Dose-/plasma concentration-related adverse effects
- Usually the main limiting factor in the treatment of epilepsy
Adverse effects usually more prominent at higher AED concentration
Severity and frequency vary amongst AEDs
Dose-/plasma concentration-related adverse effects
- Usually the main limiting factor in the treatment of epilepsy
Adverse effects usually more prominent at higher AED concentration
Severity and frequency vary amongst AEDs
Primarily represent toxic effects of the AEDs
CNS: Somnolence, fatigue, dizziness, confusion, visual disturbances (usually double-/blurred-vision), nystagmus, ataxia
Gastrointestinal: Nausea, vomiting, anorexia
Haematological: Leukopaenia, thrombocytopaenia
Psychiatric: Behavioural disturbances
Concentration-related adverse effects are usually qualitatively similar amongst the various AEDs
Dose-related adverse effects are more frequent and occur at lower plasma concentrations in patients receiving AED combination therapy
- Influenced by additive neurologic effects of AEDs
- Particularly primarily during initiation of therapy but may disappear as tolerance develops
Concentration-related adverse effects are usually qualitatively similar amongst the various AEDs
Dose-related adverse effects are more frequent and occur at lower plasma concentrations in patients receiving AED combination therapy
- Influenced by additive neurologic effects of AEDs
- Particularly primarily during initiation of therapy but may disappear as tolerance develops
Occurrence and severity of dose-related adverse effects may be minimised by
Initiating therapy at a low dose and slowly increasing the dose
Avoiding large dosage changes
Restricting therapy to one drug only (if clinically feasible)
Adjusting the administration schedule, e.g.,
- Administration of largest dose at bedtime
- Dividing a daily dose into smaller doses given more frequently
- Use of sustained-release formulations
Reducing the total daily dose (if clinically safe)
Idiopathic-/hypersensitivity-related adverse effects
All current AEDs (except some 2nd-generation AEDs) have been associated with the development of rare (<0.1%) but serious idiosyncratic reactions
Aplastic anaemia
Hepatotoxicity (especially with 1st-generation AEDs) Pancreatitis (e.g., sodium valproate)
Lupus-like reaction
Exfoliative dermatitis
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Most likely to occur in first few months of therapy
Chronic (systemic) adverse effects
Long-term AED therapy may lead to a variety of chronic adverse effects
Tends to be drug-specific and not directly related to plasma concentration of AED
Usually not life-threatening but may have impact on patient’s overall quality-of-life
May often be avoided or minimised by appropriate preventative measures
Chronic (systemic) adverse effects
Long-term AED therapy may lead to a variety of chronic adverse effects
Tends to be drug-specific and not directly related to plasma concentration of AED
Usually not life-threatening but may have impact on patient’s overall quality-of-life
May often be avoided or minimised by appropriate preventative measures
Risk factors associated with chronic AED-related adverse effects
Long duration of therapy
Presence of polytherapy
Prolonged administration of high dosages
Repeated or prolonged episodes of acute toxicity
Poor diet
Poor hygiene
Institutionalisation
Adverse effects
Connective Tissue
- Gingival hyperplasia (chronic phenytoin therapy)
- Hirsutism (chronic phenytoin therapy)
- Alopecia (sodium valproate)
Neurological
- Encephalopathy (prolonged phenytoin treatment at high doses; phenobarbitone)
- Peripheral neuropathy ( long-term phenytoin treatment at high doses experience sensory loss; carbamazepine and phenobarbitone)
May or may not improve with decrease in AED dose
May respond with folate supplementation
Gastrointestinal
- Increased weight gain ( sodium valproate in children)
Gradually reverses spontaneously with discontinuation of treatment
- Anorexia and weight loss (felbamate)
Reversible with discontinuation of drug
Haematological
- Blood dyscrasias (nearly all AEDs)
- Megaloblastic anaemia (RARE, phenytoin, carbamazepine and phenobarbitone)
Neonatal congenital defects (phenytoin, carbamazepine and phenobarbitone)
Endocrine
- Osteomalacia ( phenytoin, phenobarbitone and carbamazepine (hepatic enzyme inducers))
Attributed to INCREASE hepatic metabolism of vitamin D and/or inhibition of calcium absorption
- Hyperglycaemia
Uncommon adverse effect associated with phenytoin treatment
Attributed to phenytoin’s effect on glucose homeostasis (exact mechanism unknown)
ADR
Connective Tissue
Connective Tissue
- Gingival hyperplasia (chronic phenytoin therapy)
- Hirsutism (chronic phenytoin therapy)
- Alopecia (sodium valproate)
ADR
Neurological
Neurological
- Encephalopathy (prolonged phenytoin treatment at high doses; phenobarbitone)
- Peripheral neuropathy ( long-term phenytoin treatment at high doses experience sensory loss; carbamazepine and phenobarbitone)
May or may not improve with decrease in AED dose
May respond with folate supplementation
ADR
Gastrointestinal
Gastrointestinal
- Increased weight gain ( sodium valproate in children)
Gradually reverses spontaneously with discontinuation of treatment
- Anorexia and weight loss (felbamate)
Reversible with discontinuation of drug
ADR
Haematological
Haematological
- Blood dyscrasias (nearly all AEDs)
- Megaloblastic anaemia (RARE, phenytoin, carbamazepine and phenobarbitone)
Neonatal congenital defects (phenytoin, carbamazepine and phenobarbitone)
- Psychological
With exception of phenytoin, phenobarbitone and ethosuximide, all other 1st- and 2nd-generation AEDs may be associated with an increased risk of suicidality
ADR
Endocrine
Endocrine
- Osteomalacia ( phenytoin, phenobarbitone and carbamazepine (hepatic enzyme inducers))
Attributed to INCREASE hepatic metabolism of vitamin D and/or inhibition of calcium absorption
- Hyperglycaemia
Uncommon adverse effect associated with phenytoin treatment
Attributed to phenytoin’s effect on glucose homeostasis (exact mechanism unknown)
ADR
Psychological
Psychological
With exception of phenytoin, phenobarbitone and ethosuximide, all other 1st- and 2nd-generation AEDs may be associated with an increased risk of suicidality (suicidal thoughts and behaviour)
Recommendations
- No changes to ongoing therapy without first discussing with physician
- Closer monitoring of symptoms
Gabapentin ADR
Weight gain,
peripheral oedema,
behavioural changes
Lamotrigine ADR
Rash (incl. SJS/TENS),
hypersensitivity (a/w renal/hepatic failure, DIVC, arthritis)
Tics, insomnia
Levetiracetam ADR
Irritability, behavioural changes
Oxcarbazepine ADR
Hyponatraemia (more common in elderly), rash
Tiagabine ADR
Stupor or spike-wave stupor
Muscle weakness
Topiramate ADR
Renal stones, open-angle glaucoma, hypohidrosis
Metabolic acidosis, weight loss, language dysfunction
Zonisamide ADR
Renal stones, hypohidrosis, rash
Irritability,sensitivity, weight loss
