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Transcript
Pharmacology 19c - Epilepsy and Anticonvulsants
Anil Chopra
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To introduce the concept of the epilepsies as therapeutic targets
To outline the mechanisms of action of current drugs
To introduce the principles of the clinical pharmacology of these drugs
To 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 underemployment.
 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
EPILEPSY
50 : 50
IDIOPATHIC
MONOGENIC
uncommon
POLYGENIC
common
1%
49%
SYMPTOMATIC
ACQUIRED
INHERITED
common
Tumour
Stroke
Infection
Head injury
uncommon
MCMs
Vascular Malfs
Metabolic (PMEs)
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:
Reduce glutamate-mediated excitation:
Limit sustained repetitive firing
(Na+ channel):
Calcium T-channels
Unknown
Benzodiazepines, Phenobarbital, Vigabatrin, Tiagabine,
Felbamate, Topiramate, Valproic Acid.
Felbamate, Topiramate, Gabapentin
Phenytoin, Carbamazepine, Valproic Acid, Felbamate,
Limotrigine, Topiramate
oxcarbazepine
ethosuximide
levetiracetam
When to treat:
• Partial epilepsy - Carbamazepine or Limotigrine first line
• Generalized epilepsy – Valporic Acid first line
• Many are “broad spectrum” & used in both generalized and partial epilepsy: e.g.
Valporic Acid, 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