Adverse effects of ASMs Flashcards
[Dose/Plasma concentration-related adverse effects]
4 broad classes of dose-related ADRs
- 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
[Dose/Plasma concentration-related adverse effects]
CNS side effects include:
- Somnolence
- Fatigue
- Dizziness
- Visual disturbances (double/blurred vision)
- Nystagmus (vision condition, uncontrolled eye movement)
- Ataxia (poor muscle control, clumsy movement)
- Mental changes
- Coma
[Dose/Plasma concentration-related adverse effects]
GI side effects include:
Which drugs more a/w these SEs?
- Nausea
- Vomiting
Carbamazepine
Valproate
Phenytoin
[Dose/Plasma concentration-related adverse effects]
Psychiatric side effects include:
Which drugs more a/w these SEs?
- Behavioural disturbances (irritability, aggression, mood changes)
Levetiracetam
[Dose/Plasma concentration-related adverse effects]
Cognition side effects include:
Which drugs more a/w these SEs?
- Speech fluency
- Psychomotor slowing
- Memory
Topiramate
[Dose/Plasma concentration-related adverse effects]
Hyponatremia is a possible dose-related ADR of which drug?
Carbamazepine
[Dose/Plasma concentration-related adverse effects]
When are dose-related ADRs most prominent?
- 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
[Dose/Plasma concentration-related adverse effects]
Mitigation of dose-related ADRs
- Initiate at low dose, titrate slowly
- Avoid large dose changes
- Restrict therapy to one drug only
- 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)
[Idiopathic/hypersensitivity-related adverse effects]
Which ASMs are associated with hypersensitivity ADRs?
All current ASMs (except some 2nd gen ASMs) have been a/w development of rare (<0.1%) but serious idiosyncratic reactions
[Idiopathic/hypersensitivity-related adverse effects]
When are hypersensitivity ADRs most likely to occur?
Most likely occur in first few months of therapy
[Idiopathic/hypersensitivity-related adverse effects]
Name the reactions that may occur
- Blood dyscrasias (aplastic anemia, agranulocytosis)
- Hepatotoxicity
- Pancreatitis
- Lupus-like reaction
- Exfoliative dermatitis
- TEN/SJS
- Hyperammonemia
[Idiopathic/hypersensitivity-related adverse effects]
- ASMs a/w blood dyscrasias
Blood dyscrasias
- All ASMs can cause blood dyscrasias
- Carbamazepine (Aplastic anemia)
- Valproate (possibly)
[Idiopathic/hypersensitivity-related adverse effects]
- ASMs a/w Hepatotoxicity
Hepatotoxicity
- 1st gen ASMs: phenytoin, valproate, carbamazpine
[Idiopathic/hypersensitivity-related adverse effects]
- ASMs a/w Pancreatitis
Pancreatitis
- Sodium valproate
[Idiopathic/hypersensitivity-related adverse effects]
- ASMs a/w TEN/SJS
- Carbamazepine
- Phenytoin
- Lamotrigine
[Idiopathic/hypersensitivity-related adverse effects]
- ASMs a/w hyperammonemia
Hyperammonemia
- Sodium valproate
=> Hyperammonemia encephalopathy (drowsiness, lethargy, changes in level of consciousness, slowing cognition, neurological deficits)
[Chronic adverse effects]
Characteristics of chronic ADRs
- 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
[Chronic adverse effects]
Gingival hyperplasia
Phenytoin
[Chronic adverse effects]
Hirsutism
Phenytoin
- common in children and young adults
[Chronic adverse effects]
Alopecia
Sodium valproate
[Chronic adverse effects]
What neurological effects may occur, and due to which ASMs?
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
[Chronic adverse effects]
What metabolic effects may occur, and due to which ASMs?
- Increased weight gain
- Sodium valproate - reverses spontaneously with discontinuation of treatment
- Anorexia and weight loss
- Topiramate - reversible with discontinuation
[Chronic adverse effects]
What endocrine effects may occur, and due to which ASMs?
How do they cause this ADR?
Osteomalacia
- Phenytoin
- Phenobarbital
- Carbamazepine
Hepatic enzyme inducers => incr clearance of Vit D => secondary hyperparathyroidism => incr bone turnover => reduce bone density => osteomalacia
[Chronic adverse effects]
What haematological effects may occur, and due to which ASMs?
- Blood dyscrasias
- Nearly all ASMs
- Particularly Carbamazepine for aplastic anemia
- Sodium valproate
- Megaloblastic anemia (rare <1%)
- Phenytoin (predominantly)
- Phenobarbital
- Carbamazepine
[Chronic adverse effects]
What neonatal congenital defects may occur, and due to which ASMs?
- Major malformation risk
- *Valproate (high)
- *Phenobarbital (high) - dose-dependent risk
- *Topiramate (high) - dose-dependent risk
- *Phenytoin (moderate)
- *Carbamazepine (moderate) - dose-dependent risk
- Neonetal cognition
- *Valproate (high)
- *Phenytoin (moderate)
- Phenobarbital
- Topiramate (emerging data)
[Chronic adverse effects]
Which ASMs cause suicidal ideations?
- 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
[Hypersensitivity reaction]
- Can range from?
mild maculopapular rash
SJS
TEN
AHS - anticonvulsant hypersensitivity syndrome
[Hypersensitivity reaction]
What are the risk management strategies for the various drugs a/w hypersensitivity reactions?
- Carbamazepine - PGx testing
- Lamotrigine - dosing guidance
- Identify potential cross-sensitivity reaction
Also: Phenytoin
[Hypersensitivity reaction]
Pharmacogenetic testing for Carbamazepine
- What allele
- Relevant for which population
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
[Hypersensitivity reaction]
Lamotrigine risk of serious cutaneous reaction is higher with:
Risk of serious cutaneous reaction is higher with:
- High starting doses
- Rapid dose escalation
- Concomitant valproate (inhibitor)
[Hypersensitivity reaction]
Comment on Lamotrigine initial dosing guidance
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
[Hypersensitivity reaction]
Cross-sensitivity reaction is between ASMs with what structure?
List examples of ASMs with this structure.
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
SEs of Levetiracetam (IC4)
- (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
SEs of Lamotrigine (IC4)
- (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
SEs of Topiramate (IC4)
- 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
Carbamazepine CI
- 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
Major DDIs of Sodium Valproate
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
