Pharmacology: Ant-epileptic drugs Flashcards
What are the broad principles causing epilepsy?
- increased excitatory activity
- decreased inhibitory activity
- loss of homeostatic control
- spread of neuronal hyperactivity
What are grand mal and petit mal seizures?
Grand mal - tonic clonic seizures
Petit mal - absence seizures
What are the dangers of severe epilepsy?
- Physical injury from a fall or crash
- Hypoxia
- Sudden death in epilepsy (500 per year)
- Brain damage
- Cognitive impairment
- Severe psychiatric disease
What are the causes of epilepsy?
Primary (2/3rds) is idiopathic
Secondary (1/3rd) medical conditions affecting the brain eg vascular disease, tumours
What can precipitate an epileptic seizure?
Sensory stimuli: flashing lights, strobes
Brain disease: stroke, haemorrhage, drugs, alcohol, SOL
Metabolic: hypoglycaemia, hypocalcaemia, hyponatraemia
Infection: Febrile convulsion in infants
Therapeutics: some drugs can lower the seizure threshold
What are the therapeutic targets for epileptic drugs?
- Voltage gated sodium channels (to block)
2. GABA mediated inhibition (enhance)
What is the mechanism of action of a voltage gated sodium channel blocker?
The blocker can only access the binding site when the channel is open during depolarisation - so the blocker is voltage dependent.
The blocker prolongs the inactivated state of the channel and the firing rate goes back to normal.
When the membrane potential returns to normal the blocker detaches from the binding site.
List some voltage gated sodium channel blockers
- Carbamezepine
- Phenytoin
- Lamotrigine
What is the half life of carbamezapine?
Initial T1/2 is around 30 hours however it affects its own phase 1 metabolism so with repeated use T1/2 is around 15 hours.
What are the ADRs of carbamezapine?
CNS - dizziness, drowsiness, ataxia, numbness, tingling
GI - nausea and vomiting
CV - can alter BP, contraindicated with AV conduction problems
Rarely - severe bone marrow depression
What are the drug-drug interactions of carbamezapine?
Its a strong CYP450 inducer so can effect many other drugs inc phenytoin
Decreases warfarin, systemic corticosteroids, oral contraceptives
Antidepressants interfere with action of carbamezapine
What types of epilepsy are treated with carbamezapine?
Generalised tonic-clonc
All partial seizures
(Not absence)
What is the half life of phenytoin?
Zero order kinetics at therapeutic concentrations so half life is very variable - 6-24hours
What are the ADRs of phenytoin?
CNS: dizziness, ataxia, headache, nystagmus, nervousness
Gingival hyperplasia
Rashes: (2-5%) (v high) Steven johnson syndrome
What are the drug-drug interactions of phenytoin?
CYP450 inducer
Decreases conc of oral contraceptives
Cimetidine (H2 receptor antagonist) increases concs of phenytoin
Competitive binding with valproate, NSAIDs increases plasma levels
How can plasma levels of phenytoin be measured?
Can use salivary levels as a quick and non invasive method to indicator free plasma conc levels
What types of epilepsy are treated with phenytoin?
Generalised tonic-clonc
All partial seizures
(Not absence)
What is the half life of lamotrigine?
Linear PK - T1/2 is 24 hours
What are the ADRs of lamotrigine?
ADRs are less marked compared to the other VGSC blockers
CNS: dizziness, ataxia, sleepiness, nausea, serious skin rashes occur in 0.5% of cases
What are the drug-drug interactions of lamotrigine?
Can be used as an adjunct therapy with other anti-epileptics.
Oral contraceptives reduce conc of lamotrigine
Valproate increases conc
What types of epilepsy are treated with lamotrigine?
Partial seizures
Generalised tonic clonic
Absence seizures
Increasingly first line for epilepsy, less ADRs and appears safer in pregnancy.
Not first line in paediatrics because of risk of severe skin rashes
What is the general role of GABA in the brain?
Has a major role in post-synaptic inhibition
Therefore acts as a natural anti-convulsant
What are the broad ways drugs act to enhance GABA mediated inhibition?
1 - Bind to the GABAa receptor (agonists)
2 - Target GABA metabolism eg inhibit GABA inactivation, inhibit GABA reuptake, increase synthesis of GABA
How does the GABA work to produce an inhibitory effect?
GABA binds to its receptor causing the channel to open and Cl- to enter the neurone. This increases the threshold for action potential generation (makes membrane potential more negative) and reduces likelihood of hyper-excitability.
List some drugs that enhance GABA mediated inhibition
- Valproate
- Benzodiazepines eg diazepam, lorazepam, clonazepam
What is the half life for valproate?
15 hours
How does valproate work?
Acts at more than one site so is a ‘dirty drug’
- weak inhibitor of GABA inactivation enzymes
- weak stimulus of GABA synthesising enzymes
- voltage gated sodium blocker
- weak calcium channel blocker
What are some ADRs of valproate?
Less severe than other anti-epileptic drugs
CNS: sedation, ataxia, tremor, weight gain
Hepatic: transaminases increase in 40% of patients, this can rarely lead to hepatic failure
What are the drug-drug interactions of valproate?
Can be used as an adjunct therapy with other anti-epileptics but need constant monitoring as this affects the pharmacokinetics.
Antidepressants inhibit valproate
Antipsychotics antagonise valproate by lowering the convulsive threshold
Aspirin competitively binds so increases plasma valproate
How can plasma levels of valproate be measured?
Can use salivary levels as a quick and non invasive method to indicator free plasma conc levels
What types of epilepsy are treated with valproate?
Partial seizures
Generalised tonic-clonic
Absence seizures
(same as lamotrigine)
What is the half life of benzodiazepines?
Varies 15-24 hours
What are the ADRs of benzodiazepines?
- sedation
- tolerance with chronic use
- confusion
- aggression
- dependence / withdrawal
- abrupt withdrawal can trigger seizures
- resp and CNS depression
What types of epilepsy are treated with benzodiazepines?
Side effects limit its first line use.
Lorazepam / diazepam - status epilepticus
Clonazepam - short term use for absence seizures
What factors need to be taken into account with the use of anti-epileptics in pregnancy?
Stage of pregnancy
Balance of risk:
- if mild disease could stop treatment
- severe epilepsy or status epilepticus could cause more harm to mother and baby than the drugs could
What are the dangers to a foetus of anti-epileptics?
- congenital malformations
- valproate causes neural tube defects
- facial and digit hypoplasia
- learning difficulties
What is the percentage risk of birth defects normally vs with the use of anti-epileptic drugs?
Risk of birth defects usually 2%
Use of anti-epileptics during pregnancy increases this to 10%
What is the safest AED to prescribe during pregnancy?
Lamotrigine is thought to be safest. Should always give alongisde a vit K supplement in the 3rd trimester (AEDs associated with vit K deficiency in new borns)
(generally avoid valproate due to increased risk of neural tube defects)
Why is status epilepticus a medical emergency?
Mortality around 20%
Can get hypoxia, brain damage, lactic acidosis
How do you manage status epilepticus?
- Priorities are ABC
- exclude hypoglycaemia
- need to administer a fast acting drug eg lorazepam or phenytoin
- if failing consider ITU for paralysis and ventilation
