Anti-epileptic drugs Flashcards
What is epilepsy
Chronic disorder characterised by recurrent episodes of seizures
What is the pathophysiology of epilepsy
Increased excitatory activity
Decreased inhibitory activity
Loss of control of neuronal membrane potential
Neurones heavily Depolarise and increased rate of discharge
Spread of hyperactivity by synaptic transmission
What are the types of epilepsy
Partial:
Simple
Complex
Secondarily generalised
Generalised:
Tonic clonic
Absence
Status epilepticus
What are the causes of epilepsy
Primary: idiopathic, 70% Secondary to Brain damage: Head injury Asphyxia Infection Stroke/haemorrhage Malignancy
What are precipitants of epilepsy
Sensory: flashing lights Alcohol Drugs Stroke/haemorrhage Metabolic: hypo/hyperglycaemia, hypo/hypernatraemia Infections
What are main therapeutic targets of antiepileptic drugs
Inhibition of Voltage gated Na channels
Enhance GABA-mediated inhibition
What are the types of VG Na Channel inhibitors
Carbamazepine
Lamotrigine
Phenytoin
What is mechanism of action of VG Na channel inhibitors
Inhibit INACTIVE VG Na channels
Prolong inactive state
Preferentially act on neurones with high frequency depolarisation + discharge
Due to higher proportion of inactive Na channels
Reset rate of discharge in neurones with high rate of discharge
What are PK properties of carbamazepine
Protein binding 70% CYP450 inducer Induces own metabolism Starting T1/2 30hr Repeated use T1/2 15hr Linear PK
What are side effects of carbamazepine
Dizziness, drowsiness, ataxia, numbness Vomiting Variation in BP Rash Neutropenia
What are DDIs of carbamazepine
CYP450 induction - raises levels of: Warfarin Phenytoin Oral contraceptives Corticosteroids
Reduced activity with Antidepressants
What monitoring is required with Carbamazepine
Adjust dose to therapeutic effect
Due to decreasing T1/2 with repeated use
What are indications of carbamazepine
All partial seizures
Tonic clonic seizures
Not absence seizures
What are PK properties of phenytoin
Protein binding 90%
CYP450 inducer
Non linear PK at therapeutic dose
Variable T1/2
What are side effects of phenytoin
Dizziness, headache, ataxia, nystagmus
Gingivial hyperplasia
Rash
Stevens Johnson syndrome
What are DDIs of phenytoin
Increased phenytoin levels (PK binding) with:
NSAID
Valproate
Salicylate
Decrease oral contraceptive levels (CYP450)
Increased phenytoin levels w Cimetidine
What drug monitoring is required with phenytoin
Free plasma concentration levels
Salivary levels - indicator for plasma levels
What are indications for phenytoin
All partial seizures
Tonic clonic seizures
Not absence seizures
What are PK properties of lamotrigine
Linear PK
Not CYP450 inducer
What are side effects of lamotrigine
Dizziness, ataxia
Nausea
Rash
(Fewer SEs)
What are DDIs of lamotrigine
Adjunct to other AEDs
Reduced activity LTG with oral contraceptives
Potentiation of LTG with valproate
(fewer DDIs)
What are indications of Lamotrigine
All partial seizures
Tonic clonic seizures
Absence seizures
AED of choice for women of child bearing age
Not first line for children (increased rate of SEs)
What is mechanism of action of AEDs enhancing GABA-mediated inhibition
GABA agonists:
Positive allosteric binding at GABA receptors
At benzodiazepine binding site
Enhance GABA activity at receptor
Affect GABA metabolism:
Activate GABA synthesising enzymes
Inhibit GABA re-uptake enzymes
Increase GABA levels
How does GABA activity mediate inhibition
GABA is a natural anticonvulsant
40% synapses in brain are GABA-ergic
GABA receptor is Cl channel causing hyperpolarisation
What is mechanism of action of valproate
Affects GABA metabolism:
Inhibit GABA reuptake
Activate GABA synthesis
What are PK properties of valproate
90% protein bound
Linear PK
What are side effects of valproate
CNS - ataxia, tremor, sedation
Hepatic - raised transaminases, hepatic failure
What are DDIs of valproate
Around Adjunct therapy w other AEDs
Decreased valproate activity w antidepressants
Decreased valproate activity w antipsychotics
Potentate valproate activity w aspirin (PK binding)
What drug monitoring is required with valproate
Free plasma conc levels
Salivary levels
What are indications of valproate
All partial seizures
Tonic clonic seizures
Absence seizures
What is mechanism of action of benzodiazepines
GABA receptor agonist
Bind to Benzodiazepine binding site on GABA receptors
Enhance GABA activity
What are PK properties of benzodiazepines
90% protein bound
Linear PK
What are side effects of benzodiazepines
Confusion Sedation Tolerance (long term use) Dependence + withdrawal (long term use) Rebound seizure with abrupt withdrawal Resp + CVS depression
What are DDIs of benzodiazepines
IV flumazenil causing rebound seizure
What are indications of benzodiazepines
Status epilepticus: lorazepam, diazepam
Absence seizure: clonazepam - short term
What are prescribing rules of antiepileptic drugs
Monotherapy is the aim
Drug choice dependent on patient + condition
If first line ineffective, Switch to another AED before starting combination therapy
Patient must remain under review
Start at low dose + titrate to therapeutic effect
Significant seizures can be treated by sedation + paralysis + intubation in ITU
What are general indications of anti epileptic drugs
First line for generalised: valproate
First line for partial: carbamazepine
First line for women of CBA: lamotrigine
First line for Status epilepticus: lorazepam
What are prescribing rules for women of child bearing age
Balance risk of seizure + teratogenic risk of drug
Assess individual: severity/frequency of seizure, history of status epilepticus
What are the risks of medication to foetus
Phenytoin + carbamazepine:
Increased failure rate of conception
Valproate:
Neural tube defects
Neuro developmental defects - autism, learning disability
Any AEDs:
Increased risk of birth defects
Congenital malformations
Facial/digital hypoplasia
What are prescribing rules for pregnant women
Aim for Monotherapy Lowest dose Lamotrigine is safest Avoid valproate Prescribe Folate supplements (NTDs) Prescribe Vit K supplements in last trimester: AEDs associated with vitamin K deficiency in newborn
What is management of Status Epilepticus
ABC
Exclude hypoglycaemia
1st line: IV lorazepam (preferred to diazepam due to longer T1/2 so better control)
2nd line: IV Phenytoin (cardiac monitoring needed)
Sedation + Paralysis + Intubation at ITU if above fails
