Pharmacology 19c - Epilepsy and Anticonvulsants
Anil Chopra
1To introduce the concept of the epilepsies as therapeutic targets
2To outline the mechanisms of action of current drugs
3To introduce the principles of the clinical pharmacology of these drugs
4To outline how they are used therapeutically
Epilepsy
Epilepsy is a common, serious neurological disorder
Lifetime risk of epileptic seizure is 4%
Active epilepsy affects 1 in 200 people
300,000 cases in UK (1000 deaths), around 50 million cases worldwide
There is a stigma attached with epileptics resulting in social exclusion and under-employment.
25% have epilepsy resistant to medical treatment
Costs the NHS £1bn/year
The characteristic symptom in epilepsy is recurrent unprovoked seizures. This consists of excessive synchronised discharge of a set of cerebral neurones. These are normally sudden and transient.
Clinical manifestations depend on the part of the brain involved and include a variety of motor, psychic, and sensory phenomena with or without alteration in consciousness or awareness. In most situations, epilepsy is said to be present when two or more attacks have occurred.
There are 2 main types of epilepsy:
General: this is where seizures are caused by excessive discharge of neurones all over the cerebral hemispheres.
Arise from the whole cerebrum and consciousness is always lost – sometimes briefly as in absence seizures
Broken down into absence, tonic, tonic-clonic, clonic, myoclonic and atonic forms
Focal: this is when the seizure is caused by excessive discharge of neurones in one particular part of the brain.
Arise from a specific often small loci in one hemisphere
Simple partial seizures – occur without alteration in consciousness
Complex partial seizures – awareness is altered or lost
A secondary generalised seizure is a seizure with partial onset (often a simple partial seizure or aura) which spreads to a generalised attack
Broken down according to site on onset – e.g. temporal lobe, frontal lobe etc
Causes of Epilepsy
There are a number of different genes that can be affected which can lead to epilepsy syndromes. These can include genes that code for
-voltage gated ion channels
-ligand gated ion channels
-non-ion channels
Anti-Epileptic Drugs
Treatment of epilepsy is about balancing the benefits and harms of the various drugs.
Benefits – seizure suppression
Harms:
-Psychosocial consequences (illness status, self-esteem, education, employment).
-Idiosyncratic & dose-related adverse drug reactions
-Teratogenicity – birth defects (approx. 5% MCM risk for monoPx)
-Wrong Anti Epileptic Drug can result in poor control and possibly worsening of epilepsy.
The decision to treat is made on the types of seizures, the frequency of seizures, the cause of the seizures and what effect they are having on the patient’s life.
There are a number of different generalised modes of action:
Enhance GABA inhibition: / Benzodiazepines, Phenobarbital, Vigabatrin, Tiagabine, Felbamate, Topiramate, Valproic Acid.Reduce glutamate-mediated excitation: / Felbamate, Topiramate, Gabapentin
Limit sustained repetitive firing / Phenytoin, Carbamazepine, Valproic Acid, Felbamate, Limotrigine, Topiramate
(Na+ channel): / oxcarbazepine
Calcium T-channels / ethosuximide
Unknown / levetiracetam
When to treat:
•Partial epilepsy - Carbamazepine or Limotigrine first line
•Generalized epilepsy – ValporicAcid first line
•Many are “broad spectrum” & used in both generalized and partial epilepsy: e.g.ValporicAcid, Topiramate, Limotigrine.
•Ethosuximide- childhood absence epilepsy only
•Clobazam, Vigabatrin, Gabapentin may worsen generalized epilepsy(absence and myoclonic seizures).
Name–Phenytoin
Usage
Used mainly as a partial epileptic.
Mode of Action
Blocks voltage gated ion channels. (Na+ channels)
Side Effects and Pharmacokinetics
–Hepatic metabolism: oxidation (CYP2C9 >2C19), followed by hydroxylation then conjugation and renal excretion of non-active metabolites.
–The metabolism differs between individuals which means that enzyme saturation points differ. You should therefore start off on a low-dose and increase every fortnight.
–½ life of 20 hours
–Once daily dosage
–P450 enzyme inducer
Side Effects:
Ataxia, dizziness, sedation, hypersensitivity, rash, fever, gingival hypertrophy, folate deficiency, megaloblastic anaemia, vit K deficiency, depression, hirsutism, peripheral neuropathy, osteomalacia, reduced bone density, hypocalcaemia, hepatitis, vasculitis, myopathy, coagulation defects, bone marrow hypoplasia.
It has a large number of drug interactions:
•Amiodarone, cimetidine and Isoniazid are inhibitors of phenytoin metabolism, with increased levels
•Aspirin displaces phenytoin from protein binding.
•Valproate - displaces phenytoin from protein binding and also inhibits phenytoin metabolism. A problem if levels are near saturation, leading to phenytoin toxicity with normal total PHT levels (measure free PHT levels with this drug combination). Avoid combination where possible.
•WARFARIN - Complex pharmacokinetics, with an initial increase in anticoagulation, after which concentration of warfarin can decrease. Monitor INRs closely after any change in phenytoin dose.
•Carbamazepine, limotigrine, Topiramate, corticosteroid, cyclosporin, levels all lowered.
•Estrogen containing OCP efficacy reduced (50ug eostradiol req)
•Vit K deficiency (pregnancy).
Name–Carbamazepine
Usage
Used in partial and generalized secondary seizures
Mode of Action
Blocks voltage gated Na+ channels. Its active metabolite is carbamazepine epoxide.
Side effects and Pharmacokinetics
-Metabolism: Hepatic oxidation then conjugation. Carbamazepine is a potent hepatic enzyme inducer.
-½ life of from 5-26 hours.
-Dose 3x daily
Side Effects:
Ataxia, dizziness, sedation, hypersensitivity, rash, fever, diplopia, vit K deficiency, depression, impotence, osteomalacia, reduced bone density, hyponatraemia, hepatitis, bone marrow dyscrasias, nephritis .
It also has a number of drug interactions:
-Phenytoin and phenobarbital induce carbamazepine metabolism
-Valproic acid causes a 4-fold increase in carbamazepine epoxide levels via the inhibition of epoxide hydrolase. Limotigrine increases epoxide levels to a lesser extent.
-Macrolide antibiotics (e.g., erythromycin) inhibit metabolism: can increase levels 2-3X (avoid!)
-Ca2+ channel blockers (diltiazem/verapamil) can double Carbamazepine levels.
-Fluoxetine may increase CBZ levels
-Reduces levels of a wide variety of Anti epileptic drugs
-OCP - inform patients
-Warfarin
Name - lamotrigine
Usage–Partial and generalized epilepsy - wide spectrum
Mode of Action–Blocks voltage gated Na+ channels.
Side effects and Pharmacokinetics
-½ life 29 hrs (monoPx), 15 hrs (enzyme inducing co-medication), 60 hrs (valproate co-medication).
-Metabolised by hepatic glucuronidation (no phase 1 metabolism).
Side effects
Main one is rash, others are less common and include headache, blood dyscrasia, ataxia, diplopia and dizziness, sedation, insomnia, mood disturbance.
It also has a number of drug interactions
•Lamotigrine does not inhibit or induce hepatic enzymes, so does not alter metabolism of OCP or warfarin
•Enzyme inducing drugs reduce half-life and lower levels
•Valproic acid increases half-life by unknown mechanism to 60 hours, doubling levels and can precipitate toxicity/severe rash.
•OCP can lower levels by 1/3 (as can pregnancy)
•Lamotigrine dosage thus needs to be modified according to co-medication. E.g. Lamotigrine dose needs to be halved if being taken with valproic acid.
Name–valproate
Usage–Partial or generalized epilepsy - wide spectrum
Mode of Action–enhance GABA mediated inhibition.
Side Effects and Pharmacokinetics
-½ life of 4-12 hours
-Metabolism: Hepatic oxidation and then conjugation. Potent inhibitor of hepatic enzymes
Side Effects
Severe hepatic toxicity (especially young), pancreatitis, drowsiness, encephalopathy (ammonia driven), tremor, blood dyscrasias, hair thinning and loss, weight gain, endocrine (PCO).
It has a number of drug interactions
–Valproate is a potent inhibitor of both oxidation and glucuronidation
–Phenytoin, phenobarbital, lamotigrine levels all increased
–Carbamazepine epoxide levels increased
–Levels reduced by hepatic enzyme inducers (e.g., PHT, PB, CBZ)
–Antacids may impair absorption
–Some NSAIDs, aspirin, phenylbutazone displace valproate from its albumin binding sites and may result in toxicity.
Anti-Epileptic Drug (AED) Therapy:
Balance of benefit and harm
Benefits:
Seizure suppression – so reduction in seizure related harm
Harms:
Psychosocial consequences – employment, stigma etc
Idiosyncratic and dose related adverse drug reactions
Teratogencity (5% risk of major abnormalities with mono-therapy, 5-10% with 2 drugs, 10-20% with 3)
Wrong AED, poor control, worsening of epilepsy
Factors influencing the decision to treat:
Number of seizures at presentation
Seizure type and severity
Cause of seizure
Factors influencing AED choice:
Personal preference
Dogma rather than scientific eveidence
Principles of AED Therpay:
Be clear about indication for use
Discuss risks and benefits
Accurate classification of epilepsy
One AED where possible
Correct dose = minimum dose that controls seizures without intolerable side effects
Therapeutic drug monitoring of little benefit - except in polypharmacy (interactions) and assesemnt of compliance and toxicity
Always consider potential drug interactions
Never withdraw drugs suddenly
Make one change at a time – if withdrawing add in new before removing old
Consider Teratogencity
Treatment of newly diagnosed epilepsy:
First drug = 60% success
Alternative monotherpay = 5% success
Polytherapy = 5% success
Overall = 30% failure to control with drugs
Teratogenicity:
- Background risk of congenital malformation = 1%
- Risk with 1 AED = 3-5%
- Risk with 2 AED’s = 5-10%
- Increased risk of neural tube defects also
- Risk of individual drugs not clearly defined
- Have to weigh up risk to mother from seizure related injury against risk of Teratogencity
- Take folate to reduce risk of neural tube defects