during initiation of therapy, but may disappear as tolerance develops
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8
Q

[Dose/Plasma concentration-related adverse effects]

Mitigation of dose-related ADRs

A
  1. Initiate at low dose, titrate slowly
  2. Avoid large dose changes
  3. Restrict therapy to one drug only
  4. Adjust administration schedule
  • largest dose at bedtime to avoid SEs during daytime
  • divide daily dose into smaller doses given more frequently
  • sustained-release formulations to achieve baseline level throughout the day
  • reduce total daily dose (if clinically safe)
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9
Q

[Idiopathic/hypersensitivity-related adverse effects]

Which ASMs are associated with hypersensitivity ADRs?

A

All current ASMs (except some 2nd gen ASMs) have been a/w development of rare (<0.1%) but serious idiosyncratic reactions

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10
Q

[Idiopathic/hypersensitivity-related adverse effects]

When are hypersensitivity ADRs most likely to occur?

A

Most likely occur in first few months of therapy

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11
Q

[Idiopathic/hypersensitivity-related adverse effects]

Name the reactions that may occur

A
  • Blood dyscrasias (aplastic anemia, agranulocytosis)
  • Hepatotoxicity
  • Pancreatitis
  • Lupus-like reaction
  • Exfoliative dermatitis
  • TEN/SJS
  • Hyperammonemia
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12
Q

[Idiopathic/hypersensitivity-related adverse effects]

  • ASMs a/w blood dyscrasias
A

Blood dyscrasias

  • All ASMs can cause blood dyscrasias
  • Carbamazepine (Aplastic anemia)
  • Valproate (possibly)
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13
Q

[Idiopathic/hypersensitivity-related adverse effects]

  • ASMs a/w Hepatotoxicity
A

Hepatotoxicity

  • 1st gen ASMs: phenytoin, valproate, carbamazpine
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14
Q

[Idiopathic/hypersensitivity-related adverse effects]

  • ASMs a/w Pancreatitis
A

Pancreatitis

  • Sodium valproate
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15
Q

[Idiopathic/hypersensitivity-related adverse effects]

  • ASMs a/w TEN/SJS
A
  • Carbamazepine
  • Phenytoin
  • Lamotrigine
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16
Q

[Idiopathic/hypersensitivity-related adverse effects]

  • ASMs a/w hyperammonemia
A

Hyperammonemia

  • Sodium valproate

=> Hyperammonemia encephalopathy (drowsiness, lethargy, changes in level of consciousness, slowing cognition, neurological deficits)

17
Q

[Chronic adverse effects]

Characteristics of chronic ADRs

A
  • Due to long-term ASM therapy
  • Tend to be drug-specific, not directly related to plasma conc. of ASM
  • Usually not life-threatening, but might affect QoL
18
Q

[Chronic adverse effects]

Gingival hyperplasia

A

Phenytoin

19
Q

[Chronic adverse effects]

Hirsutism

A

Phenytoin

  • common in children and young adults
20
Q

[Chronic adverse effects]

Alopecia

A

Sodium valproate

21
Q

[Chronic adverse effects]

What neurological effects may occur, and due to which ASMs?

A

Peripheral neuropathy

Phenytoin tx at high doses

  • may experience sensory loss
  • may or may not improve with decrease in ASM dose
  • may respond with folate supplementation (low evidence, in folate deficiency)

Carbamazepine

Phenobarbital

22
Q

[Chronic adverse effects]

What metabolic effects may occur, and due to which ASMs?

A
  1. Increased weight gain
  • Sodium valproate - reverses spontaneously with discontinuation of treatment
  1. Anorexia and weight loss
  • Topiramate - reversible with discontinuation
23
Q

[Chronic adverse effects]

What endocrine effects may occur, and due to which ASMs?

How do they cause this ADR?

A

Osteomalacia

  • Phenytoin
  • Phenobarbital
  • Carbamazepine

Hepatic enzyme inducers => incr clearance of Vit D => secondary hyperparathyroidism => incr bone turnover => reduce bone density => osteomalacia

24
Q

[Chronic adverse effects]

What haematological effects may occur, and due to which ASMs?

A
  1. Blood dyscrasias
  • Nearly all ASMs
  • Particularly Carbamazepine for aplastic anemia
  • Sodium valproate
  1. Megaloblastic anemia (rare <1%)
  • Phenytoin (predominantly)
  • Phenobarbital
  • Carbamazepine
25
Q

[Chronic adverse effects]

What neonatal congenital defects may occur, and due to which ASMs?

A
  1. Major malformation risk
  • *Valproate (high)
  • *Phenobarbital (high) - dose-dependent risk
  • *Topiramate (high) - dose-dependent risk
  • *Phenytoin (moderate)
  • *Carbamazepine (moderate) - dose-dependent risk
  1. Neonetal cognition
  • *Valproate (high)
  • *Phenytoin (moderate)
  • Phenobarbital
  • Topiramate (emerging data)
26
Q

[Chronic adverse effects]

Which ASMs cause suicidal ideations?

A
  • Carbamazepine
  • Valproate
  • Lamotrigine
  • Levetiracetam
  • Topiramate
  • Gabapentin
  • Pregabalin
  • Oxcarbazepine

Suicidality in epilepsy is multifactorial
Stopping/refusing to start ASM can result in serious harm and death
Closer monitoring of symptoms required
Advice pt not to stop ongoing therapy without discussion with physician

27
Q

[Hypersensitivity reaction]

  • Can range from?
A

mild maculopapular rash
SJS
TEN
AHS - anticonvulsant hypersensitivity syndrome

28
Q

[Hypersensitivity reaction]

What are the risk management strategies for the various drugs a/w hypersensitivity reactions?

A
  1. Carbamazepine - PGx testing
  2. Lamotrigine - dosing guidance
  3. Identify potential cross-sensitivity reaction

Also: Phenytoin

29
Q

[Hypersensitivity reaction]

Pharmacogenetic testing for Carbamazepine

  • What allele
  • Relevant for which population
A

HLA-B*1502

  • Strong association b/w HLA-B*1502 carriers and risk of CBZ-induced SJS/TEN
  • Relevant for Hans Chinese and other Asian ethnic groups (e.g., Malays, Indians, Thai)
  • Asians 10x more risk than caucasians

If pt tested positive, avoid both Carbamazepine and Phenytoin

30
Q

[Hypersensitivity reaction]

Lamotrigine risk of serious cutaneous reaction is higher with:

A

Risk of serious cutaneous reaction is higher with:

  • High starting doses
  • Rapid dose escalation
  • Concomitant valproate (inhibitor)
31
Q

[Hypersensitivity reaction]

Comment on Lamotrigine initial dosing guidance

A

Generally: slow titration

In patient taking concomitant valproate (an inhibitor),

  • Lower dose, divide up the higher doses

In patient taking concomitant CBZ/PHT/PHB (inducers),

  • Higher dose, divide up the higher doses
32
Q

[Hypersensitivity reaction]

Cross-sensitivity reaction is between ASMs with what structure?

List examples of ASMs with this structure.

A

ASMs with aromatic rings

  • Hypothesized to be able to form arene-oxide intermediate, become immunogenic through interactions with proteins or cellular macromolecules
  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Lamotrigine
  • Oxcarbazepine
33
Q

SEs of Levetiracetam (IC4)

A
  • (COMMON): Headache, vertigo, cough, depression, insomnia
  • (IC7) somnolence, asthenia, dizziness, coordination difficulties (esp first 4 weeks)
  • (IC7) Behavioural disturbances: Irritability, aggression
  • (RARE): Agranulocytosis, suicide, delirium, dyskinesia
34
Q

SEs of Lamotrigine (IC4)

A
  • (COMMON): Headache, irritability/aggression, tiredness
  • (IC7) Dizziness, N/V, headache, incoordination, tremor, somnolence, asthenia, headache
  • (IC7) Rash, SJS/TEN, DRESS
  • (RARE): Agranulocytosis, hallucination, movement disorders (worsens Parkinson’s disease), SJS/TEN, hepatic failure
35
Q

SEs of Topiramate (IC4)

A
  • Cognition dysfunction: psychomotor slowing, speech, memory
  • Metabolic: weight loss
  • Neonatal congenital defects: major malformation risk
  • (IC7) Somnolence, ataxia, fatigue, nausea
  • (IC7) Glaucoma, hyperammonemia, metabolic acidosis, hyperthermia, paresthesias, renal stones
  • (COMMON): Depression, somnolence, fatigue, nausea, weight change
  • (RARE): Neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure
36
Q

Carbamazepine CI

A
  • Hypersensitivity to CBZ or TCA (structurally related)
  • Concurrent/withing 14 days of discontinuation of MAOi (enhances toxic effect on MAOi)
  • Avoid use in mod-severe renal impairment
37
Q

Major DDIs of Sodium Valproate

A

CNS depressants

  • psychotropics: benzodiazepines, antihistamines, hydroxyzine, opioid agonists, antidepressants, MAOi
  • alcohol
  • enhance CNS depressant effects

Carbapenems

  • dcr serum conc. of valproate

Lamotrigine

  • incr serm conc. of lamotrigine
  • lamotrigine dose reduction needed

Salicylate

  • hepatotoxicity

3153 Seizure & Epilepsy (13 decks)

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